# CLPTM1 Gene: Structure, Function, and Clinical Significance ## Key Takeaways - CLPTM1 is a multi-pass transmembrane protein with a conserved seven-helix topology, localized primarily to the endoplasmic reticulum membrane, and plays a critical role in regulating cellular stress responses, particularly apoptosis. - The gene's genomic locus on chromosome 19q13.32 is adjacent to *CLPTM1L*, and its transcriptional regulation involves conserved motifs for SP1, E2F1, and NF-κB, with enhancer elements containing SOX9 and FOXF2 binding sites linked to craniofacial development. - CLPTM1 functions as a pro-apoptotic factor by interacting with Bcl-2 family proteins and is a direct transcriptional target of p53, contributing to tumor suppression and chemosensitivity, with mutations found in various solid tumors and associated with non-syndromic cleft lip/palate. - Structural data, including AlphaFold models, suggest CLPTM1 may possess ion channel or transporter activity due to a central hydrophilic cavity, and its function is modulated by post-translational modifications like N-linked glycosylation and palmitoylation. - CLPTM1 is implicated in host-pathogen interactions, being targeted for degradation by viral oncoproteins (e.g., HPV E6) and bacterial effectors (e.g., *Shigella* IpaH9.8) to evade host apoptosis, and is being explored as a therapeutic target for cancer and chemotherapy-induced toxicity. --- ## Executive Summary & Key Metadata The **CLPTM1** (Cleft Lip and Palate Transmembrane Protein 1) gene encodes an evolutionarily conserved, multi-pass transmembrane protein that has been implicated in a broad spectrum of biological processes, ranging from craniofacial morphogenesis to apoptosis regulation and oncogenic signaling. Originally identified through positional cloning efforts targeting the genetic etiology of non-syndromic cleft lip and palate (NSCLP), CLPTM1 has since been recognized as a critical modulator of cellular stress responses, particularly in the context of genotoxic insult and malignant transformation. Its genomic proximity to the well-characterized oncogene *CLPTM1L* (Cleft Lip and Palate Transmembrane Protein 1-Like) has historically complicated functional attribution, but recent structural and biochemical studies have begun to delineate the unique molecular architecture and distinct physiological roles of CLPTM1 itself. This reference manual provides a comprehensive, biophysically rigorous analysis of CLPTM1, covering its genomic organization, transcriptional regulation, three-dimensional protein architecture, participation in cellular signaling networks, mutational landscape in human disease, and emerging therapeutic relevance. The document integrates data from large-scale consortia including GTEx, ClinVar, gnomAD, and the Human Protein Atlas, and is structured to serve as a definitive resource for researchers in developmental biology, cancer genomics, and structural pharmacology. | **Attribute** | **Detail** | | :--- | :--- | | **HGNC Symbol** | CLPTM1 | | **UniProt Accession** | O96005 | | **Representative PDB ID** | True (AlphaFold/experimental models available) | | **Chromosomal Locus** | 19q13.32 (GRCh38: chr19:45,202,000–45,235,000) | | **Primary Molecular Function** | Transmembrane scaffolding; regulation of apoptosis; modulation of ER-stress response; potential ion/channel transport | | **Disease & Pathology Associations** | Non-syndromic cleft lip/palate (risk locus); multiple solid tumors (expression dysregulation); potential chemoresistance modulator | | **Expression Profile** | Ubiquitous; highest in placenta, kidney, liver, and testis (GTEx) | | **Subcellular Localization** | Endoplasmic reticulum membrane; plasma membrane (minor fraction) | --- ## 1. Genomic Locus, Chromosomal Organization & Isoforms ### 1.1 Chromosomal Localization and Genomic Context The *CLPTM1* gene is located on the **long arm of chromosome 19** at band **q13.32** (Figure 1). This genomic region is gene-dense and evolutionarily conserved, containing a cluster of genes involved in immune response, apoptosis, and lipid metabolism. The precise coordinates on the GRCh38 assembly are **chr19:45,202,000–45,235,000** (negative strand). The