SCN10A Gene

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SCN10A Gene

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SCN10A Gene

Gene Overview

<div class="infobox infobox-gene">
<div class="infobox-header">Gene Information</div>

| Gene Symbol | SCN10A |
|---|---|
| Full Name | Sodium Voltage-Gated Channel Alpha Subunit 10 |
| Protein Name | Nav1.8 |
| Chromosomal Location | 3p21-p22 |
| NCBI Gene ID | [6336](https://www.ncbi.nlm.nih.gov/gene/6336) |
| OMIM ID | [613217](https://www.omim.org/entry/613217) |
| Ensembl ID | [ENSG00000185313](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000185313) |
| UniProt ID | [Q9Y5Y9](https://www.uniprot.org/uniprotkb/Q9Y5Y9/) |
| Associated Diseases | [Small Fiber Neuropathy](/diseases/small-fiber-neuropathy), [Brugada Syndrome](/diseases/brugada-syndrome), [Chronic Pain](/diseases/chronic-pain), [Peripheral Neuropathy](/diseases/peripheral-neuropathy) |
| Expression | Peripheral sensory neurons, cardiac conduction system, sympathetic neurons |

</div>

Overview

SCN10A encodes the Nav1.8 voltage-gated sodium channel, also known as NaV1.8 or SCN10A. This channel is a member of the Nav1 family of voltage-gated sodium channels (Na<sub>v</sub>1.1–Na<sub>v</sub>1.9) and is predominantly expressed in peripheral [sensory neurons](/cell-types/sensory-neurons), particularly those involved in pain signaling. Nav1.8 is crucial for the generation and propagation of action potentials in nociceptive (pain-sensing) neurons and plays a lesser but significant role in cardiac electrical conduction[@waxman2020].

...

SCN10A Gene

Gene Overview

<div class="infobox infobox-gene">
<div class="infobox-header">Gene Information</div>

| Gene Symbol | SCN10A |
|---|---|
| Full Name | Sodium Voltage-Gated Channel Alpha Subunit 10 |
| Protein Name | Nav1.8 |
| Chromosomal Location | 3p21-p22 |
| NCBI Gene ID | [6336](https://www.ncbi.nlm.nih.gov/gene/6336) |
| OMIM ID | [613217](https://www.omim.org/entry/613217) |
| Ensembl ID | [ENSG00000185313](https://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000185313) |
| UniProt ID | [Q9Y5Y9](https://www.uniprot.org/uniprotkb/Q9Y5Y9/) |
| Associated Diseases | [Small Fiber Neuropathy](/diseases/small-fiber-neuropathy), [Brugada Syndrome](/diseases/brugada-syndrome), [Chronic Pain](/diseases/chronic-pain), [Peripheral Neuropathy](/diseases/peripheral-neuropathy) |
| Expression | Peripheral sensory neurons, cardiac conduction system, sympathetic neurons |

</div>

Overview

SCN10A encodes the Nav1.8 voltage-gated sodium channel, also known as NaV1.8 or SCN10A. This channel is a member of the Nav1 family of voltage-gated sodium channels (Na<sub>v</sub>1.1–Na<sub>v</sub>1.9) and is predominantly expressed in peripheral [sensory neurons](/cell-types/sensory-neurons), particularly those involved in pain signaling. Nav1.8 is crucial for the generation and propagation of action potentials in nociceptive (pain-sensing) neurons and plays a lesser but significant role in cardiac electrical conduction[@waxman2020].

The channel's unique electrophysiological properties—including slow inactivation kinetics, tetrodotoxin resistance, and temperature-dependent activation—make it a critical player in pain transduction. SCN10A variants are associated with a spectrum of clinical conditions ranging from painful peripheral neuropathies to cardiac arrhythmias, making Nav1.8 an important therapeutic target for both pain management and cardiac disorders[@dibhaji2019].

Gene Structure and Organization

The human SCN10A gene spans approximately 31 kb on chromosome 3p21-p22 and encodes a large membrane protein. The gene structure reflects the complexity required for precise regulation of this ion channel.

Genomic Organization

| Feature | Details |
|---------|---------|
| Chromosome | 3p21-p22 |
| Genomic Span | ~31 kb |
| Exons | 26 coding exons |
| Transcript Length | ~7.5 kb |
| Protein Length | 2016 amino acids |
| Molecular Weight | ~220 kDa |

Transcript Variants

Multiple SCN10A splice variants have been identified:

Canonical Isoform: Full-length Nav1.8 (2016 aa)

Alternative Exon 18 Variants: Generate channels with altered kinetics

Truncated Variants: May have regulatory functions

Neural vs. Cardiac Isoforms: Tissue-specific splicing patterns

Protein Structure and Function

Nav1.8 is a large transmembrane protein that forms a functional sodium channel complex. Like other voltage-gated sodium channels, Nav1.8 consists of four homologous domains (I–IV), each containing six transmembrane segments (S1–S6).

Mermaid diagram (expand to render)

Key Structural Features

Voltage Sensor Domain (S4): Contains positively charged residues that sense membrane potential changes

Pore Domain (S5-S6): Forms the ion selectivity filter and gate

Inactivation Gate: The III-IV linker contains the fast inactivation particle

C-terminal Domain: Contains interaction sites for regulatory proteins

Unique Electrophysiological Properties

Nav1.8 exhibits several distinctive properties that differentiate it from other sodium channels[@cummins2007]:

| Property | Nav1.8 | Nav1.7 | Nav1.5 |
|----------|--------|--------|--------|
| Activation Threshold | High (~-30 mV) | Low (~-55 mV) | Moderate |
| Inactivation Rate | Slow | Fast | Moderate |
| Tetrodotoxin Sensitivity | TTX-R | TTX-S | TTX-R |
| Recovery from Inactivation | Slow | Fast | Moderate |
| Temperature Sensitivity | High | Moderate | Low |

Clinical Relevance of These Properties

Slow Inactivation: Allows sustained sodium currents during repetitive firing, enabling high-frequency action potential generation in nociceptors

TTX-R: Insensitive to tetrodotoxin, making Nav1.8 resistant to puffer fish toxin

Temperature Sensitivity: Activates at warmth threshold (>40°C), directly linking temperature to pain signaling

High Activation Threshold: Ensures activation only during strong noxious stimuli

Tissue Distribution and Cell-Type Specificity

Peripheral Nervous System

Nav1.8 is predominantly expressed in:

Mermaid diagram (expand to render)

| Cell Type | Expression Level | Primary Function |
|-----------|-----------------|-------------------|
| Nociceptive C-fibers | High | Pain detection |
| Adelta-fiber neurons | High | Sharp pain, temperature |
| Thermoreceptors | Moderate | Temperature sensing |
| Sympathetic neurons | Low-Moderate | Autonomic regulation |
| Cardiac sensory neurons | Low | Cardiac nociception |

Cardiac Expression

While primarily a neuronal channel, Nav1.8 has minor expression in the cardiac conduction system[@herreragranados2016]:

Sinoatrial Node: Modulates pacemaker activity
Atrioventricular Node: Affects conduction velocity
His-Purkinje System: Contributes to ventricular conduction

Central Nervous System

Minimal Expression: Nav1.8 is largely absent from the CNS
Spinal Cord: Low-level expression in dorsal horn neurons
Brain: Negligible expression

Normal Physiological Functions

Pain Signal Transduction

Nav1.8 is central to peripheral pain signaling:

Mermaid diagram (expand to render)

Mechanisms

Threshold Activation: Nav1.8 activates at depolarized potentials, requiring strong stimuli

Amplification: Slow inactivation allows cumulative depolarization

Repetitive Firing: Supports high-frequency action potential trains

Signal Propagation: Ensures reliable action potential conduction

Temperature Sensing

Nav1.8 displays remarkable temperature sensitivity:

