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GeneE
25 sources retrieved Β· Most recent: April 2026 Β· Index updated 15 days ago
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SH2D1A
SH2 domain containing 1A
Chromosome X Β· Xq25
NCBI Gene: 4068Ensembl: ENSG00000183918.18HGNC: HGNC:10820UniProt: O60880
153PubMed Papers
21Diseases
0Drugs
45Pathogenic Variants
RESEARCH IMPACT
Trending
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
protein bindingprotein-macromolecule adaptor activitynatural killer cell activationregulation of immune responseX-linked lymphoproliferative diseaselymphomalymphoproliferative syndromeX-linked lymphoproliferative syndrome
✦AI Summary

SH2D1A encodes SAP (SLAM-associated protein), a cytoplasmic adapter protein that regulates signaling through the SLAM family of receptors on T and NK cells 1. SAP functions by recruiting FYN kinase to phosphorylate and activate SLAM receptors, thereby enhancing NK cell-mediated cytotoxicity and conjugate formation with target cells 2. The protein is predominantly expressed in activated T cells and NK cells, where its expression is tightly regulated by Ets-1/Ets-2 transcription factors and rapid mRNA decay mechanisms involving the 3' UTR 3. Loss-of-function mutations in SH2D1A cause X-linked lymphoproliferative syndrome type 1 (XLP1), a severe immunodeficiency characterized by heightened susceptibility to Epstein-Barr virus (EBV) infection 4. XLP1 patients experience impaired CD8+ T cell proliferation and dysregulated interferon signaling upon EBV infection, contributing to hemophagocytic lymphohistiocytosis (HLH)β€”a life-threatening hyperinflammatory syndrome 5. SH2D1A variants account for approximately 17.8% of X-linked HLH cases in clinical cohorts 6. SAP expression is critical for proper T follicular helper (TFH) cell differentiation and germinal center formation, essential for adaptive immunity 2. These findings establish SH2D1A as a key regulator of immune homeostasis and EBV control.

Sources cited
1
SH2D1A encodes SAP protein expressed in activated T cells and NK cells, contains an SH2 domain, and interacts with SLAM receptors
PMID: 11054674
2
SAP (SH2D1A) is a distinguishing feature of follicular helper CD4 T cells and is important for germinal center formation and B cell help
PMID: 21314428
3
SH2D1A expression is regulated by Ets-1 and Ets-2 transcription factors and has rapid mRNA decay through 3' UTR-mediated mechanisms
PMID: 15459902
4
SH2D1A mutations cause X-linked lymphoproliferative disease (XLP) with susceptibility to EBV and impaired humoral immunity; multiple isoforms exist with different functional capacities
PMID: 24369347
5
SH2D1A upregulation occurs in responsive CD8+ T cell clusters during EBV infection; impaired CD8+ T cell proliferation and dysregulated interferon signaling occur in EBV-HLH with XLP1
PMID: 38642164
6
SH2D1A mutations account for 17.8% of X-linked HLH cases in a large North American cohort of suspected genetic HLH
PMID: 32542393
7
SH2D1A mutations are recognized as a genetic cause of X-linked lymphoproliferative disease that can present with hemophagocytic lymphohistiocytosis
PMID: 32107531
8
SH2D1A deficiency is associated with EBV susceptibility and ALPS-like lymphoproliferative phenotypes; SAP protein expression assays are useful diagnostic tests
PMID: 34447369
Disease Associationsβ“˜21
X-linked lymphoproliferative diseaseOpen Targets
0.82Strong
lymphomaOpen Targets
0.47Moderate
lymphoproliferative syndromeOpen Targets
0.44Moderate
X-linked lymphoproliferative syndromeOpen Targets
0.43Moderate
genetic disorderOpen Targets
0.40Weak
autoinflammatory syndromeOpen Targets
0.37Weak
neurodegenerative diseaseOpen Targets
0.24Weak
systemic lupus erythematosusOpen Targets
0.10Suggestive
atrial fibrillationOpen Targets
0.10Suggestive
combined immunodeficiency due to CTPS1 deficiencyOpen Targets
0.09Suggestive
Hodgkins lymphomaOpen Targets
0.09Suggestive
combined immunodeficiency with skin granulomasOpen Targets
0.09Suggestive
immunodeficiency 18Open Targets
0.09Suggestive
severe combined immunodeficiency due to CARD11 deficiencyOpen Targets
0.09Suggestive
common variable immunodeficiencyOpen Targets
0.09Suggestive
Chronic mucocutaneous candidosisOpen Targets
0.09Suggestive
agammaglobulinemia 8, autosomal dominantOpen Targets
0.09Suggestive
infectionOpen Targets
0.09Suggestive
isolated agammaglobulinemiaOpen Targets
0.09Suggestive
