# SASH1 Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- SASH1 encodes a scaffold/adaptor protein with an N-terminal SH3 domain and three SAM domains, crucial for signal transduction in pigmentation, immunity, and tumor suppression.
- Germline mutations in SASH1, predominantly missense variants in the SAM2 domain, cause autosomal dominant disorders like dyschromatosis universalis hereditaria (DUH) and lentiginous phenotypes, often linked to dysregulated cAMP signaling.
- Somatic inactivation of SASH1, frequently via promoter hypermethylation, is a recurrent event in multiple solid malignancies (e.g., breast, hepatocellular, lung cancer), correlating with aggressive tumor behavior and poor prognosis.
- SASH1 acts as a tumor suppressor by negatively regulating the PI3K/AKT pathway, stabilizing E-cadherin at adherens junctions via IQGAP1, and modulating TGF-β signaling, thereby inhibiting cell proliferation, migration, and epithelial-to-mesenchymal transition.
- SASH1 plays essential roles in developmental processes, including melanocyte differentiation, endothelial-to-hematopoietic transition, and glial cell migration in the central nervous system, with its loss contributing to pathologies like spinal cord injury.

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## Executive Summary & Key Metadata

The SAM and SH3 domain-containing protein 1 (SASH1) gene encodes a ubiquitous scaffold/adaptor protein that has emerged as a critical nexus in diverse physiological processes, ranging from melanocyte differentiation and pigmentation to immune signaling, endothelial-to-hematopoietic transition, and tumor suppression. Initially identified through a positional cloning effort targeting the frequently deleted chromosomal region 6q24.3 in breast cancer, SASH1 has since been implicated in the pathogenesis of multiple solid malignancies, hereditary pigmentation disorders, and vascular pathologies. Its structural architecture—comprising an N-terminal SH3 domain, two central SAM domains, and a C-terminal SAM domain—positions it as a prototypical member of the SLy/SASH1 family of signal adapter proteins. The clinical relevance of SASH1 is underscored by the identification of over a dozen germline mutations causing dyschromatosis universalis hereditaria (DUH), lentiginous phenotypes, and a rare autosomal-recessive syndrome featuring pigmentation defects, palmoplantar keratoderma, and skin carcinoma. Concurrently, somatic downregulation of SASH1—frequently via promoter hypermethylation—correlates with aggressive tumor behavior and poor prognosis across multiple cancer types. This reference manual provides a comprehensive, biophysically grounded analysis of the SASH1 gene, from its genomic architecture and protein domain organization to its signaling networks, pathogenic mutation spectrum, and therapeutic implications.

| **Attribute** | **Value** |
|---|---|
| HGNC Symbol | SASH1 |
| UniProt Accession | O94885 |
| Representative PDB ID | true (SAM domain structures available; see Section 2) |
| Chromosomal Locus | 6q24.3 |
| Gene Size (GRCh38) | ~220 kb (spanning approximately 124,900,000–125,120,000 bp on chromosome 6) |
| Primary Molecular Function | Scaffold/adaptor protein; signal transduction in pigmentation, immunity, and tumor suppression |
| Key Structural Domains | SH3 domain (N-terminal); three SAM domains (two central, one C-terminal) |
| Disease & Pathology Associations | Dyschromatosis universalis hereditaria (DUH); lentiginous phenotypes; breast, colon, lung, ovarian, hepatocellular, and other cancers; preeclampsia; pulmonary hypertension; spinal cord injury |
| Expression Pattern | Ubiquitous; high in brain, melanocytes, lymphocytes, and vascular endothelium |

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## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Localization and Genomic Architecture

The SASH1 gene is located on the long arm of human chromosome 6 at cytogenetic band 6q24.3. This locus is of particular oncological significance, as loss of heterozygosity (LOH) at 6q24 is a recurrent event in several malignancies, including breast cancer, ovarian cancer, and colon cancer, suggesting the presence of one or more tumor suppressor genes within this interval. The SASH1 genomic locus spans approximately 220 kilobases (kb) of genomic DNA and is oriented on the minus strand of chromosome 6 (GRCh38/hg38: chr6:124,900,000–125,120,000). The gene comprises 19 exons, with the translation initiation codon located in exon 2 and the stop codon in exon 19. The large intronic regions—some exceeding 30 kb—harbor numerous regulatory elements, including putative enhancers and CpG islands that are subject to epigenetic regulation.

### 1.2 Promoter Architecture and Epigenetic Regulation

The SASH1 promoter region is characterized by a dense CpG island spanning approximately 1.2 kb upstream of the transcription start site (TSS) and extending into exon 1. This CpG island is a target for DNA methyltransferases, and its hypermethylation has been demonstrated in multiple cancer types. In breast cancer, promoter methylation of SASH1 was detected in a significant proportion of tumor samples and correlated with reduced mRNA expression. Similarly, hepatocellular carcinoma (HCC) tissues exhibited frequent SASH1 promoter methylation, which was associated with transcriptional silencing. These findings establish promoter hypermethylation as a major mechanism of SASH1 inactivation in cancer, complementing genetic deletion or mutation.

The promoter region contains consensus binding sites for several transcription factors, including Sp1, AP-1, and p53. The p53 binding site is of particular interest given the documented role of p53 in regulating SASH1 expression through a POMC-dependent feedback loop. Chromatin immunoprecipitation (ChIP) studies have confirmed p53 occupancy at the SASH1 promoter following DNA damage or UV irradiation, leading to transcriptional activation. Additionally, the promoter is responsive to TGF-β signaling, with SMAD proteins cooperating with other transcription factors to modulate SASH1 expression in a cell-type-specific manner.

### 1.3 Enhancer Elements and Long-Range Chromatin Interactions

Beyond the proximal promoter, several putative enhancer elements have been identified within the SASH1 locus through chromatin state annotations (e.g., H3K27ac and H3K4me1 marks) from ENCODE and Roadmap Epigenomics data. These enhancers are located in introns 1, 3, and 7 and may mediate cell-type-specific expression. In melanocytes, a distal enhancer approximately 50 kb upstream of the TSS has been implicated in the high-level expression of SASH1, potentially through interactions with the melanocyte master regulator MITF. Three-dimensional chromatin conformation capture (Hi-C) data indicate that the SASH1 promoter engages in long-range interactions with these enhancer regions in a tissue-dependent manner, although the precise trans-acting factors remain to be fully characterized.

### 1.4 Alternative Splicing and Isoform Diversity

The SASH1 gene undergoes alternative splicing to generate multiple transcript variants. The canonical transcript (NM_015278) encodes the full-length 1,247-amino acid protein. However, at least five additional splice variants have been cataloged in Ensembl and RefSeq databases, differing primarily in the usage of alternative 5' exons and the inclusion or exclusion of exons 10 and 14. These variants predict protein isoforms with altered domain architectures:

- **Isoform 1 (canonical, 1,247 aa):** Contains the N-terminal SH3 domain, two central SAM domains (SAM1 and SAM2), and the C-terminal SAM domain (SAM3).
- **Isoform 2 (1,097 aa):** Lacks exon 10, resulting in a deletion within the linker region between SAM1 and SAM2. This isoform may exhibit altered protein-protein interaction specificity.
- **Isoform 3 (832 aa):** Uses an alternative promoter in intron 5, producing a truncated protein that retains only the C-terminal SAM domain. This isoform is expressed at low levels in normal tissues but may be upregulated in certain cancers.
- **Isoform 4 (1,180 aa):** Retains intron 13, introducing a premature stop codon that removes the C-terminal SAM domain. This isoform is predicted to undergo nonsense-mediated decay (NMD) under normal conditions but may escape NMD in stressed cells.

The functional significance of these isoforms is an active area of investigation. It is plausible that tissue-specific splicing generates isoforms with distinct binding partners or subcellular localization patterns, thereby fine-tuning SASH1's biological output. For instance, the C-terminal SAM domain is essential for homo- and heterodimerization with other SAM domain-containing proteins, such as Eph receptors; isoforms lacking this domain may act as dominant-negative regulators.

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

### 2.1 Primary Structure and Domain Organization

The SASH1 protein (UniProt O94885) is a 1,247-amino-acid polypeptide with a predicted molecular mass of approximately 137 kDa. Sequence analysis reveals a modular architecture comprising the following domains, arranged from N-terminus to C-terminus:

1. **SH3 domain (residues ~45–110):** Src Homology 3 domain, a conserved module of approximately 60 amino acids that mediates protein-protein interactions by binding to proline-rich motifs (PxxP) in target proteins. The SASH1 SH3 domain is most closely related to those found in the SLY family of adaptor proteins.

2. **SAM1 domain (residues ~380–450):** Sterile Alpha Motif, a ~70-residue domain that mediates homo- and heterotypic protein interactions. SAM domains can form dimers, oligomers, or even polymerize into helical filaments. The SAM1 domain of SASH1 has been shown to interact with the SAM domain of EphA4 and other Eph receptors.

3. **SAM2 domain (residues ~520–590):** A second SAM domain, separated from SAM1 by a linker region of approximately 70 residues. The presence of two tandem SAM domains is a defining feature of the SLy/SASH1 family.

4. **SAM3 domain (residues ~1,170–1,240):** A C-terminal SAM domain, separated from SAM2 by a large, unstructured region of approximately 580 residues. This C-terminal SAM domain is critical for SASH1's interaction with TNKS2 (tankyrase 2), which regulates SASH1 protein stability and melanocyte stem cell maintenance.

### 2.2 Structural Biology of the SAM Domains

High-resolution structural information for SASH1 SAM domains has been obtained through X-ray crystallography and NMR spectroscopy. The SAM domain fold consists of a five-helix bundle (α1–α5) with a characteristic "mid-loop" that participates in domain swapping and dimerization. The SAM1 domain of SASH1 (PDB entries available for the SAM-SAM complex with EphA4) adopts a canonical SAM fold and forms a heterodimer with the EphA4 SAM domain through a conserved hydrophobic interface. This interaction is mediated by residues on the α1 and α5 helices, which pack against complementary hydrophobic surfaces on the partner SAM domain. Mutations that disrupt this interface—such as those affecting conserved leucine and isoleucine residues—abrogate SASH1-EphA4 binding and impair downstream signaling.

The SAM2 domain has been structurally characterized in the context of the SASH1-TNKS2 interaction. TNKS2, a poly(ADP-ribose) polymerase, binds to SASH1 via its ankyrin repeat domain, recognizing a short linear motif within the SAM2 region. This interaction promotes the PARsylation of SASH1, targeting it for ubiquitin-mediated degradation. The structural basis for this recognition involves a hydrophobic pocket on the ankyrin repeat domain that accommodates a conserved phenylalanine residue in SASH1.

### 2.3 The SH3 Domain and Proline-Rich Interactions

The N-terminal SH3 domain of SASH1 is predicted to adopt the canonical SH3 fold, comprising a β-barrel of five or six antiparallel β-strands flanked by variable loops. SH3 domains typically bind to proline-rich sequences with the consensus PxxP motif, although non-canonical interactions have also been described. In the context of SASH1, the SH3 domain has been implicated in binding to IQGAP1, a scaffold protein that regulates cytoskeletal dynamics and cell adhesion. This interaction is critical for SASH1's role in melanocyte transepithelial migration and breast cancer metastasis suppression. The precise binding interface remains to be determined at atomic resolution, but molecular docking studies suggest that the SH3 domain engages a proline-rich region in IQGAP1's N-terminus.

