Is CHEK2 p.Val455= (c.1365C>G) pathogenic?

CHEK2 p.Val455= (c.1365C>G) is classified Benign/Likely benign in CHEK2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-12). Very rare (popmax 0.0022%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Val455= (c.1365C>G)?

CHEK2 p.Val455= (c.1365C>G) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Val455= (c.1365C>G) in the general population?

CHEK2 p.Val455= (c.1365C>G) is very rare (popmax 0.0022%, sas) (gnomAD).

CHEK2 p.Val455=

c.1365C>G · rs1287444894 · VCV1137226

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.006	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP -1.3, phastCons 1
Overall
CADD	4.919	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/90,852 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000138% 2/1,453,170 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.Val455=
Coding: c.1365C>G
MANE Select: NM_007194
dbSNP: rs1287444894
Type: single nucleotide variant
Location: chr22:28695137 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 455: 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.Val455Ala Uncertain significance ★ ⚠ same residue
CHEK2 p.Val455Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Val455Phe Uncertain significance ★ ⚠ same residue
CHEK2 p.Val455fs Pathogenic ★ 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
CHEK2 c.1008+2T>G 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-val455 (accessed [today's date]).

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