PIK3CA
Chr 3phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha
Also known as: CCM4, CLAPO, CLOVE, CWS5, HMH, MCAP, MCM, MCMTC
The protein encoded by PIK3CA is the catalytic subunit of phosphatidylinositol 3-kinase that phosphorylates phosphoinositides using ATP, functioning in critical cellular signaling pathways. Somatic gain-of-function mutations cause multiple overgrowth and vascular malformation syndromes including CLOVE syndrome, megalencephaly-capillary malformation-polymicrogyria syndrome, and CLAPO syndrome, while germline mutations cause Cowden syndrome 5 with autosomal dominant inheritance. The pathogenic mechanism involves hyperactivation of the PI3K-AKT-mTOR pathway leading to increased cell growth and proliferation.
Refuted — evidence has disproved this relationship
3 total gene-disease associations curated
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Among the most LoF-intolerant genes (~top 3%)
Extremely missense-constrained (top ~0.01%)
The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).
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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
200 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 1 | 1 | 0 | 2 |
Likely Pathogenic | 0 | 4 | 0 | 0 | 4 |
VUS | 1 | 90 | 0 | 1 | 92 |
Likely Benign | 0 | 1 | 3 | 68 | 72 |
Benign | 0 | 0 | 0 | 0 | 0 |
| Total | 1 | 96 | 4 | 69 | 170 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
PIK3CA · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Canadian Profiling and Targeted Agent Utilization Trial (CAPTUR)
RECRUITINGPrevalence Of Germline Gene Mutations In Patients With Myeloproliferative Neoplasms With Family History
NOT YET RECRUITINGFeasibility of Targeted Bronchial Washing for Molecular Testing by Next Generation Sequencing in Early-stage Lung Cancer
ACTIVE NOT RECRUITINGA Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations
RECRUITINGA Study to Evaluate the Effectiveness and Safety of Inavolisib in Participants With Endocrine-resistant, PIK3CA-mutated, Hormone Receptor-positive, HER2-negative Locally Advanced or Metastatic Breast Cancer
RECRUITINGElacestrant and Exemestane for Patients With Pretreated HR+/HER2- Metastatic Breast Cancer and [18F] FES-avid Lesions (COMBINE)
NOT YET RECRUITINGDisitamab Vedotin + Pyrotinib Versus THP in the First-line Treatment for HER2+ Advanced Breast Cancer Clinical Trial
RECRUITINGA Study of LOXO-783 in Patients With Breast Cancer/Other Solid Tumors
ACTIVE NOT RECRUITINGA Multicenter, Single-Arm, Phase II Exploratory Study of Eribulin in Combination With Anlotinib for HER2-Negative Recurrent/Metastatic Breast Cancer Previously Treated With Antibody-Drug Conjugates
RECRUITINGSapanisertib and Serabelisib (PIKTOR) With Paclitaxel and a Substudy With an Insulin-Suppressing Diet in Patients With Advanced/Recurrent Endometrial Cancer
RECRUITINGLevels of Circulating Tumor DNA as a Predictive Marker for Early Switch in Treatment for Patients With Metastatic (Stage IV) Breast Cancer
ACTIVE NOT RECRUITINGTesting Different Amounts of the Combination of Drugs M1774 and ZEN-3694 for the Treatment of Recurrent Ovarian and Endometrial Cancer
RECRUITINGExternal Resources
Links to major genomics databases and tools