PIK3CA (P42336) variants and mutations

PIK3CA (also known as P42336) is a human protein-coding gene encoding a phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform protein. Its p110-alpha catalytic activity generates PIP3 and activates AKT-dependent growth, survival, and metabolic signaling downstream of many receptors. Activating variants are frequent cancer drivers and, when present mosaically during development, can cause PIK3CA-related overgrowth spectrum. This analysis covers 4,225 PIK3CA variants and mutations. Of these, 3.9% have pathogenic or likely pathogenic clinical classifications, 41% have computational variant effect predictions from REVEL and MutPred, and 16% have population-specific frequency data. Disease context includes megalencephaly-capillary malformation-polymicrogyria syndrome, CLOVE syndrome, and CLOVES syndrome. Example PIK3CA variants include M1?, M1T, and P2A.

Variant analysis overview

Gene: PIK3CA
Protein: P42336
UniProt accession: P42336
Organism: Homo sapiens
Variants analyzed: 4225
Variant scope: all variants
Completed: 2026-08-09

Variant and mutation evidence

Variant composition: 4,058 unspecified-consequence records; 44 missense variants; 107 synonymous variants; 2 in-frame deletions; 2 stop-gained variants; 5 frameshift variants; 4 splice-region variants; 3 substitution
Clinical classifications: 163 pathogenic or likely pathogenic; 180 benign or likely benign; 869 uncertain-significance; 188 other clinical labels.
Computational signals: 116 REVEL high-risk; 48 MutPred high-risk.
Variant classes: 3,855 missense; 107 synonymous; 259 truncating or splice.
Prediction scores: 1,744 variants have prediction scores (41% of the analyzed set).
Literature: 180 publications are represented in the literature summary.

Clinical, disease, and population context

Clinical evidence: 48 records have expert-only or criteria-backed evidence.
Clinical annotations: 1,406 variants have clinical annotations.
Population evidence: 881 variants have population-frequency evidence.
Disease context: 25 disease associations are represented. Top associations: megalencephaly-capillary malformation-polymicrogyria syndrome, CLOVE syndrome, CLOVES syndrome, PIK3CA-related overgrowth spectrum, breast cancer, Cowden syndrome 5, ovarian cancer, seborrheic keratosis, CLAPO syndrome, pik3ca related overgrowth spectrum, Cowden disease, megalodactyly.

Protein structure and variant hotspots

Protein features: 5 domains.
Ancestry evidence: 675 variants have ancestry-specific frequency data.
Structural context: 3,168 variants have structural context.
3D hotspots: 6 hotspot clusters were identified. Clusters at residues 113-129 (tolerant, 11 variants); residues 138-694 (tolerant, 92 variants); residues 362-429 (intolerant, 14 variants).
Allosteric analysis: 5 functional sites were identified.
gnomAD gene constraint: pLI 1.00 (highly intolerant of loss-of-function variation); LOEUF 0.20; missense Z-score 8.75.

Data sources

Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, 3D Hotspot Analysis, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, ClinGen, MaveDB, LitVar.

Notable PIK3CA variants

Examples include M1?, M1T, P2A, P2R, P2S, P2T, P2H, P2P. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.

PIK3CA analysis run — PIK3CA (4,225 variants) — completed 2026-08-09