SH2D4A
Chr 8SH2 domain containing 4A
Also known as: PPP1R38, SH2A
The SH2D4A protein enables phosphatase binding and inhibits estrogen-induced cell proliferation by competing with phospholipase C gamma for estrogen receptor binding, and may function in T-cell development. Mutations cause autosomal recessive developmental and epileptic encephalopathy with movement abnormalities, typically presenting in infancy with seizures, developmental delay, and movement disorders. The gene shows tolerance to loss-of-function variation (pLI near zero), consistent with the recessive inheritance pattern observed clinically.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Tolerant to missense variation
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
211 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 75 | 0 | 75 |
Likely Pathogenic | 0 | 0 | 3 | 0 | 3 |
VUS | 0 | 80 | 19 | 0 | 99 |
Likely Benign | 0 | 1 | 4 | 0 | 5 |
Benign | 0 | 0 | 1 | 0 | 1 |
| Total | 0 | 81 | 102 | 0 | 183 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
SH2D4A · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools