SCN2A

Chr 2

sodium voltage-gated channel alpha subunit 2

ENSG00000136531UniProt: Q99250

Mediates the voltage-dependent sodium ion permeability of excitable membranes. Assuming opened or closed conformations in response to the voltage difference across the membrane, the protein forms a sodium-selective channel through which Na(+) ions may pass in accordance with their electrochemical gradient (PubMed:1325650, PubMed:17021166, PubMed:28256214, PubMed:29844171). Implicated in the regulation of hippocampal replay occurring within sharp wave ripples (SPW-R) important for memory (By similarity)

Primary Disease Associations & Inheritance

UniProtSeizures, benign familial infantile, 3
UniProtDevelopmental and epileptic encephalopathy 11
UniProtEpisodic ataxia 9
0
ClinVar variants
0
Pathogenic / LP
1.00
pLI score· haploinsufficient
2
Active trials
Clinical Summary— SCN2A
⚡
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.
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (3)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

clinvarCount: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

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 7.92
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.
6.46Z-score
OE missense 0.44 (0.41–0.48)
469 obs / 1061.0 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.0.44 (0.41–0.48)
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.1.01
0≤1.21.6
LoF obs/exp: 5 / 82.7Missense obs/exp: 469 / 1061.0Syn Z: -0.13

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

SCN2A · protein map & ClinVar variants

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

Gene2Phenotype Curations

SCN2A-related nonspecific severe intellectual disability

definitive
ADLoss Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variant

SCN2A-related infantile epileptic encephalopathy

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

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Autism-related phenotypes in a heterozygous Scn2aR854Q mouse model and their partial rescue via a potassium channel opener.
Ismail H et al.·Neuropharmacology
2026Functional
Human microglia in brain assembloids display region-specific diversity and respond to hyperexcitable neurons carrying SCN2A mutation.
Wu J et al.·Sci Adv
2026🔓 Open Access
Mechanisms of SCN2A loss of function do not predict presence or phenotype of epilepsy.
Tan M et al.·Epilepsia
2026Functional
Case Report: Prenatal imaging and genetic integrated diagnosis of SCN2A encephalopathy-a case of cryptical cortical dysplasia caused by a loss-of-function frameshift genetic variant.
Zhu L et al.·Front Neurosci
2026🔓 Open AccessCase report
Functional Characterization of a De Novo SCN2A Mixed Variant Linked to Early Infantile Developmental and Epileptic Encephalopathy.
Corradi A et al.·Neurol Genet
2026🔓 Open AccessFunctional
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
16P11.2 Deletion Syndrome16p11.2 Duplications1Q21.1 Deletion

Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight

RECRUITING
NCT01238250Simons SearchlightStarted 2010-10
High-riskBipolar DisorderAtypical Depression

A Cohort Study of Disease Prediction Model for High-risk Population With Bipolar Disorder

RECRUITING
NCT07031661Shanghai Mental Health CenterStarted 2024-10-15
This was an observational study with no intervention.

External Resources

Links to major genomics databases and tools