SCN8A

Summary

SCN8A (sodium voltage-gated channel alpha subunit 8, HGNC:10596) is a protein-coding gene on chromosome 12q13.13, encoding Sodium channel protein type 8 subunit alpha (Q9UQD0). Pore-forming subunit of a voltage-gated sodium channel complex assuming opened or closed conformations in response to the voltage difference across membranes and through which sodium ions selectively pass along their electrochemical gradient.

This gene encodes a member of the sodium channel alpha subunit gene family. The encoded protein forms the ion pore region of the voltage-gated sodium channel. This protein is essential for the rapid membrane depolarization that occurs during the formation of the action potential in excitable neurons. Mutations in this gene are associated with cognitive disability, pancerebellar atrophy and ataxia. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 6334 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex neurodevelopmental disorder (Definitive, ClinGen) — +7 more curated relationships
• GWAS associations: 6
• Clinical variants (ClinVar): 2,442 total — 134 pathogenic, 192 likely-pathogenic
• Phenotypes (HPO): 126
• Druggable target: yes — 25 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001330260

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10596
Approved symbol	SCN8A
Name	sodium voltage-gated channel alpha subunit 8
Location	12q13.13
Locus type	gene with protein product
Status	Approved
Aliases	Nav1.6, NaCh6, PN4, CerIII, CIAT
Ensembl gene	ENSG00000196876
Ensembl biotype	protein_coding
OMIM	600702
Entrez	6334

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 11 protein_coding, 3 nonsense_mediated_decay, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000354534, ENST00000355133, ENST00000545061, ENST00000546961, ENST00000548086, ENST00000550891, ENST00000551216, ENST00000599343, ENST00000627620, ENST00000627665, ENST00000636458, ENST00000636945, ENST00000637540, ENST00000637709, ENST00000638820, ENST00000662684, ENST00000667214, ENST00000668547, ENST00000703687

RefSeq mRNA: 4 — MANE Select: NM_001330260 NM_001177984, NM_001330260, NM_001369788, NM_014191

CCDS: CCDS44891, CCDS53794, CCDS81692, CCDS91697

Canonical transcript exons

ENST00000627620 — 27 exons

Exon	Start	End
ENSE00000743945	51768865	51769335
ENSE00000837833	51769868	51769985
ENSE00000837839	51774189	51774362
ENSE00000837848	51786542	51786826
ENSE00001155130	51789281	51789418
ENSE00001192898	51770529	51770683
ENSE00001192917	51751355	51751593
ENSE00001275393	51745903	51746035
ENSE00001275398	51721546	51721908
ENSE00001275406	51706422	51706715
ENSE00001275412	51705417	51705623
ENSE00001275428	51701144	51701207
ENSE00001275435	51699570	51699791
ENSE00001602336	51686368	51686457
ENSE00001624891	51765671	51766027
ENSE00001631331	51780649	51780771
ENSE00001637332	51788695	51788748
ENSE00001673780	51702773	51702914
ENSE00001696487	51790398	51790502
ENSE00001708832	51762503	51762676
ENSE00001767741	51689005	51689096
ENSE00001776102	51684174	51684292
ENSE00003579049	51687091	51687219
ENSE00003762406	51662764	51663093
ENSE00003766428	51794371	51794641
ENSE00003901804	51591233	51591359
ENSE00003902256	51806282	51812864

Expression profiles

Bgee: expression breadth ubiquitous, 194 present calls, max score 95.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.1273 / max 160.2299, expressed in 1133 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125506	2.8721	703
125504	2.5650	892
125505	0.3090	127
125508	0.1629	68
125507	0.1470	76
125512	0.0385	19
125503	0.0329	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	95.76	gold quality
middle temporal gyrus	UBERON:0002771	95.13	gold quality
postcentral gyrus	UBERON:0002581	91.86	gold quality
parietal lobe	UBERON:0001872	91.42	gold quality
primary visual cortex	UBERON:0002436	90.91	gold quality
superior frontal gyrus	UBERON:0002661	89.86	gold quality
endothelial cell	CL:0000115	89.85	gold quality
entorhinal cortex	UBERON:0002728	89.06	gold quality
occipital lobe	UBERON:0002021	88.51	gold quality
lateral nuclear group of thalamus	UBERON:0002736	88.21	gold quality
buccal mucosa cell	CL:0002336	87.42	gold quality
right hemisphere of cerebellum	UBERON:0014890	86.38	gold quality
prefrontal cortex	UBERON:0000451	85.85	gold quality
cerebellar hemisphere	UBERON:0002245	85.75	gold quality
cerebellar cortex	UBERON:0002129	85.70	gold quality
frontal cortex	UBERON:0001870	84.88	gold quality
cerebellum	UBERON:0002037	84.51	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	84.42	gold quality
neocortex	UBERON:0001950	83.95	gold quality
right frontal lobe	UBERON:0002810	83.91	gold quality
cerebral cortex	UBERON:0000956	83.56	gold quality
pons	UBERON:0000988	83.04	gold quality
Brodmann (1909) area 9	UBERON:0013540	82.52	gold quality
stromal cell of endometrium	CL:0002255	82.44	gold quality
cortical plate	UBERON:0005343	81.54	gold quality
Ammon’s horn	UBERON:0001954	81.30	gold quality
telencephalon	UBERON:0001893	81.20	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.83	gold quality
cerebellar vermis	UBERON:0004720	80.66	gold quality
cingulate cortex	UBERON:0003027	80.03	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.43
E-MTAB-8060	no	58.95

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, ESR1, IL10, MYF6, TNF

miRNA regulators (miRDB)

266 targeting SCN8A, 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-6867-5P	100.00	82.21	3464
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-3163	100.00	77.23	8605
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4534	99.99	66.58	1907

Literature-anchored findings (GeneRIF, showing 40)

