Menu
GeneBe

SCN9A

sodium voltage-gated channel alpha subunit 9, the group of Sodium voltage-gated channel alpha subunits

Basic information

Region (hg38): 2:166195184-166376001

Links

ENSG00000169432NCBI:6335OMIM:603415HGNC:10597Uniprot:Q15858AlphaFoldGenCCjaxSfariGnomADPubmedClinVar

Phenotypes

GenCC

Source: genCC

  • channelopathy-associated congenital insensitivity to pain, autosomal recessive (Strong), mode of inheritance: AR
  • hereditary sensory and autonomic neuropathy type 2 (Supportive), mode of inheritance: AR
  • paroxysmal extreme pain disorder (Supportive), mode of inheritance: AD
  • channelopathy-associated congenital insensitivity to pain, autosomal recessive (Supportive), mode of inheritance: AD
  • primary erythermalgia (Supportive), mode of inheritance: AD
  • sodium channelopathy-related small fiber neuropathy (Supportive), mode of inheritance: AD
  • channelopathy-associated congenital insensitivity to pain, autosomal recessive (Strong), mode of inheritance: AR
  • epilepsy (Refuted Evidence), mode of inheritance: AD
  • primary erythermalgia (Definitive), mode of inheritance: AD
  • generalized epilepsy with febrile seizures plus, type 7 (Strong), mode of inheritance: AD
  • paroxysmal extreme pain disorder (Strong), mode of inheritance: AD
  • primary erythermalgia (Strong), mode of inheritance: AD
  • generalized epilepsy with febrile seizures plus, type 7 (Limited), mode of inheritance: AD
  • channelopathy-associated congenital insensitivity to pain, autosomal recessive (Limited), mode of inheritance: Semidominant
  • epilepsy (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Paroxysmal extreme pain disorderAD/ARNeurologicIn Primary erythermalgia, medical treatment (with specific sodium channel blocking agents such as XEN402) has been reported as beneficial; Individuals with Paroxysmal extreme pain disorder have been reported as responding to medical therapy (eg, carbamazepine) in terms of clinical manifestations (attacks of pain) as well as psychomotor development in someDermatologic; Neurologic13636703; 4111621; 4112340; 1536168; 10724194; 14985375; 15958509; 16216943; 17167479; 17145499; 17679678; 17470132; 19304393; 19763161; 21441906; 21698661; 22035805; 23596073; 24817410
Many treatments have been attempted (with inconsistent success) in Erythermalgia, primary, and some have been described by patients as providing subjective relief from symptoms; Indifference to pain, congenital, can result in injuries, some of which may in theory be preventable with early diagnosis and preventive measures

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SCN9A gene.

