SCN5A

Summary

SCN5A (sodium voltage-gated channel alpha subunit 5, HGNC:10593) is a protein-coding gene on chromosome 3p22.2, encoding Sodium channel protein type 5 subunit alpha (Q14524). Pore-forming subunit of Nav1.5, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is an integral membrane protein and tetrodotoxin-resistant voltage-gated sodium channel subunit. This protein is found primarily in cardiac muscle and is responsible for the initial upstroke of the action potential in an electrocardiogram. Defects in this gene have been associated with long QT syndrome type 3 (LQT3), atrial fibrillation, cardiomyopathy, and Brugada syndrome 1, all autosomal dominant cardiac diseases. Alternative splicing results in several transcript variants encoding different isoforms.

Source: NCBI Gene 6331 — RefSeq curated summary.

At a glance

• Gene–disease (curated): dilated cardiomyopathy 1E (Definitive, ClinGen) — +14 more curated relationships
• GWAS associations: 193
• Clinical variants (ClinVar): 4,569 total — 274 pathogenic, 143 likely-pathogenic
• Phenotypes (HPO): 105
• Druggable target: yes — 108 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000335

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10593
Approved symbol	SCN5A
Name	sodium voltage-gated channel alpha subunit 5
Location	3p22.2
Locus type	gene with protein product
Status	Approved
Aliases	Nav1.5, LQT3, HB1, HBBD, PFHB1, IVF, HB2, HH1, SSS1, CDCD2, CMPD2, ICCD
Ensembl gene	ENSG00000183873
Ensembl biotype	protein_coding
OMIM	600163
Entrez	6331

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 9 protein_coding, 4 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000327956, ENST00000333535, ENST00000413689, ENST00000414099, ENST00000423572, ENST00000449557, ENST00000450102, ENST00000455624, ENST00000464652, ENST00000476683, ENST00000491944, ENST00000713730, ENST00000713731, ENST00000718272, ENST00000718273, ENST00000970295

RefSeq mRNA: 9 — MANE Select: NM_000335 NM_000335, NM_001099404, NM_001099405, NM_001160160, NM_001160161, NM_001354701, NM_001407185, NM_001407187, NM_198056

CCDS: CCDS46796, CCDS46797, CCDS46798, CCDS46799, CCDS54569, CCDS54570

Canonical transcript exons

ENST00000423572 — 28 exons

Exon	Start	End
ENSE00001293012	38562415	38562537
ENSE00001299736	38606669	38606810
ENSE00001300049	38598918	38599050
ENSE00001300791	38604729	38604908
ENSE00001301918	38560147	38560428
ENSE00001302724	38580931	38581371
ENSE00001304836	38566409	38566582
ENSE00001306185	38587400	38587573
ENSE00001308928	38576661	38576781
ENSE00001315108	38585691	38586041
ENSE00001320962	38605951	38606148
ENSE00001322079	38603712	38604083
ENSE00001328382	38575297	38575451
ENSE00001329449	38597729	38597967
ENSE00001330780	38608151	38608214
ENSE00001414724	38609734	38609964
ENSE00001425187	38556441	38556578
ENSE00001647919	38555656	38555760
ENSE00001779170	38633035	38633359
ENSE00003464330	38620843	38620971
ENSE00003534979	38554279	38554549
ENSE00003562400	38622400	38622489
ENSE00003585523	38630311	38630429
ENSE00004014126	38557231	38557284
ENSE00004014127	38613743	38613834
ENSE00004014128	38579334	38579492
ENSE00004014129	38548062	38551558
ENSE00004021056	38649531	38649687

Expression profiles

Bgee: expression breadth ubiquitous, 161 present calls, max score 95.49.

FANTOM5 (CAGE): breadth broad, TPM avg 2.8378 / max 306.5993, expressed in 695 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
41716	2.8309	695
41715	0.0069	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	95.49	gold quality
heart left ventricle	UBERON:0002084	93.12	gold quality
cardiac ventricle	UBERON:0002082	92.91	gold quality
right atrium auricular region	UBERON:0006631	92.69	gold quality
cardiac atrium	UBERON:0002081	91.94	gold quality
left ventricle myocardium	UBERON:0006566	91.09	gold quality
heart right ventricle	UBERON:0002080	88.93	gold quality
heart	UBERON:0000948	88.05	gold quality
myocardium	UBERON:0002349	87.83	gold quality
cardiac muscle of right atrium	UBERON:0003379	85.22	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.53	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.13	gold quality
secondary oocyte	CL:0000655	74.40	silver quality
sural nerve	UBERON:0015488	72.76	gold quality
vena cava	UBERON:0004087	72.38	silver quality
pigmented layer of retina	UBERON:0001782	71.27	silver quality
ventricular zone	UBERON:0003053	70.42	gold quality
middle temporal gyrus	UBERON:0002771	67.56	gold quality
gingival epithelium	UBERON:0001949	66.66	gold quality
Brodmann (1909) area 23	UBERON:0013554	65.56	gold quality
ganglionic eminence	UBERON:0004023	65.11	gold quality
germinal epithelium of ovary	UBERON:0001304	64.07	gold quality
gingiva	UBERON:0001828	64.02	gold quality
endocervix	UBERON:0000458	62.34	gold quality
cervix squamous epithelium	UBERON:0006922	62.33	gold quality
superficial temporal artery	UBERON:0001614	62.25	gold quality
adrenal tissue	UBERON:0018303	62.24	gold quality
ascending aorta	UBERON:0001496	62.11	gold quality
thoracic aorta	UBERON:0001515	62.09	gold quality
ectocervix	UBERON:0012249	61.78	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.87

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ANK3, CTNNB1, ESR1, ESR2, FOXK1, FOXO1, GTF3A, IL10, IRF6, MAFB, MYOG, NFKBIA, PARP1, SP1, TBX5, TCF7L2, THRA, TNF, USF1, VSX2

miRNA regulators (miRDB)

83 targeting SCN5A, 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-6798-5P	100.00	65.77	699
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
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-513B-5P	99.99	69.96	2150
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-4446-5P	99.72	69.19	2544

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• A G-to-T mutation at position 4372 was identified by direct sequencing and was predicted to change a glycine for an arginine (G1406R) between the DIII-S5 and DIII-S6 domain of the SCN5A sodium channel protein. (PMID:11748104)
• Results support the concept that loss of function of the cardiac Na(+) channel is responsible for the Brugada syndrome. (PMID:11786529)
• Mutation analysis seems to show SUNDS of Asia and Brugada syndrome of Europe are phenotypically and genetically the same. (PMID:11823453)
• Associated with Brugada syndrome, but patients may not have known mutation. (PMID:11960580)
• three new SCN5A mutations in Brugada syndrome patients are all located within domain I of SCN5A, a region not previously considered important in the development of ventricular arrhythmias (PMID:12051963)
• Longer conduction intervals on baseline ECG were observed in patients with established SCN5A mutations. Brugada-syndrome patients with and without SCN5A mutations can be differentiated by phenotypical differences. (PMID:12106943)
• identified a variant of the cardiac sodium channel gene SCN5A that is associated with arrhythmia in African Americans and linked with arrhythmia risk in an African-American family (PMID:12193783)
• Drug-induced long-QT syndrome associated with a subclinical SCN5A mutation (PMID:12208804)
• SCN5A is more widely distributed than previously thought and encodes the pore-forming alpha-subunit of the tetrodotoxin-resistant Na+ current in jejunum smooth muscle cells. (PMID:12358675)
• regulation of gating by syntrophin gamma 2 (PMID:12429735)
• Early & late openings in cell-attached patches expressing human cardiac NaCh alpha-subunit & in ventricular cells of one normal & three failing human hearts showed that the late current is generated by a single population of channels in both. (PMID:12431447)
• SNP S1103Y in the cardiac sodium channel gene SCN5A is associated with cardiac arrhythmias and sudden death in a white family (PMID:12471205)
• Familial Atrial standstill was associated with the concurrence of a cardiac sodium channel mutation and rare polymorphisms in the atrial-specific Cx40 gene (PMID:12522116)
• SCN5A mutation is modulated by the SCN5a polymorphism in humans (PMID:12569159)
• Congenital long QT syndrome and 2:1 atrioventricular block may be due to mutation of the SCN5A gene (LQT3). (PMID:12574983)
• Another gene other than the SCN5A may be associated with Brugada syndrome. (PMID:12639704)
• missense mutations in KCNQ1 and SCN5A in a case of congenital Long QT Syndrome (PMID:12820704)
• Four variants of SCN5A are present in human myocardium and exhibit functional differences having implications for the choice of background sequence for experiments with heterologous expression systems, and possibly electrophysiological function in vivo (PMID:14500339)
• A base sequence deletion in SCN5A causes long QT syndrome in two family members. (PMID:14654377)
• SCN5A the gene encoding the pore-forming subunit of the cardiac Na+ channel, have been associated with cardiac rhythm syndromes. (PMID:14720472)
• Mutations in the SCN5A gene encoding the cardiac voltage-gated Na+ channel (hNav1.5) are associated with Brugada syndrome. (PMID:15057319)
• Na(v)1.5 can be ubiquitinated in heart tissues and that the ubiquitin-protein ligase Nedd4-2 acts on Na(v)1.5 by decreasing the channel density at the cell surface. The effect of Nedd4-2 requires the PY-motif of Nav1.5. (PMID:15217910)
• Two novel SCN5A mutations have been found in Japanese patients with Brugada syndrome. (PMID:15277732)
• SCN5A gene is not commonly involved in the pathogenesis of the Brugada Syndrome and associated disorders. (PMID:15306732)
• Calmodulin mediates Ca2+ sensitivity of Nav1.2 and Nav1.5 sodium channels (PMID:15316014)
• report of a novel mutation in SCN5A associated with Brugada syndrome in Koreans (PMID:15338453)
• A heterozygous G-to-A mutation at position 3823(D1275N) in a highly conserved residue of exon 21 is associated with an autosomal dominant cardiac conduction disorder, sinus node dysfunction, arrhythmia, ventricular dilatation & dysfunction. (PMID:15466643)
• Acute and chronic cell hypoxia regulate sodium currents by recombinant hNa(v)1.5 alpha. (PMID:15504354)
• ankyrin-G participates in a common pathway for localization of voltage-gated Na(v) channels at sites of function in multiple excitable cell types (PMID:15579534)
• Phenylalanine deletion alters the voltage dependence of fast inactivation via a reduction in the gating charge. (PMID:15665061)
• Heritable SCN5A defects are associated with susceptibility to early-onset DCM and atrial fibrillation. Similar or even identical mutations may lead to heart failure, arrhythmia, or both. (PMID:15671429)
• Chimeric channels of NaV1.4 and NaV1.5 also indicated that the C-terminal domain is largely responsible for calmodulin effects on inactivation (PMID:15746172)
• mechanisms for S1759 involvement in slow inactivation and for antagonism between fast and slow inactivation (PMID:15805167)
• A novel intronic mutation in the SCN5A gene in a large family with Brugada syndrome was identified. (PMID:15808832)
• Brugada syndrome is an inherited cardiac disorder caused by mutations in the SCN5A gene encoding the cardiac sodium channel alpha-subunit, and potentially leads to ventricular fibrillation and sudden death. (PMID:15828879)
• a human cardiac sodium channel mutation(E161K) may have a role in sick sinus syndrome, conduction disease and Brugada syndrome (PMID:15910881)
• The Y1102 allele is a risk factor in blacks for sudden cardiac death in the absence of obvious morphological findings or mild to moderate cardiomegaly. (PMID:16061744)
• Up-regulation of neonatal Na(v)1.5 occurs as an integral part of the metastatic process in human breast cancer (PMID:16061851)
• These results suggest that SCN5A has a newly identified exon for alternative splicing and is more widely expressed than previously thought. (PMID:16115203)
• This suggests that genetic determinants located in KCNQ1, KCNE1, KCNH2 and SCN5A influence QTc length in healthy individuals and may represent risk factors for arrhythmias or cardiac sudden death in patients with cardiovascular diseases. (PMID:16132053)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Scn5a	ENSMUSG00000032511
rattus_norvegicus	Scn5a	ENSRNOG00000015049

