SCN8A
Chr 12ADsodium voltage-gated channel alpha subunit 8
Also known as: BFIS5, CERIII, CIAT, DEE13, EIEE13, MED, MYOCL2, NaCh6
The protein forms the ion pore region of voltage-gated sodium channels and is essential for rapid membrane depolarization during action potential formation in excitable neurons. Mutations cause a spectrum of autosomal dominant conditions including developmental and epileptic encephalopathy, benign familial infantile seizures, cognitive impairment with or without cerebellar ataxia, and familial myoclonus. Disease can result from multiple mechanisms depending on the specific variant, with gain-of-function effects being commonly observed, though the gene's extreme constraint against loss-of-function variants suggests haploinsufficiency may also contribute to pathogenicity.
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Among the most LoF-intolerant genes (~top 3%)
Extremely missense-constrained (top ~0.01%)
Nav1.6 is a monomeric alpha subunit that cannot form dominant-negative complexes. Pathogenic missense variants cause GOF (increased persistent current, impaired inactivation) leading to severe DEE. LOF variants cause a milder phenotype with ID and movement disorder. G2P's "dominant negative" classification does not map straightforwardly to the biophysical consequences of SCN8A variants — the functional data consistently demonstrate GOF or LOF, not DN.
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.
ClinVar Variant Classifications
200 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 | 9 | 0 | 0 | 16 |
Likely Pathogenic | 8 | 10 | 1 | 0 | 19 |
VUS | 3 | 96 | 4 | 2 | 105 |
Likely Benign | 0 | 0 | 19 | 39 | 58 |
Benign | 0 | 0 | 0 | 0 | 0 |
Conflicting | — | 2 | |||
| Total | 18 | 115 | 24 | 41 | 200 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
SCN8A · 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