Is CHEK2 p.Pro85Leu (c.254C>T) pathogenic?

CHEK2 p.Pro85Leu (c.254C>T) is classified Benign/Likely benign in CHEK2 (ClinVar, Multiple submitters, 28 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0792); Rare (popmax 0.714%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Pro85Leu (c.254C>T)?

CHEK2 p.Pro85Leu (c.254C>T) is associated with hereditary neoplastic syndrome, bone osteosarcoma, hereditary breast ovarian cancer syndrome (ClinVar).

How common is CHEK2 p.Pro85Leu (c.254C>T) in the general population?

CHEK2 p.Pro85Leu (c.254C>T) is rare (popmax 0.714%, afr) (gnomAD).

What do computational predictors say about CHEK2 p.Pro85Leu (c.254C>T)?

AlphaMissense predicts likely benign (score 0.0792) — an in-silico prediction, not a clinical call.

CHEK2 p.Pro85Leu

c.254C>T · rs17883862 · VCV5594

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 28 submitters

AlphaMissense

likely benign

0.0792 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.714%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0792	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -9.35	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 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	18.34	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 0.714% African / African-American · 536/75,018 alleles

Filtering AF 0.664% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.645%

Overall 0.0546% 881/1,613,706 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.714%	140
Ashkenazi Jewishnot grpmax-eligible	0.392%	255
Admixed American	0.143%	698
Remaining individualsnot grpmax-eligible	0.0992%	1,008
Middle Eastern	0.0495%	2,020
European (non-Finnish)	0.00644%	15,523
South Asian	0.0022%	45,517

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.Pro85Leu
Coding: c.254C>T
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: bone osteosarcoma hereditary breast ovarian cancer syndrome breast cancer 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.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-pro85leu (accessed [today's date]).

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