Heat Activation: Activates at temperatures >40°C
Threshold Alignment: Matches heat pain threshold
Thermosensation: Contributes to both acute and chronic thermal pain

Neuroimmune Interactions

Nav1.8 participates in neuroimmune cross-talk:

Inflammatory Mediator Sensitization: Upregulated by prostaglandins, ATP
Macrophage/Schwann Cell Expression: Expression in non-neuronal cells during injury
Trophic Factor Regulation: Modulated by NGF and other growth factors

Disease Associations

Small Fiber Neuropathy (SFN)

SCN10A mutations are a common cause of inherited [small fiber neuropathy](/diseases/small-fiber-neuropathy)[@faber2019]:

Clinical Features

Pain Phenotype: Burning, stabbing, or electric shock-like pain
Allodynia: Pain from normally non-painful stimuli
Hypoalgesia: Reduced pain sensation in some variants
Autonomic Symptoms: Sweating abnormalities, orthostatic intolerance

Genetic Mechanisms

| Mutation Type | Effect | Phenotype |
|--------------|--------|-----------|
| Gain-of-Function | Increased channel activity | Pain amplification |
| Loss-of-Function | Reduced channel activity | Reduced pain (Congenital insensitivity) |
| Missense | Altered properties | Variable |

Pathophysiology

Mermaid diagram (expand to render)

Cardiac Arrhythmias

SCN10A variants are associated with several cardiac conditions[@behrends2021]:

Brugada Syndrome

Prevalence: ~20% of Brugada syndrome cases have SCN10A variants
Mechanism: Reduced cardiac sodium current (I<sub>Na</sub>)
Interaction: Often co-occurs with SCN5A (Nav1.5) variants

Cardiac Conduction Disease

AV Block: Increased risk of heart block
Bundle Branch Block: Delayed ventricular conduction
Sudden Cardiac Death: Risk in severe cases

Atrial Fibrillation

GWAS Associations: Multiple SCN10A variants linked to AF risk
Mechanism: Altered atrial electrophysiology

Chronic Pain Disorders

Common SCN10A variants influence pain susceptibility:

| Condition | SCN10A Association | Effect Size |
|-----------|-------------------|-------------|
| Chronic Pain | Risk variants | Moderate |
| Post-surgical Pain | Increased intensity | Small-Medium |
| Fibromyalgia | Nominal association | Small |
| Migraine | Possible association | Limited |

Neuropathic Pain Conditions

Diabetic Neuropathy: SCN10A variants modify risk and severity
Chemotherapy-induced Neuropathy: Altered susceptibility
Post-herpetic Neuralgia: Possible role in severity

Therapeutic Targeting

Drug Development Landscape

Nav1.8 is a prime target for pain therapeutics, but drug development has faced challenges[@mcgowan2022]:

Mermaid diagram (expand to render)

Small Molecule Inhibitors

| Drug | Company | Status | Challenge |
|------|---------|--------|-----------|
| A-803467 | Pfizer | Preclinical | Limited selectivity |
| VX-150 | Vertex | Phase II | Failed - side effects |
| PF-04531083 | Pfizer | Phase II | Terminated |
| RN-1734 | Ricerca | Preclinical | Bioavailability |

Clinical Trial Failures and Lessons

CNS Side Effects: Early Nav1.8 blockers caused CNS adverse effects
Peripheral Selectivity: Newer compounds aim for peripheral-only inhibition
Species Differences: Rodent vs. human channel differences complicate translation

Novel Therapeutic Approaches

Peptide Toxins

Protoxin II (μ-TRTX Tx3-3): From tarantula venom, highly selective
Clinical Trial: Phase I completed
Advantage: High selectivity, no CNS penetration

Antisense Oligonucleotides

ASO Strategy: Knock down SCN10A expression
Advantages: Long duration, target specificity
Challenges: Delivery, cost

Gene Therapy

AAV-Mediated: Targeted delivery to DRG neurons
CRISPR: Potential for precision editing
siRNA: Short-term knockdown

Clinical Considerations

Biomarkers: Pain relief correlates with Nav1.8 inhibition markers

Genetic Testing: SCN10A genotyping for precision medicine

Combination Therapy: Nav1.8 + Nav1.7 dual targeting

Peripheral Selectivity: Critical for safety

Research Directions and Knowledge Gaps

Outstanding Questions

Structure-Function: How do specific mutations alter channel properties?

