Is CLCN1 p.Phe464= (c.1392C>T) pathogenic?

CLCN1 p.Phe464= (c.1392C>T) is classified Conflicting classifications of pathogenicity in CLCN1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-25). Ultra-rare (popmax 0.0164%, nfe); Associated with myotonia congenita, autosomal dominant.

What condition is associated with CLCN1 p.Phe464= (c.1392C>T)?

CLCN1 p.Phe464= (c.1392C>T) is associated with myotonia congenita, autosomal dominant, myotonia congenita, autosomal recessive, Batten-Turner congenital myopathy (ClinVar).

How common is CLCN1 p.Phe464= (c.1392C>T) in the general population?

CLCN1 p.Phe464= (c.1392C>T) is ultra-rare (popmax 0.0164%, nfe) (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.Phe464=

c.1392C>T · rs201919331 · VCV289005

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, nfe)

Conditions

myotonia congenita, autosomal dominant

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 -1.8	GERP -4.7
Overall
CADD	3.772	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% European (non-Finnish) · 194/1,180,016 alleles

Filtering AF 0.0145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0138%

Overall 0.0169% 272/1,614,178 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.193%	519
Remaining individualsnot grpmax-eligible	0.0224%	4,465
European (non-Finnish)grpmax	0.0164%	6,083
African / African-American	0.008%	12,508
East Asian	0.00223%	44,880

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: CLCN1
Protein: p.Phe464=
Coding: c.1392C>T
MANE Select: NM_000083
dbSNP: rs201919331
Type: single nucleotide variant
Location: chr7:143332864 (GRCh38)
Gene constraint: LOEUF 1.026 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.34 · 9 PDB
Residue 464: an α-helix

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 Batten-Turner congenital myopathy

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 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
CLCN1 c.2172+1G>T 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-phe464 (accessed [today's date]).

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