Is CHEK2 p.Asp296Val (c.887A>T) pathogenic?

CHEK2 p.Asp296Val (c.887A>T) is classified Uncertain significance in CHEK2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-11). AlphaMissense: likely pathogenic (0.8355); Very rare (popmax 0.00178%, amr); Associated with hereditary breast carcinoma.

What condition is associated with CHEK2 p.Asp296Val (c.887A>T)?

CHEK2 p.Asp296Val (c.887A>T) is associated with hereditary breast carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is CHEK2 p.Asp296Val (c.887A>T) in the general population?

CHEK2 p.Asp296Val (c.887A>T) is very rare (popmax 0.00178%, amr) (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.Asp296Val (c.887A>T)?

AlphaMissense predicts likely pathogenic (score 0.8355) — an in-silico prediction, not a clinical call.

CHEK2 p.Asp296Val

c.887A>T · rs777397542 · VCV491650

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8355 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00178%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.8355	likely pathogenic
REVEL	0.557	indeterminate
SaProt	LLR -13.46	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.29	acceptor loss · deltas
Pangolin	Δ0.24	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.9	GERP 1.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	28.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00178% Admixed American · 1/56,278 alleles

Overall 0.000144% 2/1,384,092 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00178%	56,278
European (non-Finnish)	8.95e-05%	1,117,240

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.Asp296Val
Coding: c.887A>T
MANE Select: NM_007194
dbSNP: rs777397542
Type: single nucleotide variant
Location: chr22:28703526 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 296: a β-strand; the protein kinase domain

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

Also linked: hereditary neoplastic syndrome

For Hereditary breast cancer (Orphanet):

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

Similar variants

CHEK2 p.Asp296Glu Uncertain significance ★★ ⚠ same residue
CHEK2 p.Asp296Gly Uncertain significance ★★ ⚠ same residue
CHEK2 p.Asp296His Uncertain significance ★★ ⚠ same residue
CHEK2 p.Asp296Tyr Uncertain significance ★★ ⚠ same residue
CHEK2 p.Asp296Asn Uncertain significance ★ ⚠ same residue
CHEK2 p.Asp296fs Pathogenic ★ 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-asp296val (accessed [today's date]).

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