PIK3R2

Chr 19

phosphoinositide-3-kinase regulatory subunit 2

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

NCBI Gene: 5296ENSG00000105647UniProt: O00459

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]

Primary Disease Associations & Inheritance

UniProtMegalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome 1
471
ClinVar variants
24
Pathogenic / LP
0.02
pLI score
0
Active trials
Clinical Summary— PIK3R2
🧬
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.
📋
ClinVar Variants
24 Pathogenic / Likely Pathogenic· 189 VUS of 471 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.49LOEUF
pLI 0.016
Z-score 3.88
OE 0.29 (0.18–0.49)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.33Z-score
OE missense 0.68 (0.62–0.75)
295 obs / 431.3 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.29 (0.18–0.49)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.68 (0.62–0.75)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.93
0≤1.21.6
LoF obs/exp: 10 / 34.7Missense obs/exp: 295 / 431.3Syn Z: 0.80

ClinVar Variant Classifications

471 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15
Likely Pathogenic9
VUS189
Likely Benign182
Benign59
Conflicting17
15
Pathogenic
9
Likely Pathogenic
189
VUS
182
Likely Benign
59
Benign
17
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
6
8
0
15
Likely Pathogenic
1
6
2
0
9
VUS
11
153
21
4
189
Likely Benign
0
17
62
103
182
Benign
0
17
29
13
59
Conflicting
—17
Total13199122120471

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

View 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.

Gene2Phenotype Curations

PIK3R2-related megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome

definitive
ADGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — PIK3R2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
SNAI1 promotes epithelial-mesenchymal transition and maintains cancer stem cell-like properties in thymic epithelial tumors through the PIK3R2/p-EphA2 Axis.
E H et al.·J Exp Clin Cancer Res
2024
Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria.
Akula SK et al.·JAMA Neurol
2023Functional
PIK3R2/Pik3r2 Activating Mutations Result in Brain Overgrowth and EEG Changes.
Shi X et al.·Ann Neurol
2020
Megalencephaly syndromes associated with mutations of core components of the PI3K-AKT-MTOR pathway: PIK3CA, PIK3R2, AKT3, and MTOR.
Dobyns WB et al.·Am J Med Genet C Semin Med Genet
2019Review
PIK3R2 predicts poor outcomes for patients with melanoma and contributes to the malignant progression via PI3K/AKT/NF-κB axis.
Wang J et al.·Clin Transl Oncol
2023Cohort
Clinical-Genetic Approach to Conditions with Macrocephaly and ASD/Behaviour Abnormalities: Variants in PTEN and PPP2R5D Are the Most Recurrent Gene Mutations in a Patient-Oriented Diagnostic Strategy.
L'Erario FF et al.·Genes (Basel)
2025
Characterization of PANoptosis-related genes with immunoregulatory features in osteoarthritis.
Lan Z et al.·Int Immunopharmacol
2024
Genetic etiology of ventriculomegaly in 73 fetuses identified by High-Throughput sequencing.
Chenyue Z et al.·Sci Rep
2025
Novel Small-Molecule miR-124 Inducer Acts as "a Physiological Brake" of Inflammation in Ulcerative Colitis by Targeting the PIK3R2/PI3K/Akt Axis.
Wang T et al.·J Med Chem
2025
The ClinGen Brain Malformation Variant Curation Expert Panel: Rules for somatic variants in AKT3, MTOR, PIK3CA, and PIK3R2.
Lai A et al.·Genet Med
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools