Is CHEK2 p.Met331Val (c.991A>G) pathogenic?

CHEK2 p.Met331Val (c.991A>G) is classified Uncertain significance in CHEK2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-09). AlphaMissense: ambiguous (0.4931); Very rare (popmax 0.0011%, sas); Associated with hereditary breast carcinoma.

What condition is associated with CHEK2 p.Met331Val (c.991A>G)?

CHEK2 p.Met331Val (c.991A>G) is associated with hereditary breast carcinoma, hereditary neoplastic syndrome, CHEK2-related cancer predisposition (ClinVar).

How common is CHEK2 p.Met331Val (c.991A>G) in the general population?

CHEK2 p.Met331Val (c.991A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Hereditary breast cancer inherited?

Typically Autosomal dominant, Multigenic/multifactorial (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CHEK2 p.Met331Val (c.991A>G)?

AlphaMissense predicts ambiguous (score 0.4931) — an in-silico prediction, not a clinical call.

CHEK2 p.Met331Val

c.991A>G · rs1555915357 · VCV483395

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4931 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.4931	ambiguous
REVEL	0.329	indeterminate
SaProt	LLR -7.49	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.6, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	25.9	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

Grpmax group 0.0011% South Asian · 1/91,074 alleles

Overall 6.2e-05% 1/1,613,462 alleles · very rare exomes 1/1,461,222 · genomes 0/152,240 · 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: CHEK2
Protein: p.Met331Val
Coding: c.991A>G
MANE Select: NM_007194
dbSNP: rs1555915357
Type: single nucleotide variant
Location: chr22:28699855 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 331: an α-helix; the protein kinase domain

Full CHEK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary breast carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome CHEK2-related cancer predisposition

For Hereditary breast cancer (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult, Elderly

Similar variants

CHEK2 p.Met331Thr Uncertain significance ★★ ⚠ same residue
CHEK2 p.Met331Ile Uncertain significance ★ ⚠ same residue
CHEK2 p.Met331Leu Uncertain significance ★ ⚠ same residue
CHEK2 p.Met331Lys Uncertain significance ★ ⚠ same residue
CHEK2 p.Met331fs Pathogenic ★ same residue
CHEK2 c.1008+1G>A Likely pathogenic ★★ same condition
CHEK2 c.1008+1G>T Likely pathogenic ★★ same condition
CHEK2 c.1008+2T>A Likely pathogenic ★★ 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/chek2-p-met331val (accessed [today's date]).

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