SCN11A

Summary

SCN11A (sodium voltage-gated channel alpha subunit 11, HGNC:10583) is a protein-coding gene on chromosome 3p22.2, encoding Sodium channel protein type 11 subunit alpha (Q9UI33). Sodium channel mediating the voltage-dependent sodium ion permeability of excitable membranes.

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.

Source: NCBI Gene 11280 — RefSeq curated summary.

At a glance

• Gene–disease (curated): obsolete autosomal dominant hereditary sensory and autonomic neuropathy (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 1,644 total — 4 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 27
• Druggable target: yes — 15 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001349253

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10583
Approved symbol	SCN11A
Name	sodium voltage-gated channel alpha subunit 11
Location	3p22.2
Locus type	gene with protein product
Status	Approved
Aliases	Nav1.9, NaN, SNS-2
Ensembl gene	ENSG00000168356
Ensembl biotype	protein_coding
OMIM	604385
Entrez	11280

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 6 protein_coding, 3 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 2 retained_intron

ENST00000302328, ENST00000444237, ENST00000456224, ENST00000665106, ENST00000668754, ENST00000674755, ENST00000674979, ENST00000675223, ENST00000675269, ENST00000675672, ENST00000675892, ENST00000676045, ENST00000676176, ENST00000676333

RefSeq mRNA: 2 — MANE Select: NM_001349253 NM_001349253, NM_014139

CCDS: CCDS33737

Canonical transcript exons

ENST00000302328 — 30 exons

Exon	Start	End
ENSE00001138454	38850481	38850751
ENSE00001138487	38871445	38871708
ENSE00001138499	38872193	38872294
ENSE00001138508	38879950	38880123
ENSE00001138515	38883233	38883387
ENSE00001138525	38885288	38885402
ENSE00001138533	38886125	38886238
ENSE00001138541	38894533	38894964
ENSE00001138549	38896845	38897225
ENSE00001138559	38899894	38900073
ENSE00001138570	38903865	38904103
ENSE00001138582	38905192	38905321
ENSE00001138592	38907949	38908122
ENSE00001138604	38908997	38909194
ENSE00001138612	38910066	38910207
ENSE00001138623	38919935	38920001
ENSE00001138634	38921076	38921255
ENSE00001138641	38925415	38925509
ENSE00001150355	38926803	38926931
ENSE00001506717	38867321	38867458
ENSE00001506718	38945411	38945512
ENSE00001506721	38946789	38946907
ENSE00001594956	38870691	38870744
ENSE00001793257	38863195	38863299
ENSE00003864173	38845764	38847742
ENSE00003866488	38953629	38953759
ENSE00003872912	39032380	39032503
ENSE00003878121	38960283	38960423
ENSE00003903126	38950096	38950369
ENSE00003904106	39051861	39051944

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 89.03.

FANTOM5 (CAGE): breadth broad, TPM avg 0.5989 / max 27.0525, expressed in 293 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
41720	0.4730	248
41721	0.0948	40
41719	0.0312	19

Top tissues by expression

276 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	89.03	gold quality
dorsal root ganglion	UBERON:0000044	85.66	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.17	gold quality
trigeminal ganglion	UBERON:0001675	78.47	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	74.19	gold quality
left testis	UBERON:0004533	70.15	gold quality
right testis	UBERON:0004534	69.73	gold quality
testis	UBERON:0000473	69.11	gold quality
sural nerve	UBERON:0015488	65.91	gold quality
spleen	UBERON:0002106	65.62	gold quality
colonic epithelium	UBERON:0000397	64.36	silver quality
ventricular zone	UBERON:0003053	59.29	gold quality
rectum	UBERON:0001052	58.95	gold quality
placenta	UBERON:0001987	58.54	gold quality
urinary bladder	UBERON:0001255	57.71	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	57.47	gold quality
muscle layer of sigmoid colon	UBERON:0035805	56.88	gold quality
bone marrow cell	CL:0002092	56.47	silver quality
ganglionic eminence	UBERON:0004023	56.39	gold quality
spinal cord	UBERON:0002240	55.88	gold quality
lower lobe of lung	UBERON:0008949	55.85	silver quality
prefrontal cortex	UBERON:0000451	55.55	gold quality
amygdala	UBERON:0001876	55.45	gold quality
cranial nerve II	UBERON:0000941	55.43	gold quality
tibialis anterior	UBERON:0001385	55.16	silver quality
right uterine tube	UBERON:0001302	55.15	gold quality
nucleus accumbens	UBERON:0001882	54.83	gold quality
omental fat pad	UBERON:0010414	54.70	gold quality
subcutaneous adipose tissue	UBERON:0002190	54.68	gold quality
peritoneum	UBERON:0002358	54.66	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.65

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, ESR2, IL10, TNF

miRNA regulators (miRDB)

66 targeting SCN11A, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-5696	99.98	72.36	4487
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-4458	99.96	71.64	1650
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-202-3P	99.84	71.41	1290
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085

Literature-anchored findings (GeneRIF, showing 26)

• we demonstrate that the tetrodotoxin-insensitive sodium channel Na(V)1.9 underlies the neurotrophin-evoked excitation (PMID:12384689)
• Results provide evidence that Nav1.9 plays a crucial role in the generation of heat and mechanical pain hypersensitivity, both in subacute and chronic inflammatory pain models. (PMID:21857998)
• we identified a specific de novo missense mutation in SCN11A in individuals with the congenital inability to experience pain who suffer from recurrent tissue damage and severe mutilations. (PMID:24036948)
• The results demonstrate that Nav1.8 and Nav1.9 are present in human lingual nerve neuromas, with significant correlations between the level of expression of Nav1.8 and symptoms of pain. (PMID:24144460)
• Gain-of-function mutations in SCN11A can be causative of an autosomal-dominant episodic pain disorder. (PMID:24207120)
• missense mutations of Nav1.9 in individuals with painful peripheral neuropathy (PMID:24776970)
• A G699R substitution in the Nav1.9 domain II S4-S5 linker renders dorsal root ganglion neurons hyperexcitable, via depolarized resting membrane potential, reduced current threshold and increased evoked firing in small-fiber neuropathy. (PMID:25791876)
• A missense mutation (p.V1184A) in NaV1.9 leads to cold-aggravated peripheral pain. (PMID:26645915)
• autosomal dominant Congenital insensitivity to pain reflects the second gain-of-function mutation of SCN11A. (PMID:26746779)
• Recently Nav1.9, a voltage-gated sodium channel subtype, has been established as a genetic influence for certain peripheral pain syndromes. (PMID:27224030)
• Results show the expression of Nav1.9 channels within the human colon for the first time. Furthermore, Nav1.9 channel expression is decreased in Hirschsprung’s disease versus normal controls. (PMID:27297039)
• We identified a missense mutation of p.Arg225Cys in SCN11A in a four-generation Chinese family with early-onset familial episodic pain and adult onset familial essential tremor syndrome. (PMID:28298626)
• a U-shaped relationship between the resting potential and the neuronal action potential threshold explains why NaV1.9 mutations that evoke small degrees of membrane depolarization cause hyperexcitability and familial episodic pain disorder or painful neuropathy, while mutations evoking larger membrane depolarizations cause hypoexcitability and insensitivity to pain. (PMID:28530638)
• SCN11A single-nucleotide polymorphisms affect Postoperative pain sensitivity in Chinese Han women after Gynecological surgery. The SNP rs33985936 and rs13080116 may serve as novel predictors for Postoperative pain. (PMID:28953656)
• data suggest an important contribution of NaV1.9 to itch signaling. (PMID:30395542)
• The frequency of (potentially) pathogenic variants was 5.1% (n=58/1139) for SCN9A, 3.7% (n=42/1139) for SCN10A and 2.9% (n=33/1139) for SCN11A in pure small fibre neuropathy. (PMID:30554136)
• A total of 11 mutations in SCN11A: p.R222H in seven families, and p.R225C, p.F814C, p.F1146S, or p.V1184A, in independent families. A founder mutation, SCN11A p.R222H was confirmed to be frequently observed in patients with Familial episodic limb pain in Japan. And identification of two novel missense variants of SCN11A, p.F814C and p.F1146S. (PMID:30557356)
• Findings suggest that higher PBMC SCN11A expression levels may be associated with certain behavioral bipolar disorder (BD) sub-phenotypes, including lack of alcohol dependence and psychosis, among BD patients. (PMID:31498915)
• A 49-residue sequence motif in the C terminus of Nav1.9 regulates trafficking of the channel to the plasma membrane. (PMID:31822564)
• Alcohol-aggravated episodic pain in humans with SCN11A mutation and ALDH2 polymorphism. (PMID:32132394)
• Painful and painless mutations of SCN9A and SCN11A voltage-gated sodium channels. (PMID:32601768)
• Contributions of NaV1.8 and NaV1.9 to excitability in human induced pluripotent stem-cell derived somatosensory neurons. (PMID:34930944)
• Understanding the physiological role of NaV1.9: Challenges and opportunities for pain modulation. (PMID:37061202)
• The influence of Nav1.9 channels on intestinal hyperpathia and dysmotility. (PMID:37186898)
• Elevated SCN11A concentrations associated with lower serum lipid levels in patients with major depressive disorder. (PMID:38734669)
• Genetic Analysis of SCN11A, SCN10A, and SCN9A in Familial Episodic Pain Syndrome (FEPS) in Japan and Proposal of Clinical Diagnostic Criteria. (PMID:38999942)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Scn11a	ENSMUSG00000034115
rattus_norvegicus	Scn11a	ENSRNOG00000032884

Paralogs (26): CACNA1G (ENSG00000006283), SCN4A (ENSG00000007314), CACNA1S (ENSG00000081248), CACNA1I (ENSG00000100346), CACNA1F (ENSG00000102001), NALCN (ENSG00000102452), SCN2A (ENSG00000136531), SCN7A (ENSG00000136546), CACNA1A (ENSG00000141837), SCN1A (ENSG00000144285), CACNA1B (ENSG00000148408), CACNA1C (ENSG00000151067), CATSPER3 (ENSG00000152705), SCN3A (ENSG00000153253), CACNA1D (ENSG00000157388), TPCN2 (ENSG00000162341), CATSPER2 (ENSG00000166762), SCN9A (ENSG00000169432), CATSPER1 (ENSG00000175294), SCN5A (ENSG00000183873), SCN10A (ENSG00000185313), TPCN1 (ENSG00000186815), CATSPER4 (ENSG00000188782), CACNA1H (ENSG00000196557), SCN8A (ENSG00000196876), CACNA1E (ENSG00000198216)

Protein

Protein identifiers

Sodium channel protein type 11 subunit alpha — Q9UI33 (reviewed: Q9UI33)

Alternative names: Peripheral nerve sodium channel 5, Sensory neuron sodium channel 2, Sodium channel protein type XI subunit alpha, Voltage-gated sodium channel subunit alpha Nav1.9, hNaN

All UniProt accessions (6): A0A6Q8PF78, A0A6Q8PFM8, A0A6Q8PGN4, A0A6Q8PGY3, A0A6Q8PGY6, Q9UI33

UniProt curated annotations — full annotation on UniProt →

Function. Sodium channel mediating 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 sodium ions may pass in accordance with their electrochemical gradient. Involved in membrane depolarization during action potential in nociceptors which function as key relay stations for the electrical transmission of pain signals from the periphery to the central nervous system. Also involved in rapid BDNF-evoked neuronal depolarization.

Subunit / interactions. The voltage-resistant sodium channel consists of an ion conducting pore forming alpha-subunit regulated by one or more auxiliary subunits SCN1B, SCN2B and SCN3B.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in the dorsal root ganglia and trigeminal ganglia, olfactory bulb, hippocampus, cerebellar cortex, spinal cord, spleen, small intestine and placenta.

