PIK3CA

Chr 3

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

Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides (PubMed:15135396, PubMed:23936502, PubMed:28676499). Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) (PubMed:15135396, PubMed:28676499). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Participates in cellular signaling in response to various growth factors. Involved in the activation of AKT1 upon stimulation by receptor tyrosine kinases ligands such as EGF, insulin, IGF1, VEGFA and PDGF. Involved in signaling via insulin-receptor substrate (IRS) proteins. Essential in endothelial cell migration during vascular development through VEGFA signaling, possibly by regulating RhoA activity. Required for lymphatic vasculature development, possibly by binding to RAS and by activation by EGF and FGF2, but not by PDGF. Regulates invadopodia formation through the PDPK1-AKT1 pathway. Participates in cardiomyogenesis in embryonic stem cells through a AKT1 pathway. Participates in vasculogenesis in embryonic stem cells through PDK1 and protein kinase C pathway. In addition to its lipid kinase activity, it displays a serine-protein kinase activity that results in the autophosphorylation of the p85alpha regulatory subunit as well as phosphorylation of other proteins such as 4EBP1, H-Ras, the IL-3 beta c receptor and possibly others (PubMed:23936502, PubMed:28676499). Plays a role in the positive regulation of phagocytosis and pinocytosis (By similarity)

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

763

ClinVar variants

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— PIK3CA

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Gene-Disease Validity (ClinGen)

hereditary breast carcinoma · ADRefuted

Refuted — evidence has disproved this relationship

3 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

37 Pathogenic / Likely Pathogenic· 357 VUS of 763 total submissions

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

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.

0.12LOEUF

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?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.

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?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.0.05 (0.02–0.12)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.34 (0.30–0.38)

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.0.78

0≤1.21.6

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

ClinVar Variant Classifications

763 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12

Likely Pathogenic25

VUS357

Likely Benign366

Benign1

Conflicting2

Pathogenic

Likely Pathogenic

357

VUS

366

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	7	5	0	12
Likely Pathogenic	2	14	9	0	25
VUS	7	325	21	4	357
Likely Benign	0	3	65	298	366
Benign	0	0	1	0	1
Conflicting	—				2
Total	9	349	101	302	763

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.

Gene2Phenotype Curations

PIK3CA-related overgrowth spectrum disorder with or without megalencephaly, capillary malformation, polymicrogyria and lipomatous overgrowth

definitive

ADGain Of FunctionAltered Gene Product Structure

Dev. DisordersSkeletal

G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

PHOSPHATIDYLINOSITOL 3-KINASE, CATALYTIC, ALPHA; PIK3CA

MIM #171834 · *

Breast cancer, somatic

MIM #114480