SCN8A

Chr 12AD

sodium voltage-gated channel alpha subunit 8

Also known as: BFIS5, CERIII, CIAT, DEE13, EIEE13, MED, MYOCL2, NaCh6

NCBI Gene: 6334 ENSG00000196876 UniProt: Q9UQD0 OMIM: 600702

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the sodium channel alpha subunit gene family. The encoded protein forms the ion pore region of the voltage-gated sodium channel. This protein is essential for the rapid membrane depolarization that occurs during the formation of the action potential in excitable neurons. Mutations in this gene are associated with cognitive disability, pancerebellar atrophy and ataxia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

?Myoclonus, familial, 2MIM #618364

Cognitive impairment with or without cerebellar ataxiaMIM #614306

Developmental and epileptic encephalopathy 13MIM #614558

Seizures, benign familial infantile, 5MIM #617080

Clinical highlights

Management implications

Most epileptic-encephalopathy variants are gain-of-function and respond to (often high-dose) sodium-channel blockers.GOF SCN8A epilepsy often needs high-dose sodium-channel blockers; LOF does not.

SCN8A: treatment depends on gain/loss of function

Gene-disease validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitivesufficient evidence for diagnostic panels

Interpreting a novel variant

Both gain of function and loss of function mechanisms are described for this gene and which one applies is variant-dependent. Do not assume a null variant is — or isn't — the pathogenic class without checking the specific variant against curated evidence.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.13

LOEUF· LoF intol.

GOF/LOF*

Mechanism· annotated

📖

GeneReview available — SCN8A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Treatment implicationsDepends on gain/loss of function

SCN8A-related epilepsy / neurodevelopmental disorder

GOF SCN8A epilepsy often needs high-dose sodium-channel blockers; LOF does not.

Most epileptic-encephalopathy variants are gain-of-function and respond to (often high-dose) sodium-channel blockers.

Gain-of-function

Gain-of-function (the majority, DEE13) → sodium-channel blockers, often high-dose — oxcarbazepine (often first-line, especially in children), carbamazepine, phenytoin, lamotrigine.

Loss-of-function

Loss-of-function (absence epilepsy / ID) → sodium-channel blockers may worsen; avoid.

Gardella & Møller 2019, Epilepsia. Confirm with a neurologist and current guidelines. Functional class (GOF/LOF) is from published functional/segregation data, never inferred from the variant. As of 2026-07. Curated from the clinical genetics/neurology literature (cited per gene). Decision-support, not prescribing.

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.13LOEUF

pLI 1.000

Z-score 7.81

OE 0.06 (0.03–0.13)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

7.64Z-score

OE missense 0.35 (0.32–0.38)

391 obs / 1106.1 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.06 (0.03–0.13)

0≤0.351.4

Missense OE?0.35 (0.32–0.38)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 5 / 80.7Missense obs/exp: 391 / 1106.1Syn Z: 1.61

ClinVar Variant Classifications

0 submitted variants in ClinVar

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.

Paralog Hotspots

SCN1A / SCN2A / SCN8A

Positions in SCN8A where a homologous residue in SCN1A / SCN2A / SCN8A has at least one curated Pathogenic or Likely pathogenic variant in ClinVar. A tick here suggests a residue worth scrutinizing when interpreting a VUS in SCN8A.