Is CLCN1 p.His29Pro (c.86A>C) pathogenic?

CLCN1 p.His29Pro (c.86A>C) is classified Conflicting classifications of pathogenicity in CLCN1 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1091); Rare (popmax 0.693%, mid); Associated with myotonia congenita, autosomal dominant.

What condition is associated with CLCN1 p.His29Pro (c.86A>C)?

CLCN1 p.His29Pro (c.86A>C) is associated with myotonia congenita, autosomal dominant, myotonia congenita, autosomal recessive, Batten-Turner congenital myopathy (ClinVar).

How common is CLCN1 p.His29Pro (c.86A>C) in the general population?

CLCN1 p.His29Pro (c.86A>C) is rare (popmax 0.693%, mid) (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.His29Pro (c.86A>C)?

AlphaMissense predicts likely benign (score 0.1091) — an in-silico prediction, not a clinical call.

CLCN1 p.His29Pro

c.86A>C · rs146160029 · VCV359091

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.1091 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.693%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

myotonia congenita, autosomal dominant

Computational evidence

Protein change
AlphaMissense	0.1091	likely benign
REVEL	0.809	moderately pathogenic-leaning
SaProt	LLR -4.97	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.27	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 6.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 36 kb · p 0.08 · regional, not allelic
Overall
CADD	23.7	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 0.693% Middle Eastern · 42/6,060 alleles

Filtering AF 0.527% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.469%

Overall 0.374% 6,030/1,613,774 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.693%	144
European (non-Finnish)	0.464%	215
Remaining individualsnot grpmax-eligible	0.416%	240
Admixed American	0.133%	750
South Asian	0.0966%	1,035
African / African-American	0.0707%	1,415
Finnishnot grpmax-eligible	0.0391%	2,556
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869

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.His29Pro
Coding: c.86A>C
MANE Select: NM_000083
dbSNP: rs146160029
Type: single nucleotide variant
Location: chr7:143316298 (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 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-his29pro (accessed [today's date]).

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