Is CHEK2 p.Arg148Ser (c.444G>T) pathogenic?

CHEK2 p.Arg148Ser (c.444G>T) is classified Uncertain significance in CHEK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-17). AlphaMissense: likely pathogenic (0.991); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Arg148Ser (c.444G>T)?

CHEK2 p.Arg148Ser (c.444G>T) is associated with hereditary neoplastic syndrome (ClinVar).

How common is CHEK2 p.Arg148Ser (c.444G>T) in the general population?

CHEK2 p.Arg148Ser (c.444G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CHEK2 p.Arg148Ser (c.444G>T)?

AlphaMissense predicts likely pathogenic (score 0.991) — an in-silico prediction, not a clinical call.

CHEK2 p.Arg148Ser

c.444G>T · rs1298109942 · VCV1740692

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.991 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.991	likely pathogenic · top 8% in CHEK2
REVEL	0.621	indeterminate
SaProt	LLR -13.65	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.84	donor gain · deltas
Pangolin	Δ0.78	gain · loss 0.29 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.1	GERP -1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHEK2
Protein: p.Arg148Ser
Coding: c.444G>T
MANE Select: NM_007194
dbSNP: rs1298109942
Type: single nucleotide variant
Location: chr22:28725243 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 148: the fha domain; a β-strand

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.Arg148= Uncertain significance ★★ same residue
CHEK2 p.Arg148Gly Uncertain significance ★★ ⚠ same residue
CHEK2 p.Arg148Lys Uncertain significance ★★ same residue
CHEK2 p.Arg148Thr Uncertain significance ★★ ⚠ same residue
CHEK2 p.Arg148delinsIleAlaLeuMetAsnHisCysTer 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

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-arg148ser (accessed [today's date]).

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