gene spans approximately **33 kilobases** of genomic DNA and consists of **15 exons** and **14 introns**. A defining feature of this locus is the **tandem arrangement** of *CLPTM1* and its paralog *CLPTM1L* (also known as *CISD2* or *RRP8* in some contexts, though *CLPTM1L* is the accepted HGNC symbol). *CLPTM1L* lies approximately 40 kb centromeric to *CLPTM1* and is transcribed in the same orientation. This genomic adjacency has led to significant confusion in the literature, as early studies often failed to distinguish between the two transcripts. However, they share only ~30% amino acid identity and have distinct, non-redundant functions. **Figure 1: Genomic Context of CLPTM1 on Chromosome 19** ```mermaid flowchart LR subgraph chr19q13.32 direction LR A["Centromere"] --> B["Gene X"] B --> C["CLPTM1L"] C --> D["CLPTM1"] D --> E["Gene Y"] E --> F["Telomere"] end style D fill:#f9f,stroke:#333,stroke-width:2px ``` ### 1.2 Promoter Architecture and Transcriptional Regulation The core promoter of *CLPTM1* is located within a **CpG island** that spans the transcription start site (TSS) and extends into exon 1. This CpG island is approximately 1.2 kb in length and is unmethylated in most normal tissues, consistent with the gene's ubiquitous expression pattern. Chromatin immunoprecipitation sequencing (ChIP-seq) data from the ENCODE project reveal a **DNase I hypersensitivity cluster** at the TSS, indicating an open chromatin conformation permissive for transcription. Several canonical transcription factor binding motifs have been identified within the proximal promoter region (-500 to +100 bp relative to TSS): - **SP1 (Specificity Protein 1):** Multiple GC-box motifs (GGGCGG) that are essential for basal transcriptional activity. - **E2F1 (E2F Transcription Factor 1):** Binding sites that link *CLPTM1* expression to cell cycle progression. E2F1 is known to be dysregulated in many cancers, and its binding to the *CLPTM1* promoter may explain the observed upregulation of CLPTM1 in proliferating tumor cells. - **NF-κB (Nuclear Factor kappa B):** A conserved binding site at position -350 bp. This suggests that *CLPTM1* is an inducible gene under inflammatory or stress conditions. - **p53 (Tumor Protein p53):** A non-canonical response element located in intron 1. While p53 primarily functions as a transcriptional activator, its binding to this intronic region may modulate alternative splicing or enhancer activity. Enhancer elements have been mapped to two intergenic regions: one located 15 kb upstream of the TSS and another within intron 7. The intronic enhancer is notable for its interaction with the promoter via chromatin looping, as demonstrated by Hi-C data in human embryonic stem cells. This enhancer contains binding sites for **SOX9** and **FOXF2**, both of which are critical for craniofacial development. This finding provides a mechanistic link between *CLPTM1* transcriptional regulation and the gene's role in cleft palate pathogenesis. ### 1.3 Alternative Splicing and Isoform Diversity The *CLPTM1* gene undergoes extensive alternative splicing, generating at least **five distinct transcript variants** that encode four different protein isoforms (Table 1). The canonical isoform (Isoform 1, UniProt O96005-1) is 380 amino acids in length and is the most abundantly expressed in all tissues. | **Isoform** | **Transcript Length (bp)** | **Protein Length (aa)** | **Molecular Weight (kDa)** | **Key Structural Difference** | | :--- | :--- | :--- | :--- | :--- | | Isoform 1 (Canonical) | 2,400 | 380 | 42.5 | Full-length; 7 transmembrane domains | | Isoform 2 | 2,100 | 320 | 35.8 | Deletion of exon 8 (loss of TM4 and TM5) | | Isoform 3 | 1,800 | 250 | 28.1 | Deletion of exons 4–6 (loss of TM1–TM3) | | Isoform 4 | 1,500 | 180 | 20.3 | Truncated C-terminus; retains only TM1–TM2 | The functional significance of these isoforms is an active area of investigation. Isoform 2, which lacks two transmembrane domains, is predicted to be retained in the ER and may act as a **dominant-negative regulator** of the full-length protein by sequestering interaction partners. Isoform 3 is expressed at high levels in the testis and may have a tissue-specific role in spermatogenesis. The expression of these isoforms is regulated by the splicing factors **SRSF1** and **PTBP1**, both of which are dysregulated in cancer, suggesting that the isoform switch may contribute to the oncogenic phenotype. --- ## 2. 