Is CHEK2 p.Phe475Ile (c.1423T>A) pathogenic?

CHEK2 p.Phe475Ile (c.1423T>A) is classified Conflicting classifications of pathogenicity in CHEK2 (ClinVar, Conflicting submitters, 16 submitters; last evaluated 2026-01-16). AlphaMissense: likely benign (0.1492); Very rare (popmax 0.00267%, afr); Associated with hereditary breast carcinoma.

What condition is associated with CHEK2 p.Phe475Ile (c.1423T>A)?

CHEK2 p.Phe475Ile (c.1423T>A) is associated with hereditary breast carcinoma, bone osteosarcoma, hereditary breast ovarian cancer syndrome (ClinVar).

How common is CHEK2 p.Phe475Ile (c.1423T>A) in the general population?

CHEK2 p.Phe475Ile (c.1423T>A) is very rare (popmax 0.00267%, afr) (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.Phe475Ile (c.1423T>A)?

AlphaMissense predicts likely benign (score 0.1492) — an in-silico prediction, not a clinical call.

CHEK2 p.Phe475Ile

c.1423T>A · rs370968992 · VCV141046

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 16 submitters

AlphaMissense

likely benign

0.1492 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.1492	likely benign
REVEL	0.098	moderately benign-leaning
SaProt	LLR -4.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -2.2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	17.11	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,798 alleles

Filtering AF 0.00165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00188% 30/1,596,050 alleles · very rare exomes 24/1,443,914 · genomes 6/152,136 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,399
European (non-Finnish)	0.00237%	42,130

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.Phe475Ile
Coding: c.1423T>A
MANE Select: NM_007194
dbSNP: rs370968992
Type: single nucleotide variant
Location: chr22:28694070 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 475: 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: bone osteosarcoma hereditary breast ovarian cancer syndrome colorectal cancer breast cancer prostate cancer hereditary neoplastic syndrome CHEK2-related cancer predisposition

For Hereditary breast cancer (Orphanet):

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

Similar variants

CHEK2 p.Phe475= Conflicting classifications of pathogenicity ★ same residue
CHEK2 p.Phe475Val Uncertain significance ★ ⚠ same residue
CHEK2 p.Phe475fs 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
CHEK2 c.1008+2T>G Likely pathogenic ★★ same condition
CHEK2 c.1009-1G>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-phe475ile (accessed [today's date]).

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