Disease relevance. Neuropathy, hereditary sensory and autonomic, 7 (HSAN7) [MIM:615548] A form of hereditary sensory and autonomic neuropathy, a genetically and clinically heterogeneous group of disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and by sensory and/or autonomic abnormalities. HSAN7 is characterized by congenital inability to experience pain resulting in self-mutilations, slow-healing wounds, and multiple painless fractures. mild muscle weakness, delayed motor development, slightly reduced motor and sensory nerve conduction velocities, hyperhidrosis and gastrointestinal dysfunction. The disease is caused by variants affecting the gene represented in this entry. Episodic pain syndrome, familial, 3 (FEPS3) [MIM:615552] An autosomal dominant neurologic disorder characterized by paroxysmal pain mainly affecting the distal lower extremities and occasionally the upper body, especially the joints of fingers and arms. The pain is exacerbated with fatigue. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activity is not sensitive to inhibition by tetrodotoxin.

Domain organisation. The sequence contains 4 internal repeats, each with 5 hydrophobic segments (S1, S2, S3, S5, S6) and one positively charged segment (S4). Segments S4 are probably the voltage-sensors and are characterized by a series of positively charged amino acids at every third position.

Similarity. Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.9/SCN11A subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UI33-1	1	yes
Q9UI33-2	2, Scn12a-s
Q9UI33-3	3

RefSeq proteins (2): NP_001336182, NP_054858 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001696	Na_channel_asu	Family
IPR005821	Ion_trans_dom	Domain
IPR010526	Na_trans_assoc_dom	Domain
IPR027359	Volt_channel_dom_sf	Homologous_superfamily
IPR043203	VGCC_Ca_Na	Family
IPR044564	Na_chnl_inactivation_gate	Domain
IPR058542	IQ_SCN5A_C	Domain

Pfam: PF00520, PF06512, PF24609

Catalyzed reactions (Rhea), 1 shown:

• Na(+)(in) = Na(+)(out) (RHEA:34963)

UniProt features (99 total): topological domain 29, transmembrane region 24, sequence variant 20, glycosylation site 8, intramembrane region 4, repeat 4, sequence conflict 4, splice variant 3, disulfide bond 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UI33-F1	69.66	0.10

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (2): 283–322, 776–787

Glycosylation sites (8): 290, 338, 781, 1209, 1216, 1222, 1230, 1568

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-445095	Interaction between L1 and Ankyrins
R-HSA-5576892	Phase 0 - rapid depolarisation
R-HSA-1266738	Developmental Biology
R-HSA-373760	L1CAM interactions
R-HSA-397014	Muscle contraction
R-HSA-422475	Axon guidance
R-HSA-5576891	Cardiac conduction
R-HSA-9675108	Nervous system development

MSigDB gene sets: 268 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GSE45365_NK_CELL_VS_CD8_TCELL_UP, GOBP_CIRCADIAN_RHYTHM, GOBP_EXCRETION, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_SENSORY_PERCEPTION_OF_TEMPERATURE_STIMULUS, GOBP_BEHAVIOR, GOBP_RESPONSE_TO_COLD, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_RESPONSE_TO_PROSTAGLANDIN_E, GOBP_INFLAMMATORY_RESPONSE, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_DETECTION_OF_MECHANICAL_STIMULUS_INVOLVED_IN_SENSORY_PERCEPTION, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT

GO Biological Process (51): thigmotaxis (GO:0001966), acute inflammatory response (GO:0002526), chronic inflammatory response (GO:0002544), axonogenesis (GO:0007409), circadian rhythm (GO:0007623), response to heat (GO:0009408), response to xenobiotic stimulus (GO:0009410), response to toxic substance (GO:0009636), response to high light intensity (GO:0009644), response to auditory stimulus (GO:0010996), neuronal action potential (GO:0019228), sensory perception of pain (GO:0019233), response to prostaglandin E (GO:0034695), sodium ion transmembrane transport (GO:0035725), thermosensory behavior (GO:0040040), mast cell degranulation (GO:0043303), cell motility (GO:0048870), detection of temperature stimulus involved in sensory perception of pain (GO:0050965), detection of mechanical stimulus involved in sensory perception of pain (GO:0050966), reflex (GO:0060004), micturition (GO:0060073), skeletal muscle organ development (GO:0060538), artery development (GO:0060840), behavioral response to acetic acid induced pain (GO:0061367), behavioral response to formalin induced pain (GO:0061368), cellular response to cold (GO:0070417), calcium ion transmembrane transport (GO:0070588), response to nitric oxide (GO:0071731), cardiac muscle cell action potential involved in contraction (GO:0086002), membrane depolarization during action potential (GO:0086010), action potential initiation (GO:0099610), cAMP/PKA signal transduction (GO:0141156), sensory perception of itch (GO:0160025), calcitonin gene-related peptide receptor signaling pathway (GO:1990408), small intestine smooth muscle contraction (GO:1990770), action potential (GO:0001508), monoatomic ion transport (GO:0006811), sodium ion transport (GO:0006814), inflammatory response (GO:0006954), G protein-coupled receptor signaling pathway (GO:0007186)

GO Molecular Function (4): voltage-gated sodium channel activity (GO:0005248), monoatomic ion channel activity (GO:0005216), monoatomic cation channel activity (GO:0005261), sodium channel activity (GO:0005272)

GO Cellular Component (10): voltage-gated sodium channel complex (GO:0001518), plasma membrane (GO:0005886), axon (GO:0030424), neuronal cell body (GO:0043025), axonal growth cone (GO:0044295), C-fiber (GO:0044299), extracellular exosome (GO:0070062), membrane (GO:0016020), monoatomic ion channel complex (GO:0034702), cell body (GO:0044297)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
L1CAM interactions	1
Cardiac conduction	1
Axon guidance	1
Nervous system development	1
Muscle contraction	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
behavior	2
inflammatory response	2
response to temperature stimulus	2
response to chemical	2
sensory perception of pain	2
cellular anatomical structure	2
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
rhythmic process	1
response to stress	1
response to light intensity	1
response to mechanical stimulus	1
action potential	1
transmission of nerve impulse	1
sensory perception	1
response to prostaglandin	1
response to alcohol	1
response to ketone	1
sodium ion transport	1
monoatomic cation transmembrane transport	1
mast cell activation involved in immune response	1
mast cell mediated immunity	1
lysosome localization	1
leukocyte degranulation	1
establishment of organelle localization	1
cellular process	1
detection of temperature stimulus involved in sensory perception	1
detection of mechanical stimulus involved in sensory perception	1
response to external stimulus	1
sodium channel activity	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
monoatomic ion channel activity	1
monoatomic cation transmembrane transporter activity	1
monoatomic cation channel activity	1
sodium ion transmembrane transporter activity	1
sodium channel complex	1
plasma membrane protein complex	1
membrane	1

Protein interactions and networks

STRING

1196 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SCN11A	GPKOW	Q92917	925
SCN11A	SCN4B	Q8IWT1	903
SCN11A	SLC38A3	Q99624	855
SCN11A	SLC38A4	Q969I6	825
SCN11A	SLC38A5	Q8WUX1	766
SCN11A	SLC38A2	Q96QD8	765
SCN11A	SLC38A1	Q9H2H9	765
SCN11A	SCN1B	Q07699	746
SCN11A	NAV1	Q8NEY1	722
SCN11A	NTRK2	Q16620	705
SCN11A	TRPV1	Q8NER1	695
SCN11A	TRPA1	O75762	676
SCN11A	P2RX3	P56373	618
SCN11A	NANOGP8	Q6NSW7	602
SCN11A	SCN1A	P35498	598

IntAct

2 interactions, top by confidence:

A	B	Type	Score
bipA	SCN11A	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (4): SCN11A (Affinity Capture-MS), SCN11A (Cross-Linking-MS (XL-MS)), SCN11A (Proximity Label-MS), SCN11A (Proximity Label-MS)

ESM2 similar proteins: A2APX8, A2ASI5, B1AWN6, C9D7C2, D0E0C2, O08562, O35505, O46669, O73700, O88420, O88457, P02719, P04774, P04775, P08104, P0DMA5, P15381, P15389, P15390, P22002, P27732, P35498, P35499, P35500, Q01815, Q07652, Q13936, Q14524, Q15858, Q20JQ7, Q28371, Q28644, Q2XVR3, Q2XVR4, Q2XVR5, Q2XVR6, Q2XVR7, Q62205, Q62968, Q6QIY3

Diamond homologs: A2APX8, A2ASI5, B1AWN6, B1AYL1, D0E0C2, F1LQQ7, O00555, O08562, O46669, O73705, O73706, O73707, O88420, O88457, P02719, P04774, P04775, P08104, P0DMA5, P15389, P15390, P27884, P35498, P35499, P35500, P54282, P56699, P97445, Q01118, Q02789, Q05973, Q14524, Q15858, Q15878, Q20JQ7, Q28371, Q28644, Q2XVR3, Q2XVR4, Q2XVR5

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
SCN11A	“up-regulates quantity”	sodium(1+)	relocalization
FGF13	“down-regulates activity”	SCN11A	binding
FGF12	“down-regulates activity”	SCN11A	binding
FGF14	“down-regulates activity”	SCN11A	binding
FGF11	“down-regulates activity”	SCN11A	binding
SCN11A	up-regulates	Action_potential
NEDD4L	“down-regulates quantity by destabilization”	SCN11A	ubiquitination
ESR1	“down-regulates quantity by repression”	SCN11A	“transcriptional regulation”
ESR2	“down-regulates quantity by repression”	SCN11A	“transcriptional regulation”
TNF	“up-regulates quantity by expression”	SCN11A	“transcriptional regulation”
TNF	“up-regulates activity”	SCN11A
IL10	“down-regulates quantity by repression”	SCN11A	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1644 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	3
Uncertain significance	951
Likely benign	481
Benign	93

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
426113	NM_001349253.2(SCN11A):c.1187T>C (p.Leu396Pro)	Pathogenic
872004	NM_001349253.2(SCN11A):c.665G>A (p.Arg222His)	Pathogenic
89011	NM_001349253.2(SCN11A):c.2432T>C (p.Leu811Pro)	Pathogenic
89013	NM_001349253.2(SCN11A):c.2423C>G (p.Ala808Gly)	Pathogenic
3336794	NM_001349253.2(SCN11A):c.197A>C (p.Tyr66Ser)	Likely pathogenic
422331	NM_001349253.2(SCN11A):c.1717G>A (p.Val573Met)	Likely pathogenic
804348	NM_001349253.2(SCN11A):c.2423C>A (p.Ala808Asp)	Likely pathogenic

SpliceAI

4488 predictions. Top by Δscore:

Variant	Effect	Δscore
3:38850479:A:AC	donor_gain	1.0000
3:38850480:C:CC	donor_gain	1.0000
3:38850480:CTAA:C	donor_gain	1.0000
3:38867319:A:AC	donor_gain	1.0000
3:38870687:TCA:T	donor_loss	1.0000
3:38870688:CA:C	donor_loss	1.0000
3:38870689:A:C	donor_loss	1.0000
3:38870741:TTGCC:T	acceptor_loss	1.0000
3:38870743:GCCTG:G	acceptor_loss	1.0000
3:38870744:CCTGC:C	acceptor_loss	1.0000
3:38870745:C:CC	acceptor_gain	1.0000
3:38870745:CT:C	acceptor_loss	1.0000
3:38870746:T:G	acceptor_loss	1.0000
3:38871619:C:T	acceptor_gain	1.0000
3:38885411:C:CT	acceptor_gain	1.0000
3:38899893:CCACT:C	donor_gain	1.0000
3:38903867:AATT:A	donor_gain	1.0000
3:38903867:AATTC:A	donor_gain	1.0000
3:38905190:AC:A	donor_gain	1.0000
3:38905191:CC:C	donor_gain	1.0000
3:38905191:CCCTT:C	donor_gain	1.0000
3:38905317:TGTGG:T	acceptor_gain	1.0000
3:38905318:GTGG:G	acceptor_gain	1.0000
3:38905319:TGG:T	acceptor_gain	1.0000
3:38905320:GG:G	acceptor_gain	1.0000
3:38905320:GGC:G	acceptor_loss	1.0000
3:38905322:C:CC	acceptor_gain	1.0000
3:38905323:T:C	acceptor_loss	1.0000
3:38908995:ACCT:A	donor_gain	1.0000
3:38908996:CCTC:C	donor_gain	1.0000

