SCN11A

Chr 3

sodium voltage-gated channel alpha subunit 11

Also known as: FEPS3, HSAN7, NAV1.9, NaN, PN5, SCN12A, SNS-2

NCBI Gene: 11280 ENSG00000168356 UniProt: Q9UI33

The protein forms voltage-gated sodium channels that mediate sodium ion permeability in excitable membranes and is highly expressed in nociceptive neurons where it transmits pain signals from the periphery to the central nervous system. Mutations cause familial episodic pain syndrome-3 and hereditary sensory and autonomic neuropathy type VII with autosomal dominant inheritance. The gene shows minimal constraint against loss-of-function variants (very low pLI score), suggesting the associated phenotypes may involve other mutational mechanisms.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

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 highly expressed in nociceptive neurons of dorsal root ganglia and trigeminal ganglia. It mediates brain-derived neurotrophic factor-evoked membrane depolarization and is a major effector of peripheral inflammatory pain hypersensitivity. Mutations in this gene have been associated with hereditary sensory and autonomic neuropathy type VII and familial episodic pain syndrome-3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2017]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtNeuropathy, hereditary sensory and autonomic, 7

UniProtEpisodic pain syndrome, familial, 3

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · hereditary sensory and autonomic neuropathy type 7 · AD · ClinGen 2026

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.83

LOEUF

GOF*

Mechanism· G2P

📖

GeneReview available — SCN11A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.83LOEUF

pLI 0.000

Z-score 2.84

OE 0.66 (0.53–0.83)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.96Z-score

OE missense 0.91 (0.86–0.96)

881 obs / 965.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.66 (0.53–0.83)

0≤0.351.4

Missense OE?0.91 (0.86–0.96)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 53 / 80.5Missense obs/exp: 881 / 965.3Syn Z: -0.25

Background carrier burden — how many people carry a rare variant somewhere in SCN11A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 28

2,148 rare PASS variants

Rare truncating (LoF)

1 in 380

310 rare PASS variants

Rare synonymous (reference)

1 in 68

812 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SCN11A. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 38	1 in 360
South Asian	~43k	1 in 30	1 in 560
Remaining (unassigned)	~30k	1 in 26	1 in 560
European (Finnish)	~27k	1 in 150	1 in 530
Admixed American	~22k	1 in 27	1 in 200
African / African American	~21k	1 in 30	1 in 620
East Asian	~20k	1 in 38	1 in 770
Ashkenazi Jewish	~13k	1 in 99	1 in 1,600
Middle Eastern	~2,884	1 in 32	≈ 1 in 960

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 20 of 26 coding exons well covered in gnomAD exomes; exons 9, 11, 20, 21, 24, 28 marginal. Genomes: all 26.? see exons ↓