# CFI Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- Complement Factor I (CFI) is a serine protease essential for regulating complement activation by cleaving C3b and C4b, but only in the presence of cofactors like Factor H (FH) or Membrane Cofactor Protein (MCP).
- Pathogenic *CFI* mutations, often heterozygous loss-of-function variants, are a significant cause of atypical hemolytic uremic syndrome (aHUS) and complete Factor I deficiency, leading to uncontrolled complement amplification and increased susceptibility to severe bacterial infections.
- Rare coding variants in *CFI*, such as p.Gly119Arg, are strongly associated with an increased risk of age-related macular degeneration (AMD), indicating a role for complement dysregulation in retinal pathogenesis.
- Gene therapy using AAV vectors to deliver the *CFI* gene is a promising therapeutic strategy for CFI deficiency and AMD, aiming to restore functional Factor I levels in affected tissues.
- Systemic complement inhibitors, such as the C5 inhibitor eculizumab, are the standard of care for aHUS caused by *CFI* mutations, effectively blocking the terminal complement cascade and preventing thrombotic microangiopathy.
- Pathogens like *Salmonella* Typhimurium and *Streptococcus pyogenes* have evolved mechanisms to hijack host CFI, using it to degrade complement components deposited on their surfaces, thereby evading opsonization and immune clearance.

---

## Executive Summary & Key Metadata

Complement Factor I (CFI) encodes a critical serine protease that serves as the central enzymatic regulator of the complement cascade. This 88 kDa plasma glycoprotein exerts its regulatory function by cleaving the alpha-chains of C3b and C4b, but only when these substrates are bound to obligatory cofactors such as Factor H (FH), C4b-binding protein (C4BP), Membrane Cofactor Protein (MCP/CD46), or Complement Receptor 1 (CR1). This catalytic activity prevents uncontrolled amplification of the alternative pathway (AP) and downregulates the classical and lectin pathways, thereby protecting host tissues from complement-mediated damage [1].

The clinical relevance of CFI is underscored by its association with a broad spectrum of diseases, ranging from rare monogenic disorders like atypical hemolytic uremic syndrome (aHUS) and complete Factor I deficiency to complex polygenic conditions such as age-related macular degeneration (AMD) and C3 glomerulopathy (C3G). The gene's structure, regulatory complexity, and the functional consequences of its variants are the focus of this definitive reference manual.

| **Attribute** | **Detail** |
| :--- | :--- |
| **HGNC Symbol** | CFI |
| **UniProt Accession** | P05156 |
| **Representative PDB ID** | 5FCG (Crystal structure of the complex between Factor I and Factor H) |
| **Chromosomal Locus** | 4q25 |
| **Gene Size** | ~63 kb |
| **Primary Molecular Function** | Serine-type endopeptidase activity; cleaves C3b and C4b complement components in the presence of cofactors to downregulate complement activation. |
| **Disease Associations** | Atypical Hemolytic Uremic Syndrome (aHUS), Age-Related Macular Degeneration (AMD), Complement Factor I Deficiency, C3 Glomerulopathy (C3G), Recurrent Infections, Systemic Lupus Erythematosus (SLE) [2, 3, 4, 5, 6] |

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Localization and Gene Architecture

The *CFI* gene is located on the long arm of chromosome 4 at cytogenetic band 4q25. The gene spans approximately 63 kilobases (kb) of genomic DNA and is oriented on the minus strand. The genomic structure is complex, comprising 13 exons interspersed with 12 introns. The coding sequence translates into a pre-pro-protein of 583 amino acids, which undergoes extensive post-translational processing to yield the mature, secreted 583-amino acid heavy chain (50 kDa) and 244-amino acid light chain (38 kDa) held together by a single disulfide bond [1].

The promoter region of *CFI* lacks a canonical TATA box. Transcriptional initiation is driven by an initiator (Inr) element and proximal cis-acting sequences, which are essential for basal transcriptional activation [7]. This promoter architecture permits constitutive expression primarily in the liver, which is the major source of circulating plasma Factor I. However, extrahepatic expression has been documented in various cell types, including monocytes, fibroblasts, endothelial cells, and retinal pigment epithelium (RPE) cells, where local production may play a role in tissue-specific complement regulation [8].

### 1.2 Transcriptional Regulation

The expression of *CFI* is dynamically regulated by inflammatory cytokines. Interleukin-6 (IL-6) has been shown to upregulate *CFI* gene expression at both the transcriptional and post-transcriptional levels in HepG2 hepatoma cells [9]. This acute-phase response is critical for modulating complement activity during inflammation. The 5' flanking region contains response elements for various transcription factors, including STAT3, which mediates IL-6 signaling. Additionally, the 3' untranslated region (UTR) contains AU-rich elements that influence mRNA stability, providing a mechanism for rapid post-transcriptional control [9].

### 1.3 Alternative Splicing and Isoforms

While the primary transcript is constitutively spliced to produce the canonical mRNA, alternative splicing events have been reported. These isoforms are often tissue-specific and may encode truncated or functionally distinct proteins. For instance, a splice variant lacking exon 12 has been identified in certain tissues, which would result in a frameshift and a prematurely truncated light chain lacking the serine protease catalytic triad. The physiological relevance of these isoforms remains under investigation, but they may contribute to the regulation of local complement activity or serve as a reservoir for antigenic peptides [10]. RNA splicing analysis of pathogenic *CFI* mutations, particularly those in intronic regions, has revealed that some variants disrupt canonical splice donor or acceptor sites, leading to exon skipping or intron retention, which are mechanisms underlying Factor I deficiency in aHUS [11, 12].

## 2. 3D Protein Domain Architecture & Structural Biology

### 2.1 Domain Organization of the Heavy Chain

The mature Factor I protein is a heterodimer composed of a non-catalytic heavy chain (HC) and a catalytic light chain (LC) linked by a disulfide bond. The heavy chain is organized into several distinct structural modules:

- **FIMAC Domain (Factor I Membrane Attack Complex domain):** Located at the N-terminus (residues 1–46), this domain is unique to Factor I. Its function is not entirely clear, but it is thought to contribute to the stability of the protein and may interact with cofactors.
- **CD5 Domain (Scavenger Receptor Cysteine-Rich domain):** Residues 47–135 form a domain homologous to the CD5 antigen. This domain is involved in protein-protein interactions and is crucial for the correct folding and secretion of Factor I.
- **LDLR Repeats (Low-Density Lipoprotein Receptor class A domains):** The heavy chain contains two tandem LDLR repeats (residues 136–178 and 179–222). These domains are rich in cysteine residues and are involved in ligand binding. In Factor I, they are essential for the interaction with its cofactors and substrates.
- **SRCR Domain (Scavenger Receptor Cysteine-Rich domain):** Residues 223–326 form a second SRCR domain. This domain is critical for the structural integrity of the heavy chain and contributes to the binding interface with C3b/C4b.

### 2.2 The Catalytic Light Chain

The light chain (residues 341–583) contains the serine protease domain, which is structurally homologous to other serine proteases like trypsin and chymotrypsin. The catalytic triad is composed of **His-380**, **Asp-429**, and **Ser-525**. The active site is located in a deep cleft on the surface of the light chain. The light chain also contains a **D-histidine loop** and an **oxyanion hole** that stabilize the transition state during peptide bond hydrolysis.

### 2.3 Conformational Dynamics and Zymogen Activation

A defining feature of Factor I is its circulation in a structurally constrained, inactive "zymogen-like" conformation. The heavy chain domains (FIMAC, CD5, LDLR, SRCR) form a "closed" conformation that sterically blocks the active site of the light chain. This autoinhibition is relieved only upon binding to a cofactor-substrate complex (e.g., FH-C3b). The binding of the cofactor induces a large conformational rearrangement, opening the structure and allowing the substrate C3b to access the catalytic triad [1]. This multi-step activation mechanism ensures that Factor I does not indiscriminately degrade complement proteins in the fluid phase, restricting its activity to surfaces where complement is actively depositing.

### 2.4 Interactive 3D Visualization

To explore the intricate domain architecture and conformational states of Factor I, an interactive 3D visualizer is available. This tool allows users to rotate the molecule, highlight specific domains, and visualize the spatial relationship between the catalytic triad and the regulatory heavy chain.

[Interactive 3D Protein Visualizer: Load CFI (PDB: 5FCG)](/tools/protein-structure-viewer?source=alphafold&accession=P05156)

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 The Complement Cascade and the Role of Factor I

The complement system is a cornerstone of innate immunity, comprising three activation pathways: classical, lectin, and alternative. All three converge on the cleavage of C3 into C3a and C3b. The deposition of C3b on pathogen surfaces or host cells initiates a cascade of downstream events, including opsonization, formation of the membrane attack complex (MAC), and generation of anaphylatoxins (C3a, C5a) that recruit and activate immune cells.

Factor I is the primary soluble regulator of this cascade. Its function is to irreversibly inactivate C3b and C4b, preventing the formation and amplification of C3 convertase (C3bBb) and C5 convertase (C3bBbC3b). This regulation is essential for:

- **Protecting Host Cells:** Preventing spontaneous complement activation on self-cells.
- **Terminating the Cascade:** Limiting the duration and magnitude of the complement response.
- **Generating Degradation Products:** The cleavage products of C3b (iC3b, C3c, C3dg) and C4b (C4c, C4d) have distinct biological functions, including signaling through complement receptors on immune cells to modulate adaptive immunity.

### 3.2 The Cofactor Requirement and Substrate Specificity

Factor I alone has negligible protease activity against fluid-phase C3b or C4b. It requires a cofactor to bind the substrate and present it in a conformation amenable to cleavage. The major cofactors are:

- **Factor H (FH):** A soluble glycoprotein that binds to C3b and serves as a cofactor for Factor I-mediated cleavage of C3b. This is the primary regulatory axis of the alternative pathway in the fluid phase and on host surfaces.
- **C4b-Binding Protein (C4BP):** A soluble protein that acts as a cofactor for the cleavage of C4b, regulating the classical and lectin pathways.
- **Membrane Cofactor Protein (MCP/CD46):** A transmembrane protein expressed on most host cells that acts as a cofactor for both C3b and C4b cleavage.
- **Complement Receptor 1 (CR1/CD35):** A transmembrane protein expressed on erythrocytes and immune cells that serves as a cofactor for both C3b and C4b.

The specificity of Factor I for its substrates is determined by the cofactor. For example, FH-bound C3b is cleaved at two specific sites (Arg-1281-Ser-1282 and Arg-1298-Ser-1299) in the C3b alpha-chain, generating iC3b. In contrast, MCP-bound C3b is cleaved at a different site, leading to a slightly different degradation pattern. This cofactor-dependent specificity allows for fine-tuned regulation of complement activity in different compartments.

### 3.3 Protein-Protein Interaction Networks

The function of Factor I is entirely dependent on its interactions with other proteins. The primary interaction network includes:

- **Cofactors:** FH, C4BP, MCP, CR1.
- **Substrates:** C3b, C4b.
- **Other Regulators:** Properdin (stabilizes the AP C3 convertase, opposing Factor I function).

The interaction between Factor I and its cofactors is mediated by the heavy chain domains. Specifically, the LDLR repeats and the SRCR domain are critical for binding to FH and C4BP. Mutations in these domains often result in a secreted but non-functional protein, as they disrupt the ability to form the trimolecular complex [1, 13].

```mermaid
sequenceDiagram
    participant C3 as "C3"
    participant C3b as "C3b"
    participant FB as "Factor B"
    participant FD as "Factor D"
    participant C3C as "C3 Convertase (C3bBb)"
    participant FI as "Factor I"
    participant FH as "Factor H (Cofactor)"
    participant iC3b as "iC3b"
    C3->>C3b: Spontaneous/Pathway-mediated hydrolysis
    C3b->>FB: Binds Factor B
    FB->>FD: Cleaved by Factor D
    FD->>C3C: Forms C3 Convertase (C3bBb)
    C3C->>C3: Cleaves more C3 to C3b (Amplification Loop)
    C3b->>FI: Binds Factor I
    FI->>FH: Requires Cofactor (FH)
    FH->>FI: Forms Trimolecular Complex (FI-FH-C3b)
    FI->>iC3b: Cleaves C3b alpha-chain -> iC3b (Inactivation)
    Note over FI,iC3b: Irreversible inactivation prevents convertase formation
```

### 3.4 Non-Canonical Functions

Beyond its role in the complement cascade, Factor I has been implicated in other biological processes. Recent studies suggest a role in neuronal development, as the *C. elegans* ortholog CFI-1 (an ARID3 transcription factor, not a protease) is involved in controlling neuronal subtype identity [14, 15]. However, this is a distinct protein from the human CFI. In humans, Factor I has been shown to cleave non-complement substrates, such as the extracellular matrix protein thrombospondin, suggesting potential roles in tissue remodeling and angiogenesis. Furthermore, altered CFI expression has been linked to various cancers, including pancreatic cancer and glioblastoma, where complement regulation within the tumor microenvironment may influence tumor growth and immune evasion [16, 17].

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

Mutations in the *CFI* gene are a well-established cause of several diseases, primarily through loss-of-function mechanisms that lead to complement dysregulation. The clinical phenotype is highly variable, ranging from severe, early-onset systemic disease to late-onset, organ-specific pathology.

### 4.1 Atypical Hemolytic Uremic Syndrome (aHUS)

aHUS is a rare, life-threatening disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury. It is caused by uncontrolled activation of the alternative complement pathway, often due to genetic variants in complement genes. *CFI* mutations account for approximately 5-10% of aHUS cases [18, 19]. These mutations are typically heterozygous, loss-of-function variants that result in reduced Factor I levels or activity.

- **p.Ile357Met (c.1069A>G):** This is a recurrent pathogenic variant, particularly prevalent in Tunisian and other North African populations. It is located in the light chain near the catalytic domain and results in a significant reduction in secreted Factor I levels, leading to a severe aHUS phenotype [1, 2].
- **p.Gly287Arg (c.859G>A):** This variant, located in the SRCR domain of the heavy chain, has been associated with both aHUS and recurrent CNS inflammation, including aseptic neutrophilic meningitis [3].
- **Splice-site variants:** Intronic mutations, such as c.328+42G>A, can create cryptic splice sites, leading to aberrant mRNA splicing and reduced protein expression. These variants are often missed by standard exon-sequencing approaches and require RNA analysis or minigene assays for functional characterization [10, 11, 12].

### 4.2 Age-Related Macular Degeneration (AMD)

AMD is a leading cause of irreversible blindness in the elderly. It is a complex disease with a strong genetic component, and dysregulation of the complement system is a central pathogenic mechanism. Rare, coding variants in *CFI* are associated with a significantly increased risk of advanced AMD [3, 4].

- **p.Gly119Arg (c.355G>A):** This is the most well-studied *CFI* variant in AMD. It is located in the CD5 domain of the heavy chain. Functional studies have shown that this variant leads to reduced secretion of Factor I, resulting in lower serum Factor I levels and impaired complement regulation [5, 6, 7, 8]. The variant is a strong risk factor for AMD, with an odds ratio of approximately 2-3 [4, 9, 10].
- **p.Leu131Arg (c.392T>G):** Another rare variant associated with AMD, also located in the CD5 domain, which similarly impairs protein secretion [3].
- **Common SNPs:** Genome-wide association studies (GWAS) have identified common non-coding variants in the *CFI* locus, such as rs10033900 and rs2285714, that are associated with AMD risk [11, 12, 13, 14]. These variants likely influence gene expression levels, contributing to the polygenic risk of AMD.

### 4.3 Complete Complement Factor I Deficiency

Complete CFI deficiency is a rare autosomal recessive inborn error of immunity. It is characterized by a near-total absence of functional Factor I, leading to uncontrolled consumption of C3 and secondary deficiencies of C3, Factor B, and other downstream complement components [2, 4]. This results in a profound susceptibility to recurrent, severe infections, particularly with encapsulated bacteria such as *Neisseria meningitidis* and *Streptococcus pneumoniae* [4, 15].

- **Clinical Spectrum:** Beyond infections, patients can present with a wide range of immune dysregulatory disorders, including systemic lupus erythematosus (SLE), vasculitis, and recurrent CNS inflammation [4, 16, 17, 18, 19].
- **Genotype-Phenotype Correlation:** The severity of the phenotype is generally correlated with the degree of residual Factor I function. Null mutations (nonsense, frameshift) that completely abolish protein production result in the most severe phenotypes, while missense mutations that allow for some residual activity may present with a milder, later-onset disease [4, 15].

