SCN1A
Chr 2ADsodium voltage-gated channel alpha subunit 1
Also known as: DEE6, DEE6A, DEE6B, DRVT, EIEE6, FEB3, FEB3A, FHM3
Voltage-dependent sodium channels are heteromeric complexes that regulate sodium exchange between intracellular and extracellular spaces and are essential for the generation and propagation of action potentials in muscle cells and neurons. Each sodium channel is composed of a large pore-forming, glycosylated alpha subunit and two smaller beta subunits. This gene encodes a sodium channel alpha subunit, which has four homologous domains, each of which contains six transmembrane regions. Allelic variants of this gene are associated with generalized epilepsy with febrile seizures and epileptic encephalopathy. Alternative splicing results in multiple transcript variants. The RefSeq Project has decided to create four representative RefSeq records. Three of the transcript variants are supported by experimental evidence and the fourth contains alternate 5' untranslated exons, the exact combination of which have not been experimentally confirmed for the full-length transcript. [provided by RefSeq, Oct 2015]
Definitive — sufficient evidence for diagnostic panels
4 total gene-disease associations curated
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Among the most LoF-intolerant genes (~top 3%)
Extremely missense-constrained (top ~0.01%)
Nav1.1 is the most commonly mutated gene in epilepsy. LOF (truncation, severe missense with loss of current) causes Dravet syndrome via reduced inhibitory interneuron firing. GOF missense variants (increased persistent current) cause GEFS+. Mechanism is variant- and phenotype-dependent.12
This gene — mechanism propensity
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). 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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
References
ClinVar Variant Classifications
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
SCN1A · 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
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
A Study to Evaluate the Safety and Pharmacokinetics of RC001 in Children With Dravet Syndrome
RECRUITINGOnline Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight
RECRUITINGA Clinical Study to Evaluate the Safety and Efficacy of ETX101, an AAV9-Delivered Gene Therapy in Children With SCN1A-positive Dravet Syndrome (Australia Only)
ACTIVE NOT RECRUITINGA Clinical Study to Evaluate the Safety and Efficacy of ETX101 in Infants and Children With SCN1A-Positive Dravet Syndrome
RECRUITINGLongitudinal Study of Phenotypic and Developmental Severity in Patients With Dravet Syndrome With SCN1A Gene Mutation
RECRUITINGNeurodevelopmental Impact of Epilepsy on Autonomic Function in Dravet Syndrome
ACTIVE NOT RECRUITINGA Clinical Study to Evaluate the Safety and Efficacy of ETX101, an AAV9-Delivered Gene Therapy in Children With SCN1A-positive Dravet Syndrome
ACTIVE NOT RECRUITINGA PET-MRI Study of Serotoninergic Brainstem Pathway in Patients With Dravet Syndrome
RECRUITINGParalog Hotspots
SCN1A / SCN2A / SCN8A
scn-meta.jsonExternal Resources
Links to major genomics databases and tools