Is CHEK2 p.Ile285Phe (c.853A>T) pathogenic?

CHEK2 p.Ile285Phe (c.853A>T) is classified Uncertain significance in CHEK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-11-21). AlphaMissense: likely pathogenic (0.9389); No allele count reported in gnomAD v4.1 (AN 1,560,172); Associated with hereditary breast carcinoma.

What condition is associated with CHEK2 p.Ile285Phe (c.853A>T)?

CHEK2 p.Ile285Phe (c.853A>T) is associated with hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Ile285Phe (c.853A>T) in the general population?

CHEK2 p.Ile285Phe (c.853A>T) is no allele count reported in gnomAD v4.1 (AN 1,560,172) (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.Ile285Phe (c.853A>T)?

AlphaMissense predicts likely pathogenic (score 0.9389) — an in-silico prediction, not a clinical call.

CHEK2 p.Ile285Phe

c.853A>T · rs1555917027 · VCV530076

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9389 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,560,172)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.9389	likely pathogenic
REVEL	0.482	indeterminate
SaProt	LLR -14.08	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 6.2	GERP 1.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	25.6	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

No allele count reported in gnomAD v4.1 (AN 1,560,172). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CHEK2
Protein: p.Ile285Phe
Coding: c.853A>T
MANE Select: NM_007194
dbSNP: rs1555917027
Type: single nucleotide variant
Location: chr22:28703560 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 285: 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.Ile285Met Uncertain significance ★★ same residue
CHEK2 p.Ile285Val Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ile285= Conflicting classifications of pathogenicity ★ same residue
CHEK2 p.Ile285Leu Uncertain significance ★ ⚠ 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-ile285phe (accessed [today's date]).

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