Is CHEK2 p.Ser412Val (c.1234_1235delinsGT) pathogenic?

CHEK2 p.Ser412Val (c.12341235delinsGT) is classified Uncertain significance in CHEK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-12-20). Associated with hereditary nonpolyposis colon cancer.

What condition is associated with CHEK2 p.Ser412Val (c.1234_1235delinsGT)?

CHEK2 p.Ser412Val (c.1234_1235delinsGT) is associated with hereditary nonpolyposis colon cancer (ClinVar).

CHEK2 p.Ser412Val

c.1234_1235delinsGT · VCV3779071

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

Conditions

hereditary nonpolyposis colon cancer

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

Variant & gene context

Gene: CHEK2
Protein: p.Ser412Val
Coding: c.1234_1235delinsGT
MANE Select: NM_007194
Type: Indel
Location: chr22:28695734 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 412: an α-helix; the protein kinase domain

Full CHEK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary nonpolyposis colon cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CHEK2 p.Ser412_Leu413insTer Pathogenic/Likely pathogenic ★★ same residue
CHEK2 p.Ser412delinsValTer Pathogenic ★★ same residue
CHEK2 p.Ser412Arg Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ser412Asn Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ser412Gly Uncertain significance ★ ⚠ same residue
CHEK2 p.Ser412Ile Uncertain significance ★ ⚠ same residue
CHEK2 p.Ser412Thr Uncertain significance ★ ⚠ same residue
CHEK2 c.846+4_846+7del Pathogenic/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-ser412val (accessed [today's date]).

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