Is CHEK2 p.Lys458= (c.1374A>G) pathogenic?

CHEK2 p.Lys458= (c.1374A>G) is classified Conflicting classifications of pathogenicity in CHEK2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-10-13). Very rare (popmax 0.00447%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Lys458= (c.1374A>G)?

CHEK2 p.Lys458= (c.1374A>G) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Lys458= (c.1374A>G) in the general population?

CHEK2 p.Lys458= (c.1374A>G) is very rare (popmax 0.00447%, nfe) (gnomAD).

CHEK2 p.Lys458=

c.1374A>G · rs776093527 · VCV418576

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00447%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.044	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.27	loss · gain 0.02 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 2.2	GERP -0.26, phastCons 1
Overall
CADD	14.28	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00447% European (non-Finnish) · 52/1,162,810 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00314%

Overall 0.00339% 54/1,594,780 alleles · very rare exomes 53/1,442,554 · genomes 1/152,226 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00447%	22,362
Remaining individualsnot grpmax-eligible	0.00324%	30,890

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.Lys458=
Coding: c.1374A>G
MANE Select: NM_007194
dbSNP: rs776093527
Type: single nucleotide variant
Location: chr22:28695128 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 458: 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.Lys458Asn Uncertain significance ★★ ⚠ same residue
CHEK2 p.Lys458Ter Pathogenic ★ same residue
CHEK2 p.Lys458Arg Uncertain significance ★ ⚠ same residue
CHEK2 p.Lys458fs Pathogenic ★★ same residue
CHEK2 p.Lys458_Ala459delinsAsnSer Conflicting classifications of pathogenicity ★ 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-lys458 (accessed [today's date]).

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