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), SCN10A (ENSG00000185313), TPCN1 (ENSG00000186815), CATSPER4 (ENSG00000188782), CACNA1H (ENSG00000196557), SCN8A (ENSG00000196876), CACNA1E (ENSG00000198216)

Protein

Protein identifiers

Sodium channel protein type 5 subunit alpha — Q14524 (reviewed: Q14524)

Alternative names: Sodium channel protein cardiac muscle subunit alpha, Sodium channel protein type V subunit alpha, Voltage-gated sodium channel subunit alpha Nav1.5, hH1

All UniProt accessions (9): A0A0A0MT39, A0AAQ5BGT0, A0AAQ5BGV8, A3EY21, E9PG18, Q14524, E9PHB6, H9KVD2, K4DIA1

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming subunit of Nav1.5, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes. Navs, also called VGSCs (voltage-gated sodium channels) or VDSCs (voltage-dependent sodium channels), operate by switching between closed and open conformations depending on the voltage difference across the membrane. In the open conformation they allow Na(+) ions to selectively pass through the pore, along their electrochemical gradient. The influx of Na(+) ions provokes membrane depolarization, initiating the propagation of electrical signals throughout cells and tissues. Nav1.5 is the predominant sodium channel expressed in myocardial cells and it is responsible for the initial upstroke of the action potential in cardiac myocytes, thereby initiating the heartbeat. Required for normal electrical conduction including formation of the infranodal ventricular conduction system and normal action potential configuration, as a result of its interaction with XIRP2.

Subunit / interactions. Cannot form the same regulatory interactions with beta subunits as other Navs do. Interacts with the PDZ domain of the syntrophin SNTA1, SNTB1 and SNTB2. Interacts with NEDD4, NEDD4L, WWP2 and GPD1L. Interacts with CALM. Interacts with FGF13; the interaction is direct and FGF13 may regulate SNC5A density at membranes and function. May also interact with FGF12 and FGF14. Interacts with TMEM233. Interacts with the spider Jingzhaotoxin-I (AC P83974, AC B1P1B7, AC B1P1B8). Interacts with ANK3. Interacts with PKP2 (via N-terminus). Interacts with XIRP2; the interaction is required for normal action potential configuration in the heart.

Subcellular location. Cell membrane. Cytoplasm. Perinuclear region. Sarcolemma. T-tubule. Cell junction.

Tissue specificity. Found in jejunal circular smooth muscle cells (at protein level). Expressed in human atrial and ventricular cardiac muscle but not in adult skeletal muscle, brain, myometrium, liver, or spleen. Isoform 4 is expressed in brain.

Post-translational modifications. Ubiquitinated by NEDD4L; which promotes its endocytosis. Does not seem to be ubiquitinated by NEDD4 or WWP2. Phosphorylation at Ser-1503 by PKC in a highly conserved cytoplasmic loop slows inactivation of the sodium channel and reduces peak sodium currents. Regulated through phosphorylation by CaMK2D. Lacks the cysteine which covalently binds the conotoxin GVIIJ. This cysteine (position 868) is speculated in other sodium channel subunits alpha to be implied in covalent binding with the sodium channel subunit beta-2 or beta-4. N-glycosylated at Asn-318, probably hinders potential interaction with regulatory subunits.

