Is CHEK2 p.Ser372= (c.1116C>T) pathogenic?

CHEK2 p.Ser372= (c.1116C>T) is classified Likely benign in CHEK2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-01). Ultra-rare (popmax 0.0665%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Ser372= (c.1116C>T)?

CHEK2 p.Ser372= (c.1116C>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CHEK2 p.Ser372= (c.1116C>T) in the general population?

CHEK2 p.Ser372= (c.1116C>T) is ultra-rare (popmax 0.0665%, nfe) (gnomAD).

CHEK2 p.Ser372=

c.1116C>T · rs79357544 · VCV1692937

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0665%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.018	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.41	GERP -1, phastCons 0.98
Overall
CADD	7.577	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0665% European (non-Finnish) · 757/1,138,788 alleles

Filtering AF 0.0625% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0609%

Overall 0.0624% 882/1,414,572 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0665%	1,504
African / African-American	0.0643%	1,556
Remaining individualsnot grpmax-eligible	0.046%	2,173
South Asian	0.0358%	2,796
Middle Eastern	0.0338%	2,962
Ashkenazi Jewishnot grpmax-eligible	0.0136%	7,329
East Asian	0.0112%	8,912
Admixed American	0.0067%	14,933
Finnishnot grpmax-eligible	0.00469%	21,304

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.Ser372=
Coding: c.1116C>T
MANE Select: NM_007194
dbSNP: rs79357544
Type: single nucleotide variant
Location: chr22:28695853 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 372: the protein kinase domain; the 't-loop/activation segment' region

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

Similar variants

CHEK2 p.Ser372Ala Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ser372Phe Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ser372Pro Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ser372Thr Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ser372Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Ser372Tyr Uncertain significance ★ ⚠ same residue
CHEK2 c.1008+1G>A Likely pathogenic ★★ same condition
CHEK2 c.1008+1G>T 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-ser372 (accessed [today's date]).

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