  • Neuropathy, hereditary sensory and autonomic, type 2A;Generalized epilepsy with febrile seizures plus, type 7 (964 variants)
  • Generalized epilepsy with febrile seizures plus, type 7;Neuropathy, hereditary sensory and autonomic, type 2A (925 variants)
  • not provided (336 variants)
  • Inborn genetic diseases (310 variants)
  • Paroxysmal extreme pain disorder (219 variants)
  • Primary erythromelalgia (204 variants)
  • Channelopathy-associated congenital insensitivity to pain, autosomal recessive (203 variants)
  • not specified (111 variants)
  • Small fiber neuropathy (97 variants)
  • Inherited Erythromelalgia (85 variants)
  • Generalized epilepsy with febrile seizures plus, type 7 (26 variants)
  • Congenital Indifference to Pain (24 variants)
  • Severe myoclonic epilepsy in infancy (17 variants)
  • Generalized epilepsy with febrile seizures plus (15 variants)
  • Neuropathy, hereditary sensory and autonomic, type 2A (14 variants)
  • Febrile seizures, familial (14 variants)
  • 6 conditions (13 variants)
  • Primary erythromelalgia;Neuropathy, hereditary sensory and autonomic, type 2A;Paroxysmal extreme pain disorder;Channelopathy-associated congenital insensitivity to pain, autosomal recessive (7 variants)
  • Childhood epilepsy with centrotemporal spikes (5 variants)
  • Seizure (4 variants)
  • SCN9A-related condition (4 variants)
  • Neuropathy, hereditary sensory and autonomic, type 2A;Paroxysmal extreme pain disorder;Channelopathy-associated congenital insensitivity to pain, autosomal recessive;Primary erythromelalgia (3 variants)
  • Primary erythromelalgia;Paroxysmal extreme pain disorder;Channelopathy-associated congenital insensitivity to pain, autosomal recessive (2 variants)
  • Pain insensitivity (2 variants)
  • Neuropathy, hereditary sensory and autonomic, type 2A;Paroxysmal extreme pain disorder;Primary erythromelalgia;Channelopathy-associated congenital insensitivity to pain, autosomal recessive (2 variants)
  • Neuropathy, hereditary sensory and autonomic, type 2A;Paroxysmal extreme pain disorder;Primary erythromelalgia;Channelopathy-associated congenital insensitivity to pain, autosomal recessive;Generalized epilepsy with febrile seizures plus (1 variants)
  • Primary erythromelalgia;Channelopathy-associated congenital insensitivity to pain, autosomal recessive;Neuropathy, hereditary sensory and autonomic, type 2A;Paroxysmal extreme pain disorder (1 variants)
  • Primary erythromelalgia;Neuropathy, hereditary sensory and autonomic, type 2A;Paroxysmal extreme pain disorder;Generalized epilepsy with febrile seizures plus (1 variants)
  • See cases (1 variants)
  • SCN9A-related disorders (1 variants)
  • Abnormality of pain sensation;Acute episodes of neuropathic symptoms (1 variants)
  • Primary erythromelalgia;Generalized epilepsy with febrile seizures plus, type 7;Severe myoclonic epilepsy in infancy (1 variants)
  • Channelopathy-associated congenital insensitivity to pain, autosomal recessive;Neuropathy, hereditary sensory and autonomic, type 2A;Paroxysmal extreme pain disorder;Primary erythromelalgia (1 variants)
  • Febrile seizures, familial, 3b (1 variants)
  • Global developmental delay;Seizure;Hypoglycemia (1 variants)
  • Generalized non-motor (absence) seizure;Abnormal brainstem MRI signal intensity (1 variants)
  • Febrile seizures, familial, 1 (1 variants)
  • Paroxysmal extreme pain disorder;Neuropathy, hereditary sensory and autonomic, type 2A;Channelopathy-associated congenital insensitivity to pain, autosomal recessive;Primary erythromelalgia (1 variants)
