Is CHEK2 p.Pro484Arg (c.1451C>G) pathogenic?

CHEK2 p.Pro484Arg (c.1451C>G) is classified Uncertain significance in CHEK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-15). AlphaMissense: likely benign (0.1854); Very rare (popmax 8.49e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Pro484Arg (c.1451C>G)?

CHEK2 p.Pro484Arg (c.1451C>G) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Pro484Arg (c.1451C>G) in the general population?

CHEK2 p.Pro484Arg (c.1451C>G) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about CHEK2 p.Pro484Arg (c.1451C>G)?

AlphaMissense predicts likely benign (score 0.1854) — an in-silico prediction, not a clinical call.

CHEK2 p.Pro484Arg

c.1451C>G · rs564605612 · VCV944945

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1854 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1854	likely benign
REVEL	0.598	indeterminate
SaProt	LLR -9.77	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	27.9	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

Grpmax group 8.49e-05% European (non-Finnish) · 1/1,177,368 alleles

Overall 6.94e-05% 1/1,441,410 alleles · very rare

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.Pro484Arg
Coding: c.1451C>G
MANE Select: NM_007194
dbSNP: rs564605612
Type: single nucleotide variant
Location: chr22:28694042 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 484: 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

Also linked: hereditary breast carcinoma

Similar variants

CHEK2 p.Pro484Ser Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro484Thr Uncertain significance ★★ ⚠ same residue
CHEK2 p.Pro484= Conflicting classifications of pathogenicity ★ same residue
CHEK2 p.Pro484Ala Uncertain significance ★ ⚠ same residue
CHEK2 p.Pro484Gln Uncertain significance ★ ⚠ same residue
CHEK2 p.Pro484Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Pro484fs 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-pro484arg (accessed [today's date]).

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