Is CHKB p.Ser231Cys (c.692C>G) pathogenic?

CHKB p.Ser231Cys (c.692C>G) is classified Uncertain significance in CHKB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-06-20). AlphaMissense: likely benign (0.0748); Ultra-rare (popmax 0.0936%, eas); Associated with megaconial type congenital muscular dystrophy.

What condition is associated with CHKB p.Ser231Cys (c.692C>G)?

CHKB p.Ser231Cys (c.692C>G) is associated with megaconial type congenital muscular dystrophy (ClinVar).

How common is CHKB p.Ser231Cys (c.692C>G) in the general population?

CHKB p.Ser231Cys (c.692C>G) is ultra-rare (popmax 0.0936%, eas) (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.Ser231Cys (c.692C>G)?

AlphaMissense predicts likely benign (score 0.0748) — an in-silico prediction, not a clinical call.

CHKB p.Ser231Cys

c.692C>G · rs199783402 · VCV342174

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0748 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0936%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

megaconial type congenital muscular dystrophy

Computational evidence

Protein change
AlphaMissense	0.0748	likely benign
REVEL	0.189	benign-leaning
SaProt	LLR -9.42	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.3, phastCons 0.97
Regional constraint	o/e 1.03	unconstrained · MANE · 3,597 bp · p 0.53 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.0936% East Asian · 42/44,882 alleles

Filtering AF 0.0712% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0632%

Overall 0.00297% 48/1,614,042 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0936%	1,069
South Asian	0.00439%	22,766
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	8.47e-05%	1,180,030

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.Ser231Cys
Coding: c.692C>G
MANE Select: NM_005198
dbSNP: rs199783402
Type: single nucleotide variant
Location: chr22:50580402 (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 231: 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)

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-ser231cys (accessed [today's date]).

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