PIK3R1

Chr 5ARAD

phosphoinositide-3-kinase regulatory subunit 1

Also known as: AGM7, GRB1, IMD36, p85, p85-ALPHA, p85alpha

NCBI Gene: 5295 ENSG00000145675 UniProt: P27986 OMIM: 171833

The PIK3R1 protein is an 85 kD regulatory subunit that binds phosphatidylinositol 3-kinase to activated receptor tyrosine kinases, mediating essential insulin signaling and glucose metabolism pathways. Mutations cause autosomal recessive agammaglobulinemia and primary immunodeficiency, or autosomal dominant SHORT syndrome (short stature, hyperextensibility, ocular depression, Rieger anomaly, teething delay). This gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.23), reflecting its critical role in multiple developmental and metabolic processes.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismAR/ADLOEUF 0.233 OMIM phenotypes

Clinical Summary— PIK3R1

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Gene-Disease Validity (ClinGen)

agammaglobulinemia 7, autosomal recessive · ARLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

28 unique Pathogenic / Likely Pathogenic· 178 VUS of 400 total submissions

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

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GeneReview available — PIK3R1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.23LOEUF

pLI 1.000

Z-score 5.61

OE 0.11 (0.06–0.23)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

2.72Z-score

OE missense 0.62 (0.55–0.69)

245 obs / 397.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.11 (0.06–0.23)

0≤0.351.4

Missense OE0.62 (0.55–0.69)

0≤0.61.4

Synonymous OE0.84

0≤1.21.6

LoF obs/exp: 5 / 46.1Missense obs/exp: 245 / 397.7Syn Z: 1.56

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedPIK3R1-related agammaglobulinemiaLOFAR

definitivePIK3R1-related SHORT syndromeOTHERAD

0.4586th %ile

GOF

0.5366th %ile

LOF

0.59top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 75% of P/LP variants are LoF · LOEUF 0.23

GOF1 literature citation

DN1 literature citation

Literature Evidence

DNFunctional characterization of PIK3R1 mutations has identified not only hypomorphs with reduced inhibition of p110, but also hypomorphs and dominant negative mutants that disrupt a novel regulatory role of p85ÃÂ± on PTEN or neomorphs that activate unexpected signaling pathways.PMID:26807692

GOFOur data suggest that PIK3R1 gain-of-function leads to developmental defects in helper and regulatory T-cell subsets, the latter expanding the immunological features of PIK3R1 gain-of-function.PMID:26529633

LOFThe primary causes of SHORT syndrome are heterozygous loss-of-function mutations in the PIK3R1 gene.PMID:32778990

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.