# NM_000083.3(CLCN1):c.2005C>T (p.Arg669Cys)

https://sugi.bio/variant/clcn1-p-arg669cys

## Summary

**CLCN1 p.Arg669Cys (c.2005C>T)** is classified **Uncertain significance** in CLCN1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-06-19). AlphaMissense: likely benign (0.3204); Very rare (popmax 0.000697%, nfe); Associated with myotonia congenita, autosomal dominant.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs748537564 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.000697%, nfe)

## For patients & families {#patients}

This is a change in the CLCN1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to myotonia congenita, autosomal dominant.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive |
| Age of onset (of this condition) | Adolescent, Adult, Childhood, Infancy |
| Prevalence | 1-9 / 100 000 (Worldwide) |
| Diagnostic panels | CLCN1 is a diagnostic-grade gene on 2 Genomics England panels |

**Commonly reported features of Thomsen and Becker disease** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Myotonia — Very frequent (99-80%)
- EMG abnormality — Very frequent (99-80%)
- Muscle stiffness — Very frequent (99-80%)
- Myotonia with warm-up phenomenon — Very frequent (99-80%)
- EMG: myotonic discharges — Very frequent (99-80%)
- Myalgia — Frequent (79-30%)
- Skeletal muscle hypertrophy — Frequent (79-30%)
- Clumsiness — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006176/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CLCN1](https://sugi.bio/atlas/gene/CLCN1/) |
| Protein change (HGVS p.) | p.Arg669Cys |
| Coding change (HGVS c.) | c.2005C>T |
| MANE Select transcript | [NM_000083](https://www.ncbi.nlm.nih.gov/nuccore/NM_000083) |
| dbSNP | [rs748537564](https://www.ncbi.nlm.nih.gov/snp/rs748537564/) |
| Variant type | single nucleotide variant |
| Location | chr7:143345595-143345595 (GRCh38) |
| ClinVar | [VCV2925429](https://www.ncbi.nlm.nih.gov/clinvar/variation/2925429/) |

**All HGVS expressions:** `NC_000007.13:g.143042688C>T`, `NC_000007.14:g.143345595C>T`, `NG_009815.2:g.34470C>T`, `NG_078448.1:g.280C>T`, `NM_000083.3:c.2005C>T`, `NR_046453.2:n.1960C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.3204)
- REVEL 0.831 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -10.725 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- SpliceAI predicts **acceptor gain** (Δ 0.22) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 2.144, GERP 2.57, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 27.7**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.95** across the covering region of the MANE Select transcript (143,316,213–143,351,962), spanning 35,749 bp. Chi-square p 0.08. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.22**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.22**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.000697%** (nfe) · FAF95 0.0003% · FAF99 0.000217% · 8/1,148,152 in the highest group · 8/1,400,370 alleles overall — very rare (popmax 0.000697%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CLCN1** population constraint: LOEUF 1.026, pLI 9.683e-28, missense-Z 0.96457. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 68.34, 28% of residues very-high.

**9 experimental structure(s)** (PDB): [6COY](https://www.rcsb.org/structure/6COY), [6COZ](https://www.rcsb.org/structure/6COZ), [6QV6](https://www.rcsb.org/structure/6QV6), [6QVB](https://www.rcsb.org/structure/6QVB), [6QVC](https://www.rcsb.org/structure/6QVC), [6QVD](https://www.rcsb.org/structure/6QVD).

## What this gene does {#gene-function}

*Describes the biological roles of CLCN1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CLCN1's established molecular role includes voltage-gated chloride channel activity.


### Pathways affected {#pathways}

CLCN1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Stimuli-sensing channels](https://reactome.org/content/detail/R-HSA-2672351) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** voltage-gated chloride channel activity, protein homodimerization activity.

**Biological process:** muscle contraction, chloride transmembrane transport.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-06-19.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2023–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-11-24 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-06-19 |

## Associated conditions {#conditions}

[myotonia congenita, autosomal dominant](https://sugi.bio/atlas/disease/myotonia-congenita-autosomal-dominant/), [myotonia congenita, autosomal recessive](https://sugi.bio/atlas/disease/myotonia-congenita-autosomal-recessive/).

**Reported phenotype names (ClinVar):** Congenital myotonia, autosomal dominant form, Congenital myotonia, autosomal recessive form, not specified, AllHighlyPenetrant, THOMSEN DISEASE, Myotonia congenita autosomal dominant, BECKER DISEASE, Becker Generalized Myotonia, myotonia congenita, autosomal recessive.

## Similar variants {#similar}

Related CLCN1 variant pages (same residue, condition, or type): [CLCN1 p.Arg669=](/variant/clcn1-p-arg669), [CLCN1 p.Arg669Gly](/variant/clcn1-p-arg669gly), [CLCN1 c.1167-10T>C](/variant/clcn1-c-1167-minus-10t-c), [CLCN1 c.1401+1G>T](/variant/clcn1-c-1401-plus-1g-t), [CLCN1 c.1471+1G>A](/variant/clcn1-c-1471-plus-1g-a), [CLCN1 c.180+1G>A](/variant/clcn1-c-180-plus-1g-a), [CLCN1 c.180+3A>T](/variant/clcn1-c-180-plus-3a-t), [CLCN1 c.1930+1G>A](/variant/clcn1-c-1930-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 2925429). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*