SCN10A

Chr 3

sodium voltage-gated channel alpha subunit 10

Also known as: FEPS2, Nav1.8, PN3, SNS

NCBI Gene: 6336 ENSG00000185313 UniProt: Q9Y5Y9

Encodes a tetrodotoxin-resistant voltage-gated sodium channel alpha subunit that mediates sodium ion permeability across excitable membranes and plays a role in neuropathic pain mechanisms. Mutations cause episodic pain syndrome, familial, type 2 with autosomal dominant inheritance. This gene is not constrained against loss-of-function variants (very low pLI score), suggesting complete loss of function may be tolerated.

ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a tetrodotoxin-resistant voltage-gated sodium channel alpha subunit. The properties of the channel formed by the encoded transmembrane protein can be altered by interaction with different beta subunits. This protein may be involved in the onset of pain associated with peripheral neuropathy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.01

Clinical Summary— SCN10A

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Gene-Disease Validity (ClinGen)

Brugada syndrome · ADDisputed

Disputed — evidence questions this relationship

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 382 VUS of 706 total submissions

Explore recent and relevant literature in Research Assistant →

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?

1.01LOEUF

pLI 0.000

Z-score 1.44

OE 0.82 (0.67–1.01)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.68Z-score

OE missense 1.06 (1.01–1.11)

1144 obs / 1080.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.82 (0.67–1.01)

0≤0.351.4

Missense OE?1.06 (1.01–1.11)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 65 / 78.8Missense obs/exp: 1144 / 1080.9Syn Z: -1.93

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedSCN10A-related Brugada syndromeOTHERAD

This gene — mechanism propensity

0.7227th %ile

GOF

0.80top 10%

LOF

0.2871th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFGain-of-function mutations in the voltage-gated sodium channels SCN9A, SCN10A and SCN11A have been identified as an underlying genetic cause in a subpopulation of patients with SFN.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 30316835 ↗

ClinVar Variant Classifications

706 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS382

Likely Benign257

Benign33

Conflicting31

Likely Pathogenic

382

VUS

257

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	1	0	0	1
VUS	30	332	15	5	382
Likely Benign	0	17	91	149	257
Benign	0	0	31	2	33
Conflicting	—				31
Total	30	350	137	156	704

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap SCN10A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →