SCN4A

Chr 17ARAD

sodium voltage-gated channel alpha subunit 4

Also known as: CMS16, CMYO22A, CMYP22A, HOKPP2, HYKPP, HYPP, NAC1A, Na(V)1.4

NCBI Gene: 6329 ENSG00000007314 UniProt: P35499 OMIM: 603967

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. It is expressed in skeletal muscle, and mutations in this gene have been linked to several myotonia and periodic paralysis disorders. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Congenital myopathy 22A, classicMIM #620351

Congenital myopathy 22B, severe fetalMIM #620369

Hyperkalemic periodic paralysisMIM #170500

Hypokalemic periodic paralysis, type 2MIM #613345

Myasthenic syndrome, congenital, 16MIM #614198

Myotonia congenita, atypical, acetazolamide-responsiveMIM #608390

Paramyotonia congenitaMIM #168300

UniProtMyotonia SCN4A-related

Clinical highlights

Gene-disease validity (ClinGen)

SCN4A-related myopathy, autosomal recessive · ARDefinitivesufficient evidence for diagnostic panels

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.38

LOEUF

GOF*

Mechanism· G2P

📖

GeneReview available — SCN4A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.38LOEUF

pLI 0.013

Z-score 5.91

OE 0.26 (0.18–0.38)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.56Z-score

OE missense 0.87 (0.82–0.92)

977 obs / 1124.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.26 (0.18–0.38)

0≤0.351.4

Missense OE?0.87 (0.82–0.92)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 19 / 73.7Missense obs/exp: 977 / 1124.2Syn Z: 0.11

ClinVar Variant Classifications

0 submitted variants in ClinVar

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.

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

📖

GeneReview available — SCN4A

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Non Dystrophic MyotoniaArrythmia, Cardiac

A Single Center Prospective Study in an Estimated 570 Patients Who Underwent Genetic Screening at UZ Brussel in the Context of a Primary Cardiac Arrhythmia. Patients Showing a Variant Class 3,4 or 5 in SCN4A or CLCN1 Will Undergo a Clinical and Electrophysiological Review After IC.

NOT YET RECRUITING

NCT07183059Phase NAUniversitair Ziekenhuis BrusselStarted 2025-12-15

Electromyography

Clinical Literature

Open Research Assistant →

Landmark / reviewRecent case evidence

Full-Text Mentions

NLP-detected gene mentions in article bodies · via PubTator3

PubTator3

Sequence CLCN1 and SCN4A genes in patients with nondystrophic myotonia in Chinese people

Meng YX et al.·Medicine (Baltimore)

2022Cohort