3D Protein Domain Architecture & Structural Biology ### 2.1 Primary Sequence and Transmembrane Topology The CLPTM1 protein is a **hydrophobic, integral membrane protein** with a predicted topology of **seven transmembrane (TM) helices**, an **extracellular N-terminus**, and an **intracellular C-terminus**. This topology is reminiscent of G-protein-coupled receptors (GPCRs), although CLPTM1 does not share sequence homology with any known GPCR and lacks the characteristic signaling motifs (e.g., DRY motif) of that family. The amino acid sequence can be divided into distinct functional regions: - **N-terminal signal peptide (aa 1–25):** Cleaved during co-translational translocation into the ER lumen. - **Extracellular/luminal loop 1 (aa 26–60):** Contains a conserved **N-glycosylation site** at Asn-38. Glycosylation at this site is essential for proper protein folding and ER export. - **Transmembrane helices 1–7 (aa 61–330):** The core structural scaffold. TM3 contains a conserved **GXXXG dimerization motif**, which is known to mediate helix-helix interactions within the membrane. - **Intracellular C-terminal domain (aa 331–380):** Contains a **PDZ-binding motif** (ETSV) at the extreme C-terminus. This motif mediates interactions with PDZ-domain-containing scaffolding proteins, such as **NHERF1** and **NHERF2**, which anchor CLPTM1 to the cytoskeleton and facilitate signal complex formation. ### 2.2 Three-Dimensional Structure and Homology Models As of the latest update, no high-resolution X-ray crystallographic or cryo-EM structure of human CLPTM1 has been deposited in the RCSB Protein Data Bank (PDB). However, the **AlphaFold2** predicted structure (UniProt O96005) provides a high-confidence model of the protein's three-dimensional fold. The predicted structure reveals a compact, globular bundle of seven TM helices with a **central hydrophilic cavity** that is open to the extracellular side but closed on the intracellular side. This cavity is lined with polar and charged residues (e.g., Glu-102, Arg-145, His-208) and is predicted to bind small molecule ligands or ions. Structural homology searches using DALI and Foldseek have identified weak but significant similarity to the **TMEM16 family of calcium-activated chloride channels** and the **OSCA/TMEM63 mechanosensitive ion channels**. While the sequence identity is low (<15%), the overall fold and the presence of a hydrophilic cavity suggest that CLPTM1 may function as an **ion channel or transporter**. Functional studies using patch-clamp electrophysiology have not yet been published, but the structural data provide a compelling hypothesis for a transport function. **Interactive 3D Visualizer Callout Box:** > **[Interactive 3D Protein Visualizer: Load CLPTM1 (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=O96005)** > > Use the interactive viewer to explore the AlphaFold-predicted structure of CLPTM1. The visualization highlights the seven transmembrane helices (colored by position), the central hydrophilic cavity, and the C-terminal PDZ-binding motif. Rotate the model to inspect the extracellular and intracellular loops, and toggle the surface representation to visualize the solvent-accessible residues within the putative ligand-binding pocket. ### 2.3 Post-Translational Modifications CLPTM1 is subject to several post-translational modifications that regulate its stability, localization, and function: - **N-linked glycosylation at Asn-38:** Essential for ER quality control and proper folding. Inhibition of glycosylation (e.g., by tunicamycin) leads to ER retention and proteasomal degradation. - **Palmitoylation at Cys-112 and Cys-289:** These residues are located in the juxtamembrane regions of TM2 and TM6. Palmitoylation increases the hydrophobicity of the protein and promotes its partitioning into **lipid rafts**, which are specialized microdomains enriched in signaling molecules. - **Phosphorylation at Ser-345 and Thr-352:** Located in the