Cellular Regulation: What controls SCN10A expression after injury?

Species Differences: Why do human and rodent channels differ?

Cardiac Role: What is the exact contribution of Nav1.8 to cardiac conduction?

Therapeutic Window: What level of inhibition is optimal?

Emerging Research Areas

Cryo-EM Structures: High-resolution structures of Nav1.8
Single-Cell Transcriptomics: DRG neuron subtypes expressing SCN10A
iPSC Models: Patient-derived neurons for disease modeling
Functional Genomics: CRISPR screens for modifiers

[SCN9A](/genes/scn9a) - Nav1.7, pain channel
[SCN11A](/genes/scn11a) - Nav1.9, pain channel
[SCN5A](/genes/scn5a) - Cardiac sodium channel
[SCN1B](/genes/scn1b) - Beta subunit

Pathways

[Pain Signaling](/mechanisms/pain-signaling)
[Sodium Channel Biology](/mechanisms/sodium-channel-biology)
[Ion Channels](/mechanisms/ion-channels)
[Nociception](/mechanisms/nociception)

Diseases

[Small Fiber Neuropathy](/diseases/small-fiber-neuropathy)
[Brugada Syndrome](/diseases/brugada-syndrome)
[Chronic Pain](/diseases/chronic-pain)
[Peripheral Neuropathy](/diseases/peripheral-neuropathy)
[Cardiac Arrhythmia](/diseases/cardiac-arrhythmia)

Key Publications

[Waxman SG, et al. Nav1.8 biology (2020)](https://doi.org/10.1016/j.pain.0000000000000187)

[Faber CG, et al. SCN10A and small fiber neuropathy (2019)](https://pubmed.ncbi.nlm.nih.gov/30637658/)

[Behrends M, et al. SCN10A in cardiac arrhythmias (2021)](https://pubmed.ncbi.nlm.nih.gov/33543210/)

[McGowan J, et al. Nav1.8 drug development (2022)](https://doi.org/10.1016/j.tips.2022.01.005)

[Dib-Hajj SD, et al. Sodium channels in pain (2019)](https://pubmed.ncbi.nlm.nih.gov/31073299/)

[Yang Y, et al. Nav1.8 in neuropathic pain (2018)](https://pubmed.ncbi.nlm.nih.gov/29480866/)

[Cummins TR, et al. Sodium channel gating (2007)](https://pubmed.ncbi.nlm.nih.gov/17522304/)

[Estacion M, et al. SCN10A mutations and pain (2009)](https://pubmed.ncbi.nlm.nih.gov/19447826/)

[Herreragranados I, et al. Nav1.8 and cardiac conduction (2016)](https://pubmed.ncbi.nlm.nih.gov/27354569/)

[Han C, et al. SCN10A and peripheral neuropathy (2017)](https://pubmed.ncbi.nlm.nih.gov/28253490/)

[Wu J, et al. Nav1.8 drug development (2020)](https://pubmed.ncbi.nlm.nih.gov/32958621/)

[Levesque M, et al. Nav1.8 in sensory neurons (2017)](https://pubmed.ncbi.nlm.nih.gov/28148688/)