Disease relevance. Progressive familial heart block 1A (PFHB1A) [MIM:113900] A cardiac bundle branch disorder characterized by progressive alteration of cardiac conduction through the His-Purkinje system, with a pattern of a right bundle-branch block and/or left anterior hemiblock occurring individually or together. It leads to complete atrio-ventricular block causing syncope and sudden death. The disease is caused by variants affecting the gene represented in this entry. Long QT syndrome 3 (LQT3) [MIM:603830] A heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. The disease is caused by variants affecting the gene represented in this entry. Brugada syndrome 1 (BRGDA1) [MIM:601144] A tachyarrhythmia characterized by right bundle branch block and ST segment elevation on an electrocardiogram (ECG). It can cause the ventricles to beat so fast that the blood is prevented from circulating efficiently in the body. When this situation occurs, the individual will faint and may die in a few minutes if the heart is not reset. The disease is caused by variants affecting the gene represented in this entry. Sick sinus syndrome 1 (SSS1) [MIM:608567] The term ‘sick sinus syndrome’ encompasses a variety of conditions caused by sinus node dysfunction. The most common clinical manifestations are syncope, presyncope, dizziness, and fatigue. Electrocardiogram typically shows sinus bradycardia, sinus arrest, and/or sinoatrial block. Episodes of atrial tachycardias coexisting with sinus bradycardia (’tachycardia-bradycardia syndrome’) are also common in this disorder. SSS occurs most often in the elderly associated with underlying heart disease or previous cardiac surgery, but can also occur in the fetus, infant, or child without heart disease or other contributing factors. SSS1 onset is in utero, infancy, or early childhood. The disease is caused by variants affecting the gene represented in this entry. Familial paroxysmal ventricular fibrillation 1 (VF1) [MIM:603829] A cardiac arrhythmia marked by fibrillary contractions of the ventricular muscle due to rapid repetitive excitation of myocardial fibers without coordinated contraction of the ventricle and by absence of atrial activity. The disease is caused by variants affecting the gene represented in this entry. Sudden infant death syndrome (SIDS) [MIM:272120] SIDS is the sudden death of an infant younger than 1 year that remains unexplained after a thorough case investigation, including performance of a complete autopsy, examination of the death scene, and review of clinical history. Pathophysiologic mechanisms for SIDS may include respiratory dysfunction, cardiac dysrhythmias, cardiorespiratory instability, and inborn errors of metabolism, but definitive pathogenic mechanisms precipitating an infant sudden death remain elusive. Disease susceptibility is associated with variants affecting the gene represented in this entry. Atrial standstill 1 (ATRST1) [MIM:108770] A rare arrhythmia characterized by the absence of electrical and mechanical activity in the atria. Electrocardiographically, it is characterized by bradycardia, the absence of P waves, and a junctional narrow complex escape rhythm. The disease may be caused by variants affecting distinct genetic loci, including the gene represented in this entry. A mutation in SCN5A has been detected in combination with a rare GJA5 genotype in a large family with atrial standstill. Cardiomyopathy, dilated, 1E (CMD1E) [MIM:601154] A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. The disease is caused by variants affecting the gene represented in this entry. Atrial fibrillation, familial, 10 (ATFB10) [MIM:614022] A familial form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Channel inactivation is regulated by intracellular calcium levels. It is a tetrodotoxin-resistant voltage-gated Na(+) channel (Nav).

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. The IQ domain mediates association with calmodulin.

Miscellaneous. Na(+) channels in mammalian cardiac membrane have functional properties quite distinct from Na(+) channels in nerve and skeletal muscle. Most abundant isoform in heart. Very abundant isoform. Abundantly expressed in neonatal brain and heart, slower kinetics of activation and inactivation. Only detected in neuroblastoma in humans. High expression in brain where it accounts for nearly 50% of the total transcripts. Non-functional channel, may exist to limit the number of undesired functional Nav1.5 channels.

Similarity. Belongs to the sodium channel (TC 1.A.1.10) family. Nav1.5/SCN5A subfamily.

Isoforms (6)

UniProt ID	Names	Canonical?
Q14524-1	1, CAG-inclusive variant, Nav1.5c	yes
Q14524-2	2, Nav1.5b
Q14524-3	3
Q14524-4	4, Nav1.5e, neonatal
Q14524-5	5, Ex18del, Nav1.5a
Q14524-6	6, Ex24del, Nav1.5f

RefSeq proteins (8): NP_000326, NP_001092874, NP_001092875, NP_001153632, NP_001153633, NP_001341630, NP_001394114, NP_932173 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001696	Na_channel_asu	Family
IPR005821	Ion_trans_dom	Domain
IPR008053	Na_channel_a5su	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 (695 total): sequence variant 429, helix 64, topological domain 29, sequence conflict 27, strand 27, transmembrane region 24, modified residue 20, turn 15, glycosylation site 14, mutagenesis site 13, compositionally biased region 10, region of interest 6, splice variant 5, intramembrane region 4, repeat 4, disulfide bond 2, chain 1, domain 1

Structure

Experimental structures (PDB)

16 structures.

PDB	Method	Resolution (Å)
4DJC	X-RAY DIFFRACTION	1.35
4DCK	X-RAY DIFFRACTION	2.2
5DBR	X-RAY DIFFRACTION	2.25
6MUD	X-RAY DIFFRACTION	2.69
4OVN	X-RAY DIFFRACTION	2.8
9V3S	ELECTRON MICROSCOPY	3
6LQA	ELECTRON MICROSCOPY	3.3
7DTC	ELECTRON MICROSCOPY	3.3
9ITH	ELECTRON MICROSCOPY	3.4
9P24	ELECTRON MICROSCOPY	3.48
8VYJ	ELECTRON MICROSCOPY	3.6
4JQ0	X-RAY DIFFRACTION	3.84
8VYK	ELECTRON MICROSCOPY	3.9
2KBI	SOLUTION NMR
2L53	SOLUTION NMR
7L83	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14524-F1	68.02	0.12

