SCN4A

Chr 17

sodium voltage-gated channel alpha subunit 4

NCBI Gene: 6329ENSG00000007314UniProt: P35499

Pore-forming subunit of Nav1.4, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes. Navs, also called VGSCs (voltage-gated sodium channels) or VDSCs (voltage-dependent sodium channels), operate by switching between closed and open conformations depending on the voltage difference across the membrane. In the open conformation they allow Na(+) ions to selectively pass through the pore, along their electrochemical gradient. The influx of Na+ ions provokes membrane depolarization, initiating the propagation of electrical signals throughout cells and tissues (PubMed:12766226, PubMed:15318338, PubMed:16890191, PubMed:17898326, PubMed:18690054, PubMed:19347921, PubMed:25707578, PubMed:26659129, PubMed:26700687, PubMed:29992740, PubMed:30190309). Highly expressed in skeletal muscles, Nav1.4 generates the action potential crucial for muscle contraction (PubMed:16890191, PubMed:19347921, PubMed:25707578, PubMed:26659129, PubMed:26700687)

Primary Disease Associations & Inheritance

UniProtParamyotonia congenita
UniProtPeriodic paralysis hypokalemic 2
UniProtPeriodic paralysis hyperkalemic
UniProtPeriodic paralysis normokalemic
2460
ClinVar variants
20
Pathogenic / LP
0.01
pLI score
1
Active trials
Clinical Summary— SCN4A
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.
📋
ClinVar Variants
20 Pathogenic / Likely Pathogenic· 255 VUS of 2460 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.56Z-score
OE missense 0.87 (0.82–0.92)
977 obs / 1124.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.26 (0.18–0.38)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.87 (0.82–0.92)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99
0≤1.21.6
LoF obs/exp: 19 / 73.7Missense obs/exp: 977 / 1124.2Syn Z: 0.11

ClinVar Variant Classifications

2460 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7
Likely Pathogenic13
VUS255
Likely Benign174
Benign39
Conflicting3
7
Pathogenic
13
Likely Pathogenic
255
VUS
174
Likely Benign
39
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
0
1
0
7
Likely Pathogenic
7
4
2
0
13
VUS
2
231
20
2
255
Likely Benign
0
1
79
94
174
Benign
0
0
39
0
39
Conflicting
—3
Total1523614196491

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.

Gene2Phenotype Curations

SCN4A-related paramyotonia congenita of von Eulenburg

definitive
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

SCN4A-related hyperkalemic periodic paralysis

definitive
ADGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗

SCN4A-related hypokalemic periodic paralysis

definitive
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Guidelines on clinical presentation and management of nondystrophic myotonias.
Stunnenberg BC et al.·Muscle Nerve
2020Review
Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review.
Ohno K et al.·Int J Mol Sci
2023Review
Periodic paralysis.
Cannon SC·Handb Clin Neurol
2024Review
Toripalimab Plus Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Lung Cancer: The Phase 3 EXTENTORCH Randomized Clinical Trial.
Cheng Y et al.·JAMA Oncol
2025Clinical trial
Diagnostics in skeletal muscle channelopathies.
Vicino A et al.·Expert Rev Mol Diagn
2023Review
Periodic paralysis.
Fialho D et al.·Handb Clin Neurol
2018Review
Myotonic disorders.
Mankodi A·Neurol India
2008Review
Congenital myasthenic syndromes.
Hantaï D et al.·Curr Opin Neurol
2004Review
Mutations of SCN4A gene cause different diseases: 2 case reports and literature review.
Liu XL et al.·Channels (Austin)
2015Review
Skeletal muscle sodium channelopathies.
Nicole S et al.·Curr Opin Neurol
2015Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Biophysical and structural insights into the SCN4A E452K variant linked to myotonia and paramyotonia congenita.
Plumereau Q et al.·Sci Rep
2025🔓 Open Access
Genetic analysis of a family with skeletal muscle ion channelopathy and hereditary spastic paraplegia type 7 caused by SCN4A and SPG7 double mutations.
Yu HP et al.·Gene
2025
Clinical, electromyographic, and biophysical characterization of the rare Nav1.4 channel mutation SCN4A L1436P.
Wang FC et al.·Front Physiol
2025🔓 Open Access
High-dose flecainide for symptomatic relief in paramyotonia congenita/severe neonatal episodic laryngospasm due to SCN4A G1306E: a case report.
Ogueri V et al.·J Med Case Rep
2025🔓 Open AccessCase report
Novel SCN4A Variants Associated With Myalgic Myotonic Disorder or Paramyotonia.
Periviita V et al.·Eur J Neurol
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

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

External Resources

Links to major genomics databases and tools