### 2.4 Intrinsically Disordered Regions and Post-Translational Modifications

Approximately 40% of the SASH1 protein is predicted to be intrinsically disordered, particularly the large linker region between SAM2 and SAM3 (residues ~590–1,170). This region is enriched in phosphorylation sites, as cataloged in PhosphoSitePlus, and is likely to serve as a hub for signal-dependent protein-protein interactions. Known phosphorylation sites include:

- **Serine 519 (S519):** Located within the SAM2 domain; the S519N mutation is associated with a familial pigmentation disorder and premature hair graying. This residue lies near the TNKS2 interaction interface, and its mutation may affect protein stability or binding affinity.
- **Threonine 754 (T754):** A predicted substrate for AKT kinase; phosphorylation at this site may modulate SASH1's tumor suppressor activity.
- **Tyrosine 1,031 (Y1031):** A putative SRC family kinase substrate; phosphorylation may create a docking site for SH2 domain-containing effectors.

Additionally, SASH1 is subject to ubiquitination and PARsylation, as noted above. Caspase-3-mediated cleavage of SASH1 has been documented in lung cancer cells, generating a C-terminal fragment that translocates to the nucleus and promotes apoptosis. This cleavage occurs at a conserved Asp-Glu-Val-Asp (DEVD) motif within the disordered region, linking SASH1 to the intrinsic apoptotic pathway.

### 2.5 Interactive 3D Visualizer

[Interactive 3D Protein Visualizer: Load SASH1 (PDB: true)](/tools/protein-structure-viewer?source=alphafold&accession=O94885)

The interactive visualizer enables exploration of the SASH1 SAM domain structures in three dimensions. Users can rotate the molecule, highlight specific residues (e.g., S519), and measure distances between interaction interfaces. The tool integrates AlphaFold predictions for the full-length protein with experimentally determined structures of individual domains, providing a comprehensive view of the SASH1 architecture.

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## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 SASH1 as a Scaffold in the PI3K/AKT Pathway

One of the most extensively characterized functions of SASH1 is its role as a negative regulator of the PI3K/AKT signaling axis. In multiple cancer types—including breast cancer, hepatocellular carcinoma, thyroid cancer, pancreatic cancer, and skin squamous cell carcinoma—SASH1 overexpression suppresses AKT phosphorylation at both Thr308 and Ser473, leading to reduced downstream signaling through mTOR and its effectors. Conversely, SASH1 knockdown enhances AKT activity, promoting cell proliferation, survival, and invasion.

The molecular mechanism underlying this regulation involves SASH1's interaction with the PI3K regulatory subunit p85. SASH1 binds to p85 via its SAM domains, sequestering it away from the catalytic p110 subunit and thereby reducing PI3K activity. Additionally, SASH1 promotes the expression of PTEN, a lipid phosphatase that antagonizes PI3K signaling, through a mechanism involving the transcription factor FOXO3a. This dual regulation—direct inhibition of p85 and indirect upregulation of PTEN—positions SASH1 as a central brake on the PI3K/AKT pathway.

### 3.2 The SASH1-IQGAP1-E-Cadherin Axis in Cell Adhesion and Migration

SASH1 plays a critical role in maintaining epithelial integrity through its interaction with IQGAP1 and E-cadherin. IQGAP1 is a multifunctional scaffold protein that regulates the actin cytoskeleton, cell-cell adhesion, and cell migration. In normal epithelial cells, SASH1 binds to IQGAP1 and recruits it to adherens junctions, where it stabilizes the E-cadherin-β-catenin complex. This stabilization is essential for maintaining cell polarity and preventing epithelial-to-mesenchymal transition (EMT).

In melanocytes, the SASH1-IQGAP1-E-cadherin pathway regulates transepithelial migration during development. SASH1 knockdown in melanocytes results in reduced E-cadherin expression at the cell surface, increased cell motility, and impaired adhesion to keratinocytes. These findings have direct implications for pigmentation disorders, as aberrant melanocyte migration contributes to the mottled hyper- and hypopigmentation seen in DUH.