• Beta-scorpion toxin enhance channel activation, which could make it a model drug to replace deep brain stimulation of the subthalamic nucleus in patients with Parkinson disease. (PMID:16702217)
• Mmbrane-binding domain of ankyrin-G is critical for reducing the persistent sodium current of Nav1.6. (PMID:16775201)
• Different mechanisms underlie axonal degeneration in acute and chronic multiple sclerosis, with axonal injury at sites of coexpression of Nav1.6 and sodium-calcium exchanger in acute lesions but independent of coexpression in chronic lesions. (PMID:17805013)
• results demonstrate that genetic interactions can alter seizure severity and support the hypothesis that genetic modifiers contribute to the clinical variability observed in severe myoclonic epilepsy of infancy (PMID:17881658)
• The data of this study suggested that mutations of SCN8A are unlikely to be a major cause of autosomal dominant essential tremor in Caucasian patients. (PMID:18718804)
• he results of this study indicate that SCN8A may be a potential susceptibility gene for bipolar disorder in the Han Chinese population. (PMID:18812204)
• a variant of NaV1.6 participates in the control of podosome and invadopodia formation and suggest that intracellular sodium release mediated by NaV1.6 may regulate cellular invasion of macrophages and melanoma cells. (PMID:19136557)
• Using the whole-cell configuration of the patch-clamp technique, we investigated the Na(v)1.6 transient and persistent currents in HEK-293 cells. (PMID:20204400)
• Significant up-regulation of mRNA and protein for Nav1.6 is observed in rat hippocampal neurons following fluid percussion traumatic brain injury in an animal trial. (PMID:20421839)
• An important mechanism of electroacupuncture therapy is its regulation of Nav1.6 and Nav1.1 expression after ischemia. (PMID:20483028)
• Results show no significant difference in the size or immunofluorescence staining intensity of Na(v)1.6 nodal accumulations located at either typical or atypical nodal sites within axons in normal samples when compared to painful samples. (PMID:20600647)
• Our findings suggest that the SCN8A gene may be involved in the susceptibility to suicidal behavior among psychiatric disorder patients in the Han Chinese population. (PMID:20632842)
• Genetic variants of the SCN8A voltage-gated ion channel influence not only the phenotype of mice carrying the SCN1A mutation but also the seizure frequency. (PMID:21156207)
• The beta-subunits differentially regulate the expression and gating of Nav1.8 and Nav1.6 in dorsal root ganglion neurons. (PMID:21562192)
• We conclude that Na(V) 1.6 is upregulated in CaC and could serve as a novel molecular marker for the metastatic behavior of this carcinoma. (PMID:21630263)
• Discovered a de novo heterozygous missense mutation (c.5302A>G [p.Asn1768Asp]) in the voltage-gated sodium-channel gene SCN8A in the proband. (PMID:22365152)
• inhibition of GSK3 reduces the assembly of the FGF14.Nav channel complex, modifies FGF14-dependent regulation of Na(+) currents, and induces dissociation and subcellular redistribution of the native FGF14.Nav channel complex in hippocampal neurons. (PMID:23640885)
• Data support the contribution of gain-of-function mutations of Nav1.6 (de novo variant p.Thr767Ile) that increase excitatory pyramidal neuron excitability (PMID:24874546)
• SCN8A mutations can cause variable phenotypes, most of which can be diagnosed as unclassified early onset epileptic encephalopathies, and rarely as malignant migrating partial seizures in infancy. (PMID:24888894)
• SCN8A encephalopathy presents in infancy with multiple seizure types. (PMID:25568300)
• identified the PI3K/Akt pathway, the cell-cycle regulator Wee1 kinase, and protein kinase C (PKC) as prospective regulatory nodes of neuronal excitability through modulation of the FGF14:Nav1.6 complex. (PMID:25659151)
• These data strengthen previous findings linking gain-of-function mutations of SCN8A with EIEE and demonstrate the importance of functional testing in establishing the pathogenicity of de novo mutations. (PMID:25725044)
• The results of this study suggested that SCN8A mutation cause early onset epilepsy and intellectual disability. (PMID:25785782)
• Expression profiling of SCN8A and NDUFC2 genes in colorectal carcinoma is reported. There was no NDUFC2 differential expression in colorectal carcinoma. (PMID:25804238)
• Epileptic encephalopathy related to mutations in the SCN8A genes. (PMID:25818041)
• Human Nav1.6 channels generate larger resurgent currents than human Nav1.1 channels, but the SCN4B-derived Navbeta4 peptide does not protect either isoform from use-dependent reduction. (PMID:26182346)
• Our study establishes SCN8A as a novel gene in which a recurrent mutation causes BFIS/ICCA, expanding the clinical-genetic spectrum of combined epileptic and dyskinetic syndromes. (PMID:26677014)
• the calpain-dependent cleavage of Nav1.6 channels expressed in human embryonic kidney (HEK) 293 cells caused the upregulation of I(NaP) (PMID:26974309)
• Either the FGF14(V160A) or the FGF14(K74A/I76A) mutation was sufficient to abolish the FGF14-dependent regulation of peak transient Na(+) currents and the voltage-dependent activation and steady-state inactivation of Nav1.6; but only V160A with a concomitant alanine mutation at Tyr-158 could impede FGF14-dependent modulation of the channel fast inactivation. (PMID:26994141)
• Authors introduced mutations into Nav1.7 and Nav1.6 that either enhance or impair slow inactivation (SI) in order to investigate their effects on resurgent currents. The results show that enhanced SI is accompanied by impaired resurgent currents, which suggests that SI may interfere with open-channel block. (PMID:27174182)
• we report an infant and his father with early onset focal epileptic seizures but without cognitive or neurological impairment in whom next generation sequence analysis identified a heterozygous mutation (c.5630A > G, p. (Asn1877Ser)) in the SCN8A gene (PMID:27210545)
• Epilepsy-associated mutations in the voltage-gated sodium channel Nav1.6, but not Nav1.1, upregulate resurgent currents; cannabidiol preferentially targets these currents. (PMID:27267376)
• This study demonstrated that SCN8A - I1327V is a gain-of-function mutation with altered features that are predicted to increase neuronal excitability and seizure susceptibility. Phenytoin is an effective inhibitor of the mutant channel and may be of use in treating patients with gain-of-function mutations of SCN8A. (PMID:27375106)
• Study reports several novel variants in SCN8A that were identified by gene panel analysis in patients with epilepsy and other neurodevelopmental disorders. The predominant pathogenic mechanism appears to involve disruption of channel inactivation, leading to gain-of-function effects. (PMID:27875746)
• Pathogenic, likely pathogenic, and benign variants in SCNs were identified using databases of sodium channel variants. Benign variants were also identified from population-based databases. Eight algorithms commonly used to predict pathogenicity were compared. In addition, logistic regression was used to determine if a combination of algorithms could better predict pathogenicity. (PMID:28518218)
• SCN8A mutation is not only associated with epileptic encephalopathy, but also can be the pathogenic cause of some benign phenotypes, such as BFIS/ICCA, especially the inherited mutations. (PMID:28923014)
• These results expand the range of SCN8A variants in epileptic encephalopathy patients and illustrate the necessity of ongoing reanalysis of negative exome sequences, as advances in the knowledge of disease genes and their annotations will permit new diagnoses to be made. (PMID:29121005)
• Study represents the first evidence of the abnormal changes in voltage-gated sodium channels subtypes (including Nav1.8) and CaM/CaMKII pathway in human brain low-grade astrocytoma, providing new potential targets for molecular therapies of this disease. (PMID:29578003)
• Findings suggest that a palmitoylation-mediated KIF3A/delta-catenin/voltage-gated sodium channel Nav1.6 (Nav1.6) complex enhances the transmission of mechanical and nociceptive signals. (PMID:29588412)
• This study expands the phenotypic and functional spectrum of SCN8A variants to include inherited nonepileptic isolated myoclonus. SCN8A can be considered as a candidate gene for isolated movement disorders without seizures. (PMID:29726066)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	scn8aa	ENSDARG00000005775
danio_rerio	scn8ab	ENSDARG00000018032
mus_musculus	Scn8a	ENSMUSG00000023033
rattus_norvegicus	Scn8a	ENSRNOG00000005309

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), SCN11A (ENSG00000168356), SCN9A (ENSG00000169432), CATSPER1 (ENSG00000175294), SCN5A (ENSG00000183873), SCN10A (ENSG00000185313), TPCN1 (ENSG00000186815), CATSPER4 (ENSG00000188782), CACNA1H (ENSG00000196557), CACNA1E (ENSG00000198216)

Protein

Protein identifiers

Sodium channel protein type 8 subunit alpha — Q9UQD0 (reviewed: Q9UQD0)

Alternative names: Sodium channel protein type VIII subunit alpha, Voltage-gated sodium channel subunit alpha Nav1.6

All UniProt accessions (8): A0A1B0GVD4, A0A1B0GVM8, A0A1W2PQI5, A0A590UJP2, A0A590UK43, A0A590UK68, Q9UQD0, F8W0Q0

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming subunit of a voltage-gated sodium channel complex assuming opened or closed conformations in response to the voltage difference across membranes and through which sodium ions selectively pass along their electrochemical gradient. Contributes to neuronal excitability by regulating action potential threshold and propagation. More specifically expressed in non-neuronal cells, could play a role in sodium release from intracellular compartments and participate in the control of podosomes formation and macrophages adhesion and movement.

Subunit / interactions. The voltage-sensitive sodium channel consists of an ion-conducting pore-forming alpha subunit regulated by one or more beta-1 (SCN1B), beta-2 (SCN2B), beta-3 (SCN3B) and/or beta-4 (SCN4B) subunits. Beta-1 (SCN1B) and beta-3 (SCN3B) are non-covalently associated with alpha, while beta-2 (SCN2B) and beta-4 (SCN4B) are covalently linked by disulfide bonds. Interacts with NEDD4 and NEDD4L. Interacts with FGF13. Interacts with FGF14, GBG3, GBB2 and SCN1B. Interacts with TMEM233. Interacts with the conotoxin GVIIJ. Interacts with the spider beta/delta-theraphotoxin-Pre1a. Interacts with CALM1; the interaction modulates the inactivation rate of SCN8A.

Subcellular location. Cell membrane. Cell projection. Axon Cytoplasmic vesicle. Podosome.

Tissue specificity. Expressed in the hippocampus with increased expression in epileptic tissue compared to normal adjacent tissue (at protein level). Expressed in non-neuronal tissues, such as monocytes/macrophages.

Post-translational modifications. May be ubiquitinated by NEDD4L; which would promote its endocytosis. Phosphorylation at Ser-1497 by PKC in a highly conserved cytoplasmic loop slows inactivation of the sodium channel and reduces peak sodium currents.

Disease relevance. Cognitive impairment with or without cerebellar ataxia (CIAT) [MIM:614306] A disorder characterized by markedly delayed cognitive and motor development, attention deficit disorder, and cerebellar ataxia. Features include bilateral esophoria, strabismatic amblyopia, unsustained gaze evoked nystagmus on horizontal gaze, ataxic gait, dysmetria in the upper limbs and dysarthria, with normal strength, tone, and reflexes. The disease is caused by variants affecting the gene represented in this entry. Developmental and epileptic encephalopathy 13 (DEE13) [MIM:614558] A form of epilepsy characterized by frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst patterns, characterized by high-voltage bursts alternating with almost flat suppression phases. Patients may progress to West syndrome, which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG. DEE13 is a severe form consisting of early-onset seizures, features of autism, intellectual disability, ataxia, and sudden unexplained death in epilepsy. The disease is caused by variants affecting the gene represented in this entry. Seizures, benign familial infantile, 5 (BFIS5) [MIM:617080] A form of benign familial infantile epilepsy, a neurologic disorder characterized by afebrile seizures occurring in clusters during the first year of life, without neurologic sequelae. BFIS5 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry. Myoclonus, familial, 2 (MYOCL2) [MIM:618364] An autosomal dominant neurologic disorder characterized by upper limb isolated myoclonus without seizures or cognitive impairment. MYOCL2 is a non-progressive disease with onset in the first decade of life. The disease may be caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by tetrodotoxin and, more weakly, by its metabolite 4,9-ah-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.

Induction. Up-regulated in the hippocampus after epilepsy.

Similarity. Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.6/SCN8A subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9UQD0-1	1	yes
Q9UQD0-2	2, 5A
Q9UQD0-3	3
Q9UQD0-4	4, 18N
Q9UQD0-5	5, Delta18

RefSeq proteins (4): NP_001171455, NP_001317189, NP_001356717, NP_055006 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000048	IQ_motif_EF-hand-BS	Binding_site
IPR001696	Na_channel_asu	Family
IPR005821	Ion_trans_dom	Domain
IPR008054	Na_channel_a8su	Family
IPR010526	Na_trans_assoc_dom	Domain
IPR024583	Na_trans_cytopl	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, PF11933, PF24609

Catalyzed reactions (Rhea), 1 shown:

• Na(+)(in) = Na(+)(out) (RHEA:34963)

UniProt features (272 total): helix 63, sequence variant 46, topological domain 29, transmembrane region 24, strand 24, turn 20, sequence conflict 15, glycosylation site 8, compositionally biased region 7, disulfide bond 7, splice variant 6, region of interest 6, intramembrane region 4, repeat 4, binding site 3, modified residue 3, chain 1, mutagenesis site 1, domain 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
25II	ELECTRON MICROSCOPY	2.5
25IH	ELECTRON MICROSCOPY	2.8
9DK5	ELECTRON MICROSCOPY	2.9
25IJ	ELECTRON MICROSCOPY	3.1
8FHD	ELECTRON MICROSCOPY	3.1
8GZ2	ELECTRON MICROSCOPY	3.3
8GZ1	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UQD0-F1	68.90	0.16

Functional residue map

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

Ligand- & substrate-binding residues (3): 373; 936; 939

Post-translational modifications (3): 518, 520, 1497

Disulfide bonds (7): 281–333, 904, 904, 906–912, 944–953, 1356–1376, 1721–1736

Glycosylation sites (8): 215, 289, 295, 308, 326, 1358, 1372, 1383

Mutagenesis-validated functional residues (1):

Position	Phenotype
1416–1417	reduced inhibition by 4,9-anhydro-tetrodotoxin.

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: 468 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GCANCTGNY_MYOD_Q6, GOBP_MEMBRANE_DEPOLARIZATION_DURING_ACTION_POTENTIAL, GGGTGGRR_PAX4_03, AAAYRNCTG_UNKNOWN, GOBP_MONOATOMIC_CATION_TRANSPORT, PATIL_LIVER_CANCER, GOBP_MUSCLE_CONTRACTION, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM2, GOBP_ENSHEATHMENT_OF_NEURONS, BILD_E2F3_ONCOGENIC_SIGNATURE, MODULE_206

GO Biological Process (13): action potential (GO:0001508), sodium ion transport (GO:0006814), peripheral nervous system development (GO:0007422), sodium ion transmembrane transport (GO:0035725), myelination (GO:0042552), cardiac muscle cell action potential involved in contraction (GO:0086002), regulation of heart rate (GO:0002027), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085), cardiac muscle cell action potential (GO:0086001), regulation of muscle system process (GO:0090257), monoatomic cation transmembrane transport (GO:0098655)

GO Molecular Function (6): voltage-gated sodium channel activity (GO:0005248), sodium ion binding (GO:0031402), monoatomic ion channel activity (GO:0005216), monoatomic cation channel activity (GO:0005261), sodium channel activity (GO:0005272), protein binding (GO:0005515)

GO Cellular Component (13): voltage-gated sodium channel complex (GO:0001518), podosome (GO:0002102), plasma membrane (GO:0005886), membrane (GO:0016020), Z disc (GO:0030018), cell junction (GO:0030054), axon (GO:0030424), cytoplasmic vesicle (GO:0031410), node of Ranvier (GO:0033268), axon initial segment (GO:0043194), monoatomic ion channel complex (GO:0034702), cell projection (GO:0042995), anchoring junction (GO:0070161)

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
cellular anatomical structure	6
transport	2
main axon	2
regulation of membrane potential	1
metal ion transport	1
nervous system development	1
system development	1
sodium ion transport	1
monoatomic cation transmembrane transport	1
axon ensheathment	1
cardiac muscle cell action potential	1
cardiac muscle cell contraction	1
regulation of heart contraction	1
regulation of biological quality	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
action potential	1
muscle system process	1
regulation of system process	1
monoatomic cation transport	1
monoatomic ion transmembrane transport	1
sodium channel activity	1
alkali metal ion binding	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
binding	1
sodium channel complex	1
plasma membrane protein complex	1
actin-based cell projection	1
membrane	1
cell periphery	1
I band	1
neuron projection	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

1983 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SCN8A	NAV1	Q8NEY1	936
SCN8A	ANK3	Q12955	914
SCN8A	KCNQ2	O43526	906
SCN8A	SCNM1	Q9BWG6	889
SCN8A	FGF14	Q92915	886
SCN8A	SCN1B	Q07699	876
SCN8A	CALM1	P02593	859
SCN8A	KCNA1	Q09470	826
SCN8A	SCN4B	Q8IWT1	822
SCN8A	NFASC	O94856	759
SCN8A	CALML3	P27482	753
SCN8A	CALML5	Q9NZT1	753
SCN8A	CALML6	Q8TD86	744
SCN8A	CALML4	Q96GE6	744
SCN8A	KCNA2	P16389	733

IntAct

122 interactions, top by confidence:

A	B	Type	Score
SCN8A	FGF14	psi-mi:“MI:0915”(physical association)	0.630
FGF14	SCN8A	psi-mi:“MI:0915”(physical association)	0.630
SCN8A	SNX27	psi-mi:“MI:0407”(direct interaction)	0.440
SCN8A	SNTB1	psi-mi:“MI:0407”(direct interaction)	0.440
SCN8A	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
SCN8A	PDZK1	psi-mi:“MI:0407”(direct interaction)	0.440
SCN8A	SNTA1	psi-mi:“MI:0407”(direct interaction)	0.440
SCN8A	DLG4	psi-mi:“MI:0407”(direct interaction)	0.440
SCN8A	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
SCN8A	SNTG2	psi-mi:“MI:0407”(direct interaction)	0.440
SCN8A	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.440
SCN8A	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
MAST1	SCN8A	psi-mi:“MI:0407”(direct interaction)	0.440
SYNJ2BP	SCN8A	psi-mi:“MI:0407”(direct interaction)	0.440
SCN8A	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
SCN8A	DLG1	psi-mi:“MI:0407”(direct interaction)	0.440
SCN8A	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
DLG2	SCN8A	psi-mi:“MI:0407”(direct interaction)	0.440
SCN8A	GIPC2	psi-mi:“MI:0407”(direct interaction)	0.440
SCN8A	PDZRN3	psi-mi:“MI:0407”(direct interaction)	0.440
SCN8A	TIAM2	psi-mi:“MI:0407”(direct interaction)	0.440
SCN8A	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
SCN8A	MAGI3	psi-mi:“MI:0407”(direct interaction)	0.440
SCN8A	TAX1BP3	psi-mi:“MI:0407”(direct interaction)	0.440
PATJ	SCN8A	psi-mi:“MI:0407”(direct interaction)	0.440
SCN8A	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (15): SCN8A (Reconstituted Complex), SCN8A (Affinity Capture-Luminescence), SCN8A (Affinity Capture-Western), SCN8A (Affinity Capture-MS), SCN8A (Proximity Label-MS), FGF14 (Reconstituted Complex), SCN8A (Affinity Capture-MS), SCN8A (Positive Genetic), SCN8A (Affinity Capture-RNA), SCN8A (Cross-Linking-MS (XL-MS)), SCN8A (Affinity Capture-MS), GAPDH (Cross-Linking-MS (XL-MS)), SCN8A (Cross-Linking-MS (XL-MS)), SCN8A (Cross-Linking-MS (XL-MS)), NEDD4 (Affinity Capture-Western)

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

27 interactions.

A	Effect	B	Mechanism
SCN8A	“up-regulates quantity”	sodium(1+)	relocalization
CALM1	“down-regulates activity”	SCN8A	binding
FGF13	“down-regulates activity”	SCN8A	binding
FGF12	“down-regulates activity”	SCN8A	binding
FGF14	“down-regulates activity”	SCN8A	binding
FGF11	“down-regulates activity”	SCN8A	binding
SCN8A	up-regulates	Action_potential
CALM2	“down-regulates activity”	SCN8A	binding
CALM3	“down-regulates activity”	SCN8A	binding
CAMK2A	“up-regulates activity”	SCN8A	phosphorylation
CAMK2B	“up-regulates activity”	SCN8A	phosphorylation
CAMK2D	“up-regulates activity”	SCN8A	phosphorylation
CAMK2G	“up-regulates activity”	SCN8A	phosphorylation
NEDD4L	“down-regulates quantity by destabilization”	SCN8A	ubiquitination
ESR1	“up-regulates quantity by expression”	SCN8A	“transcriptional regulation”
TNF	“up-regulates quantity by expression”	SCN8A	“transcriptional regulation”
TNF	“up-regulates activity”	SCN8A
IL10	“down-regulates quantity by repression”	SCN8A	“transcriptional regulation”
GSK3B	“up-regulates activity”	SCN8A	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	5	51.9×	2e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	49.4×	2e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	49.4×	2e-06
Long-term potentiation	5	43.3×	3e-06
Assembly and cell surface presentation of NMDA receptors	8	36.9×	4e-09
Neurexins and neuroligins	9	32.2×	1e-09
Protein-protein interactions at synapses	5	24.1×	6e-05
RHOA GTPase cycle	5	6.8×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	11	79.9×	2e-16
protein localization to synapse	6	57.5×	9e-08
receptor clustering	7	54.6×	1e-08
regulation of postsynaptic membrane neurotransmitter receptor levels	7	43.4×	4e-08
cell-cell adhesion	10	12.7×	6e-07
protein-containing complex assembly	8	11.4×	3e-05
chemical synaptic transmission	7	6.8×	2e-03
nervous system development	8	4.6×	7e-03

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

2442 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	134
Likely pathogenic	192
Uncertain significance	1053
Likely benign	739
Benign	77