  • Neuropathy, hereditary sensory and autonomic, type 2A;Primary erythromelalgia;Paroxysmal extreme pain disorder;Channelopathy-associated congenital insensitivity to pain, autosomal recessive (1 variants)
  • Generalized epilepsy with febrile seizures plus;Primary erythromelalgia;Neuropathy, hereditary sensory and autonomic, type 2A;Paroxysmal extreme pain disorder;Channelopathy-associated congenital insensitivity to pain, autosomal recessive (1 variants)
  • Severe myoclonic epilepsy in infancy;Channelopathy-associated congenital insensitivity to pain, autosomal recessive;Primary erythromelalgia;Generalized epilepsy with febrile seizures plus, type 7;Paroxysmal extreme pain disorder (1 variants)
  • Epilepsy (1 variants)
  • Primary erythromelalgia;Generalized epilepsy with febrile seizures plus;Neuropathy, hereditary sensory and autonomic, type 2A;Paroxysmal extreme pain disorder;Channelopathy-associated congenital insensitivity to pain, autosomal recessive (1 variants)
  • Neuropathy, hereditary sensory and autonomic, type 2A;Paroxysmal extreme pain disorder;Primary erythromelalgia;Generalized epilepsy with febrile seizures plus, type 7;Channelopathy-associated congenital insensitivity to pain, autosomal recessive (1 variants)
  • Channelopathy-associated congenital insensitivity to pain, autosomal recessive;Paroxysmal extreme pain disorder;Primary erythromelalgia (1 variants)
  • Primary erythromelalgia;Paroxysmal extreme pain disorder;Neuropathy, hereditary sensory and autonomic, type 2A;Channelopathy-associated congenital insensitivity to pain, autosomal recessive (1 variants)
  • Channelopathy-associated congenital insensitivity to pain, autosomal recessive;Primary erythromelalgia;Neuropathy, hereditary sensory and autonomic, type 2A;Paroxysmal extreme pain disorder (1 variants)
  • Charcot-Marie-Tooth disease (1 variants)
  • Channelopathy-associated congenital insensitivity to pain, autosomal recessive;Primary erythromelalgia;Paroxysmal extreme pain disorder (1 variants)
  • Primary erythromelalgia;Neuropathy, hereditary sensory and autonomic, type 2A;Paroxysmal extreme pain disorder;Channelopathy-associated congenital insensitivity to pain, autosomal recessive;Generalized epilepsy with febrile seizures plus (1 variants)
  • Generalized epilepsy with febrile seizures plus, type 7;Severe myoclonic epilepsy in infancy;Primary erythromelalgia;Paroxysmal extreme pain disorder;Channelopathy-associated congenital insensitivity to pain, autosomal recessive (1 variants)
  • Autism spectrum disorder (1 variants)
  • SCN9A-related peripheral neuropathies associated with increased pain (1 variants)
  • Severe myoclonic epilepsy in infancy;Generalized epilepsy with febrile seizures plus, type 7;Primary erythromelalgia;Paroxysmal extreme pain disorder;Channelopathy-associated congenital insensitivity to pain, autosomal recessive (1 variants)
  • Channelopathy-associated congenital insensitivity to pain, autosomal recessive;Primary erythromelalgia;Paroxysmal extreme pain disorder;Neuropathy, hereditary sensory and autonomic, type 2A (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SCN9A gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type Pathogenic Likely pathogenic VUS Likely benign Benign Sum
synonymous
12
clinvar
384
clinvar
12
clinvar
408
missense
9
clinvar
11
clinvar
1131
clinvar
30
clinvar
2
clinvar
1183
nonsense
28
clinvar
6
clinvar
5
clinvar
39
start loss
0
frameshift
36
clinvar
7
clinvar
8
clinvar
51
inframe indel
1
clinvar
17
clinvar
18
splice donor/acceptor (+/-2bp)
4
clinvar
17
clinvar
1
clinvar
22
splice region
42
43
5
90
non coding
44
clinvar
130
clinvar
35
clinvar
209
Total 77 42 1218 544 49

Highest pathogenic variant AF is 0.0000263

Variants in SCN9A

This is a list of pathogenic ClinVar variants found in the SCN9A region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position Type Phenotype Significance ClinVar
2-166195246-T-A Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Paroxysmal extreme pain disorder • Primary erythromelalgia • Inherited Erythromelalgia Conflicting classifications of pathogenicity (Jan 13, 2018)331895
2-166195355-T-C Paroxysmal extreme pain disorder • Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Inherited Erythromelalgia • Primary erythromelalgia Benign/Likely benign (Jan 13, 2018)331896
2-166195390-T-G Small fiber neuropathy • Primary erythromelalgia • Paroxysmal extreme pain disorder • Channelopathy-associated congenital insensitivity to pain, autosomal recessive Uncertain significance (Jan 12, 2018)331897
2-166195468-C-T Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Primary erythromelalgia • Paroxysmal extreme pain disorder Uncertain significance (Jan 13, 2018)894401
2-166195470-A-G Primary erythromelalgia • Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Paroxysmal extreme pain disorder Uncertain significance (Jan 12, 2018)892954
2-166195570-G-A Paroxysmal extreme pain disorder • Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Inherited Erythromelalgia • Primary erythromelalgia Conflicting classifications of pathogenicity (Jan 13, 2018)331898
2-166195578-T-C Primary erythromelalgia • Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Paroxysmal extreme pain disorder Uncertain significance (Mar 30, 2018)892955
2-166195619-C-T Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Primary erythromelalgia • Paroxysmal extreme pain disorder Uncertain significance (Jan 13, 2018)893181
2-166195634-G-A Primary erythromelalgia • Paroxysmal extreme pain disorder • Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Inherited Erythromelalgia Benign/Likely benign (Jan 12, 2018)331899
2-166195686-A-C Primary erythromelalgia • Paroxysmal extreme pain disorder • Inherited Erythromelalgia • Channelopathy-associated congenital insensitivity to pain, autosomal recessive Uncertain significance (Jan 13, 2018)331900
2-166195727-G-T Paroxysmal extreme pain disorder • Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Primary erythromelalgia Uncertain significance (Jan 13, 2018)894028
2-166195744-C-T Paroxysmal extreme pain disorder • Inherited Erythromelalgia • Primary erythromelalgia • Channelopathy-associated congenital insensitivity to pain, autosomal recessive Uncertain significance (Jan 13, 2018)331901
2-166195812-G-A Small fiber neuropathy • Paroxysmal extreme pain disorder • Primary erythromelalgia • Channelopathy-associated congenital insensitivity to pain, autosomal recessive Uncertain significance (Jan 13, 2018)331902
2-166195818-A-G Paroxysmal extreme pain disorder • Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Inherited Erythromelalgia • Primary erythromelalgia Benign (Jan 12, 2018)331903
2-166195927-AG-A Small fiber neuropathy • Febrile seizures, familial • Congenital Indifference to Pain • Paroxysmal extreme pain disorder • Inherited Erythromelalgia • Generalized epilepsy with febrile seizures plus • Severe myoclonic epilepsy in infancy Uncertain significance (Jun 14, 2016)331904
2-166195943-G-T Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Paroxysmal extreme pain disorder • Primary erythromelalgia Uncertain significance (Jan 13, 2018)892995
2-166195951-G-C Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Paroxysmal extreme pain disorder • Primary erythromelalgia • Small fiber neuropathy Benign/Likely benign (Jan 13, 2018)331905
2-166195995-A-G Paroxysmal extreme pain disorder • Primary erythromelalgia • Channelopathy-associated congenital insensitivity to pain, autosomal recessive Uncertain significance (Jan 13, 2018)892996
2-166196010-C-T Paroxysmal extreme pain disorder • Inherited Erythromelalgia • Primary erythromelalgia • Channelopathy-associated congenital insensitivity to pain, autosomal recessive Benign/Likely benign (Jan 13, 2018)331906
2-166196032-C-T Small fiber neuropathy • Paroxysmal extreme pain disorder • Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Primary erythromelalgia Benign (Jan 13, 2018)331907
2-166196045-CTTAAAAAAGTT-C Severe myoclonic epilepsy in infancy • Generalized epilepsy with febrile seizures plus • Febrile seizures, familial • Paroxysmal extreme pain disorder • Small fiber neuropathy • Inherited Erythromelalgia • Congenital Indifference to Pain Benign (Jun 14, 2016)331908
2-166196132-G-A Primary erythromelalgia • Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Small fiber neuropathy • Paroxysmal extreme pain disorder Benign (Jan 13, 2018)331909
2-166196328-G-A Inherited Erythromelalgia • Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Primary erythromelalgia • Paroxysmal extreme pain disorder Conflicting classifications of pathogenicity (Jan 13, 2018)331910
2-166196349-C-A Primary erythromelalgia • Small fiber neuropathy • Channelopathy-associated congenital insensitivity to pain, autosomal recessive • Paroxysmal extreme pain disorder Benign/Likely benign (Jan 13, 2018)331911
2-166196360-T-A Paroxysmal extreme pain disorder • Inherited Erythromelalgia • Primary erythromelalgia • Channelopathy-associated congenital insensitivity to pain, autosomal recessive Benign/Likely benign (Jan 12, 2018)331912

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
SCN9Aprotein_codingprotein_codingENST00000409672 26180809
pLI Probability
LOF Intolerant
pRec Probability
LOF Recessive
Individuals with
no LOFs
Individuals with
Homozygous LOFs
Individuals with
Heterozygous LOFs
Defined p
4.75e-191.0012563501131257480.000449
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense1.069131.01e+30.9060.000052413101
Missense in Polyphen343453.440.756436036
Synonymous-1.083773511.070.00001833627
Loss of Function3.704378.30.5490.000004241050

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.001490.00146
Ashkenazi Jewish0.00009920.0000992
East Asian0.001540.00152
Finnish0.00004630.0000462
European (Non-Finnish)0.0003710.000360
Middle Eastern0.001540.00152
South Asian0.0002020.000196
Other0.0003320.000163

