PIK3R3
Chr 1phosphoinositide-3-kinase regulatory subunit 3
Also known as: p55, p55-GAMMA, p55PIK
The protein is a regulatory subunit of phosphatidylinositol 3-kinase (PI3K) that binds to activated protein-tyrosine kinases through its SH2 domains and regulates their activity in growth signaling pathways, including insulin signaling where it binds to IRS-1. Mutations cause autosomal recessive SHORT syndrome, characterized by short stature, hyperextensibility, ocular depression, Rieger anomaly, and teething delay. This gene is extremely intolerant to loss-of-function variants, indicating it is under strong evolutionary constraint.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative 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
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
PIK3R3 · 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