Is CHEK2 p.Pro92Ala (c.274C>G) pathogenic?

CHEK2 p.Pro92Ala (c.274C>G) is classified Uncertain significance in CHEK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-04). AlphaMissense: likely benign (0.0968); No allele count reported in gnomAD v4.1 (AN 1,614,018).

How common is CHEK2 p.Pro92Ala (c.274C>G) in the general population?

CHEK2 p.Pro92Ala (c.274C>G) is no allele count reported in gnomAD v4.1 (AN 1,614,018) (gnomAD).

What do computational predictors say about CHEK2 p.Pro92Ala (c.274C>G)?

AlphaMissense predicts likely benign (score 0.0968) — an in-silico prediction, not a clinical call.

CHEK2 p.Pro92Ala

c.274C>G · rs1555932172 · VCV2575331

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0968 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,614,018)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0968	likely benign
REVEL	0.301	indeterminate
SaProt	LLR -8.75	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 0.64, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	18.84	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 1,614,018). 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.Pro92Ala
Coding: c.274C>G
MANE Select: NM_007194
dbSNP: rs1555932172
Type: single nucleotide variant
Location: chr22:28734448 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 92: an α-helix

Full CHEK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CHEK2 p.Pro92Arg Uncertain significance ★★ same residue
CHEK2 p.Pro92His Uncertain significance ★★ same residue
CHEK2 p.Pro92Leu Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro92Ser Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro92Thr Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro92= Benign ★ same residue
CHEK2 p.Pro92fs Pathogenic ★ same residue
CHEK2 c.1008+1G>A Likely pathogenic ★★ same type

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-pro92ala (accessed [today's date]).

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