Is CHEK2 p.Val511Phe (c.1531G>T) pathogenic?

CHEK2 p.Val511Phe (c.1531G>T) is classified Uncertain significance in CHEK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-11). AlphaMissense: likely benign (0.0776); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Val511Phe (c.1531G>T)?

CHEK2 p.Val511Phe (c.1531G>T) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Val511Phe (c.1531G>T) in the general population?

CHEK2 p.Val511Phe (c.1531G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHEK2 p.Val511Phe (c.1531G>T)?

AlphaMissense predicts likely benign (score 0.0776) — an in-silico prediction, not a clinical call.

CHEK2 p.Val511Phe

c.1531G>T · rs1601701749 · VCV2749957

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0776 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0776	likely benign
REVEL	0.118	moderately benign-leaning
SaProt	LLR -8.88	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	0.191	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHEK2
Protein: p.Val511Phe
Coding: c.1531G>T
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 neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast carcinoma

Similar variants

CHEK2 p.Val511Ile Uncertain significance ★★ ⚠ same residue
CHEK2 p.Val511= Conflicting classifications of pathogenicity ★ same residue
CHEK2 p.Val511_Leu512insTer Likely pathogenic ★ same residue
CHEK2 p.Val511fs 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

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-val511phe (accessed [today's date]).

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