Is CLCN1 p.Ala331Ser (c.991G>T) pathogenic?

CLCN1 p.Ala331Ser (c.991G>T) is classified Likely pathogenic in CLCN1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-21). AlphaMissense: ambiguous (0.3841); Very rare (popmax 0.00051%, nfe); Associated with myotonia congenita, autosomal recessive.

What condition is associated with CLCN1 p.Ala331Ser (c.991G>T)?

CLCN1 p.Ala331Ser (c.991G>T) is associated with myotonia congenita, autosomal recessive, myotonia congenita, autosomal dominant, metachromatic leukodystrophy (ClinVar).

How common is CLCN1 p.Ala331Ser (c.991G>T) in the general population?

CLCN1 p.Ala331Ser (c.991G>T) is very rare (popmax 0.00051%, 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.

What do computational predictors say about CLCN1 p.Ala331Ser (c.991G>T)?

AlphaMissense predicts ambiguous (score 0.3841) — an in-silico prediction, not a clinical call.

CLCN1 p.Ala331Ser

c.991G>T · rs2487058978 · VCV2921633

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3841 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00051%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

myotonia congenita, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.3841	ambiguous
REVEL	0.782	moderately pathogenic-leaning
SaProt	LLR -10.81	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.27	acceptor gain · deltas
Pangolin	Δ0.32	gain · loss 0.16 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 3.6, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 36 kb · p 0.08 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00051% European (non-Finnish) · 6/1,177,620 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000411% 6/1,459,238 alleles · very 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.Ala331Ser
Coding: c.991G>T
MANE Select: NM_000083
dbSNP: rs2487058978
Type: single nucleotide variant
Location: chr7:143331243 (GRCh38)
Gene constraint: LOEUF 1.026 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.34 · 9 PDB
Residue 331: a β-strand

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 metachromatic leukodystrophy

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.Ala331Gly Uncertain significance ★★ ⚠ same residue
CLCN1 p.Ala331Thr Likely pathogenic ★ same residue
CLCN1 p.Ala331= Likely benign ★ same residue
CLCN1 p.Ala331fs Pathogenic ★ same residue
CLCN1 p.Ala331Leu Uncertain significance ★ 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

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-ala331ser (accessed [today's date]).

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