Is CHEK2 p.Val25Ile (c.73G>A) pathogenic?

CHEK2 p.Val25Ile (c.73G>A) is classified Conflicting classifications of pathogenicity in CHEK2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-09). AlphaMissense: likely benign (0.0693); Very rare (popmax 0.00267%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Val25Ile (c.73G>A)?

CHEK2 p.Val25Ile (c.73G>A) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma, prostate cancer, hereditary (ClinVar).

How common is CHEK2 p.Val25Ile (c.73G>A) in the general population?

CHEK2 p.Val25Ile (c.73G>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CHEK2 p.Val25Ile (c.73G>A)?

AlphaMissense predicts likely benign (score 0.0693) — an in-silico prediction, not a clinical call.

CHEK2 p.Val25Ile

c.73G>A · rs142243299 · VCV140965

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0693 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0693	likely benign
REVEL	0.079	moderately benign-leaning
SaProt	LLR -5.59	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	0.448	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 0.00267% African / African-American · 2/74,934 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.00062% 10/1,613,828 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,467
European (non-Finnish)	0.000678%	147,498

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.Val25Ile
Coding: c.73G>A
MANE Select: NM_007194
dbSNP: rs142243299
Type: single nucleotide variant
Location: chr22:28734649 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 25: 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 prostate cancer, hereditary

Similar variants

CHEK2 p.Val25= Benign/Likely benign ★★ same residue
CHEK2 p.Val25Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Val25Leu Uncertain significance ★ ⚠ same residue
CHEK2 p.Val25fs 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-val25ile (accessed [today's date]).

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