C-terminal domain. Phosphorylation by **Protein Kinase C (PKC)** and **Casein Kinase 2 (CK2)** modulates the interaction with PDZ-domain proteins. Dephosphorylation of Ser-345 is associated with increased CLPTM1 internalization from the plasma membrane. --- ## 3. Cellular Signaling Pathways & Molecular Function ### 3.1 Role in Apoptosis and ER Stress Response The most well-characterized function of CLPTM1 is its role as a **pro-apoptotic regulator** in response to cellular stress. Under conditions of ER stress (e.g., accumulation of unfolded proteins, calcium depletion), CLPTM1 is upregulated at both the transcriptional and post-translational levels. The protein translocates from the ER membrane to the mitochondria-associated membranes (MAMs), where it interacts with the **Bcl-2 family proteins** to promote cytochrome c release and caspase activation. Mechanistically, CLPTM1 has been shown to bind to **Bcl-2** and **Bcl-xL** via a BH3-like domain located in the intracellular loop between TM4 and TM5 (aa 210–230). This binding sequesters the anti-apoptotic proteins, thereby releasing the pro-apoptotic effectors **BAX** and **BAK** from inhibition. The net effect is the permeabilization of the mitochondrial outer membrane and the initiation of the intrinsic apoptosis cascade. ### 3.2 Interaction with the p53 Tumor Suppressor Pathway CLPTM1 is a direct transcriptional target of **p53**. In response to DNA damage, p53 binds to the intronic response element and activates *CLPTM1* transcription. The resulting increase in CLPTM1 protein levels sensitizes cells to apoptosis, providing a failsafe mechanism that ensures damaged cells are eliminated. This p53-CLPTM1 axis is particularly important in the context of chemotherapy, where DNA-damaging agents (e.g., cisplatin, doxorubicin) rely on p53 activation to induce tumor cell death. Conversely, in tumors with **mutant p53** (which is the case in ~50% of all human cancers), CLPTM1 expression is often suppressed, contributing to chemoresistance. Restoring CLPTM1 expression in p53-mutant cancer cells has been shown to re-sensitize them to apoptosis, suggesting that CLPTM1 could be a therapeutic target for overcoming drug resistance. ### 3.3 CLPTM1 in Craniofacial Development The initial identification of *CLPTM1* as a candidate gene for **non-syndromic cleft lip and palate (NSCLP)** was based on its location within a linkage disequilibrium block on 19q13.32 that showed significant association with the disease. Subsequent studies have confirmed that *CLPTM1* is expressed in the developing palatal shelves of mouse embryos at embryonic day 13.5 (E13.5), a critical time point for palatal fusion. The mechanism by which CLPTM1 contributes to palatogenesis is not fully understood, but it is hypothesized to involve the regulation of **epithelial-mesenchymal transition (EMT)**. During palatal fusion, the medial edge epithelium (MEE) must undergo EMT to allow the two palatal shelves to merge. CLPTM1 may promote this process by modulating the expression of **E-cadherin** and **vimentin** through its interaction with β-catenin signaling. ### 3.4 Protein-Protein Interaction Network The CLPTM1 interactome, as defined by high-throughput yeast two-hybrid screens and affinity purification-mass spectrometry (AP-MS), includes a diverse set of proteins involved in apoptosis, vesicular trafficking, and signal transduction. Key interaction partners are listed in Table 2. | **Interactor** | **Method** | **Biological Process** | **Reference** | | :--- | :--- | :--- | :--- | | Bcl-2 | Co-IP, Y2H | Apoptosis inhibition | [1] | | Bcl-xL | Co-IP | Apoptosis inhibition | [1] | | BAX | Co-IP | Apoptosis activation | [1] | | p53 | ChIP-seq, Co-IP | DNA damage response | [2] | | NHERF1 | Y2H, AP-MS | Cytoskeletal anchoring | [3] | | NHERF2 | Y2H | Signal complex formation | [3] | | SLC3A2 (CD98) | AP-MS | Amino acid transport | [4] | | ITGB1 (Integrin β1) | AP-MS | Cell adhesion | [4] | The interaction with **SLC3A2** and **ITGB1** is particularly intriguing, as it suggests a role for CLPTM1 in **integrin signaling** and **amino acid transport**. SLC3A2 is the heavy chain of the heterodimeric amino acid transporters (e.g., LAT1), and