AlphaMissense

11980 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:38847124:A:G	F1649S	0.998
3:38847182:A:G	W1630R	0.998
3:38847182:A:T	W1630R	0.998
3:38871639:A:G	W1189R	0.998
3:38871639:A:T	W1189R	0.998
3:38847121:G:T	A1650D	0.997
3:38847312:A:C	S1586R	0.997
3:38847312:A:T	S1586R	0.997
3:38847314:T:G	S1586R	0.997
3:38867367:A:G	L1302P	0.997
3:38871651:A:G	C1185R	0.997
3:38883242:A:C	S1070R	0.997
3:38883242:A:T	S1070R	0.997
3:38883244:T:G	S1070R	0.997
3:38847450:G:C	S1540R	0.996
3:38847450:G:T	S1540R	0.996
3:38847452:T:G	S1540R	0.996
3:38847601:A:G	L1490P	0.996
3:38883245:G:C	S1069R	0.996
3:38883245:G:T	S1069R	0.996
3:38883247:T:G	S1069R	0.996
3:38921173:G:C	S265R	0.996
3:38921173:G:T	S265R	0.996
3:38921175:T:G	S265R	0.996
3:38847413:A:G	W1553R	0.995
3:38847413:A:T	W1553R	0.995
3:38847580:A:G	L1497P	0.995
3:38847606:A:C	F1488L	0.995
3:38847606:A:T	F1488L	0.995
3:38847608:A:G	F1488L	0.995

dbSNP variants (sampled 300 via entrez): RS1000001996 (3:39006604 A>G), RS1000069063 (3:38899494 TTG>T), RS1000070048 (3:38995970 G>C), RS1000077108 (3:38961561 T>A), RS1000095214 (3:39006262 A>C), RS1000101796 (3:38913965 G>A), RS1000109531 (3:38978781 G>A,T), RS1000133148 (3:38914266 T>C), RS1000143849 (3:38944234 T>C,G), RS1000177553 (3:39012600 C>G,T), RS1000200301 (3:38869915 A>T), RS1000211546 (3:38874274 C>A,T), RS1000232507 (3:38968667 A>C), RS1000243961 (3:39016148 A>T), RS1000244418 (3:38874643 T>A)

Disease associations

OMIM: gene MIM:604385 | disease phenotypes: MIM:615548, MIM:615552, MIM:118220, MIM:608654

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary sensory and autonomic neuropathy type 7	Definitive	Autosomal dominant
familial episodic pain syndrome with predominantly lower limb involvement	Definitive	Autosomal dominant
sodium channelopathy-related small fiber neuropathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
obsolete autosomal dominant hereditary sensory and autonomic neuropathy	Definitive	AD

Mondo (8): hereditary sensory and autonomic neuropathy type 7 (MONDO:0014244), familial episodic pain syndrome with predominantly lower limb involvement (MONDO:0014247), Charcot-Marie-Tooth disease (MONDO:0015626), limb-girdle muscular dystrophy (MONDO:0016971), hereditary motor neuron disease (MONDO:0024257), sensory peripheral neuropathy (MONDO:0002321), hereditary sensory and autonomic neuropathy type 5 (MONDO:0012092), (MONDO:0017629)

Orphanet (7): Familial episodic pain syndrome (Orphanet:391384), Familial episodic pain syndrome with predominantly lower limb involvement (Orphanet:391392), Hereditary sensory and autonomic neuropathy type 7 (Orphanet:391397), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Limb-girdle muscular dystrophy (Orphanet:263), Genetic motor neuron disease (Orphanet:98505), Hereditary sensory and autonomic neuropathy type 5 (Orphanet:64752)

HPO phenotypes

27 total (27 of 27 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000975	Hyperhidrosis
HP:0000989	Pruritus
HP:0001058	Poor wound healing
HP:0001250	Seizure
HP:0001270	Motor delay
HP:0001324	Muscle weakness
HP:0001872	Abnormality of thrombocytes
HP:0001909	Leukemia
HP:0002014	Diarrhea
HP:0002019	Constipation
HP:0002045	Hypothermia
HP:0002205	Recurrent respiratory infections
HP:0002633	Vasculitis
HP:0002936	Distal sensory impairment
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0007021	Pain insensitivity
HP:0009830	Peripheral neuropathy
HP:0010741	Pedal edema
HP:0010783	Erythema
HP:0012332	Abnormal autonomic nervous system physiology
HP:0012531	Pain
HP:0012533	Allodynia
HP:0012534	Dysesthesia
HP:0032147	Erythromelalgia
HP:0200101	Decreased/absent ankle reflexes

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002367_11	Social communication problems	9.000000e-09
GCST008473_7	Visceral fat	9.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005427	social communication impairment

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D049288	Muscular Dystrophies, Limb-Girdle	C05.651.534.500.280; C10.668.491.175.500.149; C16.320.577.280

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2331043 (PROTEIN FAMILY), CHEMBL5167 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

15 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 435,543 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL11	IMIPRAMINE	4	48,893
CHEMBL12713	SERTINDOLE	4	8,984
CHEMBL1423	PIMOZIDE	4	17,310
CHEMBL193	NIFEDIPINE	4	74,353
CHEMBL23	DILTIAZEM	4	54,676
CHEMBL45816	MIBEFRADIL	4	7,838
CHEMBL54	HALOPERIDOL	4	60,883
CHEMBL558	MEXILETINE	4	15,463
CHEMBL629	AMITRIPTYLINE	4	52,595
CHEMBL633	AMIODARONE	4	29,704
CHEMBL71	CHLORPROMAZINE	4	45,827
CHEMBL113461	TEDISAMIL	3	1,251
CHEMBL475534	NITRENDIPINE	3	16,468
CHEMBL5314404	AJMALINE	3
CHEMBL87045	CIFENLINE	2	1,298

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: vgic — Voltage-gated sodium channels (Na_V)

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
ANP-230	Channel blocker	5.17	pIC50
tetrodotoxin	Pore blocker	4.4	pIC50

Binding affinities (BindingDB)

572 measured of 575 human assays (575 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
5-cyclopropyl-4-[(3R)-1-[(3,5-dichlorophenyl)methyl]piperidin-3-yl]oxy-2-fluoro-N-methylsulfonylbenzamide	IC50	0.3 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-N-cyclopropylsulfonyl-4-[[1-[(3,5-dichlorophenyl)-phenylmethyl]piperidin-4-yl]methoxy]-2-fluorobenzamide	IC50	0.8 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[(3R)-1-[[3-chloro-5-(trifluoromethoxy)phenyl]methyl]piperidin-3-yl]oxy-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	1.3 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(3,5-dichlorophenyl)-phenylmethyl]piperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	1.5 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(2S)-2-(3,5-dichlorophenyl)-1-methoxypropan-2-yl]piperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	1.6 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(1S)-1-(3,5-dichlorophenyl)-2-methoxy-2-methylpropyl]piperidin-4-yl]methoxy]-N-ethylsulfonyl-2-fluorobenzamide	IC50	1.6 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(1S)-1-(3,5-dichloro-2-fluorophenyl)ethyl]piperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	1.6 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[[1-[1-(2-chloro-4-fluorophenyl)-2,2,2-trifluoroethyl]piperidin-4-yl]methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	1.6 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[(3R)-1-[(2-chlorophenyl)methyl]piperidin-3-yl]oxy-5-cyclopropyl-N-cyclopropylsulfonyl-2-fluorobenzamide	IC50	1.7 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[(3R)-1-[(2,4-dichlorophenyl)methyl]piperidin-3-yl]oxy-2-fluoro-N-methylsulfonylbenzamide	IC50	1.7 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(1R)-1-(3,5-dichlorophenyl)-2-methoxy-2-methylpropyl]piperidin-4-yl]methoxy]-N-ethylsulfonyl-2-fluorobenzamide	IC50	1.7 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[2-(3,5-dichlorophenyl)propan-2-yl]piperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	1.7 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(1S)-1-(3,5-dichlorophenyl)ethyl]-4-methylpiperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	1.7 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(1S)-1-(3,5-dichlorophenyl)-2-methoxy-2-methylpropyl]piperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	1.8 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-2-fluoro-4-[(3R)-1-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]piperidin-3-yl]oxy-N-methylsulfonylbenzamide	IC50	1.9 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[(3R)-1-[(1S)-1-(3,5-dichlorophenyl)ethyl]piperidin-3-yl]oxy-2-fluoro-N-methylsulfonylbenzamide	IC50	1.9 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[[1-[[3-chloro-5-(trifluoromethoxy)phenyl]methyl]piperidin-4-yl]methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	1.9 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[2-(3,5-dichlorophenyl)propan-2-yl]piperidin-4-yl]methoxy]-N-ethylsulfonyl-2-fluorobenzamide	IC50	1.9 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[1-(3,5-dichlorophenyl)-2,2,2-trifluoroethyl]piperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	1.9 nM	US-9694002: Substituted benzamides and methods of use thereof
N-(azetidin-1-ylsulfonyl)-4-[(3R,6R)-1-[(2-chloro-4-fluorophenyl)methyl]-6-methylpiperidin-3-yl]oxy-5-cyclopropyl-2-fluorobenzamide	IC50	1.9 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[(3R,6R)-1-[(2-chloro-4-fluorophenyl)methyl]-6-methylpiperidin-3-yl]oxy-5-cyclopropyl-N-cyclopropylsulfonyl-2-fluorobenzamide	IC50	1.9 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[1-(3,5-dichlorophenyl)propyl]piperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	2 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[[1-[bis(3-chlorophenyl)methyl]piperidin-4-yl]methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	2 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[[1-[bis(2-chlorophenyl)methyl]piperidin-4-yl]methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	2 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-N-cyclopropylsulfonyl-4-[(3R)-1-(3,5-dichlorophenyl)piperidin-3-yl]oxy-2-fluorobenzamide	IC50	2.1 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[[1-[[2,5-bis(trifluoromethyl)phenyl]methyl]-4-methylpiperidin-4-yl]methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	2.1 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[[1-[[3-chloro-5-(trifluoromethyl)phenyl]methyl]piperidin-4-yl]methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	2.1 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[[1-[bis(4-chlorophenyl)methyl]piperidin-4-yl]methoxy]-5-cyclopropyl-N-cyclopropylsulfonyl-2-fluorobenzamide	IC50	2.1 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[(3R)-1-[(2,4-dimethylphenyl)methyl]piperidin-3-yl]oxy-2-fluoro-N-methylsulfonylbenzamide	IC50	2.1 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[[1-[5-chloro-4-(trifluoromethyl)-2-pyridinyl]-4-methylpiperidin-4-yl]methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	2.1 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(1S)-1-(2,4-dichlorophenyl)ethyl]piperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	2.2 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-N-cyclopropylsulfonyl-4-[[1-[(3,5-dichlorophenyl)methyl]piperidin-4-yl]methoxy]-2-fluorobenzamide	IC50	2.2 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[(3R)-1-[(2-chloro-4-fluorophenyl)methyl]piperidin-3-yl]oxy-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	2.2 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[[(1R,5S)-3-[3-chloro-5-(trifluoromethoxy)phenoxy]-8-azabicyclo[3.2.1]octan-8-yl]methyl]-5-cyclopropyl-N-cyclopropylsulfonyl-2-fluorobenzamide	IC50	2.2 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[4-(3,5-dichlorophenyl)sulfanylpiperidin-1-yl]methyl]-2-fluorobenzamide	IC50	2.2 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-N-cyclopropylsulfonyl-4-[[1-[(1S)-1-(3,5-dichlorophenyl)-2-methoxyethyl]piperidin-4-yl]methoxy]-2-fluorobenzamide	IC50	2.3 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[(3R)-1-[(1S)-1-(2-chloro-4-fluorophenyl)ethyl]piperidin-3-yl]oxy-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	2.3 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[(3R)-1-[(1S)-1-(5-chloro-6-cyclopropyl-2-pyridinyl)ethyl]piperidin-3-yl]oxy-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	2.3 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[(3R)-1-[2-(3-chlorophenyl)propan-2-yl]piperidin-3-yl]oxy-5-cyclopropyl-2-fluorobenzamide	IC50	2.3 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-N-cyclopropylsulfonyl-2-fluoro-4-[(3R)-1-[[4-fluoro-2-(trifluoromethyl)phenyl]methyl]piperidin-3-yl]oxybenzamide	IC50	2.4 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[[1-[[5-chloro-2-(trifluoromethyl)phenyl]methyl]-4-methylpiperidin-4-yl]methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	2.4 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(1R)-1-(3,5-dichlorophenyl)propyl]piperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	2.4 nM	US-9694002: Substituted benzamides and methods of use thereof
N-(azetidin-1-ylsulfonyl)-4-[(3R,6S)-1-[(2-chloro-4-fluorophenyl)methyl]-6-methylpiperidin-3-yl]oxy-5-cyclopropyl-2-fluorobenzamide	IC50	2.4 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(3,5-dichlorophenyl)-phenylmethyl]-3-methylazetidin-3-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	2.4 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-N-cyclopropylsulfonyl-4-[[1-[1-(3,5-dichlorophenyl)ethyl]piperidin-4-yl]methoxy]-2-fluorobenzamide	IC50	2.5 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(1R)-1-(3,5-dichlorophenyl)-2-methoxy-2-methylpropyl]piperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	2.5 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-4-[[1-[(2,4-dichlorophenyl)methyl]piperidin-4-yl]methoxy]-N-ethylsulfonyl-2-fluorobenzamide	IC50	2.5 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-N-cyclopropylsulfonyl-4-[[1-[(3,5-dichlorophenyl)-phenylmethyl]-3-methylazetidin-3-yl]methoxy]-2-fluorobenzamide	IC50	2.5 nM	US-9694002: Substituted benzamides and methods of use thereof
4-[(3R)-1-[(2-chloro-4-methylphenyl)methyl]piperidin-3-yl]oxy-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	2.5 nM	US-9694002: Substituted benzamides and methods of use thereof
5-cyclopropyl-N-cyclopropylsulfonyl-4-[(3R)-1-[(3,5-dichlorophenyl)methyl]piperidin-3-yl]oxy-2-fluorobenzamide	IC50	2.6 nM	US-9694002: Substituted benzamides and methods of use thereof