In breast cancer, loss of SASH1 expression leads to the dissociation of the IQGAP1-E-cadherin complex, promoting EMT and metastasis. Restoration of SASH1 in metastatic breast cancer cell lines re-establishes adherens junctions and suppresses invasion in vitro and in vivo. The SH3 domain of SASH1 is required for this activity, as SH3-deleted mutants fail to bind IQGAP1 and cannot rescue the epithelial phenotype.

### 3.3 SASH1 in the TGF-β Signaling Pathway

Recent studies have identified SASH1 as a modulator of TGF-β signaling in melanocytes and melanoma cells. TGF-β is a pleiotropic cytokine that regulates cell proliferation, differentiation, and immune function. In melanocytes, TGF-β signaling promotes melanin synthesis and cell migration, and its dysregulation is implicated in melanoma progression.

SASH1 suppresses TGF-β signaling by interacting with the TGF-β type I receptor (TβRI) and promoting its ubiquitin-mediated degradation. This interaction is mediated by the SAM2 domain of SASH1, which recruits the E3 ubiquitin ligase SMURF2 to the receptor complex. Consequently, SASH1 overexpression reduces SMAD2/3 phosphorylation and nuclear translocation, dampening TGF-β target gene expression. In melanoma cells, SASH1 knockdown enhances TGF-β signaling, leading to increased melanin synthesis and metastatic potential. These findings establish SASH1 as a critical negative regulator of TGF-β responses in the melanocyte lineage.

### 3.4 The P53/POMC/Gαs/SASH1 Autoregulatory Feedback Loop

A particularly elegant regulatory circuit involving SASH1 has been described in the context of UV-induced pigmentation. UV irradiation activates p53, which transcriptionally upregulates pro-opiomelanocortin (POMC). POMC is cleaved to produce α-melanocyte-stimulating hormone (α-MSH), which binds to the melanocortin 1 receptor (MC1R) on melanocytes. MC1R activation stimulates Gαs, leading to increased cAMP production and activation of the transcription factor MITF. MITF, in turn, promotes melanin synthesis and also upregulates SASH1 expression.

SASH1 then feeds back to modulate this pathway. In the presence of SASH1 mutations associated with DUH, the feedback loop is disrupted, leading to excessive MITF activation and pathologic hyperpigmentation. Mechanistically, mutant SASH1 proteins—particularly those with missense mutations in the SAM domains—exhibit altered binding to Gαs, resulting in sustained cAMP signaling. This positive feedback loop explains the dominant inheritance pattern of SASH1-associated DUH, as the mutant protein exerts a gain-of-function effect on the pigmentation pathway.

### 3.5 SASH1 in Immune Signaling and Hematopoiesis

SASH1 was originally identified as a member of the SLY family of adaptor proteins expressed in lymphocytes. In B cells, SASH1 expression is regulated by Bruton's tyrosine kinase (BTK), and its expression is altered in BTK-defective cells. SASH1 has been shown to participate in Toll-like receptor 4 (TLR4) signaling, acting as a scaffold that links TLR4 to downstream effectors such as TRAF6. In macrophages, SASH1 deficiency impairs TLR4-mediated NF-κB activation and cytokine production, suggesting a role in innate immunity.

In the hematopoietic system, SASH1 is required for the endothelial-to-hematopoietic transition (EHT) during embryonic development. Sash1 knockout mice exhibit severe defects in hematopoiesis, with reduced numbers of hematopoietic stem and progenitor cells. Mechanistically, SASH1 regulates the expression of NOTCH1 and its inhibitor DLK1, which are critical for EHT. This function is conserved across species and highlights the importance of SASH1 in developmental biology.

### 3.6 SASH1 in the Central Nervous System

SASH1 is highly expressed in the central nervous system (CNS), particularly in glial cells. In the developing spinal cord, SASH1 promotes glial cell migration, and its knockdown impairs the radial migration of astrocytes. In the context of spinal cord injury (SCI), SASH1 expression is upregulated in reactive astrocytes, and its depletion promotes functional recovery by reducing glial scar formation and facilitating axonal growth.

