Is CHKB p.Pro88Leu (c.263C>T) pathogenic?

CHKB p.Pro88Leu (c.263C>T) is classified Conflicting classifications of pathogenicity in CHKB (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-02). AlphaMissense: ambiguous (0.37); Ultra-rare (popmax 0.0451%, sas); Associated with megaconial type congenital muscular dystrophy.

What condition is associated with CHKB p.Pro88Leu (c.263C>T)?

CHKB p.Pro88Leu (c.263C>T) is associated with megaconial type congenital muscular dystrophy (ClinVar).

How common is CHKB p.Pro88Leu (c.263C>T) in the general population?

CHKB p.Pro88Leu (c.263C>T) is ultra-rare (popmax 0.0451%, sas) (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.Pro88Leu (c.263C>T)?

AlphaMissense predicts ambiguous (score 0.37) — an in-silico prediction, not a clinical call.

CHKB p.Pro88Leu

c.263C>T · rs146163970 · VCV447030

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.37 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0451%, sas)

Conditions

megaconial type congenital muscular dystrophy

Computational evidence

Protein change
AlphaMissense	0.37	ambiguous
REVEL	0.378	indeterminate
SaProt	LLR -11.96	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.94 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.5	GERP 2.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 3,597 bp · p 0.53 · regional, not allelic
Overall
CADD	29.9	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 0.0451% South Asian · 39/86,546 alleles

Filtering AF 0.0338% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0299%

Overall 0.0233% 369/1,583,094 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.363%	276
South Asiangrpmax	0.0451%	2,219
Finnishnot grpmax-eligible	0.0284%	3,518
Remaining individualsnot grpmax-eligible	0.0245%	4,081
Middle Eastern	0.0216%	4,624
European (non-Finnish)	0.0161%	6,209
Admixed American	0.00359%	27,833
African / African-American	0.00269%	37,218

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro88Leu
Coding: c.263C>T
MANE Select: NM_005198
dbSNP: rs146163970
Type: single nucleotide variant
Location: chr22:50582319 (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 88: a UniProt-annotated variant site (in mdcmc; loss of choline kinase activity; decreased amount of phosphatidylcholine in patients cells)

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.Pro88Ser Uncertain significance ★ ⚠ same residue
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

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-pro88leu (accessed [today's date]).

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