PIK3R3

Chr 1

phosphoinositide-3-kinase regulatory subunit 3

Also known as: p55, p55-GAMMA, p55PIK

NCBI Gene: 8503 ENSG00000117461 UniProt: Q92569 OMIM: 606076

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.

OMIM ResearchSummary from RefSeq, UniProt

Phosphatidylinositol 3-kinase (PI3K) phosphorylates phosphatidylinositol and similar compounds, which then serve as second messengers in growth signaling pathways. PI3K is composed of a catalytic and a regulatory subunit. The protein encoded by this gene represents a regulatory subunit of PI3K. The encoded protein contains two SH2 domains through which it binds activated protein tyrosine kinases to regulate their activity. [provided by RefSeq, Jun 2016]

OMIM ResearchGenerating clinical summary…

Multiplemechanism

Clinical Summary— PIK3R3

📋

ClinVar Variants

49 VUS of 61 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

gnomad: TimeoutError: The operation was aborted due to timeout

Population Genetics & Constraint

gnomAD

Constraint data not available from gnomAD.

This gene — mechanism propensity

0.7228th %ile

GOF

0.6638th %ile

LOF

0.2969th %ile

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.

DNprediction above median

GOFprediction above median

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

61 submitted variants in ClinVar

ClinVar

Classification Summary

VUS49

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	0	49	49
Likely Benign	1	0	1
Benign	0	0	0
Total	1	49	50

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

6 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap PIK3R3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →