Is PIK3CA p.Pro366= (c.1098C>A) pathogenic?

PIK3CA p.Pro366= (c.1098C>A) is classified Likely benign in PIK3CA (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-02). Very rare (popmax 0.0011%, sas); Associated with Cowden disease.

What condition is associated with PIK3CA p.Pro366= (c.1098C>A)?

PIK3CA p.Pro366= (c.1098C>A) is associated with Cowden disease (ClinVar).

How common is PIK3CA p.Pro366= (c.1098C>A) in the general population?

PIK3CA p.Pro366= (c.1098C>A) is very rare (popmax 0.0011%, sas) (gnomAD).

PIK3CA p.Pro366=

c.1098C>A · rs1442927984 · VCV1558132

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Cowden disease

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.077	GERP -0.86, phastCons 0.52
Overall
CADD	7.672	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,562 alleles

Overall 6.27e-05% 1/1,593,712 alleles · very rare exomes 1/1,441,574 · genomes 0/152,138 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PIK3CA
Protein: p.Pro366=
Coding: c.1098C>A
MANE Select: NM_006218
dbSNP: rs1442927984
Type: single nucleotide variant
Location: chr3:179204541 (GRCh38)
Gene constraint: LOEUF 0.221 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.50 · 135 PDB
Residue 366: a β-strand; the c2 pi3k-type domain

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.Pro366His Uncertain significance ★ 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-pro366 (accessed [today's date]).

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