### 4.4 C3 Glomerulopathy (C3G)

C3G is a group of rare kidney diseases characterized by the deposition of C3 in the glomeruli, due to uncontrolled activation of the alternative pathway. Rare variants in *CFI* have been identified in patients with C3G, often in combination with variants in other complement genes [1, 5, 6]. These variants contribute to the overall complement dysregulation, but are not usually sufficient to cause the disease on their own.

### 4.5 Other Associated Conditions

- **Recurrent Aseptic Meningitis:** As noted, specific *CFI* variants can predispose to recurrent CNS inflammation, even in the absence of a full aHUS or systemic deficiency phenotype [3, 17, 18].
- **Pancreatic Cancer:** A recent large-scale study identified an association between complement system genes, including *CFI*, and pancreatic ductal adenocarcinoma (PDAC) susceptibility and prognosis [16].
- **Osteoarthritis:** A 2025 study identified CFI as a key biomarker in osteoarthritis, linked to Natural Killer T (NKT) cell-related immune responses [2].
- **Myeloproliferative Neoplasms (MPNs):** Loss of Cfi in a mouse model exacerbated the JAK2V617F-dependent phenotype, suggesting a role for complement regulation in MPN pathogenesis [3].

## 5. Host-Pathogen & Viral Interactions

The complement system is a primary target for immune evasion by many pathogens. Given its central role in complement regulation, Factor I is an indirect target of these evasion strategies.

### 5.1 Bacterial Evasion

- ***Salmonella* Typhimurium:** A 2025 study demonstrated that invasive *Salmonella* Typhimurium strains upregulate the membrane protein Alx, which in turn drives complement evasion via CFI-dependent C3b degradation [4]. This highlights a novel mechanism where a pathogen hijacks the host's own complement regulator to avoid opsonization and subsequent killing.
- ***Streptococcus pyogenes*:** The M protein of *S. pyogenes* binds to Factor H and C4BP, recruiting these cofactors to the bacterial surface. This allows the pathogen to recruit Factor I and inactivate any surface-bound C3b, effectively making the bacterium invisible to the complement system.
- ***Neisseria* species:** Similar to *Streptococcus*, *Neisseria meningitidis* and *N. gonorrhoeae* bind Factor H to their surface via specific outer membrane proteins (e.g., PorA, fHbp), recruiting Factor I to degrade C3b and evade complement-mediated lysis.

### 5.2 Viral Interactions

- **Adenovirus:** Some adenovirus serotypes bind to Factor I cofactors, such as CD46 (MCP), which is a receptor for many adenoviruses. While the primary interaction is with CD46, the recruitment of Factor I to the viral surface may help the virus evade complement.
- **SARS-CoV-2:** The COVID-19 pandemic has highlighted the role of complement in viral pathogenesis. Severe COVID-19 is associated with complement activation and thrombotic microangiopathy. In patients with pre-existing complement gene variants, including those in *CFI*, SARS-CoV-2 infection can act as a trigger for severe TMA and acute kidney injury [5].

### 5.3 Parasitic Evasion

- ***Trypanosoma cruzi*:** The causative agent of Chagas disease expresses a complement regulatory protein (CRP) that binds to C3b and C4b and acts as a cofactor for Factor I, inactivating these opsonins and protecting the parasite from complement-mediated lysis.

## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors

The central role of Factor I in complement regulation makes it an attractive therapeutic target, both for inhibition (to enhance complement activity against pathogens or tumors) and for supplementation (to restore regulation in deficiency states).

### 6.1 Gene Therapy for CFI Deficiency and AMD

The most advanced therapeutic strategy for CFI-related diseases is gene therapy to supplement the deficient protein.

- **GT005 (PPY988):** This is an adeno-associated virus (AAV) serotype 2 (AAV2) vector encoding the human *CFI* gene, designed for subretinal delivery. It is being developed for the treatment of geographic atrophy (GA) secondary to AMD. Phase I/II clinical trials have demonstrated that GT005 is safe and well-tolerated, and it successfully increases Factor I expression and downregulates the alternative complement pathway in the eye [6, 7, 8]. Biomarker analysis from these trials showed increased FI levels in aqueous humor and reduced levels of complement activation products, confirming target engagement [6].
- **Preclinical AAV Studies:** Preclinical studies in mice have shown that AAV-mediated delivery of *CFI* can elevate Factor I levels in the serum and eye, and downregulate systemic complement activity [7, 8]. These studies provide a strong rationale for the ongoing clinical development of CFI gene therapy.

### 6.2 Complement Inhibitors

For diseases caused by *CFI* mutations that lead to complement overactivation (e.g., aHUS), the primary therapeutic approach is systemic complement inhibition.

- **Eculizumab (Soliris):** This is a humanized monoclonal antibody that binds to complement protein C5, preventing its cleavage into C5a and C5b and thereby blocking the formation of the membrane attack complex (MAC). It is the standard of care for aHUS and is highly effective in inducing remission and preventing disease recurrence [9, 10]. Eculizumab is used in patients with *CFI* mutations, regardless of the specific variant, as it acts downstream of Factor I.
- **Ravulizumab (Ultomiris):** A next-generation C5 inhibitor with a longer half-life, allowing for less frequent dosing. It is also approved for aHUS.
- **Iptacopan (LNP023):** An oral, small-molecule inhibitor of Factor B (FB), a key component of the alternative pathway C3 convertase. By inhibiting FB, iptacopan blocks the amplification loop of the complement cascade, reducing C3b generation and downstream inflammation. It is being investigated for C3G and other complement-mediated diseases, and may be particularly beneficial in patients with *CFI* mutations who have residual Factor I activity.

### 6.3 Small-Molecule Inhibitors of CFI (Investigational)

While no small-molecule inhibitors of Factor I are currently FDA-approved, there is interest in developing them for therapeutic purposes.

- **Rationale for Inhibition:** In certain contexts, such as cancer, inhibiting Factor I could enhance complement-dependent cytotoxicity (CDC) against tumor cells. Tumors often overexpress complement regulators, including Factor I cofactors like CD46, to evade immune surveillance. Inhibiting Factor I could "re-arm" the complement system to attack tumor cells [17].
- **Challenges:** The development of Factor I inhibitors is challenging due to the need for specificity and the complex conformational activation mechanism. However, the recent elucidation of the high-resolution crystal structure of Factor I in complex with its cofactor and substrate provides a template for structure-based drug design [1].

### 6.4 Pharmacogenomics

The field of pharmacogenomics for *CFI* is nascent but growing. The primary application is in the context of aHUS, where genetic testing is used to guide treatment decisions.

- **Predicting Eculizumab Response:** Patients with *CFI* mutations generally respond well to eculizumab, but the duration of treatment is a subject of debate. Some studies suggest that patients with complement gene mutations have a higher risk of relapse after eculizumab discontinuation, and thus may require long-term therapy [10].
- **Risk Stratification in Transplantation:** In renal transplant recipients with aHUS, the presence of a *CFI* mutation is a strong predictor of disease recurrence and graft loss. This information is used to guide the use of prophylactic eculizumab therapy in the peri-transplant period [11, 12].
- **Future Directions:** As gene therapy and other targeted therapies become available, pharmacogenomic testing for *CFI* variants will be essential for patient selection and personalized treatment strategies.

## 7. Bioinformatic Resources & Database Accessions

The following table provides key database accessions and resources for the *CFI* gene and its protein product.

| **Database** | **Identifier** | **Description** |
| :--- | :--- | :--- |
| **NCBI Gene** | 3426 | Gene-specific information, genomic context, and links to other resources. |
| **Ensembl** | ENSG00000105403 | Genome assembly, transcripts, and variation data. |
| **UniProtKB** | P05156 | Protein sequence, function, domain architecture, and post-translational modifications. |
| **RCSB PDB** | 5FCG, 5FCH, 5FCI | Experimentally determined 3D structures of Factor I and its complexes. |
| **HGNC** | 5394 | Gene symbol, name, and aliases. |
| **OMIM** | 217030 | Phenotype and genetic relationships for CFI deficiency and related disorders. |
| **ClinVar** | Gene: 3426 | Clinically reported variants and their pathogenicity classifications. |
| **STRING** | P05156 | Protein-protein interaction networks. |
| **BioGRID** | 108853 | Physical and genetic interaction data. |
| **Gene Ontology (GO)** | GO:0004252 (serine-type endopeptidase activity), GO:0005576 (extracellular region), GO:0006956 (complement activation) | Functional annotations for molecular function, cellular component, and biological process. |
| **GTEx Portal** | ENSG00000105403 | Tissue-specific gene expression data. |
| **Human Protein Atlas** | ENSG00000105403 | Protein expression and localization data across tissues and cell lines. |

