Is CLCN1 p.Phe494= (c.1482T>C) pathogenic?

CLCN1 p.Phe494= (c.1482T>C) is classified Likely benign in CLCN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-12). Ultra-rare (popmax 0.0132%, sas); Associated with myotonia congenita, autosomal recessive.

What condition is associated with CLCN1 p.Phe494= (c.1482T>C)?

CLCN1 p.Phe494= (c.1482T>C) is associated with myotonia congenita, autosomal recessive, myotonia congenita, autosomal dominant (ClinVar).

How common is CLCN1 p.Phe494= (c.1482T>C) in the general population?

CLCN1 p.Phe494= (c.1482T>C) is ultra-rare (popmax 0.0132%, sas) (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.Phe494=

c.1482T>C · rs745690349 · VCV511042

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Conditions

myotonia congenita, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.13	GERP 1.2, phastCons 0.98
Overall
CADD	7.19	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0132% South Asian · 12/91,066 alleles

Filtering AF 0.00751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.000744% 12/1,612,990 alleles · ultra-rare

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.Phe494=
Coding: c.1482T>C
MANE Select: NM_000083
dbSNP: rs745690349
Type: single nucleotide variant
Location: chr7:143339521 (GRCh38)
Gene constraint: LOEUF 1.026 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.34 · 9 PDB
Residue 494: an α-helix

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

Disease context

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

Also linked: myotonia congenita, autosomal dominant

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.Phe494Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CLCN1 c.1167-10T>C Pathogenic/Likely pathogenic ★★ same condition
CLCN1 c.1401+1G>T Pathogenic/Likely pathogenic ★★ same condition
CLCN1 c.1471+1G>A Pathogenic/Likely pathogenic ★★ same condition
CLCN1 c.180+1G>A Likely pathogenic ★★ same condition
CLCN1 c.180+3A>T Pathogenic/Likely pathogenic ★★ same condition
CLCN1 c.1930+1G>A Pathogenic/Likely pathogenic ★★ same condition
CLCN1 c.2172+1G>A 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-phe494 (accessed [today's date]).

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