Is CHEK2 p.Val511Ile (c.1531G>A) pathogenic?

CHEK2 p.Val511Ile (c.1531G>A) is classified Uncertain significance in CHEK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-22). AlphaMissense: likely benign (0.072); Very rare (popmax 8.49e-05%, nfe); Associated with hereditary breast carcinoma.

What condition is associated with CHEK2 p.Val511Ile (c.1531G>A)?

CHEK2 p.Val511Ile (c.1531G>A) is associated with hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Val511Ile (c.1531G>A) in the general population?

CHEK2 p.Val511Ile (c.1531G>A) is very rare (popmax 8.49e-05%, nfe) (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.Val511Ile (c.1531G>A)?

AlphaMissense predicts likely benign (score 0.072) — an in-silico prediction, not a clinical call.

CHEK2 p.Val511Ile

c.1531G>A · rs1601701749 · VCV654642

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.072 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.072	likely benign
REVEL	0.033	moderately benign-leaning
SaProt	LLR -7.62	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.36	donor loss · deltas
Constraint at this position
Conservation	phyloP -2.5	GERP -3.7
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	0.066	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,178,092 alleles

Overall 6.93e-05% 1/1,442,220 alleles · very rare

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.Val511Ile
Coding: c.1531G>A
MANE Select: NM_007194
dbSNP: rs1601701749
Type: single nucleotide variant
Location: chr22:28689146 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 511: the 'disordered' region

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

For Hereditary breast cancer (Orphanet):

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

Similar variants

CHEK2 p.Val511Phe Uncertain significance ★★ ⚠ same residue
CHEK2 p.Val511= Conflicting classifications of pathogenicity ★ same residue
CHEK2 p.Val511_Leu512insTer Likely 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
CHEK2 c.1008+2T>G Likely pathogenic ★★ same condition
CHEK2 c.1009-1G>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-val511ile (accessed [today's date]).

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