Functional residue map

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

Post-translational modifications (20): 36, 38, 457, 460, 483, 484, 486, 497, 510, 513, 513, 526, 526, 539, 571, 664, 667, 680, 680, 1503

Disulfide bonds (2): 280–335, 906–915

Glycosylation sites (14): 283, 288, 291, 318, 328, 740, 803, 864, 1365, 1374, 1380, 1388, 1736, 214

Mutagenesis-validated functional residues (13):

Position	Phenotype
1476	induces accelerated recovery from channel fast inactivation.
1610	complete loss of channel inhibition by the spider jingzhaotoxin-i.
1610	high decrease in affinity to the sea anemone toxin anthopleurin-b.
1614	4.2-fold decrease of channel inhibition potency by the spider jingzhaotoxin-i.
1802–1804	abolishes calcium response on channel inactivation.
1974	strongly reduces interaction with nedd4, nedd4l or wwp2.
1975	strongly reduces interaction with nedd4, nedd4l or wwp2.
1976	strongly reduces interaction with nedd4, nedd4l or wwp2.
1977	strongly reduces interaction with nedd4, nedd4l or wwp2.
1978	no effect on interaction with nedd4, nedd4l or wwp2.
1979	no effect on interaction with nedd4, nedd4l or wwp2.
1980	no effect on interaction with nedd4, nedd4l or wwp2.
1980	strongly reduces interaction with nedd4l.

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: 407 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_BUNDLE_OF_HIS_CELL_TO_PURKINJE_MYOCYTE_COMMUNICATION, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, CMYB_01, TTTGTAG_MIR520D, SP3_Q3, GOBP_MEMBRANE_DEPOLARIZATION_DURING_ACTION_POTENTIAL, GOBP_POSITIVE_REGULATION_OF_ACTION_POTENTIAL, GOCC_CELL_SURFACE, TATTATA_MIR374

GO Biological Process (42): regulation of heart rate (GO:0002027), cardiac conduction system development (GO:0003161), cardiac ventricle development (GO:0003231), brainstem development (GO:0003360), sodium ion transport (GO:0006814), positive regulation of sodium ion transport (GO:0010765), response to denervation involved in regulation of muscle adaptation (GO:0014894), telencephalon development (GO:0021537), cerebellum development (GO:0021549), sodium ion transmembrane transport (GO:0035725), odontogenesis of dentin-containing tooth (GO:0042475), positive regulation of action potential (GO:0045760), positive regulation of epithelial cell proliferation (GO:0050679), membrane depolarization (GO:0051899), cardiac muscle contraction (GO:0060048), regulation of ventricular cardiac muscle cell membrane repolarization (GO:0060307), regulation of atrial cardiac muscle cell membrane depolarization (GO:0060371), regulation of atrial cardiac muscle cell membrane repolarization (GO:0060372), regulation of ventricular cardiac muscle cell membrane depolarization (GO:0060373), cellular response to calcium ion (GO:0071277), cardiac muscle cell action potential involved in contraction (GO:0086002), regulation of cardiac muscle cell contraction (GO:0086004), ventricular cardiac muscle cell action potential (GO:0086005), membrane depolarization during action potential (GO:0086010), membrane depolarization during cardiac muscle cell action potential (GO:0086012), atrial cardiac muscle cell action potential (GO:0086014), SA node cell action potential (GO:0086015), AV node cell action potential (GO:0086016), bundle of His cell action potential (GO:0086043), membrane depolarization during AV node cell action potential (GO:0086045), membrane depolarization during SA node cell action potential (GO:0086046), membrane depolarization during Purkinje myocyte cell action potential (GO:0086047), membrane depolarization during bundle of His cell action potential (GO:0086048), AV node cell to bundle of His cell communication (GO:0086067), regulation of heart rate by cardiac conduction (GO:0086091), membrane depolarization during atrial cardiac muscle cell action potential (GO:0098912), regulation of sodium ion transmembrane transport (GO:1902305), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085)

GO Molecular Function (20): voltage-gated sodium channel activity (GO:0005248), calmodulin binding (GO:0005516), fibroblast growth factor binding (GO:0017134), enzyme binding (GO:0019899), protein kinase binding (GO:0019901), protein domain specific binding (GO:0019904), ankyrin binding (GO:0030506), ubiquitin protein ligase binding (GO:0031625), transmembrane transporter binding (GO:0044325), nitric-oxide synthase binding (GO:0050998), voltage-gated sodium channel activity involved in cardiac muscle cell action potential (GO:0086006), voltage-gated sodium channel activity involved in AV node cell action potential (GO:0086060), voltage-gated sodium channel activity involved in bundle of His cell action potential (GO:0086061), voltage-gated sodium channel activity involved in Purkinje myocyte action potential (GO:0086062), voltage-gated sodium channel activity involved in SA node cell action potential (GO:0086063), scaffold protein binding (GO:0097110), monoatomic ion channel activity (GO:0005216), monoatomic cation channel activity (GO:0005261), sodium channel activity (GO:0005272), protein binding (GO:0005515)

