Is CHEK2 p.Pro350Arg (c.1049C>G) pathogenic?

CHEK2 p.Pro350Arg (c.1049C>G) is classified Uncertain significance in CHEK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-03). AlphaMissense: likely pathogenic (0.9959); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Pro350Arg (c.1049C>G)?

CHEK2 p.Pro350Arg (c.1049C>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CHEK2 p.Pro350Arg (c.1049C>G) in the general population?

CHEK2 p.Pro350Arg (c.1049C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHEK2 p.Pro350Arg (c.1049C>G)?

AlphaMissense predicts likely pathogenic (score 0.9959) — an in-silico prediction, not a clinical call.

CHEK2 p.Pro350Arg

c.1049C>G · rs2145817048 · VCV1776350

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9959 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.9959	likely pathogenic · top 5% in CHEK2
REVEL	0.884	moderately pathogenic-leaning
SaProt	LLR -15.96	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	29.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

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.Pro350Arg
Coding: c.1049C>G
MANE Select: NM_007194
dbSNP: rs2145817048
Type: single nucleotide variant
Location: chr22:28696947 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 350: an α-helix; the protein kinase domain

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

Similar variants

CHEK2 p.Pro350Ala Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro350Leu Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro350Ser Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro350Gln Uncertain significance ★ ⚠ same residue
CHEK2 p.Pro350Thr Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro350= Benign ★ same residue
CHEK2 c.1008+1G>A Likely pathogenic ★★ same condition
CHEK2 c.1008+1G>T 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-pro350arg (accessed [today's date]).

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