classic Hodgkin lymphomaOpen Targets
0.09Suggestive
Lymphoproliferative syndrome, X-linked, 1UniProt
Pathogenic Variants45
NM_002351.5(SH2D1A):c.163C>T (p.Arg55Ter)Pathogenic
X-linked lymphoproliferative disease due to SH2D1A deficiency|not provided|X-linked lymphoproliferative syndrome
β˜…β˜…β˜†β˜†2025β†’ Residue 55
NM_002351.5(SH2D1A):c.138-1G>APathogenic
X-linked lymphoproliferative disease due to SH2D1A deficiency|not provided|Thyroid cancer, nonmedullary, 1
β˜…β˜…β˜†β˜†2024
NM_002351.5(SH2D1A):c.2T>C (p.Met1Thr)Pathogenic
X-linked lymphoproliferative disease due to SH2D1A deficiency|Autoinflammatory syndrome
β˜…β˜…β˜†β˜†2022β†’ Residue 1
NM_002351.5(SH2D1A):c.201+3A>GLikely pathogenic
not provided|Autoinflammatory syndrome
β˜…β˜…β˜†β˜†2019
NM_002351.5(SH2D1A):c.5A>G (p.Asp2Gly)Likely pathogenic
X-linked lymphoproliferative disease due to SH2D1A deficiency|not provided
β˜…β˜…β˜†β˜†2018β†’ Residue 2
NM_002351.5(SH2D1A):c.57_59dup (p.Leu21_Ala22insLeu)Likely pathogenic
Lymphoproliferative syndrome with absent SAP expression
β˜…β˜†β˜†β˜†2026β†’ Residue 21
NM_002351.5(SH2D1A):c.201+1G>CPathogenic
X-linked lymphoproliferative disease due to SH2D1A deficiency
β˜…β˜†β˜†β˜†2026
NM_002351.5(SH2D1A):c.126C>A (p.Cys42Ter)Pathogenic
X-linked lymphoproliferative disease due to SH2D1A deficiency
β˜…β˜†β˜†β˜†2025β†’ Residue 42
NM_002351.5(SH2D1A):c.201+1_201+4delLikely pathogenic
X-linked lymphoproliferative disease due to SH2D1A deficiency
β˜…β˜†β˜†β˜†2025
NM_002351.5(SH2D1A):c.199_201+23delLikely pathogenic
X-linked lymphoproliferative disease due to SH2D1A deficiency
β˜…β˜†β˜†β˜†2025
NM_002351.5(SH2D1A):c.137+1G>ALikely pathogenic
Thyroid cancer, nonmedullary, 1|X-linked lymphoproliferative disease due to SH2D1A deficiency
β˜…β˜†β˜†β˜†2025
NM_002351.5(SH2D1A):c.106dup (p.Ser36fs)Pathogenic
X-linked lymphoproliferative disease due to SH2D1A deficiency
β˜…β˜†β˜†β˜†2025β†’ Residue 36
NM_002351.5(SH2D1A):c.201+2T>CPathogenic
X-linked lymphoproliferative disease due to SH2D1A deficiency
β˜…β˜†β˜†β˜†2025
NM_002351.5(SH2D1A):c.245dup (p.Asn82fs)Pathogenic
X-linked lymphoproliferative disease due to SH2D1A deficiency
β˜…β˜†β˜†β˜†2024β†’ Residue 82
NM_002351.5(SH2D1A):c.138-2A>GPathogenic
X-linked lymphoproliferative disease due to SH2D1A deficiency|Nonpapillary renal cell carcinoma|Thyroid cancer, nonmedullary, 1
β˜…β˜†β˜†β˜†2024
NM_002351.5(SH2D1A):c.162C>A (p.Tyr54Ter)Likely pathogenic
X-linked lymphoproliferative disease due to SH2D1A deficiency
β˜…β˜†β˜†β˜†2024β†’ Residue 54
NM_002351.5(SH2D1A):c.201+1dupPathogenic
X-linked lymphoproliferative disease due to SH2D1A deficiency
β˜…β˜†β˜†β˜†2023
NM_002351.5(SH2D1A):c.202-8T>GLikely pathogenic
not provided
β˜…β˜†β˜†β˜†2023
NM_002351.5(SH2D1A):c.201+1G>APathogenic
X-linked lymphoproliferative disease due to SH2D1A deficiency
β˜…β˜†β˜†β˜†2023
NM_002351.5(SH2D1A):c.1A>G (p.Met1Val)Pathogenic
X-linked lymphoproliferative disease due to SH2D1A deficiency
β˜…β˜†β˜†β˜†2023β†’ Residue 1
View on ClinVar β†—
Related Genes
FYNProtein interaction100%CD8AProtein interaction99%CD84Protein interaction99%CD48Protein interaction98%LY9Protein interaction98%CD40LGProtein interaction92%
Tissue Expression6 tissues
Bone Marrow
100%
Lung
24%
Liver
12%
Heart
3%
Ovary
1%
Brain
1%
Gene Interaction Network
Click a node to explore
SH2D1AFYNCD8ACD84CD48LY9CD40LG
PROTEIN STRUCTURE
Preparing viewer…
PDB1D4T Β· 1.10 Γ… Β· X-ray
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
1.18LoF Tolerant
pLIβ“˜
0.04Tolerant
Observed/Expected LoF0.60 [0.33–1.18]
RankingsWhere SH2D1A stands among ~20K protein-coding genes
  • #2,961of 20,598
    Most Researched153 Β· top quartile
  • #1,423of 5,498
    Most Pathogenic Variants45
  • #12,353of 17,882
    Most Constrained (LOEUF)1.18
Genes detectedSH2D1A
Sources retrieved25 papers
Response timeβ€”
πŸ“„ Sources
25β–Ό
1
Pediatric hemophagocytic lymphohistiocytosis.
PMID: 32107531
Blood Β· 2020
1.00
2
Follicular helper CD4 T cells (TFH).
PMID: 21314428
Annu Rev Immunol Β· 2011
0.90
3
Single-Cell Transcriptomic Analysis of Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis.
PMID: 38642164
J Clin Immunol Β· 2024
0.80
4
Frequency and spectrum of disease-causing variants in 1892 patients with suspected genetic HLH disorders.
PMID: 32542393
Blood Adv Β· 2020
0.70
5
Single cell transcriptome sequencing indicates the cellular heterogeneity of small intestine tissue in celiac disease.
PMID: 40216823
Sci Rep Β· 2025
0.64