SCN8A

Chr 12

sodium voltage-gated channel alpha subunit 8

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

NCBI Gene: 6334 ENSG00000196876 UniProt: Q9UQD0

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]

Primary Disease Associations & Inheritance

UniProtCognitive impairment with or without cerebellar ataxia

UniProtDevelopmental and epileptic encephalopathy 13

UniProtSeizures, benign familial infantile, 5

UniProtMyoclonus, familial, 2

687

ClinVar variants

100

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— SCN8A

🧬

Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

📋

ClinVar Variants

100 Pathogenic / Likely Pathogenic· 375 VUS of 687 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

Dual constrained — LoF & missense intolerant

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.

0.13LOEUF

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?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.

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?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.0.06 (0.03–0.13)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.35 (0.32–0.38)

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.0.90

0≤1.21.6

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