Is CHKB p.Leu334Pro (c.1001T>C) pathogenic?

CHKB p.Leu334Pro (c.1001T>C) is classified Uncertain significance in CHKB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-11). AlphaMissense: ambiguous (0.4697); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with CHKB p.Leu334Pro (c.1001T>C)?

CHKB p.Leu334Pro (c.1001T>C) is associated with Inborn genetic diseases, megaconial type congenital muscular dystrophy (ClinVar).

How common is CHKB p.Leu334Pro (c.1001T>C) in the general population?

CHKB p.Leu334Pro (c.1001T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about CHKB p.Leu334Pro (c.1001T>C)?

AlphaMissense predicts ambiguous (score 0.4697) — an in-silico prediction, not a clinical call.

CHKB p.Leu334Pro

c.1001T>C · rs780983852 · VCV966051

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4697 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4697	ambiguous
REVEL	0.344	indeterminate
SaProt	LLR -12.87	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.9	GERP 0.24, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 3,597 bp · p 0.53 · regional, not allelic
Overall
CADD	24.5	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 0.00167% Admixed American · 1/59,952 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000684% 10/1,461,822 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,952
Remaining individualsnot grpmax-eligible	0.0016%	62,498
European (non-Finnish)	0.000678%	147,481

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.Leu334Pro
Coding: c.1001T>C
MANE Select: NM_005198
dbSNP: rs780983852
Type: single nucleotide variant
Location: chr22:50579757 (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 334: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: megaconial type congenital muscular dystrophy

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-leu334pro (accessed [today's date]).

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