Is PIK3CA p.Val125Met (c.373G>A) pathogenic?

PIK3CA p.Val125Met (c.373G>A) is classified Uncertain significance in PIK3CA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-15). AlphaMissense: ambiguous (0.4191); No allele count reported in gnomAD v4.1 (AN 1,610,600); Associated with Cowden disease.

What condition is associated with PIK3CA p.Val125Met (c.373G>A)?

PIK3CA p.Val125Met (c.373G>A) is associated with Cowden disease (ClinVar).

How common is PIK3CA p.Val125Met (c.373G>A) in the general population?

PIK3CA p.Val125Met (c.373G>A) is no allele count reported in gnomAD v4.1 (AN 1,610,600) (gnomAD).

What do computational predictors say about PIK3CA p.Val125Met (c.373G>A)?

AlphaMissense predicts ambiguous (score 0.4191) — an in-silico prediction, not a clinical call.

PIK3CA p.Val125Met

c.373G>A · rs1724360010 · VCV1064232

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4191 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,610,600)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Cowden disease

Computational evidence

Protein change
AlphaMissense	0.4191	ambiguous
REVEL	0.109	moderately benign-leaning
SaProt	LLR -5.58	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 11 kb · p 6.7e-17 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,610,600). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PIK3CA
Protein: p.Val125Met
Coding: c.373G>A
MANE Select: NM_006218
dbSNP: rs1724360010
Type: single nucleotide variant
Location: chr3:179199710 (GRCh38)
Gene constraint: LOEUF 0.221 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.50 · 135 PDB

Full PIK3CA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cowden disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PIK3CA p.Val125= Likely benign ★ same residue
PIK3CA p.Glu542Lys Pathogenic ★★★ ⚠ same condition
PIK3CA p.Glu726Lys Pathogenic ★★★ ⚠ same condition
PIK3CA p.Gly914Arg Pathogenic ★★★ ⚠ same condition
PIK3CA c.2015+9A>G Likely benign ★★★ same condition
PIK3CA p.Ile391Met Benign ★★★ same condition
PIK3CA p.Lys733Arg Benign ★★★ same condition
PIK3CA p.Val680= Likely benign ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pik3ca-p-val125met (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown