Is CHEK2 p.Arg406Ser (c.1216C>A) pathogenic?

CHEK2 p.Arg406Ser (c.1216C>A) is classified Uncertain significance in CHEK2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-02). AlphaMissense: ambiguous (0.4495); Very rare (popmax 0.00834%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Arg406Ser (c.1216C>A)?

CHEK2 p.Arg406Ser (c.1216C>A) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma, CHEK2-related cancer predisposition (ClinVar).

How common is CHEK2 p.Arg406Ser (c.1216C>A) in the general population?

CHEK2 p.Arg406Ser (c.1216C>A) is very rare (popmax 0.00834%, amr) (gnomAD).

What do computational predictors say about CHEK2 p.Arg406Ser (c.1216C>A)?

AlphaMissense predicts ambiguous (score 0.4495) — an in-silico prediction, not a clinical call.

CHEK2 p.Arg406Ser

c.1216C>A · rs587782527 · VCV479574

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

ambiguous

0.4495 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.4495	ambiguous
REVEL	0.15	moderately benign-leaning
SaProt	LLR -7.64	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00834% Admixed American · 5/59,978 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.000868% 14/1,613,578 alleles · very rare exomes 13/1,461,436 · genomes 1/152,142 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00834%	11,996
European (non-Finnish)	0.000763%	131,073

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.Arg406Ser
Coding: c.1216C>A
MANE Select: NM_007194
dbSNP: rs587782527
Type: single nucleotide variant
Location: chr22:28695753 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 406: the protein kinase domain; a UniProt-annotated variant site (in)

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 CHEK2-related cancer predisposition

Similar variants

CHEK2 p.Arg406Gly Uncertain significance ★★ ⚠ same residue
CHEK2 p.Arg406Pro Uncertain significance ★★ ⚠ same residue
CHEK2 p.Arg406Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Arg406His Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Arg406= Likely benign ★ same residue
CHEK2 p.Arg406delinsLeuTer Pathogenic ★ same residue
CHEK2 p.Arg406Leu Uncertain significance ★ ⚠ same residue
CHEK2 c.1008+1G>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-arg406ser (accessed [today's date]).

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