Is CHEK2 p.Pro85His (c.254C>A) pathogenic?

CHEK2 p.Pro85His (c.254C>A) is classified Uncertain significance in CHEK2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-10-29). AlphaMissense: likely benign (0.1249); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Pro85His (c.254C>A)?

CHEK2 p.Pro85His (c.254C>A) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Pro85His (c.254C>A) in the general population?

CHEK2 p.Pro85His (c.254C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHEK2 p.Pro85His (c.254C>A)?

AlphaMissense predicts likely benign (score 0.1249) — an in-silico prediction, not a clinical call.

CHEK2 p.Pro85His

c.254C>A · rs17883862 · VCV460819

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1249 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1249	likely benign
REVEL	0.141	moderately benign-leaning
SaProt	LLR -10.79	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.5	GERP 1.5, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	22.7	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHEK2
Protein: p.Pro85His
Coding: c.254C>A
MANE Select: NM_007194
dbSNP: rs17883862
Type: single nucleotide variant
Location: chr22:28734468 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 85: a UniProt-annotated variant site (found in an osteogenic sarcoma sample; somatic mutation)

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: hereditary breast carcinoma

Similar variants

CHEK2 p.Pro85Ser Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro85= Benign/Likely benign ★★ same residue
CHEK2 p.Pro85Leu Benign/Likely benign ★★ same residue
CHEK2 p.Pro85Ala Uncertain significance ★ ⚠ same residue
CHEK2 p.Pro85Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Pro85Thr Uncertain significance ★ ⚠ same residue
CHEK2 p.Pro85fs Pathogenic ★★ 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-pro85his (accessed [today's date]).

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