Is CLCN1 p.Ala331= (c.993T>C) pathogenic?

CLCN1 p.Ala331= (c.993T>C) is classified Likely benign in CLCN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-13). Absent from gnomAD v4.1; Associated with myotonia congenita, autosomal dominant.

What condition is associated with CLCN1 p.Ala331= (c.993T>C)?

CLCN1 p.Ala331= (c.993T>C) is associated with myotonia congenita, autosomal dominant, myotonia congenita, autosomal recessive (ClinVar).

How common is CLCN1 p.Ala331= (c.993T>C) in the general population?

CLCN1 p.Ala331= (c.993T>C) is absent from gnomAD v4.1 (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.Ala331=

c.993T>C · rs2116852879 · VCV1590113

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 -0.57	GERP 1.2, phastCons 0.051
Overall
CADD	8.745	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CLCN1
Protein: p.Ala331=
Coding: c.993T>C
MANE Select: NM_000083
dbSNP: rs2116852879
Type: single nucleotide variant
Location: chr7:143331245 (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 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.Ala331Ser Likely pathogenic ★★ ⚠ same residue
CLCN1 p.Ala331Gly Uncertain significance ★★ ⚠ same residue
CLCN1 p.Ala331Thr Likely pathogenic ★ 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-ala331 (accessed [today's date]).

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