ChEMBL bioactivities

10 potent at pChembl≥5 of 15 total, top 10 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.27	IC50	54	nM	PIMOZIDE
6.01	IC50	980	nM	MIBEFRADIL
5.64	IC50	2300	nM	SERTINDOLE
5.44	IC50	3600	nM	IMIPRAMINE
5.37	IC50	4300	nM	CHLORPROMAZINE
5.32	IC50	4800	nM	AMIODARONE
5.16	IC50	7000	nM	HALOPERIDOL
5.11	IC50	7800	nM	CIFENLINE
5.09	IC50	8200	nM	AJMALINE
5.05	IC50	9000	nM	DILTIAZEM

PubChem BioAssay actives

11 with measured affinity, of 30 total; 11 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(1R,5R,6R,7R,9S,11S,12S,13S,14S)-3-amino-14-(hydroxymethyl)-8,10-dioxa-2,4-diazatetracyclo[7.3.1.17,11.01,6]tetradec-3-ene-5,9,12,13,14-pentol	726284: Inhibition of voltage-gated Na channel 1.9 (unknown origin)	ic50	0.0300	uM
Pimozide	1207165: Inhibition of Na channel (species unknown)	ic50	0.0540	uM
[(1S,2S)-2-[2-[3-(1H-benzimidazol-2-yl)propyl-methylamino]ethyl]-6-fluoro-1-propan-2-yl-3,4-dihydro-1H-naphthalen-2-yl] 2-methoxyacetate	1207161: Inhibition of Na channel (species unknown)	ic50	0.9800	uM
1-[2-[4-[5-chloro-1-(4-fluorophenyl)indol-3-yl]piperidin-1-yl]ethyl]imidazolidin-2-one	1207172: Inhibition of Na channel (species unknown)	ic50	2.3000	uM
Imipramine	1207159: Inhibition of Na channel (species unknown)	ic50	3.6000	uM
Chlorpromazine	1207150: Inhibition of Na channel (species unknown)	ic50	4.3000	uM
Amiodarone	1207147: Inhibition of Na channel (species unknown)	ic50	4.8000	uM
Haloperidol	1207158: Inhibition of Na channel (species unknown)	ic50	7.0000	uM
2-(2,2-diphenylcyclopropyl)-4,5-dihydro-1H-imidazole	1207151: Inhibition of Na channel (species unknown)	ic50	7.8000	uM
(1R,9R,10S,12R,13S,14R,16S,17R,18R)-13-ethyl-8-methyl-8,15-diazahexacyclo[14.2.1.01,9.02,7.010,15.012,17]nonadeca-2,4,6-triene-14,18-diol	1207146: Inhibition of Na channel (species unknown)	ic50	8.2000	uM
Diltiazem	1207154: Inhibition of Na channel (species unknown)	ic50	9.0000	uM

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
ethyl-p-hydroxybenzoate	decreases expression	1
cypermethrin	decreases expression	1
sodium arsenite	increases expression	1
benzo(e)pyrene	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects cotreatment	1
bisphenol S	affects cotreatment, increases methylation, decreases methylation	1
Fulvestrant	affects cotreatment, increases methylation	1
Benzo(a)pyrene	increases methylation	1
Lipopolysaccharides	affects cotreatment, increases expression	1
Methapyrilene	increases methylation	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Acrylamide	increases expression	1

