Is CHEK2 p.Ile299Phe (c.895A>T) pathogenic?

CHEK2 p.Ile299Phe (c.895A>T) is classified Uncertain significance in CHEK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-01). AlphaMissense: likely pathogenic (0.8352); Very rare (popmax 9.19e-05%, nfe); Associated with hereditary breast carcinoma.

What condition is associated with CHEK2 p.Ile299Phe (c.895A>T)?

CHEK2 p.Ile299Phe (c.895A>T) is associated with hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Ile299Phe (c.895A>T) in the general population?

CHEK2 p.Ile299Phe (c.895A>T) is very rare (popmax 9.19e-05%, nfe) (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.Ile299Phe (c.895A>T)?

AlphaMissense predicts likely pathogenic (score 0.8352) — an in-silico prediction, not a clinical call.

CHEK2 p.Ile299Phe

c.895A>T · rs1555916906 · VCV2011229

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8352 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.19e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.8352	likely pathogenic
REVEL	0.547	indeterminate
SaProt	LLR -10.37	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP 0.29, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	22.8	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 9.19e-05% European (non-Finnish) · 1/1,088,440 alleles

Overall 6.65e-05% 1/1,502,942 alleles · very rare exomes 1/1,350,754 · genomes 0/152,188 · joint denominator

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.Ile299Phe
Coding: c.895A>T
MANE Select: NM_007194
dbSNP: rs1555916906
Type: single nucleotide variant
Location: chr22:28703518 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 299: 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

For Hereditary breast cancer (Orphanet):

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

Similar variants

CHEK2 p.Ile299Asn Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ile299Met Uncertain significance ★★ same residue
CHEK2 p.Ile299Ser Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ile299Thr Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ile299Val Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ile299fs Pathogenic ★ same residue
CDS1 p.Ser299Cys Uncertain significance ★ ⚠ same residue
CHEK2 c.1008+1G>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-ile299phe (accessed [today's date]).

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