Is CHKB p.Ala49Val (c.146C>T) pathogenic?

CHKB p.Ala49Val (c.146C>T) is classified Uncertain significance in CHKB (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-06). AlphaMissense: ambiguous (0.5389); Absent from gnomAD v4.1; Associated with megaconial type congenital muscular dystrophy.

What condition is associated with CHKB p.Ala49Val (c.146C>T)?

CHKB p.Ala49Val (c.146C>T) is associated with megaconial type congenital muscular dystrophy (ClinVar).

How common is CHKB p.Ala49Val (c.146C>T) in the general population?

CHKB p.Ala49Val (c.146C>T) is absent from gnomAD v4.1 (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.Ala49Val (c.146C>T)?

AlphaMissense predicts ambiguous (score 0.5389) — an in-silico prediction, not a clinical call.

CHKB p.Ala49Val

c.146C>T · rs2522792904 · VCV1937970

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5389 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

megaconial type congenital muscular dystrophy

Computational evidence

Protein change
AlphaMissense	0.5389	ambiguous
REVEL	0.224	benign-leaning
SaProt	LLR -8.34	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 3,597 bp · p 0.53 · regional, not allelic
Overall
CADD	29.2	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

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: CHKB
Protein: p.Ala49Val
Coding: c.146C>T
MANE Select: NM_005198
dbSNP: rs2522792904
Type: single nucleotide variant
Location: chr22:50582636 (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 49: a UniProt-annotated variant site (in mdcmc; loss of choline kinase activity; decreased amount of phosphatidylcholine in patients cells); 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-ala49val (accessed [today's date]).

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