Is CLCN1 p.Pro741Ala (c.2221C>G) pathogenic?

CLCN1 p.Pro741Ala (c.2221C>G) is classified Uncertain significance in CLCN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-10-03). AlphaMissense: likely benign (0.0603); Very rare (popmax 8.48e-05%, nfe); Associated with myotonia congenita, autosomal recessive.

What condition is associated with CLCN1 p.Pro741Ala (c.2221C>G)?

CLCN1 p.Pro741Ala (c.2221C>G) is associated with myotonia congenita, autosomal recessive, myotonia congenita, autosomal dominant (ClinVar).

How common is CLCN1 p.Pro741Ala (c.2221C>G) in the general population?

CLCN1 p.Pro741Ala (c.2221C>G) is very rare (popmax 8.48e-05%, 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.Pro741Ala (c.2221C>G)?

AlphaMissense predicts likely benign (score 0.0603) — an in-silico prediction, not a clinical call.

CLCN1 p.Pro741Ala

c.2221C>G · rs1226988170 · VCV1800898

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0603 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

myotonia congenita, autosomal recessive

Computational evidence

Protein change
AlphaMissense	0.0603	likely benign
REVEL	0.136	moderately benign-leaning
SaProt	LLR -6.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP -1.4	GERP 0.33
Regional constraint	o/e 0.95	unconstrained · MANE · 36 kb · p 0.08 · regional, not allelic
Overall
CADD	14.54	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 8.48e-05% European (non-Finnish) · 1/1,179,832 alleles

Overall 6.84e-05% 1/1,461,642 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.Pro741Ala
Coding: c.2221C>G
MANE Select: NM_000083
dbSNP: rs1226988170
Type: single nucleotide variant
Location: chr7:143346188 (GRCh38)
Gene constraint: LOEUF 1.026 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.34 · 9 PDB
Residue 741: the 'disordered' region

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 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-pro741ala (accessed [today's date]).

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