PIK3CA

Chr 3

phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha

Also known as: CCM4, CLAPO, CLOVE, CWS5, HMH, MCAP, MCM, MCMTC

NCBI Gene: 5290 ENSG00000121879 UniProt: P42336

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.

GeneReviews ResearchSummary from RefSeq, OMIM, Mechanism

Phosphatidylinositol 3-kinase is composed of an 85 kDa regulatory subunit and a 110 kDa catalytic subunit. The protein encoded by this gene represents the catalytic subunit, which uses ATP to phosphorylate PtdIns, PtdIns4P and PtdIns(4,5)P2. This gene has been found to be oncogenic and has been implicated in cervical cancers. A pseudogene of this gene has been defined on chromosome 22. [provided by RefSeq, Apr 2016]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtColorectal cancer

UniProtBreast cancer

UniProtOvarian cancer

UniProtHepatocellular carcinoma

Clinical highlights

Gene-disease validity (ClinGen)

hereditary breast carcinoma · ADRefutedevidence has disproved this relationship2 gene-disease associations curated in total

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

1765

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.12

LOEUF· LoF intol.

GOF*

Mechanism· G2P

📖

GeneReview available — PIK3CA

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.12LOEUF

pLI 1.000

Z-score 7.21

OE 0.05 (0.02–0.12)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

5.60Z-score

OE missense 0.34 (0.30–0.38)

191 obs / 565.7 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.12)

0≤0.351.4

Missense OE?0.34 (0.30–0.38)

0≤0.61.4

Synonymous OE?0.78

0≤1.21.6

LoF obs/exp: 3 / 66.4Missense obs/exp: 191 / 565.7Syn Z: 2.36

ClinVar Variant Classifications

0 submitted variants in ClinVar

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.

VCEP specificationsBrain MalformationsReleased

Specifications ↗Panel ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

📖

GeneReview available — PIK3CA

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Breast Cancer - ER+, HER2-, PIK3CA Gene Mutation

PI3K Pathway Activation Markers in ER-Positive, HER2-Negative Breast Cancer: A Clinicopathologic Study

NOT YET RECRUITING

NCT07387861Assiut UniversityStarted 2026-03

Not applicable- observational study

Breast CancerER-positive Breast CancerHER2-negative Breast Cancer

Levels of Circulating Tumor DNA as a Predictive Marker for Early Switch in Treatment for Patients With Metastatic (Stage IV) Breast Cancer

ACTIVE NOT RECRUITING

NCT05826964Phase PHASE2University of MiamiStarted 2023-06-12

AI+CDK4/6iSERD+CDK4/6imTOR inhibitor + AI

Hormone Receptor(HR)-Positive, Low HER2 Advanced Breast Cancer Patients (HER2 IHC 1+ or 2+ & ISH Negative)

Trastuzumab Deruxtecan vs Endocrine Therapy in Low-HER2 HR+ Advanced Breast Cancer

RECRUITING

NCT06837792Phase PHASE2Yonsei UniversityStarted 2023-10-01

Experimental treatment armControl treatment arm

HER-2 Positive Breast CancerEstrogen Receptor Positive Breast Cancer

Randomized, Open Label, Clinical Study of the Targeted Therapy, Palbociclib, to Treat Metastatic Breast Cancer

ACTIVE NOT RECRUITING

NCT02947685Phase PHASE3Alliance Foundation Trials, LLC.Started 2017-06-21

palbociclibtrastuzumabpertuzumab

HER 2 Negative Breast Cancer

A 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

RECRUITING

NCT07520760Phase PHASE2Sun Yat-sen UniversityStarted 2026-04-01

Eribulin in Combination with Anlotinib

Breast Cancer

Elacestrant and Exemestane for Patients With Pretreated HR+/HER2- Metastatic Breast Cancer and [18F] FES-avid Lesions (COMBINE)

RECRUITING

NCT07395336Phase PHASE2European Institute of OncologyStarted 2026-05-11

elacestrant and exemestane

HER2-positive Metastatic Breast CancerFirst-line Treatment

Disitamab Vedotin + Pyrotinib Versus THP in the First-line Treatment for HER2+ Advanced Breast Cancer Clinical Trial

RECRUITING

NCT06278870Phase PHASE3Sun Yat-Sen Memorial Hospital of Sun Yat-Sen UniversityStarted 2023-09-06