Is CLCN1 p.Phe428fs (c.1282_1285del) pathogenic?

CLCN1 p.Phe428fs (c.12821285del) is classified Pathogenic in CLCN1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-28). Very rare (popmax 0.00333%, amr); Associated with myotonia congenita, autosomal dominant.

What condition is associated with CLCN1 p.Phe428fs (c.1282_1285del)?

CLCN1 p.Phe428fs (c.1282_1285del) is associated with myotonia congenita, autosomal dominant, myotonia congenita, autosomal recessive (ClinVar).

How common is CLCN1 p.Phe428fs (c.1282_1285del) in the general population?

CLCN1 p.Phe428fs (c.1282_1285del) is very rare (popmax 0.00333%, amr) (gnomAD).

How is Thomsen and Becker disease inherited?

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

CLCN1 p.Phe428fs

c.1282_1285del · rs752041565 · VCV623350

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

myotonia congenita, autosomal dominant

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 12 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.9	GERP 3.5, 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 0.00333% Admixed American · 2/60,024 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000991% 16/1,614,234 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,012
South Asian	0.00329%	30,362
European (non-Finnish)	0.000932%	107,277

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: CLCN1
Protein: p.Phe428fs
Coding: c.1282_1285del
MANE Select: NM_000083
dbSNP: rs752041565
Type: Microsatellite
Location: chr7:143332750 (GRCh38)
Gene constraint: LOEUF 1.026 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.34 · 9 PDB

Full CLCN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

myotonia congenita, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: myotonia congenita, autosomal recessive

For Thomsen and Becker disease (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

CLCN1 p.Phe428Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
CLCN1 p.Ala673fs Pathogenic/Likely pathogenic ★★ same condition
CLCN1 p.Thr539fs Pathogenic/Likely pathogenic ★★ same condition
CLCN1 p.Ala437fs Pathogenic ★ same condition
CLCN1 p.Cys666fs Likely pathogenic ★ same condition
CLCN1 p.Glu928fs Pathogenic ★ same condition
CLCN1 p.Leu130fs Pathogenic ★ same condition
CLCN1 p.Leu739fs Pathogenic ★ 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/clcn1-p-phe428fs (accessed [today's date]).

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