GO Cellular Component (17): voltage-gated sodium channel complex (GO:0001518), nucleoplasm (GO:0005654), nucleolus (GO:0005730), endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), caveola (GO:0005901), cell surface (GO:0009986), intercalated disc (GO:0014704), membrane (GO:0016020), lateral plasma membrane (GO:0016328), Z disc (GO:0030018), T-tubule (GO:0030315), sarcolemma (GO:0042383), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737), monoatomic ion channel complex (GO:0034702), 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	8
protein binding	5
voltage-gated sodium channel activity involved in cardiac muscle cell action potential	4
anatomical structure development	3
sodium ion transport	2
regulation of cardiac muscle cell membrane repolarization	2
regulation of membrane depolarization	2
nuclear lumen	2
cytoplasm	2
plasma membrane	2
regulation of heart contraction	1
regulation of biological quality	1
cardiac muscle tissue development	1
cardiac chamber development	1
metal ion transport	1
regulation of sodium ion transport	1
positive regulation of monoatomic ion transport	1
response to muscle inactivity	1
regulation of muscle adaptation	1
forebrain development	1
metencephalon development	1
monoatomic cation transmembrane transport	1
odontogenesis	1
action potential	1
positive regulation of biological process	1
regulation of action potential	1
positive regulation of cell population proliferation	1
epithelial cell proliferation	1
regulation of epithelial cell proliferation	1
regulation of membrane potential	1
striated muscle contraction	1
heart contraction	1
ventricular cardiac muscle cell membrane repolarization	1
atrial cardiac muscle cell membrane repolarization	1
response to calcium ion	1
cellular response to metal ion	1
sodium channel activity	1
growth factor binding	1
kinase binding	1
cytoskeletal protein binding	1

Protein interactions and networks

STRING

1878 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SCN5A	CALM1	P02593	987
SCN5A	ANK3	Q12955	982
SCN5A	KCNH2	Q12809	978
SCN5A	KCNE2	Q9Y6J6	977
SCN5A	KCNE1	P15382	977
SCN5A	PKP2	Q99959	976
SCN5A	KCNQ1	P51787	973
SCN5A	SCN1B	Q07699	967
SCN5A	GPD1L	Q8N335	965
SCN5A	CALML3	P27482	965
SCN5A	CALML5	Q9NZT1	965
SCN5A	CALML6	Q8TD86	964
SCN5A	CALML4	Q96GE6	964
SCN5A	HCN4	Q9Y3Q4	950
SCN5A	SCN4B	Q8IWT1	950

IntAct

172 interactions, top by confidence:

A	B	Type	Score
SCN5A	CALM1	psi-mi:“MI:0407”(direct interaction)	0.930
SCN5A	CALM1	psi-mi:“MI:0914”(association)	0.930
CALM1	SCN5A	psi-mi:“MI:0407”(direct interaction)	0.930
CALM1	SCN5A	psi-mi:“MI:0915”(physical association)	0.930
SCN5A	CALM1	psi-mi:“MI:0915”(physical association)	0.930
SCN5A	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.670
SCN5A	PTPN3	psi-mi:“MI:0915”(physical association)	0.670
SCN5A	SNTG2	psi-mi:“MI:0407”(direct interaction)	0.660
SCN5A	SNTG2	psi-mi:“MI:0915”(physical association)	0.660
SCN5A	DLG1	psi-mi:“MI:0915”(physical association)	0.610
SCN5A	DLG1	psi-mi:“MI:0407”(direct interaction)	0.610
CAMK2D	SCN5A	psi-mi:“MI:0217”(phosphorylation reaction)	0.610
SCN5A	CAMK2D	psi-mi:“MI:0407”(direct interaction)	0.610
SCN5A	CAMK2D	psi-mi:“MI:0217”(phosphorylation reaction)	0.610

BioGRID (40): SCN5A (Biochemical Activity), SCN5A (Affinity Capture-MS), CRYAB (Affinity Capture-Western), CRYAB (Reconstituted Complex), SCN5A (Affinity Capture-Western), CRYAB (Two-hybrid), NEDD4L (Affinity Capture-Western), SCN5A (Two-hybrid), SCN5A (Two-hybrid), SCN5A (Two-hybrid), SCN5A (Two-hybrid), SCN5A (Two-hybrid), SCN5A (Affinity Capture-MS), NEDD4 (Reconstituted Complex), SCN5A (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

38 interactions.

A	Effect	B	Mechanism
FYN	down-regulates	SCN5A	phosphorylation
CAMK2D	down-regulates	SCN5A	phosphorylation
SCN5A	“up-regulates quantity”	sodium(1+)	relocalization
FGF13	“down-regulates activity”	SCN5A	binding
FGF12	“down-regulates activity”	SCN5A	binding
FGF14	“down-regulates activity”	SCN5A	binding
FGF11	“down-regulates activity”	SCN5A	binding
SCN5A	up-regulates	Action_potential
ESR1	“down-regulates quantity by repression”	SCN5A	“transcriptional regulation”
PKA	“up-regulates activity”	SCN5A	phosphorylation
SGK3	“up-regulates activity”	SCN5A	phosphorylation
AMPK	“up-regulates activity”	SCN5A	phosphorylation
CAMK2A	“up-regulates activity”	SCN5A	phosphorylation
CAMK2B	“up-regulates activity”	SCN5A	phosphorylation
CAMK2D	“up-regulates activity”	SCN5A	phosphorylation
CAMK2G	“up-regulates activity”	SCN5A	phosphorylation
PRKAA1	“down-regulates quantity by destabilization”	SCN5A	phosphorylation
NEDD4L	“down-regulates quantity by destabilization”	SCN5A	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 109 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	6	46.9×	2e-07
Unblocking of NMDA receptors, glutamate binding and activation	6	44.7×	2e-07
Negative regulation of NMDA receptor-mediated neuronal transmission	6	44.7×	2e-07
Long-term potentiation	6	39.1×	5e-07
Assembly and cell surface presentation of NMDA receptors	10	34.8×	3e-11
Dopamine Neurotransmitter Release Cycle	5	34.0×	1e-05
Neurexins and neuroligins	11	29.7×	2e-11
Phase 0 - rapid depolarisation	6	28.4×	3e-06