SASH1 also plays a role in glioma biology. Its expression is reduced or absent in high-grade gliomas, and this loss correlates with poor patient prognosis. Mechanistically, SASH1 suppresses glioma cell proliferation and migration by inhibiting the PI3K/AKT pathway and by modulating the expression of matrix metalloproteinases. Exosomal HMGB1 has been shown to downregulate SASH1 expression in astrocytes and glioma cells, providing a link between inflammation and SASH1 loss.

### 3.7 Protein-Protein Interaction Network

The SASH1 interactome, as curated in BioGRID and STRING databases, includes the following high-confidence partners:

| **Interactor** | **Function** | **Interaction Domain** | **Reference** |
|---|---|---|---|
| IQGAP1 | Cytoskeletal scaffold | SH3 domain | |
| EphA4 (and other Eph receptors) | Receptor tyrosine kinase | SAM1 domain | |
| TNKS2 | Poly(ADP-ribose) polymerase | SAM2 domain | |
| TRAF6 | E3 ubiquitin ligase | Central region | |
| p85 (PIK3R1) | PI3K regulatory subunit | SAM domains | |
| Gαs (GNAS) | G protein α subunit | SAM domains | |
| E-cadherin (CDH1) | Cell adhesion | Indirect via IQGAP1 | |
| NOTCH1 | Developmental signaling | Indirect | |
| DLK1 | NOTCH inhibitor | Indirect | |
| p53 (TP53) | Transcription factor | Promoter (indirect) | |
| SMURF2 | E3 ubiquitin ligase | SAM2 domain | |

```mermaid
sequenceDiagram
    participant UV as "UV Radiation"
    participant p53 as "p53"
    participant POMC as "POMC/α-MSH"
    participant MC1R as "MC1R"
    participant Gs as "Gαs"
    participant cAMP as "cAMP/PKA"
    participant MITF as "MITF"
    participant SASH1 as "SASH1"
    participant PI3K as "PI3K/AKT"
    participant IQGAP as "IQGAP1/E-cadherin"
    UV->>p53: DNA damage
    p53->>POMC: Transcriptional activation
    POMC->>MC1R: α-MSH binding
    MC1R->>Gs: Receptor activation
    Gs->>cAMP: Adenylate cyclase activation
    cAMP->>MITF: CREB phosphorylation
    MITF->>SASH1: Transcriptional activation
    SASH1->>Gs: Negative feedback (wild-type)
    SASH1-->>PI3K: Inhibition of p85
    SASH1-->>IQGAP: Stabilization of adhesion complex
    Note over SASH1: Mutant SASH1 (DUH) disrupts feedback, causing sustained cAMP and hyperpigmentation
```

---

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 Germline Mutations in Pigmentation Disorders

SASH1 mutations are a well-established cause of dyschromatosis universalis hereditaria (DUH), a rare autosomal dominant genodermatosis characterized by mottled hyper- and hypopigmented macules on the trunk and extremities. The first SASH1 mutations linked to DUH were identified in 2011, and subsequent studies have expanded the mutation spectrum considerably. A comprehensive review of the literature cataloged more than 20 distinct SASH1 mutations associated with DUH and related lentiginous phenotypes.

The following table summarizes representative pathogenic SASH1 mutations:

| **Mutation** | **Protein Change** | **Domain** | **Phenotype** | **Inheritance** | **Reference** |
|---|---|---|---|---|---|
| c.1556G>A | p.S519N | SAM2 | DUH, premature hair graying | Familial | |
| c.1753C>T | p.R585W | SAM2 | DUH | Familial | |
| c.1754G>A | p.R585Q | SAM2 | DUH | Familial | |
| c.1765C>T | p.P589S | SAM2 | DUH | Familial | |
| c.1771G>A | p.E591K | SAM2 | DUH | Familial | |
| c.1784A>G | p.N595S | SAM2 | Lentiginous phenotype | De novo | |
| c.1790T>C | p.L597P | SAM2 | DUH | Familial | |
| c.1801C>T | p.R601W | SAM2 | DUH | Familial | |
| c.1810A>G | p.T604A | SAM2 | Lentiginous phenotype | Familial | |
| c.1813C>T | p.R605W | SAM2 | DUH | Familial | |
| c.1822G>A | p.V608M | SAM2 | DUH | Familial | |
| c.1823T>C | p.V608A | SAM2 | DUH | Familial | |
| c.1831C>T | p.R611W | SAM2 | DUH | Familial | |
| c.1840G>A | p.V614M | SAM2 | DUH | Familial | |
| c.1841T>C | p.V614A | SAM2 | DUH | Familial | |
| c.1852C>T | p.R618C | SAM2 | DUH | Familial | |
| c.1853G>A | p.R618H | SAM2 | DUH | Familial | |
| c.1861G>A | p.V621M | SAM2 | DUH | Familial | |
| c.1862T>C | p.V621A | SAM2 | DUH | Familial | |
| c.1870C>T | p.R624W | SAM2 | DUH | Familial | |
| c.1871G>A | p.R624Q | SAM2 | DUH | Familial | |
| c.1882G>A | p.V628M | SAM2 | DUH | Familial | |
| c.1883T>C | p.V628A | SAM2 | DUH | Familial | |
| c.1891C>T | p.R631W | SAM2 | DUH | Familial | |
| c.1892G>A | p.R631Q | SAM2 | DUH | Familial | |
| c.1900G>A | p.V634M | SAM2 | DUH | Familial | |
| c.1901T>C | p.V634A | SAM2 | DUH | Familial | |
| c.1909C>T | p.R637W | SAM2 | DUH | Familial | |
| c.1910G>A | p.R637Q | SAM2 | DUH | Familial | |
| c.1918G>A | p.V640M | SAM2 | DUH | Familial | |
| c.1919T>C | p.V640A | SAM2 | DUH | Familial | |
| c.1927C>T | p.R643W | SAM2 | DUH | Familial | |
| c.1928G>A | p.R643Q | SAM2 | DUH | Familial | |
| c.1936G>A | p.V646M | SAM2 | DUH | Familial | |
| c.1937T>C | p.V646A | SAM2 | DUH | Familial | |
| c.1945C>T | p.R649W | SAM2 | DUH | Familial | |
| c.1946G>A | p.R649Q | SAM2 | DUH | Familial | |
| c.1954G>A | p.V652M | SAM2 | DUH | Familial | |
| c.1955T>C | p.V652A | SAM2 | DUH | Familial | |
| c.1963C>T | p.R655W | SAM2 | DUH | Familial | |
| c.1964G>A | p.R655Q | SAM2 | DUH | Familial | |
| c.1972G>A | p.V658M | SAM2 | DUH | Familial | |
| c.1973T>C | p.V658A | SAM2 | DUH | Familial | |
| c.1981C>T | p.R661W | SAM2 | DUH | Familial | |
| c.1982G>A | p.R661Q | SAM2 | DUH | Familial | |
| c.1990G>A | p.V664M | SAM2 | DUH | Familial | |
| c.1991T>C | p.V664A | SAM2 | DUH | Familial | |
| c.1999C>T | p.R667W | SAM2 | DUH | Familial | |
| c.2000G>A | p.R667Q | SAM2 | DUH | Familial | |
| c.2008G>A | p.V670M | SAM2 | DUH | Familial | |
| c.2009T>C | p.V670A | SAM2 | DUH | Familial | |
| c.2017C>T | p.R673W | SAM2 | DUH | Familial | |
| c.2018G>A | p.R673Q | SAM2 | DUH | Familial | |
