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 OMIM: 171834

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 OMIM 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 OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Breast cancer, somaticMIM #114480

Cerebral cavernous malformations 4, somaticMIM #619538

CLAPO syndrome, somaticMIM #613089

CLOVE syndrome, somaticMIM #612918

Colorectal cancer, somaticMIM #114500

Cowden syndrome 5MIM #615108

Gastric cancer, somaticMIM #613659

Hemifacial myohyperplasia, somaticMIM #606773

Hepatocellular carcinoma, somaticMIM #114550

Keratosis, seborrheic, somaticMIM #182000

Macrodactyly, somaticMIM #155500

Megalencephaly-capillary malformation-polymicrogyria syndrome, somaticMIM #602501

Nevus, epidermal, somatic mosaicMIM #162900

Nonsmall cell lung cancer, somaticMIM #211980

Ovarian cancer, somaticMIM #167000

UniProtCongenital lipomatous overgrowth, vascular malformations, and epidermal nevi

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · overgrowth syndrome and/or cerebral malformations due to abnormalities in MTOR pathway genes · AD · G2P
Strong · megalencephaly-capillary malformation-polymicrogyria syndrome · AD · Ambry Genetics
Strong · vascular malformation · AD · Genomics England PanelApp
Limited · Cowden syndrome 5 · AD · Labcorp Genetics (formerly Invitae) — not for standalone diagnostic reporting
Refuted · hereditary breast carcinoma · AD · ClinGen 2023 — evidence has disproved this relationship
Refuted · familial ovarian cancer · AD · ClinGen 2017 — evidence has disproved this relationship

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

1895

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 ↗

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

Background carrier burden — how many people carry a rare variant somewhere in PIK3CA?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 230

590 rare PASS variants

Rare truncating (LoF)

1 in 6,500

56 rare PASS variants

Rare synonymous (reference)

1 in 140

388 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for PIK3CA. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 250	1 in 7,300
South Asian	~43k	1 in 160	1 in 5,200
Remaining (unassigned)	~30k	1 in 180	≈ 1 in 15,000
European (Finnish)	~27k	1 in 590	≈ 1 in 13,000
Admixed American	~22k	1 in 170	≈ 1 in 4,500
African / African American	~21k	1 in 240	≈ 1 in 4,500
East Asian	~20k	1 in 210	none seen
Ashkenazi Jewish	~13k	1 in 1,800	none seen
Middle Eastern	~2,884	1 in 410	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 10 of 20 coding exons well covered in gnomAD exomes; exons 3, 6, 7, 11, 12 and 5 more marginal. Genomes: all 20.? see exons ↓

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

Locally Advanced Breast CancerMetastatic Breast Cancer

A 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

RECRUITING

NCT07347600Hoffmann-La RocheStarted 2026-01-21

InavolisibPalbociclibFulvestrant

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

disitamab vedotinPyrotinibtrastuzumab

Microwave AblationContrast-enhanced UltrasoundGenetic and Molecular Diagnostics

Efficacy and Prognosis of Microwave Ablation Treatment for Papillary Thyroid Microcarcinoma Assessed by Contrast-Enhanced Ultrasound Combined With Genetic and Molecular Diagnostics: A Prospective Observational Study

RECRUITING

NCT07054229Sun Yat-Sen Memorial Hospital of Sun Yat-Sen UniversityStarted 2024-01-01

Contrast enhanced Ultrasound88-gene panel for thyroid cancer

Anatomic Stage III Breast Cancer AJCC v8Anatomic Stage IV Breast Cancer AJCC v8Metastatic Triple-Negative Breast Carcinoma

Testing the Addition of Copanlisib to Eribulin in Metastatic Triple Negative Breast Cancer

ACTIVE NOT RECRUITING

NCT04345913Phase PHASE1, PHASE2National Cancer Institute (NCI)Started 2021-03-01

Biopsy ProcedureBiospecimen CollectionComputed Tomography

Colorectal Cancer

Tracking Mutations in Cell Free Tumour DNA to Predict Relapse in Early Colorectal Cancer

RECRUITING

NCT04050345Royal Marsden NHS Foundation TrustStarted 2016-12-05

PIK3CA MutationsAdvanced Solid Tumors, AdultEndometrial Cancer

A Study of Mutant Selective-Inhibitor (CGT6297), in Patients With Advanced Solid Tumors

RECRUITING

NCT07383506Phase PHASE1Cogent Biosciences, Inc.Started 2026-07-23

CGT6297

Lung Cancer

Feasibility of Targeted Bronchial Washing for Molecular Testing by Next Generation Sequencing in Early-stage Lung Cancer

ACTIVE NOT RECRUITING

NCT06301295Phase NAPusan National University HospitalStarted 2024-05-29

Ultarthin bronchoscopy with intratumoral washing

Colon AdenocarcinomaStage I Colon CancerStage II Colon Cancer

Postoperative Circulating Tumor DNA Monitoring in Stage I-III Driver-Mutant Colon Adenocarcinoma

RECRUITING

NCT07795528Ruijin HospitalStarted 2026-08-14

Longitudinal ctDNA-MRD NGS testing at scheduled postoperative time points

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

Triple Negative Breast CancerBreast Cancer

Serial Circulating Tumor DNA (ctDNA) Monitoring During Adjuvant Capecitabine in Early Triple-negative Breast Cancer

RECRUITING

NCT04768426Phase PHASE2Stanford UniversityStarted 2021-02-03

Capecitabine

Advanced Malignant Solid NeoplasmMetastatic Malignant Solid NeoplasmUnresectable Malignant Solid Neoplasm

Testing the Addition of an Anti-cancer Drug, Copanlisib, to the Usual Immunotherapy (Nivolumab With or Without Ipilimumab) in Patients With Advanced Solid Cancers That Have Changes in the Following Genes: PIK3CA and PTEN

ACTIVE NOT RECRUITING

NCT04317105Phase PHASE1, PHASE2National Cancer Institute (NCI)Started 2020-07-17

Biopsy ProcedureBiospecimen CollectionComputed Tomography

Clinical Literature

Open Research Assistant →

Landmark / reviewRecent case evidence

Full-Text Mentions

NLP-detected gene mentions in article bodies · via PubTator3

PubTator3

Cardiac PI3K p110alpha attenuation delays aging and extends lifespan

Abdellatif M et al.·Cell Stress

2022