Is CHEK2 p.Arg493= (c.1479A>G) pathogenic?

CHEK2 p.Arg493= (c.1479A>G) is classified Benign/Likely benign in CHEK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-09). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Arg493= (c.1479A>G)?

CHEK2 p.Arg493= (c.1479A>G) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Arg493= (c.1479A>G) in the general population?

CHEK2 p.Arg493= (c.1479A>G) is absent from gnomAD v4.1 (gnomAD).

CHEK2 p.Arg493=

c.1479A>G · VCV3773003

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.031	moderately benign-leaning
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.061	GERP -1.9, phastCons 0.008
Overall
CADD	6.249	PHRED · no single calibrated threshold — expert panels disagree

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.Arg493=
Coding: c.1479A>G
MANE Select: NM_007194
Type: single nucleotide variant
Location: chr22:28689198 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 493: an α-helix

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.Arg493Thr Uncertain significance ★★ ⚠ same residue
CHEK2 p.Arg493Ter Pathogenic ★ same residue
CHEK2 p.Arg493Gly Uncertain significance ★ ⚠ same residue
CHEK2 p.Arg493Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Arg493del Uncertain significance ★ same residue
CHEK2 c.1008+1G>A Likely pathogenic ★★ same condition
CHEK2 c.1008+1G>T Likely pathogenic ★★ same condition
CHEK2 c.1008+2T>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-arg493 (accessed [today's date]).

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