Is CHEK2 p.Ser194= (c.582C>T) pathogenic?

CHEK2 p.Ser194= (c.582C>T) is classified Benign/Likely benign in CHEK2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-04-03). Very rare (popmax 0.00878%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Ser194= (c.582C>T)?

CHEK2 p.Ser194= (c.582C>T) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Ser194= (c.582C>T) in the general population?

CHEK2 p.Ser194= (c.582C>T) is very rare (popmax 0.00878%, sas) (gnomAD).

CHEK2 p.Ser194=

c.582C>T · rs761126328 · VCV240747

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00878%, sas)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -1.9, phastCons 1
Overall
CADD	8.202	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00878% South Asian · 8/91,084 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00062% 10/1,613,768 alleles · very rare exomes 9/1,461,772 · genomes 1/151,996 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00878%	11,386
European (non-Finnish)	0.00017%	589,967

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.Ser194=
Coding: c.582C>T
MANE Select: NM_007194
dbSNP: rs761126328
Type: single nucleotide variant
Location: chr22:28724987 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB

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.Ser194Arg Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ser194Asn Uncertain significance ★ ⚠ same residue
CHEK2 p.Ser194Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Ser194fs 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-ser194 (accessed [today's date]).

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