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1005108	NM_001330260.2(SCN8A):c.2617G>A (p.Gly873Ser)	Pathogenic
1007517	NM_001330260.2(SCN8A):c.2674G>A (p.Val892Met)	Pathogenic
1043511	NM_001330260.2(SCN8A):c.1100T>C (p.Met367Thr)	Pathogenic
1053572	NM_001330260.2(SCN8A):c.4651dup (p.Glu1551fs)	Pathogenic
1057399	NM_001330260.2(SCN8A):c.727G>T (p.Ala243Ser)	Pathogenic
1058374	NM_001330260.2(SCN8A):c.3664_3719dup (p.Tyr1241fs)	Pathogenic
1068482	NM_001330260.2(SCN8A):c.3943G>A (p.Val1315Met)	Pathogenic
1164029	NM_001330260.2(SCN8A):c.4064del (p.Tyr1355fs)	Pathogenic
1197048	NM_001330260.2(SCN8A):c.2548C>T (p.Arg850Ter)	Pathogenic
1254380	NM_001330260.2(SCN8A):c.3914G>C (p.Arg1305Thr)	Pathogenic
1318723	NM_001330260.2(SCN8A):c.2916del (p.Leu973fs)	Pathogenic
1318747	NM_001330260.2(SCN8A):c.2539C>T (p.Arg847Ter)	Pathogenic
1318887	NM_001330260.2(SCN8A):c.1511_1512del (p.Leu503_Ser504insTer)	Pathogenic
1342316	NM_001330260.2(SCN8A):c.2901+2T>C	Pathogenic
1345807	NM_001330260.2(SCN8A):c.4423G>C (p.Gly1475Arg)	Pathogenic
1346284	NM_001330260.2(SCN8A):c.4583T>A (p.Ile1528Asn)	Pathogenic
1346826	NM_001330260.2(SCN8A):c.4613C>A (p.Thr1538Lys)	Pathogenic
1354780	NM_001330260.2(SCN8A):c.4568C>A (p.Ala1523Asp)	Pathogenic
1393473	NM_001330260.2(SCN8A):c.2364_2370+1del	Pathogenic
1399415	NM_001330260.2(SCN8A):c.632T>G (p.Val211Gly)	Pathogenic
1414886	NM_001330260.2(SCN8A):c.4586dup (p.Met1529fs)	Pathogenic
1439030	NM_001330260.2(SCN8A):c.4122_4123del (p.Glu1375fs)	Pathogenic
1448037	NM_001330260.2(SCN8A):c.4605_4606del (p.Met1536fs)	Pathogenic
1456194	NM_001330260.2(SCN8A):c.4245G>A (p.Trp1415Ter)	Pathogenic
1482151	NM_001330260.2(SCN8A):c.4487G>A (p.Gly1496Asp)	Pathogenic
1515093	NM_001330260.2(SCN8A):c.4384G>A (p.Val1462Ile)	Pathogenic
1526183	NM_001330260.2(SCN8A):c.2548C>G (p.Arg850Gly)	Pathogenic
156106	NM_001330260.2(SCN8A):c.4850G>A (p.Arg1617Gln)	Pathogenic
156107	NM_001330260.2(SCN8A):c.4398C>A (p.Asn1466Lys)	Pathogenic
156108	NM_001330260.2(SCN8A):c.4397A>C (p.Asn1466Thr)	Pathogenic

SpliceAI

5370 predictions. Top by Δscore:

Variant	Effect	Δscore
12:51591357:GCC:G	donor_gain	1.0000
12:51591360:G:GG	donor_gain	1.0000
12:51662759:TCCA:T	acceptor_loss	1.0000
12:51662760:CCAG:C	acceptor_gain	1.0000
12:51662761:CAG:C	acceptor_gain	1.0000
12:51662762:A:AG	acceptor_gain	1.0000
12:51662762:A:AT	acceptor_loss	1.0000
12:51662762:AGA:A	acceptor_gain	1.0000
12:51662763:G:A	acceptor_loss	1.0000
12:51662763:G:GA	acceptor_gain	1.0000
12:51662763:G:T	acceptor_gain	1.0000
12:51662763:GA:G	acceptor_gain	1.0000
12:51662763:GAGC:G	acceptor_gain	1.0000
12:51662763:GAGCT:G	acceptor_gain	1.0000
12:51662995:G:GT	donor_gain	1.0000
12:51663003:G:GT	donor_gain	1.0000
12:51663003:G:T	donor_gain	1.0000
12:51663090:GAAA:G	donor_gain	1.0000
12:51663094:G:GG	donor_gain	1.0000
12:51663141:GCT:G	donor_gain	1.0000
12:51687217:GGC:G	donor_gain	1.0000
12:51687218:GC:G	donor_gain	1.0000
12:51687218:GCG:G	donor_gain	1.0000
12:51687220:G:GG	donor_gain	1.0000
12:51699568:A:AG	acceptor_gain	1.0000
12:51699569:G:GG	acceptor_gain	1.0000
12:51699770:G:GT	donor_gain	1.0000
12:51699790:AA:A	donor_gain	1.0000
12:51699791:AG:A	donor_loss	1.0000
12:51699792:G:GG	donor_gain	1.0000

AlphaMissense

13237 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:51686407:C:A	N145K	1.000
12:51686407:C:G	N145K	1.000
12:51686408:T:C	C146R	1.000
12:51686410:T:G	C146W	1.000
12:51686418:T:C	M149T	1.000
12:51686419:G:A	M149I	1.000
12:51686419:G:C	M149I	1.000
12:51686419:G:T	M149I	1.000
12:51687098:T:C	F165L	1.000
12:51687100:C:A	F165L	1.000
12:51687100:C:G	F165L	1.000
12:51687146:G:C	G181R	1.000
12:51687185:T:A	W194R	1.000
12:51687185:T:C	W194R	1.000
12:51687190:C:A	N195K	1.000
12:51687190:C:G	N195K	1.000
12:51687197:G:C	D198H	1.000
12:51687198:A:C	D198A	1.000
12:51687198:A:T	D198V	1.000
12:51689054:T:C	F222L	1.000
12:51689056:C:A	F222L	1.000
12:51689056:C:G	F222L	1.000
12:51689058:G:C	R223T	1.000
12:51689058:G:T	R223M	1.000
12:51689059:G:C	R223S	1.000
12:51689059:G:T	R223S	1.000
12:51689064:T:A	L225H	1.000
12:51689064:T:C	L225P	1.000
12:51689075:A:G	K229E	1.000
12:51689076:A:T	K229I	1.000

dbSNP variants (sampled 300 via entrez): RS1000055724 (12:51688193 T>C), RS1000064442 (12:51637971 A>T), RS1000064746 (12:51740140 T>G), RS1000086411 (12:51791080 A>T), RS1000099885 (12:51637626 G>C), RS1000100700 (12:51592476 C>T), RS1000123455 (12:51785430 A>C,G), RS1000155642 (12:51701360 T>C), RS1000173820 (12:51746307 C>T), RS1000187263 (12:51747839 C>T), RS1000193218 (12:51608952 G>C), RS1000218380 (12:51644656 C>T), RS1000221297 (12:51695389 C>T), RS1000227577 (12:51792522 C>G), RS1000233113 (12:51654894 G>A)

Disease associations

OMIM: gene MIM:600702 | disease phenotypes: MIM:614306, MIM:614558, MIM:617080, MIM:618364, MIM:308350, MIM:618004, MIM:611162, MIM:108600, MIM:209850, MIM:617468, MIM:208150

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 13	Definitive	Autosomal dominant
complex neurodevelopmental disorder	Definitive	Autosomal dominant
cognitive impairment with or without cerebellar ataxia	Strong	Autosomal dominant
seizures, benign familial infantile, 5	Strong	Autosomal dominant
benign familial infantile epilepsy	Supportive	Autosomal dominant
infantile convulsions and choreoathetosis	Supportive	Autosomal dominant
undetermined early-onset epileptic encephalopathy	Supportive	Autosomal dominant
myoclonus, familial, 2	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex neurodevelopmental disorder	Definitive	AD

Mondo (24): early-infantile DEE (MONDO:0800491), cognitive impairment with or without cerebellar ataxia (MONDO:0013680), developmental and epileptic encephalopathy, 13 (MONDO:0013801), seizures, benign familial infantile, 5 (MONDO:0014903), myoclonus, familial, 2 (MONDO:0100092), developmental and epileptic encephalopathy (MONDO:0100620), neurodevelopmental disorder (MONDO:0700092), focal epilepsy (MONDO:0005384), complex neurodevelopmental disorder (MONDO:0100038), infantile spasms (MONDO:0018097), developmental and epileptic encephalopathy, 1 (MONDO:0010632), hereditary ataxia (MONDO:0100309), epilepsy (MONDO:0005027), developmental and epileptic encephalopathy, 64 (MONDO:0033373), undetermined early-onset epileptic encephalopathy (MONDO:0018614)

Orphanet (14): Early infantile developmental and epileptic encephalopathy (Orphanet:1934), Self-limited infantile epilepsy (Orphanet:306), Non-specific early-onset epileptic encephalopathy (Orphanet:442835), Non-specific syndromic intellectual disability (Orphanet:528084), West syndrome (Orphanet:3451), Infantile epileptic spasms syndrome (Orphanet:697160), Hereditary ataxia (Orphanet:183518), Malaria (Orphanet:673), Spastic ataxia (Orphanet:316226), Rare ataxia (Orphanet:102002), Arthrogryposis multiplex congenita (Orphanet:1037), Fetal akinesia deformation sequence (Orphanet:994), Early myoclonic encephalopathy (Orphanet:1935), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

126 total (30 of 126 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000348	High forehead
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000504	Abnormality of vision
HP:0000508	Ptosis
HP:0000520	Proptosis
HP:0000546	Retinal degeneration
HP:0000609	Optic nerve hypoplasia
HP:0000639	Nystagmus
HP:0000640	Gaze-evoked nystagmus
HP:0000643	Blepharospasm
HP:0000646	Amblyopia
HP:0000648	Optic atrophy
HP:0000668	Hypodontia
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000722	Compulsive behaviors
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0000961	Cyanosis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001260	Dysarthria

