Is CLCN1 p.Pro575Ser (c.1723C>T) pathogenic?

CLCN1 p.Pro575Ser (c.1723C>T) is classified Uncertain significance in CLCN1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-30). AlphaMissense: likely pathogenic (0.9106); Ultra-rare (popmax 0.0757%, eas); Associated with myotonia congenita, autosomal dominant.

What condition is associated with CLCN1 p.Pro575Ser (c.1723C>T)?

CLCN1 p.Pro575Ser (c.1723C>T) is associated with myotonia congenita, autosomal dominant, myotonia congenita, autosomal recessive (ClinVar).

How common is CLCN1 p.Pro575Ser (c.1723C>T) in the general population?

CLCN1 p.Pro575Ser (c.1723C>T) is ultra-rare (popmax 0.0757%, eas) (gnomAD).

How is Thomsen and Becker disease inherited?

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

What do computational predictors say about CLCN1 p.Pro575Ser (c.1723C>T)?

AlphaMissense predicts likely pathogenic (score 0.9106) — an in-silico prediction, not a clinical call.

CLCN1 p.Pro575Ser

c.1723C>T · rs766432255 · VCV858667

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9106 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0757%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

myotonia congenita, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.9106	likely pathogenic
REVEL	0.679	pathogenic-leaning
SaProt	LLR -13.59	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 6.1, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 36 kb · p 0.08 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0757% East Asian · 34/44,890 alleles

Filtering AF 0.0557% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0488%

Overall 0.00235% 38/1,614,048 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0757%	1,320
Remaining individualsnot grpmax-eligible	0.0016%	62,490
European (non-Finnish)	0.000254%	393,343

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.Pro575Ser
Coding: c.1723C>T
MANE Select: NM_000083
dbSNP: rs766432255
Type: single nucleotide variant
Location: chr7:143342069 (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 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-pro575ser (accessed [today's date]).

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