Is CHEK2 p.Asp497= (c.1491T>C) pathogenic?

CHEK2 p.Asp497= (c.1491T>C) is classified Benign/Likely benign in CHEK2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-11-25). Ultra-rare (popmax 0.0245%, eas); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Asp497= (c.1491T>C)?

CHEK2 p.Asp497= (c.1491T>C) is associated with hereditary neoplastic syndrome, breast cancer, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Asp497= (c.1491T>C) in the general population?

CHEK2 p.Asp497= (c.1491T>C) is ultra-rare (popmax 0.0245%, eas) (gnomAD).

CHEK2 p.Asp497=

c.1491T>C · rs762041905 · VCV232513

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, eas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.039	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.2	GERP -3.7
Overall
CADD	1.237	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0245% East Asian · 11/44,872 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.000816% 13/1,594,054 alleles · ultra-rare exomes 11/1,441,870 · genomes 2/152,184 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0245%	4,079
Remaining individualsnot grpmax-eligible	0.00322%	31,058

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.Asp497=
Coding: c.1491T>C
MANE Select: NM_007194
dbSNP: rs762041905
Type: single nucleotide variant
Location: chr22:28689186 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 497: an α-helix

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: breast cancer hereditary breast carcinoma

Similar variants

CHEK2 p.Asp497Gly Uncertain significance ★★ ⚠ same residue
CHEK2 p.Asp497Tyr Uncertain significance ★★ ⚠ same residue
CHEK2 p.Asp497Val Uncertain significance ★★ ⚠ same residue
CHEK2 p.Asp497Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Asp497fs Pathogenic/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

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-asp497 (accessed [today's date]).

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