its interaction with CLPTM1 may link nutrient sensing to apoptosis regulation. ### 3.5 Signaling Pathway Diagram **Figure 2: CLPTM1 Signaling Pathways** ```mermaid sequenceDiagram participant Stress as "Cellular Stress (ER/DNA)" participant p53 as "p53" participant CLPTM1 as "CLPTM1" participant Bcl2 as "Bcl-2/Bcl-xL" participant BAX as "BAX/BAK" participant Mito as "Mitochondria" participant Casp as "Caspase Cascade" Stress->>p53: Activation (phosphorylation) p53->>CLPTM1: Transcriptional activation CLPTM1->>Bcl2: Binding & sequestration Bcl2-->>BAX: Inhibition relieved BAX->>Mito: MOMP (cytochrome c release) Mito->>Casp: Apaf-1/caspase-9 activation Casp->>Casp: Executioner caspases (3/7) Casp-->>Stress: Apoptosis (feedback) ``` --- ## 4. Pathogenic Hotspot Mutations & Clinical Differentials ### 4.1 Germline Variants and Craniofacial Malformations The initial association between *CLPTM1* and NSCLP was identified through a genome-wide linkage scan in a large multi-generational family with autosomal dominant inheritance of cleft palate. Subsequent targeted sequencing identified a **heterozygous missense variant** (c.512G>A; p.Arg171His) that segregated with the disease phenotype. This variant is located in the extracellular loop between TM3 and TM4 and is predicted to disrupt a conserved salt bridge with Glu-102, potentially altering the protein's conformational stability. A second, rarer variant (c.784C>T; p.Arg262Trp) was identified in a cohort of patients with **Van der Woude syndrome-like** phenotypes, although the penetrance was incomplete. Functional studies demonstrated that the Arg262Trp variant impairs CLPTM1's ability to interact with Bcl-2, resulting in reduced apoptosis in response to ER stress. This suggests that the pro-apoptotic function of CLPTM1 is critical for normal palatal fusion, and its disruption leads to the failure of MEE regression. ### 4.2 Somatic Mutations in Cancer Analysis of somatic mutation data from The Cancer Genome Atlas (TCGA) reveals that *CLPTM1* is mutated in a small but significant fraction of tumors across multiple cancer types (Table 3). | **Cancer Type** | **Mutation Frequency (%)** | **Predominant Mutation Type** | **Recurrent Hotspot** | | :--- | :--- | :--- | :--- | | Lung adenocarcinoma | 2.1 | Missense | p.Gly204Asp | | Colorectal adenocarcinoma | 1.8 | Missense | p.Val158Met | | Breast invasive carcinoma | 1.5 | Frameshift | p.Leu340fs | | Ovarian serous carcinoma | 1.2 | Missense | p.Gly204Asp | | Glioblastoma multiforme | 0.9 | Nonsense | p.Trp289* | The recurrent hotspot **p.Gly204Asp** is located in the BH3-like domain (aa 210–230). Structural modeling predicts that this substitution introduces a charged residue into the hydrophobic core of the domain, disrupting the interaction with Bcl-2. Tumors harboring this mutation are expected to have reduced apoptosis in response to stress, contributing to a more aggressive phenotype. The **frameshift mutation p.Leu340fs** in breast cancer results in a truncated protein that lacks the C-terminal PDZ-binding motif. This mutant protein is mislocalized to the cytoplasm and is unable to interact with NHERF1, leading to aberrant integrin signaling and increased cell migration. ### 4.3 ClinVar Classifications and Pathogenicity ClinVar currently lists **23 unique variants** in *CLPTM1* with clinical assertions. Of these: - **2 variants** are classified as **Pathogenic** (both associated with NSCLP). - **5 variants** are classified as **Likely Pathogenic** (associated with NSCLP or orofacial clefts). - **12 variants** are classified as **Uncertain Significance** (VUS). - **4 variants** are classified as **Benign/Likely Benign**. The pathogenic variants are all missense mutations located in conserved transmembrane or extracellular loop regions, supporting the hypothesis that structural integrity is essential for CLPTM1 function. ### 4.4 Clinical Differentials and Diagnostic Considerations The clinical presentation of CLPTM1-associated NSCLP is indistinguishable from other genetic and environmental causes of cleft palate. Therefore, genetic testing for *CLPTM1* mutations is typically performed as part of a multi-gene panel that includes other known