dbNSFP

Source: dbNSFP

Function
FUNCTION: 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:7720699, PubMed:17167479, PubMed:25240195, PubMed:26680203, PubMed:15385606, PubMed:16988069, PubMed:17145499, PubMed:19369487, PubMed:24311784). It is a tetrodotoxin-sensitive Na(+) channel isoform (PubMed:7720699). Plays a role in pain mechanisms, especially in the development of inflammatory pain (PubMed:17167479, PubMed:17145499, PubMed:19369487, PubMed:24311784). {ECO:0000269|PubMed:15178348, ECO:0000269|PubMed:15385606, ECO:0000269|PubMed:16988069, ECO:0000269|PubMed:17145499, ECO:0000269|PubMed:17167479, ECO:0000269|PubMed:19369487, ECO:0000269|PubMed:24311784, ECO:0000269|PubMed:25240195, ECO:0000269|PubMed:26680203, ECO:0000269|PubMed:7720699}.;
Disease
DISEASE: Primary erythermalgia (PERYTHM) [MIM:133020]: Autosomal dominant disease characterized by recurrent episodes of severe pain associated with redness and warmth in the feet or hands. {ECO:0000269|PubMed:14985375, ECO:0000269|PubMed:15385606, ECO:0000269|PubMed:15955112, ECO:0000269|PubMed:15958509, ECO:0000269|PubMed:16216943, ECO:0000269|PubMed:16392115, ECO:0000269|PubMed:16702558, ECO:0000269|PubMed:16988069, ECO:0000269|PubMed:18945915, ECO:0000269|PubMed:19369487, ECO:0000269|PubMed:24311784}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Indifference to pain, congenital, autosomal recessive (CIP) [MIM:243000]: A disorder characterized by congenital inability to perceive any form of pain, in any part of the body. All other sensory modalities are preserved and the peripheral and central nervous systems are apparently intact. Patients perceive the sensations of touch, warm and cold temperature, proprioception, tickle and pressure, but not painful stimuli. There is no evidence of a motor or sensory neuropathy, either axonal or demyelinating. {ECO:0000269|PubMed:20635406}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Paroxysmal extreme pain disorder (PEPD) [MIM:167400]: Autosomal dominant paroxysmal disorder of pain and autonomic dysfunction. The distinctive features are paroxysmal episodes of burning pain in the rectal, ocular, and mandibular areas accompanied by autonomic manifestations such as skin flushing. {ECO:0000269|PubMed:17145499, ECO:0000269|PubMed:18945915, ECO:0000269|PubMed:25285947}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Generalized epilepsy with febrile seizures plus 7 (GEFS+7) [MIM:613863]: A rare autosomal dominant, familial condition with incomplete penetrance and large intrafamilial variability. Patients display febrile seizures persisting sometimes beyond the age of 6 years and/or a variety of afebrile seizure types. This disease combines febrile seizures, generalized seizures often precipitated by fever at age 6 years or more, and partial seizures, with a variable degree of severity. {ECO:0000269|PubMed:19763161}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Febrile seizures, familial, 3B (FEB3B) [MIM:613863]: Seizures associated with febrile episodes in childhood without any evidence of intracranial infection or defined pathologic or traumatic cause. It is a common condition, affecting 2-5% of children aged 3 months to 5 years. The majority are simple febrile seizures (generally defined as generalized onset, single seizures with a duration of less than 30 minutes). Complex febrile seizures are characterized by focal onset, duration greater than 30 minutes, and/or more than one seizure in a 24 hour period. The likelihood of developing epilepsy following simple febrile seizures is low. Complex febrile seizures are associated with a moderately increased incidence of epilepsy. {ECO:0000269|PubMed:19763161}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Pathway
Taste transduction - Homo sapiens (human);Developmental Biology;Phase 0 - rapid depolarisation;Cardiac conduction;Muscle contraction;Interaction between L1 and Ankyrins;L1CAM interactions;Axon guidance (Consensus)

Recessive Scores

pRec
0.199

Intolerance Scores

loftool
0.0121
rvis_EVS
0.33
rvis_percentile_EVS
73.63

Haploinsufficiency Scores

pHI
0.324
hipred
N
hipred_score
0.422
ghis
0.464

Essentials

essential_gene_CRISPR
N
essential_gene_CRISPR2
N
essential_gene_gene_trap
N
gene_indispensability_pred
N
gene_indispensability_score
0.179

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumHigh
CancerMediumMediumMedium

Mouse Genome Informatics

Gene name
Scn9a
Phenotype
immune system phenotype; renal/urinary system phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; taste/olfaction phenotype;

Gene ontology

Biological process
sodium ion transport;inflammatory response;response to toxic substance;post-embryonic development;neuronal action potential;sensory perception of pain;regulation of ion transmembrane transport;sodium ion transmembrane transport;behavioral response to pain;membrane depolarization during action potential
Cellular component
voltage-gated sodium channel complex;plasma membrane;integral component of plasma membrane;axon
Molecular function
voltage-gated ion channel activity;voltage-gated sodium channel activity;sodium ion binding