Is CHKB p.Ala374Val (c.1121C>T) pathogenic?

CHKB p.Ala374Val (c.1121C>T) is classified Uncertain significance in CHKB (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-04). AlphaMissense: likely pathogenic (0.963); Very rare (popmax 8.48e-05%, nfe); Associated with megaconial type congenital muscular dystrophy.

What condition is associated with CHKB p.Ala374Val (c.1121C>T)?

CHKB p.Ala374Val (c.1121C>T) is associated with megaconial type congenital muscular dystrophy (ClinVar).

How common is CHKB p.Ala374Val (c.1121C>T) in the general population?

CHKB p.Ala374Val (c.1121C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Megaconial congenital muscular dystrophy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CHKB p.Ala374Val (c.1121C>T)?

AlphaMissense predicts likely pathogenic (score 0.963) — an in-silico prediction, not a clinical call.

CHKB p.Ala374Val

c.1121C>T · rs751958642 · VCV844986

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.963 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

megaconial type congenital muscular dystrophy

Computational evidence

Protein change
AlphaMissense	0.963	likely pathogenic
REVEL	0.742	pathogenic-leaning
SaProt	LLR -14.81	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 3,597 bp · p 0.53 · regional, not allelic
Overall
CADD	31.0	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,782 alleles

Overall 6.84e-05% 1/1,461,370 alleles · very rare

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: CHKB
Protein: p.Ala374Val
Coding: c.1121C>T
MANE Select: NM_005198
dbSNP: rs751958642
Type: single nucleotide variant
Location: chr22:50579248 (GRCh38)
Gene constraint: LOEUF 1.015 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.54 · 3 PDB
Residue 374: a UniProt-annotated variant site (in mdcmc; loss of choline kinase activity; decreased amount of phosphatidylcholine in patients cells); a UniProt-annotated variant site (in mdcmc); an α-helix

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

Disease context

megaconial type congenital muscular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Megaconial congenital muscular dystrophy (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

CHKB p.Gln51Ter Pathogenic/Likely pathogenic ★★ same condition
CHKB c.*208T>G Uncertain significance ★★ same condition
CHKB p.Ala361Val Uncertain significance ★★ ⚠ same condition
CHKB p.Arg344Trp Uncertain significance ★★ ⚠ same condition
CHKB p.Arg62Cys Uncertain significance ★★ ⚠ same condition
CHKB p.Gln309Glu Uncertain significance ★★ same condition
CHKB p.Glu214Asp Uncertain significance ★★ ⚠ same condition
CHKB p.Glu336Lys Uncertain significance ★★ ⚠ 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/chkb-p-ala374val (accessed [today's date]).

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