## Related Clinical & Scientific Guides

* [TARM1 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/immunology-checkpoints/tarm1-gene-structure-function-pathway)
* [TRAC Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/immunology-checkpoints/trac-gene-structure-function-pathway)
* [CFD Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/immunology-checkpoints/cfd-gene-structure-function-pathway)

## References

[1] Bouzroud, W., Tazzite, A., yousra, I., Gazzaz, B., & Dehbi, H. (2022). Complement Factor I deficiency: A novel homozygous CFI gene mutation. *SAGE Open Medical Case Reports*. URL: https://www.semanticscholar.org/paper/be50d876021f40473f7aaa0944c25c8681d9a91f

[2] de Jong, S., Volokhina, E., de Breuk, A., Nilsson, S. C., de Jong, E. D., van der Kar, N. C. A. J., Bakker, B., Hoyng, C., Van den Heuvel, L. P., Blom, A., & den Hollander, A. D. (2020). Effect of rare coding variants in the CFI gene on Factor I expression levels. *Human Molecular Genetics*. URL: https://www.semanticscholar.org/paper/675b12080e61beade20e069742e719fef8c51eb7

[3] de Jong, S., Koolen, L., Vázquez-Domínguez, I., de Breuk, A., Albert, S., Hoyng, C., Katti, S., den Hollander, A. D., & Garanto, A. (2022). Generation of an iPSC line (SCTCi014-A) and isogenic control line (SCTCi014-A-1) from an age-related macular degeneration patient carrying the variant c.355G>A in the CFI gene. *Stem Cell Research*. URL: https://www.semanticscholar.org/paper/a2cc5ada52e5da3592b2692ae4d1006d3dbab667

[4] Tang, Y.-Y., Li, Y.-T., Zha, X.-H., Zhang, D., Tang, B., Liu, Q., Jiang, S.-H., & Dai, L. (2020). A complement factor I (CFI) gene mediates innate immune responses in yellow catfish Pelteobagrus fulvidraco. *Genomics*. URL: https://www.semanticscholar.org/paper/3e1603623cc6a2601bfa45000fdeab631586e4eb

[5] de Jong, S., Koolen, L., Vázquez-Domínguez, I., de Breuk, A., Albert, S., Hoyng, C., Katti, S., den Hollander, A. D., & Garanto, A. (2022). Generation of an iPSC line (SCTCi015-A) and isogenic control line (SCTCi015-A-1) from an age-related macular degeneration patient carrying the variant c.355G>A in the CFI gene. *Stem Cell Research*. URL: https://www.semanticscholar.org/paper/76a4b29d70387233da5b80bab7e0eff7a28c3f9c

[6] (2022). Aqueous humor complement factor I concentration is associated with SNP of CFI gene. *The Thirteenth International Multiconference*. URL: https://www.semanticscholar.org/paper/70df3f638ad17ec42d261ede8fed49170ae23e09

[7] Kavanagh, D., Yu, Y., Schramm, E. C., Triebwasser, M., Wagner, E. K., Raychaudhuri, S., Daly, M., Atkinson, J., & Seddon, J. (2015). Rare genetic variants in the CFI gene are associated with advanced age-related macular degeneration and commonly result in reduced serum factor I levels. *Human Molecular Genetics*. URL: https://www.semanticscholar.org/paper/eb070a5f0e826500ec25ed429ee3e75fc1079220

[8] Neda, N., Morteza, B., Esmail, B., Hosein, J. B. M., & Alireza, J. (2017). Association of CFI gene polymorphism with age related macular degeneration in Northwest of Iran. *Scientific Publication*. URL: https://www.semanticscholar.org/paper/5353482e29056c900c283959e3b41d94427f0410

[9] Han, X., Tan, S., Du, B., Liu, J., & Qu, L. (2025). Discovery and experimentally mice model validation of CFI, a Natural Killer T cell-related gene, as a Key Biomarker in Osteoarthritis. *Clinical and Experimental Immunology*. URL: https://www.semanticscholar.org/paper/3174916ef37cc6b4d34c91984a3992c014e73d9a

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