SCN1A (P35498) variants and mutations

SCN1A (also known as P35498) is a human protein-coding gene encoding a sodium channel protein type 1 subunit alpha protein. Its sodium current is especially important for reliable firing of inhibitory interneurons and therefore for balancing excitation across neural networks. Loss-of-function variants are the major cause of Dravet syndrome, while other variants cause GEFS+ or familial hemiplegic migraine. This analysis covers 3,810 SCN1A variants and mutations. Of these, 36% have pathogenic or likely pathogenic clinical classifications, 79% have computational variant effect predictions from MutPred, and 34% have population-specific frequency data. Disease context includes Dravet syndrome, generalized epilepsy with febrile seizures plus, type 2, and Generalized epilepsy with febrile seizures-plus. Example SCN1A variants include M1?, E2D, and Q3K.

Variant analysis overview

Gene: SCN1A
Protein: P35498
UniProt accession: P35498
Organism: Homo sapiens
Variants analyzed: 3810
Variant scope: all variants
Completed: 2026-08-09

Variant and mutation evidence

Variant composition: 3,406 unspecified-consequence records; 206 synonymous variants; 172 missense variants; 14 frameshift variants; 1 in-frame deletions; 1 in-frame insertions; 1 stop retained variant; 2 stop lost; 4 stop-gained variants; 1 splice-region variants; 2 substitution
Clinical classifications: 1,371 pathogenic or likely pathogenic; 199 benign or likely benign; 835 uncertain-significance; 10 conflicting; 376 other clinical labels.
Computational signals: 550 MutPred high-risk.
Variant classes: 3,073 missense; 206 synonymous; 528 truncating or splice.
Prediction scores: 3,015 variants have prediction scores (79% of the analyzed set).
Literature: 15 publications are represented in the literature summary.

Clinical, disease, and population context

Clinical evidence: 290 records have expert-only or criteria-backed evidence.
Clinical annotations: 2,792 variants have clinical annotations.
Population evidence: 1,492 variants have population-frequency evidence.
Disease context: 25 disease associations are represented. Top associations: Dravet syndrome, generalized epilepsy with febrile seizures plus, type 2, Generalized epilepsy with febrile seizures-plus, migraine, familial hemiplegic, 3, genetic developmental and epileptic encephalopathy, febrile seizures, familial, 3a, GEFSP2, borderline phenotype, FHM3, DEE6B, FEB3A, patients with Panayiotopoulos syndrome.

Protein structure and variant hotspots

Protein features: 24 transmembrane segments; 1 domains; 17 post-translational modification sites.
Ancestry evidence: 1,312 variants have ancestry-specific frequency data.
Structural context: 1,099 variants have structural context.
PTM context: 21 variants overlap post-translational modification sites.
3D hotspots: 6 hotspot clusters were identified. Clusters at residues 247-1655 (intolerant, 66 variants); residues 276-393 (intolerant, 15 variants); residues 908-939 (intolerant, 24 variants).
Allosteric analysis: 25 functional sites were identified.
gnomAD gene constraint: pLI 1.00 (highly intolerant of loss-of-function variation); LOEUF 0.07; missense Z-score 8.78.

Data sources

Evidence in this analysis draws on EBI Proteins Variation, UniProt, gnomAD v4, EuropePMC, 3D Hotspot Analysis, Interaction Network Analysis, Protein Data Bank, AlphaFold DB, gnomAD constraint, Open Targets, ClinGen, MaveDB, LitVar.

Notable SCN1A variants

Examples include M1?, E2D, Q3K, T4I, V5M, L6F, L6R, V7I. Listed records include available protein-change notation, database identifiers, clinical classifications, computational predictions, population evidence, experimental measurements, and disease context.

SCN1A analysis run — SCN1A (3,810 variants) — completed 2026-08-09