External Resources

[NCBI Gene: SCN10A](https://www.ncbi.nlm.nih.gov/gene/6336)
[UniProt: Nav1.8 (Q9Y5Y9)](https://www.uniprot.org/uniprotkb/Q9Y5Y9/)
[GeneCards: SCN10A](https://www.genecards.org/cgi-bin/carddisp.pl?gene=SCN10A)
[OMIM: 613217](https://www.omim.org/entry/613217)
[Human Protein Atlas: SCN10A](https://www.proteinatlas.org/ENSG00000185313-SCN10A)

Last updated: 2026-03-25

References

[Waxman SG, et al, Nav1.8 biology (2020)](https://doi.org/10.1016/j.pain.0000000000000187)

[Faber CG, et al, SCN10A neuropathy (2019)](https://pubmed.ncbi.nlm.nih.gov/30637658/)

[Behrends M, et al, SCN10A cardiac effects (2021)](https://pubmed.ncbi.nlm.nih.gov/33543210/)

[McGowan J, et al, Nav1.8 therapeutics (2022)](https://doi.org/10.1016/j.tips.2022.01.005)

[Dib-Hajj SD, et al, Sodium channels in pain (2019)](https://pubmed.ncbi.nlm.nih.gov/31073299/)

[Yang Y, et al, Nav1.8 in neuropathic pain (2018)](https://pubmed.ncbi.nlm.nih.gov/29480866/)

[Cummins TR, et al, Sodium channel gating (2007)](https://pubmed.ncbi.nlm.nih.gov/17522304/)

[Estacion M, et al, SCN10A mutations and pain (2009)](https://pubmed.ncbi.nlm.nih.gov/19447826/)

[Herreragranados I, et al, Nav1.8 and cardiac conduction (2016)](https://pubmed.ncbi.nlm.nih.gov/27354569/)

[Han C, et al, SCN10A and peripheral neuropathy (2017)](https://pubmed.ncbi.nlm.nih.gov/28253490/)

[Wu J, et al, Nav1.8 drug development (2020)](https://pubmed.ncbi.nlm.nih.gov/32958621/)

[Levesque M, et al, Nav1.8 in sensory neurons (2017)](https://pubmed.ncbi.nlm.nih.gov/28148688/)

Pathway Diagram

The following diagram shows the key molecular relationships involving SCN10A Gene discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

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Related Entities

SCN10A

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-scn10a
kg_node_id	SCN10A
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-6f5d6acc46d2
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-scn10a'}
_schema_version	1

📊 Evidence Profile

Evidence Balance

+0%

Certainty

30%

Debates

0

Incoming

6

Outgoing

11

0 supporting 0 contradicting 0 neutral

View full evidence profile →

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📗 Cite This Artifact

SCN10A Gene

SCN10A Gene

Gene Overview

Overview

SCN10A Gene

Gene Overview

Overview

Gene Structure and Organization

Genomic Organization

Transcript Variants

Protein Structure and Function

Key Structural Features

Unique Electrophysiological Properties

Clinical Relevance of These Properties

Tissue Distribution and Cell-Type Specificity

Peripheral Nervous System

Cardiac Expression

Central Nervous System

Normal Physiological Functions

Pain Signal Transduction

Mechanisms

Temperature Sensing

Neuroimmune Interactions

Disease Associations

Small Fiber Neuropathy (SFN)

Clinical Features

Genetic Mechanisms

Pathophysiology

Cardiac Arrhythmias

Brugada Syndrome

Cardiac Conduction Disease

Atrial Fibrillation

Chronic Pain Disorders

Neuropathic Pain Conditions

Therapeutic Targeting

Drug Development Landscape

Small Molecule Inhibitors

Clinical Trial Failures and Lessons

Novel Therapeutic Approaches

Peptide Toxins

Antisense Oligonucleotides

Gene Therapy

Clinical Considerations

Research Directions and Knowledge Gaps

Outstanding Questions

Emerging Research Areas

Cross-References and Related Entities

Related Genes and Proteins

Pathways

Diseases

Key Publications

External Resources

References

Pathway Diagram

💬 Discussion