Is CHEK2 p.Pro85Arg (c.254C>G) pathogenic?

CHEK2 p.Pro85Arg (c.254C>G) is classified Conflicting classifications of pathogenicity in CHEK2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-02). AlphaMissense: likely benign (0.1118); Very rare (popmax 0.00381%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Pro85Arg (c.254C>G)?

CHEK2 p.Pro85Arg (c.254C>G) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Pro85Arg (c.254C>G) in the general population?

CHEK2 p.Pro85Arg (c.254C>G) is very rare (popmax 0.00381%, nfe) (gnomAD).

What do computational predictors say about CHEK2 p.Pro85Arg (c.254C>G)?

AlphaMissense predicts likely benign (score 0.1118) — an in-silico prediction, not a clinical call.

CHEK2 p.Pro85Arg

c.254C>G · rs17883862 · VCV233261

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1118 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00381%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1118	likely benign
REVEL	0.27	benign-leaning
SaProt	LLR -10.38	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	22.5	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 0.00381% European (non-Finnish) · 45/1,179,764 alleles

Filtering AF 0.00291% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00285% 46/1,613,588 alleles · very rare exomes 45/1,461,498 · genomes 1/152,090 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00381%	26,217
Remaining individualsnot grpmax-eligible	0.0016%	62,466

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.Pro85Arg
Coding: c.254C>G
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.Pro85His Uncertain significance ★★ ⚠ same residue
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.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-pro85arg (accessed [today's date]).

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