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST003628_10	Clozapine-induced agranulocytosis/granulocytopenia in treatment-resistant schizophrenia	4.000000e-06
GCST003813_1	Response to antidepressants and depression	5.000000e-07
GCST007576_394	Chronotype	7.000000e-10
GCST007576_43	Chronotype	7.000000e-10
GCST008258_17	Alcohol use disorder (consumption score)	5.000000e-08
GCST008757_33	Alcohol consumption	2.000000e-09

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0007645	longitudinal alcohol consumption measurement
EFO:0009458	alcohol use disorder measurement

MeSH disease descriptors (9)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D004828	Epilepsies, Partial	C10.228.140.490.360
D004827	Epilepsy	C10.228.140.490
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625
C531684	Hereditary spinal ataxia (supp.)
C535522	Infantile convulsions and paroxysmal choreoathetosis, familial (supp.)
C564815	Spastic Ataxia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL2331043 (PROTEIN FAMILY), CHEMBL4523624 (PROTEIN-PROTEIN INTERACTION), CHEMBL4523671 (PROTEIN COMPLEX), CHEMBL5202 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

25 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 480,660 (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
CHEMBL698	TETRACAINE	4	43,379
CHEMBL113461	TEDISAMIL	3	1,251
CHEMBL475534	NITRENDIPINE	3	16,468
CHEMBL5314404	AJMALINE	3
CHEMBL3544913	VIXOTRIGINE	3	374
CHEMBL3707392	ELECLAZINE	3	111
CHEMBL507974	TETRODOTOXIN	3	1,034
CHEMBL87045	CIFENLINE	2	1,298
CHEMBL2325014	PF-05089771	2	219
CHEMBL3707218	FUNAPIDE	2
CHEMBL4633566	DS-1971	2
CHEMBL4650313	ZANDATRIGINE	2
CHEMBL2324748	PF-05150122	1
CHEMBL2324776	PF-05186462	1

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4512905	SCN8A		0.00	0

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 (15 total), top 15:

Ligand	Action	Affinity	Parameter
tetrodotoxin	Pore blocker	8.2	pIC50
XPC-5462	Channel blocker	7.99	pIC50
4,9-anhydro-tetrodotoxin	Inhibition	7.8	pIC50
GNE-616	Inhibition	7.54	pKd
zandatrigine	Inhibition	7.29	pIC50
XPC-7224	Channel blocker	7.11	pIC50
GNE-131	Inhibition	7.04	pIC50
relutrigine	Inhibition	6.85	pIC50
funapide	Inhibition	6.77	pIC50
ATX-II	Slows inactivation	6.7	pEC50
AFT-II	Slows inactivation	6.5	pEC50
AM-6120	Inhibition	6.22	pIC50
Bc-III	Slows inactivation	6.0	pEC50
cannabidiol	Channel blocker	5.52	pIC50
PF-04885614	Inhibition	5.38	pIC50

Binding affinities (BindingDB)

970 measured of 1042 human assays (1042 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
(S)-N-((R or S)-(4- chloro-3- (trifluoromethyl) phenyl)(4- chlorophenyl) methyl)-2- oxooxazolidine-5- carboxamide	IC50	0.4 nM	US-12516046: 2-oxo-oxazolidine-5-carboxamides as NAV1.8 inhibitors
(S)—N—((R)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(4-chlorophenyl)methyl)-2-oxooxazolidine-5-carboxamide and (S)—N—((S)-(5-chloro-6-(trifluoromethyl)pyridin-2-yl)(4-chlorophenyl)methyl)-2-oxooxazolidine-5-carboxamide	IC50	0.6 nM	US-12516046: 2-oxo-oxazolidine-5-carboxamides as NAV1.8 inhibitors
(S)-N-((R or S)-(4- chloro-3- methylphenyl)(4- chlorophenyl) methyl)-2- oxooxazolidine-5- carboxamide	IC50	0.6 nM	US-12516046: 2-oxo-oxazolidine-5-carboxamides as NAV1.8 inhibitors
(S)-N-(bis(3- chloro-4- fluorophenyl) methyl)-2- oxooxazolidine-5- carboxamide	IC50	0.7 nM	US-12516046: 2-oxo-oxazolidine-5-carboxamides as NAV1.8 inhibitors
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
(S)—N—((R)-(3-chloro-4-fluorophenyl)(4-chlorophenyl)methyl)-2-oxooxazolidine-5-carboxamide and (S)—N—((S)-(3-chloro-4-fluorophenyl)(4-chlorophenyl)methyl)-2-oxooxazolidine-5-carboxamide	IC50	0.9 nM	US-12516046: 2-oxo-oxazolidine-5-carboxamides as NAV1.8 inhibitors
(S)-N-((R or S)-(3- chloro-4-(trifluoro- methoxy)phenyl)(1- (trifluoromethyl)- 1H-pyrazol-4- yl)methyl)-2- oxooxazolidine-5- carboxamide	IC50	1.2 nM	US-12516046: 2-oxo-oxazolidine-5-carboxamides as NAV1.8 inhibitors
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
(S)-N-((R or S)-(4- chloro-2- (trifluoromethoxy) phenyl)(4- chlorophenyl) methyl)-2- oxooxazolidine-5- carboxamide	IC50	1.6 nM	US-12516046: 2-oxo-oxazolidine-5-carboxamides as NAV1.8 inhibitors
(S)—N—((R)-(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2-oxooxazolidine-5-carboxamide and (S)—N—((S)-(3-chloro-2,4-difluorophenyl)(6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)-2-oxooxazolidine-5-carboxamide	IC50	1.6 nM	US-12516046: 2-oxo-oxazolidine-5-carboxamides as NAV1.8 inhibitors
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
(S)-N-((R or S)-(3- chloro-4-cyano- phenyl)(5-chloro-6- (trifluoromethyl) pyridin-3-yl)methyl)- 2-oxooxazolidine-5- carboxamide	IC50	1.7 nM	US-12516046: 2-oxo-oxazolidine-5-carboxamides as NAV1.8 inhibitors
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
(S)-N-((R or S)-(4- chloro-3- methylphenyl)(4- chlorophenyl) methyl)-2- oxooxazolidine-5- carboxamide	IC50	1.8 nM	US-12516046: 2-oxo-oxazolidine-5-carboxamides as NAV1.8 inhibitors
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
(5S)-N-((3-chloro- 4-fluorophenyl)(5- fluoro-6- (trifluoromethyl) pyridin-2-yl)methyl)- 2-oxooxazolidine- 5-carboxamide	IC50	2.1 nM	US-12516046: 2-oxo-oxazolidine-5-carboxamides as NAV1.8 inhibitors
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

ChEMBL bioactivities

1972 potent at pChembl≥5 of 2040 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.22	IC50	0.06	nM	CHEMBL4061793
10.05	IC50	0.09	nM	CHEMBL4062780
9.10	IC50	0.8	nM	CHEMBL3617063
9.00	IC50	1	nM	CHEMBL5833484
9.00	IC50	1	nM	CHEMBL5742330
9.00	IC50	1	nM	CHEMBL6011164
9.00	IC50	1	nM	CHEMBL3678273
8.96	IC50	1.1	nM	SAXITOXIN
8.92	IC50	1.2	nM	CHEMBL5182397
8.70	IC50	2	nM	CHEMBL5871830
8.70	IC50	2	nM	CHEMBL5744537
8.70	IC50	2	nM	CHEMBL6024655
8.70	IC50	2	nM	CHEMBL5870618
8.70	IC50	2	nM	CHEMBL5860643
8.70	IC50	2	nM	CHEMBL5956982
8.70	IC50	2	nM	CHEMBL3683097
8.64	IC50	2.3	nM	TETRODOTOXIN
8.59	IC50	2.6	nM	CHEMBL5196342
8.54	IC50	2.9	nM	CHEMBL5193659
8.52	IC50	3	nM	CHEMBL5748509
8.52	IC50	3	nM	CHEMBL5742330
8.52	IC50	3	nM	CHEMBL3678270
8.47	IC50	3.4	nM	CHEMBL5194703
8.40	IC50	4	nM	CHEMBL5764406
8.40	IC50	4	nM	CHEMBL5953924
8.39	IC50	4.1	nM	CHEMBL5183619
8.38	IC50	4.2	nM	CHEMBL5197040
8.33	IC50	4.7	nM	CHEMBL4090731
8.30	IC50	5	nM	CHEMBL5818848
8.30	IC50	5	nM	CHEMBL3683093
8.26	IC50	5.461	nM	CHEMBL4217988
8.24	IC50	5.8	nM	CHEMBL4217988
8.22	IC50	6	nM	CHEMBL3678272
8.21	EC50	6.2	nM	CHEMBL4742035
8.20	EC50	6.31	nM	CHEMBL4742035
8.15	IC50	7	nM	CHEMBL5847585
8.15	IC50	7	nM	CHEMBL6031316
8.15	IC50	7	nM	CHEMBL5844365
8.15	IC50	7	nM	CHEMBL3678274
8.10	IC50	8	nM	CHEMBL5954138
8.10	IC50	8	nM	CHEMBL5860643
8.05	IC50	9	nM	CHEMBL5954138
8.05	IC50	9	nM	CHEMBL5751525
8.05	IC50	9	nM	CHEMBL5833484
8.00	IC50	10	nM	CHEMBL5871830
8.00	IC50	10	nM	CHEMBL5762999
8.00	IC50	10	nM	CHEMBL5765991
8.00	IC50	10	nM	CHEMBL5884546
8.00	IC50	10	nM	CHEMBL5756729
8.00	IC50	10	nM	CHEMBL5817529