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	9	51.3×	5e-11
protein localization to synapse	6	45.1×	6e-07
receptor clustering	6	36.7×	1e-06
regulation of postsynaptic membrane neurotransmitter receptor levels	7	34.0×	4e-07
protein-containing complex assembly	9	10.1×	3e-05
cell-cell adhesion	9	9.0×	6e-05
protein localization to plasma membrane	7	7.5×	2e-03
chemical synaptic transmission	8	6.1×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

4569 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	274
Likely pathogenic	143
Uncertain significance	2083
Likely benign	1268
Benign	72

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1012143	NM_000335.5(SCN5A):c.4265_4294del (p.Asp1422_Arg1431del)	Pathogenic
1069871	NC_000003.11:g.(?38655228)(38663986_?)del	Pathogenic
1071777	NM_000335.5(SCN5A):c.334dup (p.Tyr112fs)	Pathogenic
1072446	NM_000335.5(SCN5A):c.2618C>G (p.Ser873Ter)	Pathogenic
1072847	NM_000335.5(SCN5A):c.934+1G>A	Pathogenic
1073629	NM_000335.5(SCN5A):c.4320dup (p.Tyr1441fs)	Pathogenic
1073809	NM_000335.5(SCN5A):c.4085del (p.Cys1362fs)	Pathogenic
1074266	NC_000003.11:g.(?38674520)(38674804_?)del	Pathogenic
1075437	NM_000335.5(SCN5A):c.4837A>T (p.Lys1613Ter)	Pathogenic
1076513	NM_000335.5(SCN5A):c.901del (p.Trp301fs)	Pathogenic
1076515	NM_000335.5(SCN5A):c.3758del (p.Met1253fs)	Pathogenic
1076635	NM_000335.5(SCN5A):c.3394G>T (p.Glu1132Ter)	Pathogenic
1184975	NM_000335.5(SCN5A):c.809_812dup (p.Phe272fs)	Pathogenic
1185878	NM_000335.5(SCN5A):c.3762del (p.Leu1255fs)	Pathogenic
1187556	NM_000335.5(SCN5A):c.2230G>T (p.Glu744Ter)	Pathogenic
1214434	NM_000335.5(SCN5A):c.2274del (p.Ile759fs)	Pathogenic
1299249	NM_000335.5(SCN5A):c.4313dup (p.Trp1439fs)	Pathogenic
1361908	NM_000335.5(SCN5A):c.1589del (p.Phe530fs)	Pathogenic
1374462	NM_000335.5(SCN5A):c.578G>A (p.Trp193Ter)	Pathogenic
1375303	NM_000335.5(SCN5A):c.4316G>A (p.Trp1439Ter)	Pathogenic
1386100	NM_000335.5(SCN5A):c.2533dup (p.Val845fs)	Pathogenic
1406093	NM_000335.5(SCN5A):c.1452del (p.Gly485fs)	Pathogenic
1408176	NM_000335.5(SCN5A):c.217C>T (p.Gln73Ter)	Pathogenic
1434817	NM_000335.5(SCN5A):c.4420_4423del (p.Gln1474fs)	Pathogenic
1449654	NM_000335.5(SCN5A):c.4492AAG[1] (p.Lys1499del)	Pathogenic
1451878	NM_000335.5(SCN5A):c.4373del (p.Phe1458fs)	Pathogenic
1452285	NM_000335.5(SCN5A):c.5443_5446del (p.Asp1815fs)	Pathogenic
1454071	NM_000335.5(SCN5A):c.2091G>A (p.Trp697Ter)	Pathogenic
1455694	NM_000335.5(SCN5A):c.1555del (p.Ser519fs)	Pathogenic
1455926	NM_000335.5(SCN5A):c.475_482+3del	Pathogenic

SpliceAI

5420 predictions. Top by Δscore:

Variant	Effect	Δscore
3:38554278:CCCA:C	donor_gain	1.0000
3:38554545:TTGTT:T	acceptor_gain	1.0000
3:38554546:TGTT:T	acceptor_gain	1.0000
3:38554547:GTT:G	acceptor_gain	1.0000
3:38554548:TT:T	acceptor_gain	1.0000
3:38554550:C:A	acceptor_loss	1.0000
3:38554550:C:CC	acceptor_gain	1.0000
3:38554551:T:A	acceptor_loss	1.0000
3:38555651:CTCA:C	donor_loss	1.0000
3:38555653:CACCA:C	donor_loss	1.0000
3:38555654:A:AC	donor_gain	1.0000
3:38555654:A:T	donor_loss	1.0000
3:38555655:C:CC	donor_gain	1.0000
3:38555753:CCCC:C	acceptor_gain	1.0000
3:38555754:CCC:C	acceptor_gain	1.0000
3:38555754:CCCC:C	acceptor_gain	1.0000
3:38555755:CC:C	acceptor_gain	1.0000
3:38555755:CCC:C	acceptor_gain	1.0000
3:38555756:CC:C	acceptor_gain	1.0000
3:38555757:C:CC	acceptor_gain	1.0000
3:38555757:C:T	acceptor_gain	1.0000
3:38555761:G:C	acceptor_gain	1.0000
3:38555761:G:GC	acceptor_gain	1.0000
3:38556439:A:AC	donor_gain	1.0000
3:38556575:CATA:C	acceptor_gain	1.0000
3:38556579:C:CC	acceptor_gain	1.0000
3:38556579:CT:C	acceptor_loss	1.0000
3:38556580:T:G	acceptor_loss	1.0000
3:38562413:AC:A	donor_gain	1.0000
3:38562414:CC:C	donor_gain	1.0000

