Is CHEK2 p.Val469= (c.1407G>A) pathogenic?

CHEK2 p.Val469= (c.1407G>A) is classified Benign/Likely benign in CHEK2 (ClinVar, Multiple submitters, 18 submitters; last evaluated 2026-02-03). Rare (popmax 0.591%, afr); Associated with Breast and/or ovarian cancer.

What condition is associated with CHEK2 p.Val469= (c.1407G>A)?

CHEK2 p.Val469= (c.1407G>A) is associated with Breast and/or ovarian cancer, hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome (ClinVar).

How common is CHEK2 p.Val469= (c.1407G>A) in the general population?

CHEK2 p.Val469= (c.1407G>A) is rare (popmax 0.591%, afr) (gnomAD).

CHEK2 p.Val469=

c.1407G>A · rs17881378 · VCV136744

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 18 submitters

gnomAD v4.1

Rare

rare (popmax 0.591%, afr)

Conditions

Breast and/or ovarian cancer

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 0.39	GERP -0.34, phastCons 0.99
Overall
CADD	8.468	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.591% African / African-American · 443/74,914 alleles

Filtering AF 0.546% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.528%

Overall 0.0311% 497/1,595,958 alleles · rare exomes 233/1,443,720 · genomes 264/152,238 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.591%	169
Middle Eastern	0.0452%	2,212
Remaining individualsnot grpmax-eligible	0.0434%	2,303
Admixed American	0.03%	3,333
South Asian	0.0011%	90,968
European (non-Finnish)	0.000509%	196,584

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.Val469=
Coding: c.1407G>A
MANE Select: NM_007194
dbSNP: rs17881378
Type: single nucleotide variant
Location: chr22:28694086 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 469: the protein kinase domain

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

Disease context

Breast and/or ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary breast ovarian cancer syndrome hereditary neoplastic syndrome hereditary breast carcinoma CHEK2-related cancer predisposition

Similar variants

CHEK2 p.Val469Ala Uncertain significance ★★ same residue
CHEK2 p.Val469Glu Uncertain significance ★★ ⚠ same residue
CHEK2 p.Val469Gly Uncertain significance ★★ ⚠ same residue
CHEK2 p.Val469Met Uncertain significance ★★ ⚠ same residue
CHEK2 p.Val469fs Pathogenic ★ same residue
CHEK2 p.Val469del Uncertain significance ★ same residue
CHEK2 c.1008+1G>A Likely pathogenic ★★ same condition
CHEK2 c.1008+1G>T 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-val469 (accessed [today's date]).

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