SCN4A
Chr 17ARADsodium voltage-gated channel alpha subunit 4
Also known as: CMS16, CMYO22A, CMYP22A, HOKPP2, HYKPP, HYPP, NAC1A, Na(V)1.4
SCN4A encodes the alpha subunit of a voltage-gated sodium channel expressed in skeletal muscle that generates and propagates action potentials. Mutations cause a spectrum of muscle disorders including periodic paralyses (hyperkalemic and hypokalemic), myotonias (paramyotonia congenita, acetazolamide-responsive myotonia congenita), congenital myopathies, and congenital myasthenic syndrome through gain-of-function mechanisms. Inheritance is autosomal dominant for most phenotypes, with autosomal recessive inheritance reported for some congenital myopathy presentations.
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
300 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 7 | 0 | 0 | 0 | 7 |
Likely Pathogenic | 4 | 2 | 0 | 0 | 6 |
VUS | 3 | 166 | 5 | 1 | 175 |
Likely Benign | 0 | 0 | 36 | 66 | 102 |
Benign | 0 | 0 | 0 | 0 | 0 |
Conflicting | — | 1 | |||
| Total | 14 | 168 | 41 | 67 | 291 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
SCN4A · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
External Resources
Links to major genomics databases and tools