Is CHKB p.Phe189fs (c.565_568del) pathogenic?

CHKB p.Phe189fs (c.565568del) is classified Pathogenic/Likely pathogenic in CHKB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-16). Very rare (popmax 0.00144%, nfe); Associated with megaconial type congenital muscular dystrophy.

What condition is associated with CHKB p.Phe189fs (c.565_568del)?

CHKB p.Phe189fs (c.565_568del) is associated with megaconial type congenital muscular dystrophy (ClinVar).

How common is CHKB p.Phe189fs (c.565_568del) in the general population?

CHKB p.Phe189fs (c.565_568del) is very rare (popmax 0.00144%, nfe) (gnomAD).

How is Megaconial congenital muscular dystrophy inherited?

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

CHKB p.Phe189fs

c.565_568del · rs752436924 · VCV632393

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Conditions

megaconial type congenital muscular dystrophy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 11
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.6	GERP 2.6, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00144% European (non-Finnish) · 17/1,179,980 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00112% 18/1,613,344 alleles · very rare exomes 17/1,461,118 · genomes 1/152,226 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,468
European (non-Finnish)grpmax	0.00144%	69,411

Remaining individuals 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.Phe189fs
Coding: c.565_568del
MANE Select: NM_005198
dbSNP: rs752436924
Type: Deletion
Location: chr22:50581433 (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 189: 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 c.582-13_582-11del Benign/Likely benign ★★ same condition
CHKB p.Gln198fs Pathogenic ★ same condition
CHKB p.Met179fs Pathogenic ★ same condition
CHKB p.Thr155fs Pathogenic ★ same condition
CHKB c.736+5_736+7del Uncertain significance ★ same condition
CHKB c.819-16_819-7del Uncertain significance ★ same condition
CHKB p.Arg99_Arg104del Uncertain significance ★ same condition
CHKB p.Phe352_Trp353delinsLeu 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-phe189fs (accessed [today's date]).

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