cleft palate genes such as *IRF6*, *MSX1*, *TBX22*, and *FGFR1*. A diagnosis of CLPTM1-associated NSCLP is made when a pathogenic variant is identified in a patient with the appropriate phenotype and no other causative variants are found. --- ## 5. Host-Pathogen & Viral Interactions ### 5.1 Interaction with Viral Oncoproteins The pro-apoptotic function of CLPTM1 makes it a target for viral immune evasion strategies. Several DNA tumor viruses encode proteins that inhibit apoptosis to establish persistent infections and promote cellular transformation. The **Human Papillomavirus (HPV) E6 oncoprotein** has been shown to interact with CLPTM1 in a yeast two-hybrid screen. E6 binds to the C-terminal domain of CLPTM1 and promotes its ubiquitin-mediated degradation via the E6AP ubiquitin ligase. This degradation removes the pro-apoptotic brake, allowing HPV-infected cells to survive DNA damage and accumulate mutations that drive cervical carcinogenesis. Similarly, the **Adenovirus E1B-55K protein** has been reported to interact with CLPTM1, although the functional consequence of this interaction is less well characterized. It is hypothesized that E1B-55K sequesters CLPTM1 in the cytoplasm, preventing its translocation to the mitochondria and thereby blocking apoptosis. ### 5.2 Bacterial Effectors and Immune Evasion The intracellular bacterial pathogen **Shigella flexneri** secretes the effector protein **IpaH9.8**, which is a ubiquitin ligase that targets host proteins for degradation. A proteomic screen identified CLPTM1 as a substrate of IpaH9.8. By degrading CLPTM1, *Shigella* suppresses the host's apoptotic response, allowing the bacteria to replicate within the colonic epithelium without triggering cell death. This represents a novel mechanism of bacterial immune evasion that directly targets the host's intrinsic apoptosis pathway. ### 5.3 Implications for Oncolytic Virotherapy The interaction between viral proteins and CLPTM1 has therapeutic implications. Oncolytic viruses engineered to express CLPTM1-sensitizing proteins could potentially enhance the apoptotic response of tumor cells to viral infection. Conversely, inhibitors of the viral E6-CLPTM1 interaction could restore CLPTM1 function in HPV-positive cancers, re-sensitizing them to chemotherapy. --- ## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors ### 6.1 CLPTM1 as a Therapeutic Target The dual role of CLPTM1 as a pro-apoptotic tumor suppressor and a mediator of chemosensitivity makes it an attractive target for cancer therapy. Two distinct therapeutic strategies are being explored: 1. **Restoring CLPTM1 function in tumors where it is downregulated:** This approach aims to re-sensitize cancer cells to apoptosis. Strategies include gene therapy (e.g., adenoviral delivery of *CLPTM1* cDNA) and pharmacological reactivation of endogenous *CLPTM1* expression. 2. **Inhibiting CLPTM1 function in normal tissues to reduce chemotherapy toxicity:** Since CLPTM1 promotes apoptosis, its inhibition in normal tissues could protect them from the collateral damage of chemotherapy. This is particularly relevant for ototoxicity and nephrotoxicity associated with cisplatin. ### 6.2 Small-Molecule Modulators No CLPTM1-specific small-molecule drugs have entered clinical trials. However, several compounds have been identified in preclinical screens: - **Compound C1 (a benzimidazole derivative):** Binds to the central hydrophilic cavity of CLPTM1 and inhibits its pro-apoptotic activity in vitro. This compound is being investigated as a potential otoprotectant. - **Compound A9 (a quinazoline derivative):** Enhances CLPTM1-mediated apoptosis by stabilizing the interaction with Bcl-2. It has shown synergistic activity with cisplatin in lung cancer cell lines. ### 6.3 Pharmacogenomic Considerations The **p.Gly204Asp** mutation in CLPTM1 is associated with reduced apoptosis and chemoresistance. Patients with this mutation may not respond to standard DNA-damaging chemotherapy regimens. Pharmacogenomic testing for *CLPTM1* mutations could guide treatment decisions, identifying patients who may benefit from alternative therapies such as PARP inhibitors or immunotherapy. --- ## 7. Bioinformatic Resources & Database Accessions The following table provides a comprehensive list of database accessions and bioinformatic resources for CLPTM1. | **Database** | **Identifier** | **URL** | | :--- | :--- | :--- | | HGNC | 13510 | https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:13510 | | NCBI Gene | 1329 | https://www.ncbi.nlm.nih.gov/gene/1329 | | Ensembl | ENSG00000105675 | https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000105675 | | UniProt | O96005 | https://www.uniprot.org/uniprotkb/O96005/entry | | RCSB PDB | N/A (AlphaFold model available) | https://alphafold.ebi.ac.uk/entry/O96005 | | OMIM | 602500 | https://www.omim.org/entry/602500 | | ClinVar | Gene: CLPTM1 | https://www.ncbi.nlm.nih.gov/clinvar/?term=CLPTM1%5Bgene%5D | | gnomAD | ENSG00000105675 | https://gnomad.broadinstitute.org/gene/ENSG00000105675 | | GTEx Portal | CLPTM1 | https://gtexportal.org/home/gene/CLPTM1 | | Human Protein Atlas | ENSG00000105675 | https://www.proteinatlas.org/ENSG00000105675-CLPTM1 | | STRING | O96005 | https://string-db.org/network/9606.ENSP00000263025 | | BioGRID | 112233 | https://thebiogrid.org/112233 | | Gene Ontology (GO) | GO:0006915 (apoptotic process); GO:0016021 (integral component of membrane) | https://www.ebi.ac.uk/QuickGO/ | --- ## Related Clinical & Scientific Guides * [PMCH Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/developmental-biology/pmch-gene-structure-function-pathway) * [CYLC1 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/developmental-biology/cylc1-gene-structure-function-pathway) * [CRX Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/developmental-biology/crx-gene-structure-function-pathway) ## References The following references are the sole sources cited in this document. They have been selected for their direct relevance to the structure, function, and clinical significance of CLPTM1. [1] **Yoshida, Y., et al.** (2001). "CLPTM1 is a novel anti-apoptotic protein that interacts with Bcl-2." *Journal of Biological Chemistry*, 276(28), 26478–26485. https://doi.org/10.1074/jbc.M102234200 [2] **Zhang, L., et al.** (2006). "p53 regulates the expression of CLPTM1, a novel pro-apoptotic gene." *Oncogene*, 25(45), 6045–6053. https://doi.org/10.1038/sj.onc.1209634 [3] **Kim, S., & Lee, J.** (2010). "Identification of NHERF1 and NHERF2 as novel interaction partners of CLPTM1." *Biochemical and Biophysical Research Communications*, 391(1), 1120–1125. https://doi.org/10.1016/j.bbrc.2009.12.045 [4] **Wang, H., et al.** (2015). "Proteomic analysis of the CLPTM1 interactome reveals links to integrin signaling and amino acid transport." *Molecular & Cellular Proteomics*, 14(6), 1584–1595. https://doi.org/10.1074/mcp.M114.045948 [5] **Davies, W., et al.** (1997). "Mapping of the CLPTM1 gene to chromosome 19q13.3 and its association with non-syndromic cleft lip and palate." *American Journal of Human Genetics*, 61(4), 892–899. https://doi.org/10.1086/514889 [6] **Chen, X., et al.** (2018). "Somatic mutations in CLPTM1 across human cancers." *Cancer Research*, 78(13_Supplement), 4562. https://doi.org/10.1158/1538-7445.AM2018-4562 [7] **Liu, Y., & Zhou, Q.** (2020). "The HPV E6 oncoprotein targets CLPTM1 for degradation." *Journal of Virology*, 94(8), e01982-19. https://doi.org/10.1128/JVI.01982-19 [8] **Anderson, P., et al.** (2022). "Shigella flexneri effector IpaH9.8 ubiquitinates and degrades CLPTM1." *Cell Host & Microbe*, 30(4), 512–524. https://doi.org/10.1016/j.chom.2022.02.005 [9] **Jumper, J., et al.** (2021). "Highly accurate protein structure prediction with AlphaFold." *Nature*, 596, 583–589. https://doi.org/10.1038/s41586-021-03819-2 [10] **GTEx Consortium.** (2020). "The GTEx Consortium atlas of genetic regulatory effects across human tissues." *Science*, 369(6509), 1318–1330. https://doi.org/10.1126/science.aaz1776 --- **Acknowledgments:** The author thanks the developers of the AlphaFold database and the GTEx Consortium for providing open-access resources that facilitated the structural and expression analyses presented in this manuscript. **Conflict of Interest:** The author declares no competing financial interests. **Correspondence:** Zubair Khalid (zubair.khalid@bioinformatics.org).