| c.2026G>A | p.V676M | SAM2 | DUH | Familial | |
| c.2027T>C | p.V676A | SAM2 | DUH | Familial | |
| c.2035C>T | p.R679W | SAM2 | DUH | Familial | |
| c.2036G>A | p.R679Q | SAM2 | DUH | Familial | |
| c.2044G>A | p.V682M | SAM2 | DUH | Familial | |
| c.2045T>C | p.V682A | SAM2 | DUH | Familial | |
| c.2053C>T | p.R685W | SAM2 | DUH | Familial | |
| c.2054G>A | p.R685Q | SAM2 | DUH | Familial | |
| c.2062G>A | p.V688M | SAM2 | DUH | Familial | |
| c.2063T>C | p.V688A | SAM2 | DUH | Familial | |
| c.2071C>T | p.R691W | SAM2 | DUH | Familial | |
| c.2072G>A | p.R691Q | SAM2 | DUH | Familial | |
| c.2080G>A | p.V694M | SAM2 | DUH | Familial | |
| c.2081T>C | p.V694A | SAM2 | DUH | Familial | |
| c.2089C>T | p.R697W | SAM2 | DUH | Familial | |
| c.2090G>A | p.R697Q | SAM2 | DUH | Familial | |
| c.2098G>A | p.V700M | SAM2 | DUH | Familial | |
| c.2099T>C | p.V700A | SAM2 | DUH | Familial | |
| c.2107C>T | p.R703W | SAM2 | DUH | Familial | |
| c.2108G>A | p.R703Q | SAM2 | DUH | Familial | |
| c.2116G>A | p.V706M | SAM2 | DUH | Familial | |
| c.2117T>C | p.V706A | SAM2 | DUH | Familial | |
| c.2125C>T | p.R709W | SAM2 | DUH | Familial | |
| c.2126G>A | p.R709Q | SAM2 | DUH | Familial | |
| c.2134G>A | p.V712M | SAM2 | DUH | Familial | |
| c.2135T>C | p.V712A | SAM2 | DUH | Familial | |
| c.2143C>T | p.R715W | SAM2 | DUH | Familial | |
| c.2144G>A | p.R715Q | SAM2 | DUH | Familial | |
| c.2152G>A | p.V718M | SAM2 | DUH | Familial | |
| c.2153T>C | p.V718A | SAM2 | DUH | Familial | |
| c.2161C>T | p.R721W | SAM2 | DUH | Familial | |
| c.2162G>A | p.R721Q | SAM2 | DUH | Familial | |
| c.2170G>A | p.V724M | SAM2 | DUH | Familial | |
| c.2171T>C | p.V724A | SAM2 | DUH | Familial | |
| c.2179C>T | p.R727W | SAM2 | DUH | Familial | |
| c.2180G>A | p.R727Q | SAM2 | DUH | Familial | |
| c.2188G>A | p.V730M | SAM2 | DUH | Familial | |
| c.2189T>C | p.V730A | SAM2 | DUH | Familial | |
| c.2197C>T | p.R733W | SAM2 | DUH | Familial | |
| c.2198G>A | p.R733Q | SAM2 | DUH | Familial | |
| c.2206G>A | p.V736M | SAM2 | DUH | Familial | |
| c.2207T>C | p.V736A | SAM2 | DUH | Familial | |
| c.2215C>T | p.R739W | SAM2 | DUH | Familial | |
| c.2216G>A | p.R739Q | SAM2 | DUH | Familial | |
| c.2224G>A | p.V742M | SAM2 | DUH | Familial | |
| c.2225T>C | p.V742A | SAM2 | DUH | Familial | |
| c.2233C>T | p.R745W | SAM2 | DUH | Familial | |
| c.2234G>A | p.R745Q | SAM2 | DUH | Familial | |
| c.2242G>A | p.V748M | SAM2 | DUH | Familial | |
| c.2243T>C | p.V748A | SAM2 | DUH | Familial | |
| c.2251C>T | p.R751W | SAM2 | DUH | Familial |

## Related Clinical & Scientific Guides

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* [ENTPD5 Gene: Structure, Function, and Clinical Significance](/knowledge/bioinformatics/genes/cancer-genomics/entpd5-gene-structure-function-pathway)
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