SCN3A

Chr 2AD

sodium voltage-gated channel alpha subunit 3

Also known as: DEE62, EIEE62, FFEVF4, NAC3, Nav1.3

NCBI Gene: 6328ENSG00000153253UniProt: Q9NY46

Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with 24 transmembrane domains and one or more regulatory beta subunits. They are responsible for the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family, and is found in a cluster of five alpha subunit genes on chromosome 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 62MIM #617938
AD
Epilepsy, familial focal, with variable foci 4MIM #617935
AD
587
ClinVar variants
19
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— SCN3A
🧬
Gene-Disease Validity (ClinGen)
developmental and epileptic encephalopathy · 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
19 Pathogenic / Likely Pathogenic· 414 VUS of 587 total submissions

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.
0.17LOEUF
pLI 1.000
Z-score 7.63
OE 0.10 (0.06–0.17)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
4.62Z-score
OE missense 0.60 (0.56–0.64)
629 obs / 1050.1 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.10 (0.06–0.17)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.60 (0.56–0.64)
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.1.08
0≤1.21.6
LoF obs/exp: 8 / 83.1Missense obs/exp: 629 / 1050.1Syn Z: -1.24

ClinVar Variant Classifications

587 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11
Likely Pathogenic8
VUS414
Likely Benign127
Benign1
Conflicting26
11
Pathogenic
8
Likely Pathogenic
414
VUS
127
Likely Benign
1
Benign
26
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
10
0
11
Likely Pathogenic
1
6
1
0
8
VUS
18
363
27
6
414
Likely Benign
0
12
35
80
127
Benign
0
0
1
0
1
Conflicting
—26
Total193827486587

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

SCN3A · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

SCN3A-related focal epilepsy

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Developmental and epileptic encephalopathy 62

MIM #617938

Molecular basis of disorder known

Autosomal dominant

Epilepsy, familial focal, with variable foci 4

MIM #617935

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — SCN3A
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical exome sequencing: results from 2819 samples reflecting 1000 families.
Trujillano D et al.·Eur J Hum Genet
2017
Exome Sequencing and the Identification of New Genes and Shared Mechanisms in Polymicrogyria.
Akula SK et al.·JAMA Neurol
2023Functional
Biological concepts in human sodium channel epilepsies and their relevance in clinical practice.
Brunklaus A et al.·Epilepsia
2020
Targeted blockade of aberrant sodium current in a stem cell-derived neuron model of SCN3A encephalopathy.
Qu G et al.·Brain
2024Functional
SCN3A-related neurodevelopmental disorder: Clinical case reports and biophysical characterization.
Ghovanloo MR et al.·Channels (Austin)
2025Case report
Neurodevelopmental disorder associated with de novo SCN3A pathogenic variants: two new cases and review of the literature.
Inuzuka LM et al.·Brain Dev
2020Review
SCN1A mutations and epilepsy.
Mulley JC et al.·Hum Mutat
2005Review
SCN3A-Related Neurodevelopmental Disorder: A Spectrum of Epilepsy and Brain Malformation.
Zaman T et al.·Ann Neurol
2020
Clinical spectrum of SCN2A mutations.
Shi X et al.·Brain Dev
2012Review
Mutations in SCN3A cause early infantile epileptic encephalopathy.
Zaman T et al.·Ann Neurol
2018
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools