PIK3R2

Chr 19AD

phosphoinositide-3-kinase regulatory subunit 2

Also known as: MPPH, MPPH1, P85B, p85, p85-BETA, p85beta

Phosphatidylinositol 3-kinase (PI3K) is a lipid kinase that phosphorylates phosphatidylinositol and similar compounds, creating second messengers important in growth signaling pathways. PI3K functions as a heterodimer of a regulatory and a catalytic subunit. The protein encoded by this gene is a regulatory component of PI3K. Three transcript variants, one protein coding and the other two non-protein coding, have been found for this gene. [provided by RefSeq, Apr 2019]

OMIMResearchGenerating clinical summary…
GOFmechanismADLOEUF 0.491 OMIM phenotype
VCEP Guidelines: Brain MalformationsReleased
View SpecificationsClinGen Panel
Clinical SummaryPIK3R2
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Gene-Disease Validity (ClinGen)
overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Moderate LoF intolerance
LoF Constraint?
0.49LOEUF
pLI 0.016
Z-score 3.88
OE 0.29 (0.180.49)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?
2.33Z-score
OE missense 0.68 (0.620.75)
295 obs / 431.3 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?
LoF OE?0.29 (0.180.49)
00.351.4
Missense OE?0.68 (0.620.75)
00.61.4
Synonymous OE?0.93
01.21.6
LoF obs/exp: 10 / 34.7Missense obs/exp: 295 / 431.3Syn Z: 0.80
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitivePIK3R2-related megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndromeGOFAD

This gene — mechanism propensity

DN
0.6452th %ile
GOF
0.72top 25%
LOF
0.3164th %ile

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.

GOFprediction above median · 1 literature citation
DNprediction 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.

Literature Evidence

GOFMultiple PIK3R1 and PIK3R2 mutations demonstrate gain of function, including disruption of a novel mechanism of pathway regulation wherein p85? dimers bind and stabilize PTEN.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

  1. 1.PMID 21984976

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

PIK3R2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

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