ChEMBL screening assays

33 unique, capped per target: 16 functional, 15 binding, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3430568	Functional	Inhibition of Na channel (species unknown)	Simulation of multiple ion channel block provides improved early prediction of compounds’ clinical torsadogenic risk. — Cardiovasc Res
CHEMBL4880115	Binding	Na+ channel CEREP ligand profiling	Data for DCP probe A-079
CHEMBL4629776	ADMET	Inhibition of human Nav1.9 at resting state expressed in HEK293 cells at 10 uM at -120 mV holding potential by 10 Hz single pulse protocol based manual patch clamp assay relative to control	Discovery of Potent, Selective, and State-Dependent NaV1.7 Inhibitors with Robust Oral Efficacy in Pain Models: Structure-Activity Relationship and Optimization of Chroman and Indane Aryl Sulfonamides. — J Med Chem

Cellosaurus cell lines

4 cell lines: 3 induced pluripotent stem cell, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_9S45	RCi003-A	Induced pluripotent stem cell	Female
CVCL_9S46	RCi003-B	Induced pluripotent stem cell	Female
CVCL_YN15	HEK-293 hNav1.9	Transformed cell line	Female
CVCL_YN19	UKERi313-R1	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

102 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT03783923	PHASE3	TERMINATED	A Study of Deflazacort (Emflaza®) in Participants With Limb-Girdle Muscular Dystrophy 2I (LGMD2I)
NCT06246513	PHASE3	ACTIVE_NOT_RECRUITING	A Trial to Learn More About an Experimental Gene Therapy Called Bidridistrogene Xeboparvovec (SRP-9003) as a Possible Treatment for Limb Girdle Muscular Dystrophy 2E/R4
NCT01526564	PHASE3	COMPLETED	Clinical Study on Acetyl-L-Carnitine
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT04054375	PHASE2	COMPLETED	Weekly Steroids in Muscular Dystrophy
NCT00873782	PHASE1	COMPLETED	Safety Study of Transvenous Limb Perfusion in Human Muscular Dystrophy
NCT01344798	PHASE1	COMPLETED	Clinical Study of AAV1-gamma-sarcoglycan Gene Therapy for Limb Girdle Muscular Dystrophy Type 2C
NCT02050776	PHASE1	WITHDRAWN	Stem Cell Therapy in Limb Girdle Muscular Dystrophy
NCT02245711	PHASE1	WITHDRAWN	Cell Therapy in Limb Girdle Muscular Dystrophy
NCT05876780	PHASE1	ACTIVE_NOT_RECRUITING	A Gene Transfer Single Dose Study to Evaluate the Safety, Tolerability and Efficacy of SRP-9003 in Non-Ambulatory and Ambulatory Participants With Limb Girdle Muscular Dystrophy, Type 2E/R4 (Beta-Sarcoglycan [β-SG] Deficiency)
NCT05906251	PHASE1	TERMINATED	A Gene Transfer Study to Evaluate the Safety, Tolerability and Efficacy of SRP-6004 in Ambulatory Participants With Limb Girdle Muscular Dystrophy, Type 2B/R2 (LGMD2B/R2, Dysferlin [DYSF] Related)
NCT06747273	PHASE1	TERMINATED	Study to Evaluate the Safety, Tolerability, and Efficacy of SRP-9004 Administered by Systemic Infusion in Limb Girdle Muscular Dystrophy Type 2D/R3 Participants in the United States
NCT01289704	PHASE2/PHASE3	UNKNOWN	Treadmill, Stretching and Proprioceptive Exercise (TreSPE) Rehabilitation Program for Charcot-Marie-Tooth Neuropathy Type 1A (CMT1A)
NCT00541164	PHASE1/PHASE2	COMPLETED	Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease
NCT05361031	PHASE1/PHASE2	COMPLETED	The Safety and Tolerability of Engensis (VM202) in Patients With Charcot-Marie-Tooth Disease Subtype 1A (CMT1A)
NCT07223632	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Treatment of Charcot-Marie-Tooth Disease, Axonal, Type 2S (CMT2S) in an Individual Patient
NCT00149045	Not specified	COMPLETED	Follow up and Observation of Charcot Marie Tooth Disease in Families
NCT01193075	Not specified	RECRUITING	Natural History Evaluation of Charcot Marie Tooth Disease (CMT) Types CMT1B, CMT2A, CMT4A, CMT4C, and Others
NCT01203085	Not specified	COMPLETED	Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale for Children With CMT
NCT01455623	Not specified	COMPLETED	Development and Validation of a Disability Severity Index for CMT
NCT01918826	Not specified	UNKNOWN	Evaluation of the Analgesic Efficiency of the Transcutaneous Neurostimulation in the Charcot Syndrome Marie Tooth on the Pains of Lower Limbs
NCT02001038	Not specified	COMPLETED	Survey of Current Management of Orthopaedic Complications in CMT Patients
NCT02011204	Not specified	COMPLETED	Study of Electrical Impedance Myography (EIM) in ALS
NCT02194010	Not specified	COMPLETED	Disability Severity Scale (DSI) and Hereditary Motor and Sensory Neuropathy Overall Disability Scale (HMSN-R-ODS)
NCT02429947	Not specified	COMPLETED	An Analysis of the Symptomatic Domains Most Relevant to Charcot Marie Tooth Neuropathy (CMT) Patients
NCT02532244	Not specified	COMPLETED	Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02788734	Not specified	COMPLETED	Patient Reported Outcomes Measures (PROM) in Carpal Tunnel Therapies in Patients With Inherited Neuropathies
NCT02979145	Not specified	UNKNOWN	Charcot-Marie-Tooth Disease (CMT) Infant Scale (INC-6611)
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03460951	Not specified	COMPLETED	Diffusion Tensor Imaging in Chronic Inflammatory Demyelinating Polyneuropathy (PIDC)