PubChem BioAssay actives

115 with measured affinity, of 297 total; 50 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
5-chloro-2-fluoro-4-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethylamino)-N-(1,3-thiazol-2-yl)benzenesulfonamide	1710504: Inhibition of human Nav1.6 alpha expressed in HEK293 cells incubated for 5 mins with 6 consecutive train pulses to -10 mV at 0.1 Hz and holding potential of -65 mV by Qube-automated patch clamp assay	ic50	0.0001	uM
5-chloro-4-[[(8R)-6,6-dimethyl-2,3,5,7-tetrahydro-1H-pyrrolizin-8-yl]methylamino]-2-fluoro-N-(1,3-thiazol-2-yl)benzenesulfonamide	1710504: Inhibition of human Nav1.6 alpha expressed in HEK293 cells incubated for 5 mins with 6 consecutive train pulses to -10 mV at 0.1 Hz and holding potential of -65 mV by Qube-automated patch clamp assay	ic50	0.0001	uM
4-[2-(2-amino-3H-benzimidazol-5-yl)-4-chlorophenoxy]-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide	1300006: Inhibition of full length human Nav1.6 channel expressed in HEK cells co-expressing human sodium channel subunit beta1 at holding potential -35 mV by automated voltage clamp analysis	ic50	0.0008	uM
[(3aS,4R,10aS)-2,6-diamino-10,10-dihydroxy-3a,4,8,9-tetrahydro-1H-pyrrolo[1,2-c]purin-4-yl]methyl carbamate	1525393: Inhibition of human Nav1.6 expressed in HEK293 cells by electrophysiology assay	ic50	0.0011	uM
(3S)-N-[(4-chlorophenyl)-[4-chloro-3-(trifluoromethyl)phenyl]methyl]-5-oxopyrrolidine-3-carboxamide	1880269: Inhibition of human Nav1.8 channel stably expressed in HEK293 cells assessed as sodium current flow at holding potential of -90mV by whole-cell voltage clamp assay	ic50	0.0012	uM
(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	1525393: Inhibition of human Nav1.6 expressed in HEK293 cells by electrophysiology assay	ic50	0.0023	uM
(3S)-N-[(4-chlorophenyl)-[4-fluoro-3-(trifluoromethyl)phenyl]methyl]-5-oxopyrrolidine-3-carboxamide	1880269: Inhibition of human Nav1.8 channel stably expressed in HEK293 cells assessed as sodium current flow at holding potential of -90mV by whole-cell voltage clamp assay	ic50	0.0026	uM
(3S)-N-[(3-chloro-4-fluorophenyl)-[5-fluoro-6-(trifluoromethyl)-2-pyridinyl]methyl]-5-oxopyrrolidine-3-carboxamide	1880269: Inhibition of human Nav1.8 channel stably expressed in HEK293 cells assessed as sodium current flow at holding potential of -90mV by whole-cell voltage clamp assay	ic50	0.0029	uM
(3S)-N-[(3-chloro-4-fluorophenyl)-(4-chlorophenyl)methyl]-5-oxopyrrolidine-3-carboxamide	1880269: Inhibition of human Nav1.8 channel stably expressed in HEK293 cells assessed as sodium current flow at holding potential of -90mV by whole-cell voltage clamp assay	ic50	0.0034	uM
(3S)-N-[(4-chlorophenyl)-[4-(trifluoromethoxy)phenyl]methyl]-5-oxopyrrolidine-3-carboxamide	1880269: Inhibition of human Nav1.8 channel stably expressed in HEK293 cells assessed as sodium current flow at holding potential of -90mV by whole-cell voltage clamp assay	ic50	0.0041	uM
(3S)-N-[(3-chloro-2,4-difluorophenyl)-[5-chloro-6-(trifluoromethyl)-3-pyridinyl]methyl]-5-oxopyrrolidine-3-carboxamide	1880269: Inhibition of human Nav1.8 channel stably expressed in HEK293 cells assessed as sodium current flow at holding potential of -90mV by whole-cell voltage clamp assay	ic50	0.0042	uM
5-chloro-4-[[(8S)-6,6-dimethyl-2,3,5,7-tetrahydro-1H-pyrrolizin-8-yl]methylamino]-2-fluoro-N-(1,3-thiazol-2-yl)benzenesulfonamide	1710504: Inhibition of human Nav1.6 alpha expressed in HEK293 cells incubated for 5 mins with 6 consecutive train pulses to -10 mV at 0.1 Hz and holding potential of -65 mV by Qube-automated patch clamp assay	ic50	0.0047	uM
3-cyano-4-[2-[2-[(2-piperidin-4-ylethylamino)methyl]-4-pyridinyl]-4-[3-(trifluoromethyl)phenyl]phenoxy]-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide	1365879: Inhibition of human Nav1.6 expressed in HEK cells by patch clamp electrophysiology method	ic50	0.0055	uM
4-[2-(3-amino-1,2-benzoxazol-5-yl)-4-chlorophenoxy]-2,5-difluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide	1300006: Inhibition of full length human Nav1.6 channel expressed in HEK cells co-expressing human sodium channel subunit beta1 at holding potential -35 mV by automated voltage clamp analysis	ic50	0.0110	uM
2,6-difluoro-4-[[2-fluoro-6-[[methyl(propan-2-yl)amino]methyl]phenyl]methylamino]-N-(1,3-thiazol-4-yl)benzenesulfonamide	1616304: Inhibition of recombinant human full length Nav1.6 co-expressed with human SCN1B in HEK293 cells measured after 20 mins at -45 mV holding potential by whole cell patch clamp assay	ic50	0.0200	uM
5-chloro-2-fluoro-4-[[(1S)-1-phenylethyl]amino]-N-(1,3-thiazol-2-yl)benzenesulfonamide	1616304: Inhibition of recombinant human full length Nav1.6 co-expressed with human SCN1B in HEK293 cells measured after 20 mins at -45 mV holding potential by whole cell patch clamp assay	ic50	0.0200	uM
(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(1R,4S,7S,13S,16R,21R,24S,27S,30S,33S,36S,39S,42R,45S,48S,51S,54S,57S,60R,65R,68S,71S,74S)-27,57-bis(4-aminobutyl)-21-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-24-(3-amino-3-oxopropyl)-54,74-bis(3-carbamimidamidopropyl)-13,51-bis(2-carboxyethyl)-45-(carboxymethyl)-39-[(1R)-1-hydroxyethyl]-48-(hydroxymethyl)-30,36,68-tris(1H-indol-3-ylmethyl)-71-(2-methylpropyl)-7,33-bis(2-methylsulfanylethyl)-3,6,9,12,15,22,25,28,31,34,37,40,43,46,49,52,55,58,67,70,73,76,81-tricosaoxo-4-propan-2-yl-18,19,62,63,78,79-hexathia-2,5,8,11,14,23,26,29,32,35,38,41,44,47,50,53,56,59,66,69,72,75,82-tricosazatricyclo[40.34.4.216,60]dooctacontane-65-carbonyl]amino]hexanoyl]amino]hexanoyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	1388449: Inhibition of Nav1.6 (unknown origin)	ic50	0.0260	uM
(4S)-6-fluoro-4-[(2R,4S)-2-pyridin-2-yl-4-(trifluoromethyl)piperidin-1-yl]-N-pyrimidin-4-yl-3,4-dihydro-2H-chromene-7-sulfonamide	1587766: Inhibition of full length human Nav1.6 expressed in CHO cells at -60 mV holding potential by manual patch clamp electrophysiology method	kd	0.0290	uM
4-[[2-(azetidin-1-ylmethyl)-6-fluorophenyl]methylamino]-5-chloro-2-fluoro-N-(1,3-thiazol-4-yl)benzenesulfonamide	1616304: Inhibition of recombinant human full length Nav1.6 co-expressed with human SCN1B in HEK293 cells measured after 20 mins at -45 mV holding potential by whole cell patch clamp assay	ic50	0.0300	uM
5-cyclopropyl-N-cyclopropylsulfonyl-2-fluoro-4-[(6-methylspiro[2.5]octan-6-yl)methoxy]benzamide	1525393: Inhibition of human Nav1.6 expressed in HEK293 cells by electrophysiology assay	ic50	0.0380	uM
5-chloro-2-fluoro-4-[[(1R)-2-methoxy-1-phenylethyl]amino]-N-(1,3-thiazol-2-yl)benzenesulfonamide	1616304: Inhibition of recombinant human full length Nav1.6 co-expressed with human SCN1B in HEK293 cells measured after 20 mins at -45 mV holding potential by whole cell patch clamp assay	ic50	0.0400	uM
5-chloro-4-[[(1S)-1-(2,4-difluorophenyl)ethyl]amino]-2-fluoro-N-(1,3-thiazol-2-yl)benzenesulfonamide	1616304: Inhibition of recombinant human full length Nav1.6 co-expressed with human SCN1B in HEK293 cells measured after 20 mins at -45 mV holding potential by whole cell patch clamp assay	ic50	0.0400	uM
4-[[2-[[tert-butyl(methyl)amino]methyl]-6-fluorophenyl]methylamino]-2,6-difluoro-N-(1,3-thiazol-4-yl)benzenesulfonamide	1616304: Inhibition of recombinant human full length Nav1.6 co-expressed with human SCN1B in HEK293 cells measured after 20 mins at -45 mV holding potential by whole cell patch clamp assay	ic50	0.0400	uM
5-cyclopropyl-N-cyclopropylsulfonyl-4-[(4,4-difluoro-1-methylcyclohexyl)methoxy]-2-fluorobenzamide	1960146: Inhibition of human Nav1.6 alpha subunit expressed in HEK293 cells co-expressing beta1 subunit at -35 mV holding potential by PatchXpress automated voltage clamp electrophysiology technique	ic50	0.0490	uM
3-chloro-4-(1-phenylpropylamino)-N-(1,3-thiazol-2-yl)benzenesulfonamide	1616304: Inhibition of recombinant human full length Nav1.6 co-expressed with human SCN1B in HEK293 cells measured after 20 mins at -45 mV holding potential by whole cell patch clamp assay	ic50	0.0500	uM
4-[[(3R)-1-benzylpyrrolidin-3-yl]-methylamino]-2-fluoro-5-methyl-N-(1,3-thiazol-4-yl)benzenesulfonamide	2030283: Inhibition of human Nav1.6 expressed in HEK293 cells by automated patch-clamp assay	ic50	0.0510	uM
Pimozide	1207165: Inhibition of Na channel (species unknown)	ic50	0.0540	uM
4-[[2-[(2,2-dimethylazetidin-1-yl)methyl]-6-fluorophenyl]methylamino]-2,6-difluoro-N-(1,3-thiazol-4-yl)benzenesulfonamide	1616304: Inhibition of recombinant human full length Nav1.6 co-expressed with human SCN1B in HEK293 cells measured after 20 mins at -45 mV holding potential by whole cell patch clamp assay	ic50	0.0600	uM
2,6-difluoro-4-[[(1S)-1-(2-fluorophenyl)ethyl]amino]-N-(1,3-thiazol-4-yl)benzenesulfonamide	1616304: Inhibition of recombinant human full length Nav1.6 co-expressed with human SCN1B in HEK293 cells measured after 20 mins at -45 mV holding potential by whole cell patch clamp assay	ic50	0.0600	uM
(4S)-4-[[(2S)-6-amino-2-[[(2S)-5-carbamimidamido-2-[[(1R,4S,7S,13S,16R,21R,24S,27S,30S,33S,36S,39S,42R,45S,48S,51S,54S,57S,60R,65R,68S,71S,74S)-27,51,74-tris(4-aminobutyl)-24-(3-amino-3-oxopropyl)-21-[[(2S)-2-[[(2S)-2-aminopent-4-ynoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-68-[(5-bromo-1H-indol-3-yl)methyl]-33-butyl-4,54-bis(3-carbamimidamidopropyl)-13-(2-carboxyethyl)-45-(carboxymethyl)-39-[(1R)-1-hydroxyethyl]-48-(hydroxymethyl)-30,36-bis(1H-indol-3-ylmethyl)-57-methyl-7,71-bis(2-methylpropyl)-3,6,9,12,15,22,25,28,31,34,37,40,43,46,49,52,55,58,67,70,73,76,81-tricosaoxo-18,19,62,63,78,79-hexathia-2,5,8,11,14,23,26,29,32,35,38,41,44,47,50,53,56,59,66,69,72,75,82-tricosazatricyclo[40.34.4.216,60]dooctacontane-65-carbonyl]amino]pentanoyl]amino]hexanoyl]amino]-5-[[(2S,3S)-1-amino-3-methyl-1-oxopentan-2-yl]amino]-5-oxopentanoic acid	1363505: Inhibition of human Nav1.6 expressed in HEK293 cells at holding potential of -125 mV after 10 mins by patchxpress-based electrophysiology assay	ic50	0.0660	uM
2,6-difluoro-4-[[(1S)-1-(2-fluoro-5-methoxyphenyl)ethyl]amino]-N-(1,3-thiazol-4-yl)benzenesulfonamide	1616304: Inhibition of recombinant human full length Nav1.6 co-expressed with human SCN1B in HEK293 cells measured after 20 mins at -45 mV holding potential by whole cell patch clamp assay	ic50	0.0700	uM
3-[(1R,4S,7S,13S,16R,21R,24S,27S,30S,33S,36S,39S,42R,45S,48S,51S,54S,57S,60R,65R,68S,71S,74S)-65-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-amino-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxohexan-2-yl]carbamoyl]-27,57-bis(4-aminobutyl)-21-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-24-(3-amino-3-oxopropyl)-54,74-bis(3-carbamimidamidopropyl)-51-(2-carboxyethyl)-45-(carboxymethyl)-39-[(1R)-1-hydroxyethyl]-48-(hydroxymethyl)-30,36,68-tris(1H-indol-3-ylmethyl)-71-(2-methylpropyl)-7,33-bis(2-methylsulfanylethyl)-3,6,9,12,15,22,25,28,31,34,37,40,43,46,49,52,55,58,67,70,73,76,81-tricosaoxo-4-propan-2-yl-18,19,62,63,78,79-hexathia-2,5,8,11,14,23,26,29,32,35,38,41,44,47,50,53,56,59,66,69,72,75,82-tricosazatricyclo[40.34.4.216,60]dooctacontan-13-yl]propanoic acid	1818597: Inhibition of human Nav1.6 stably expressed in cells with train pulses to -20 mV at 0.1 Hz and holding potential of -85 mV by whole-cell Qube-automated patch clamp assay	ic50	0.0750	uM
5-chloro-2-fluoro-4-[[(1S)-1-pyridin-3-ylethyl]amino]-N-(1,3-thiazol-2-yl)benzenesulfonamide	1616304: Inhibition of recombinant human full length Nav1.6 co-expressed with human SCN1B in HEK293 cells measured after 20 mins at -45 mV holding potential by whole cell patch clamp assay	ic50	0.0800	uM
4-[2-oxo-1-(2-piperidin-1-ylethyl)quinolin-6-yl]oxybenzonitrile	1891571: Inhibition of human Nav1.8 by FRET based membrane potential assay	ic50	0.0800	uM
N-[7-(1-adamantylmethoxy)-6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl]cyclopropanesulfonamide	1410606: Inhibition of inactivated state of recombinant human NaV1.6 expressed in HEK293 cell membranes coexpressing Nav beta1 subunit assessed as decrease in sodium current amplitude at -35 mV holding potential by QPatch-HT/Qube384 automated voltage clamp method	ic50	0.0920	uM
3-chloro-4-(1-phenylethylamino)-N-(1,3-thiazol-2-yl)benzenesulfonamide	1616304: Inhibition of recombinant human full length Nav1.6 co-expressed with human SCN1B in HEK293 cells measured after 20 mins at -45 mV holding potential by whole cell patch clamp assay	ic50	0.1000	uM
(4S)-4-amino-5-[[(2S)-1-[[(1R,4S,7S,13S,16R,21R,24S,27S,30S,33S,36S,39S,42R,45S,48S,51S,54S,57S,60R,65R,68S,71S,74S)-65-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S,3S)-1-amino-3-methyl-1-oxopentan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]carbamoyl]-27,74-bis(4-aminobutyl)-24-(3-amino-3-oxopropyl)-68-[(5-bromo-1H-indol-3-yl)methyl]-33-butyl-4,54-bis(3-carbamimidamidopropyl)-13-(2-carboxyethyl)-45-(carboxymethyl)-39-[(1R)-1-hydroxyethyl]-48-(hydroxymethyl)-30,36-bis(1H-indol-3-ylmethyl)-51,57-dimethyl-7,71-bis(2-methylpropyl)-3,6,9,12,15,22,25,28,31,34,37,40,43,46,49,52,55,58,67,70,73,76,81-tricosaoxo-18,19,62,63,78,79-hexathia-2,5,8,11,14,23,26,29,32,35,38,41,44,47,50,53,56,59,66,69,72,75,82-tricosazatricyclo[40.34.4.216,60]dooctacontan-21-yl]amino]-1-oxopent-4-yn-2-yl]amino]-5-oxopentanoic acid	1363505: Inhibition of human Nav1.6 expressed in HEK293 cells at holding potential of -125 mV after 10 mins by patchxpress-based electrophysiology assay	ic50	0.1040	uM
5-chloro-2-fluoro-4-[[(1S)-1-(2-fluoro-5-methoxyphenyl)ethyl]amino]-N-(1,3-thiazol-4-yl)benzenesulfonamide	1616304: Inhibition of recombinant human full length Nav1.6 co-expressed with human SCN1B in HEK293 cells measured after 20 mins at -45 mV holding potential by whole cell patch clamp assay	ic50	0.1100	uM
4-[(3S,4S)-3-(3,4-difluorophenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy-3,5-difluoro-N-(6-fluoro-2-pyridinyl)benzenesulfonamide	1754512: Inhibition of human Nav1.6 by V1/2 protocol based analysis	ic50	0.1100	uM
5-chloro-4-[[(1S)-1-(2,5-difluorophenyl)ethyl]amino]-2-fluoro-N-(1,3-thiazol-4-yl)benzenesulfonamide	1616304: Inhibition of recombinant human full length Nav1.6 co-expressed with human SCN1B in HEK293 cells measured after 20 mins at -45 mV holding potential by whole cell patch clamp assay	ic50	0.1190	uM
4-[[(1S)-1-[5-(azetidin-1-ylmethyl)-2-fluorophenyl]ethyl]amino]-5-chloro-2-fluoro-N-(1,3-thiazol-4-yl)benzenesulfonamide	1616304: Inhibition of recombinant human full length Nav1.6 co-expressed with human SCN1B in HEK293 cells measured after 20 mins at -45 mV holding potential by whole cell patch clamp assay	ic50	0.1200	uM
3-chloro-4-[[(1S)-1-phenylethyl]amino]-N-(1,3-thiazol-2-yl)benzenesulfonamide	1616304: Inhibition of recombinant human full length Nav1.6 co-expressed with human SCN1B in HEK293 cells measured after 20 mins at -45 mV holding potential by whole cell patch clamp assay	ic50	0.1300	uM
(3S)-3-amino-4-oxo-4-[[(1R,4S,7S,10S,13S,16S,19R,24R,27S,30S,33S,36S,39S,42S,45R,51S,54S,57S,60R,65R,68S,71S,74S,77S,83S)-7,30,36,42,57-pentakis(4-aminobutyl)-77-benzyl-39,68-bis(3-carbamimidamidopropyl)-24-[[(2S)-1-[[(2S)-1-[[(2S)-3-carboxy-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-[[(1S,2R)-1-carboxy-2-hydroxypropyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]carbamoyl]-4,13-bis(2-carboxyethyl)-10,16,83-tris(carboxymethyl)-27,71-bis[(4-hydroxyphenyl)methyl]-54-(1H-imidazol-5-ylmethyl)-51-(2-methylpropyl)-33,74-bis(2-methylsulfanylethyl)-2,5,8,11,14,17,26,29,32,35,38,41,44,47,50,53,56,59,66,69,72,75,78,81,84,91-hexacosaoxo-21,22,62,63,87,88-hexathia-3,6,9,12,15,18,25,28,31,34,37,40,43,46,49,52,55,58,67,70,73,76,79,82,85,90-hexacosazatricyclo[43.40.4.219,60]hennonacontan-65-yl]amino]butanoic acid	1525393: Inhibition of human Nav1.6 expressed in HEK293 cells by electrophysiology assay	ic50	0.1300	uM
4-[[(1S)-1-(5-cyano-2-fluorophenyl)ethyl]amino]-2,6-difluoro-N-(1,3-thiazol-4-yl)benzenesulfonamide	1616304: Inhibition of recombinant human full length Nav1.6 co-expressed with human SCN1B in HEK293 cells measured after 20 mins at -45 mV holding potential by whole cell patch clamp assay	ic50	0.1400	uM
4-[2-(5-amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-(1,3-thiazol-4-yl)benzenesulfonamide	1525393: Inhibition of human Nav1.6 expressed in HEK293 cells by electrophysiology assay	ic50	0.1600	uM
(7S)-1’-[[5-(trifluoromethyl)furan-2-yl]methyl]spiro[6H-furo[2,3-f][1,3]benzodioxole-7,3’-indole]-2’-one	1525393: Inhibition of human Nav1.6 expressed in HEK293 cells by electrophysiology assay	ic50	0.1700	uM
(4S)-4-[[(2S)-6-amino-2-[[(2S)-5-carbamimidamido-2-[[(1R,4S,7S,13S,16R,21R,24S,27S,30S,33S,36S,39S,42R,45S,48S,51S,54S,57S,60R,65R,68S,71S,74S)-27,51,74-tris(4-aminobutyl)-24-(3-amino-3-oxopropyl)-21-[[(2S)-2-[[(2S)-2-aminopent-4-ynoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-33-butyl-4,54-bis(3-carbamimidamidopropyl)-13-(2-carboxyethyl)-45-(carboxymethyl)-39-[(1R)-1-hydroxyethyl]-48-(hydroxymethyl)-30,36,68-tris(1H-indol-3-ylmethyl)-57-methyl-7,71-bis(2-methylpropyl)-3,6,9,12,15,22,25,28,31,34,37,40,43,46,49,52,55,58,67,70,73,76,81-tricosaoxo-18,19,62,63,78,79-hexathia-2,5,8,11,14,23,26,29,32,35,38,41,44,47,50,53,56,59,66,69,72,75,82-tricosazatricyclo[40.34.4.216,60]dooctacontane-65-carbonyl]amino]pentanoyl]amino]hexanoyl]amino]-5-[[(2S,3S)-1-amino-3-methyl-1-oxopentan-2-yl]amino]-5-oxopentanoic acid	1363505: Inhibition of human Nav1.6 expressed in HEK293 cells at holding potential of -125 mV after 10 mins by patchxpress-based electrophysiology assay	ic50	0.1830	uM
N-[7-(1-adamantylmethoxy)-6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl]methanesulfonamide	1410606: Inhibition of inactivated state of recombinant human NaV1.6 expressed in HEK293 cell membranes coexpressing Nav beta1 subunit assessed as decrease in sodium current amplitude at -35 mV holding potential by QPatch-HT/Qube384 automated voltage clamp method	ic50	0.1900	uM
5-cyclopropyl-4-[[1-[(1S)-1-(3,5-dichlorophenyl)ethyl]piperidin-4-yl]methoxy]-2-fluoro-N-methylsulfonylbenzamide	1831651: Inhibition of human Nav1.6 expressed in CHO cells by whole cell voltage clamp analysis	ic50	0.1980	uM
4-[4-chloro-2-(2-methylpyrazol-3-yl)phenoxy]-3-cyano-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide	1457693: Inhibition of human NaV1.6 expressed in HEK cells assessed as half inactivation potential at -120 mV holding potential by automated patch clamp method	ic50	0.1990	uM

CTD chemical–gene interactions

30 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects methylation	2
Tretinoin	increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
bisphenol F	affects cotreatment, decreases expression	1
bisphenol A	affects cotreatment, decreases expression	1
arsenite	affects binding, decreases reaction	1
decamethrin	affects activity	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
prothioconazole	decreases expression	1
NSC 689534	affects binding, increases expression	1
Temozolomide	affects response to substance	1
Sunitinib	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cannabidiol	decreases activity	1
Carmustine	affects response to substance	1
Copper	affects binding, increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment	1
Melphalan	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	decreases methylation	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression	1
Genistein	decreases expression	1

ChEMBL screening assays

173 unique, capped per target: 148 binding, 16 functional, 7 admet, 2 toxicity

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
CHEMBL4040129	ADMET	Inhibition of human NaV1.6 expressed in HEK cells assessed as half inactivation potential at -120 mV holding potential by automated patch clamp method	Discovery of Clinical Candidate 4-[2-(5-Amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-1,3-thiazol-4-ylbenzenesulfonamide (PF-05089771): Design and Optimization of Diaryl Ether Aryl Sulfonamides as Selective Inhibitors of NaV1.7. — J Med Chem

Cellosaurus cell lines

2 cell lines: 1 induced pluripotent stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C0II	CIPi002-A	Induced pluripotent stem cell	Female
CVCL_LC68	PrecisION hNav1.6-HEK	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT03347526	PHASE3	SUSPENDED	A Novel Approach to Infantile Spasms
NCT03421496	PHASE3	TERMINATED	A Study to Assess Cannabidiol Oral Solution With Vigabatrin as Initial Therapy in Participants With Infantile Spasms
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT04289467	PHASE2	RECRUITING	Treatment of Refractory Infantile Spasms With Fenfluramine
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT04727970	PHASE1	COMPLETED	Tricaprilin Infantile Spasms Pilot Study
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT05818553	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	A Clinical Trial of PRAX-562 in Subjects With Developmental and Epileptic Encephalopathies (DEE)
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT00006191	Not specified	COMPLETED	Effect of Levetiracetam on Brain Excitability
NCT02960347	Not specified	COMPLETED	Examining the Efficacy of tDCS in the Attenuation of Epileptic Paroxysmal Discharges and Clinical Seizures
NCT06938542	Not specified	ENROLLING_BY_INVITATION	Palliative Care Needs of Children With Rare Diseases and Their Families
NCT07585643	Not specified	NOT_YET_RECRUITING	IBIS - Investigating Reliability of BIS and SEDLINE Monitoring in Children With Developmental and Epileptic Encephalopathies (DEE).
NCT03876444	PHASE2/PHASE3	UNKNOWN	Intravenous Methylprednisolone Versus Oral Prednisolone for Infantile Spasms
NCT05279118	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Ketogenic Diet vs ACTH for the Treatment of Children With West Syndrome
NCT05364021	PHASE1/PHASE2	COMPLETED	Study to Investigate LP352 in Subjects With Developmental and Epileptic Encephalopathies
NCT06983158	PHASE1/PHASE2	SUSPENDED	A Clinical Trial of CAP-002 Gene Therapy in Pediatric Patients With Syntaxin-Binding Protein 1 (STXBP1) Encephalopathy
NCT04937062	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Phenylbutyrate for Monogenetic Developmental and Epileptic Encephalopathy
NCT04302116	Not specified	RECRUITING	Vigabatrin With High Dose Prednisolone Combination Therapy vs Vigabatrin Alone for Infantile Spasm
NCT05538936	Not specified	COMPLETED	The Effect of Spa and Massage on Babies on Colic Symptoms
NCT06149663	Not specified	AVAILABLE	Intermediate-Size Expanded Access Protocol (EAP) for LP352
NCT06266234	Not specified	RECRUITING	Characterization by Automated System on Infantile Spasmes
NCT06380192	Not specified	RECRUITING	Developmental and Epileptic Encephalopathy of Genetic Etiology: Natural History Through Reuse of Clinical Data
NCT07396883	Not specified	NOT_YET_RECRUITING	Developmental and Epileptic Encephalopathies Diagnosed Via Long-read Genome Sequencing
NCT07413211	Not specified	RECRUITING	Genetic Developmental and Epileptic Encephalopathy Natural History Study for Clinical Trial Readiness
NCT07531511	Not specified	NOT_YET_RECRUITING	SLC6A1-NDD Prospective Longitudinal Natural History Study