AlphaMissense

13350 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:38550853:A:G	L1840P	1.000
3:38550922:A:G	F1817S	1.000
3:38550948:A:C	F1808L	1.000
3:38550948:A:T	F1808L	1.000
3:38550950:A:G	F1808L	1.000
3:38550980:A:G	W1798R	1.000
3:38550980:A:T	W1798R	1.000
3:38551188:G:C	C1728W	1.000
3:38551233:C:A	W1713C	1.000
3:38551233:C:G	W1713C	1.000
3:38551235:A:G	W1713R	1.000
3:38551235:A:T	W1713R	1.000
3:38551272:G:C	S1700R	1.000
3:38551272:G:T	S1700R	1.000
3:38551274:T:G	S1700R	1.000
3:38551480:C:T	G1631D	1.000
3:38556478:C:T	G1467D	1.000
3:38556479:C:G	G1467R	1.000
3:38556487:A:G	L1464P	1.000
3:38556487:A:T	L1464H	1.000
3:38556489:G:C	N1463K	1.000
3:38556489:G:T	N1463K	1.000
3:38556508:C:T	G1457E	1.000
3:38556509:C:A	G1457W	1.000
3:38556509:C:G	G1457R	1.000
3:38556509:C:T	G1457R	1.000
3:38557267:C:A	W1421C	1.000
3:38557267:C:G	W1421C	1.000
3:38557269:A:G	W1421R	1.000
3:38557269:A:T	W1421R	1.000

dbSNP variants (sampled 300 via entrez): RS1000020890 (3:38593005 C>T), RS1000052461 (3:38588554 C>G,T), RS1000096147 (3:38616553 T>A,G), RS1000108138 (3:38582230 G>A), RS1000127049 (3:38642842 A>C), RS1000140694 (3:38582478 G>A), RS1000187324 (3:38624402 A>T), RS1000197986 (3:38575170 G>A), RS1000215192 (3:38618738 A>G), RS1000230381 (3:38642326 G>A), RS1000284283 (3:38635689 G>A), RS1000313225 (3:38574964 T>C), RS1000318422 (3:38576977 C>T), RS1000318808 (3:38630215 C>G), RS1000351546 (3:38552719 G>A)

Disease associations

OMIM: gene MIM:600163 | disease phenotypes: MIM:113900, MIM:601144, MIM:601154, MIM:603829, MIM:603830, MIM:614022, MIM:608567, MIM:115200, MIM:192600, MIM:600996, MIM:604772, MIM:617468, MIM:208150, MIM:192500, MIM:107970, MIM:615745, MIM:194200, MIM:602588, MIM:209850, MIM:115080, MIM:613688, MIM:613751, MIM:604169

GenCC curated gene-disease

Disease	Classification	Inheritance
Brugada syndrome 1	Definitive	Autosomal dominant
dilated cardiomyopathy 1E	Definitive	Autosomal dominant
long QT syndrome 3	Definitive	Autosomal dominant
progressive familial heart block, type 1A	Strong	Autosomal dominant
sick sinus syndrome 1	Strong	Autosomal recessive
Brugada syndrome	Supportive	Autosomal dominant
atrial standstill	Supportive	Autosomal dominant
familial isolated dilated cardiomyopathy	Supportive	Autosomal dominant
familial sick sinus syndrome	Supportive	Autosomal dominant
paroxysmal familial ventricular fibrillation	Supportive	Autosomal dominant
familial atrial fibrillation	Supportive	Autosomal dominant
progressive familial heart block	Supportive	Autosomal dominant
congenital heart disease	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (4)

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

Disease	Classification	Inheritance
arrhythmogenic right ventricular cardiomyopathy	Limited	AD
dilated cardiomyopathy 1E	Definitive	AD
SCN5A-related cardiac rhythm disorder	Definitive	AD
congenital heart disease	Disputed	AD

Mondo (51): progressive familial heart block, type 1A (MONDO:0007240), Brugada syndrome 1 (MONDO:0011001), dilated cardiomyopathy 1E (MONDO:0011003), ventricular fibrillation, paroxysmal familial, type 1 (MONDO:0011376), long QT syndrome 3 (MONDO:0011377), atrial fibrillation, familial, 10 (MONDO:0013530), sick sinus syndrome 1 (MONDO:0024562), cardiac rhythm disease (MONDO:0007263), Brugada syndrome (MONDO:0015263), familial sick sinus syndrome (MONDO:0012061), cardiomyopathy (MONDO:0004994), dilated cardiomyopathy (MONDO:0005021), arrhythmogenic right ventricular cardiomyopathy (MONDO:0016587), familial dilated cardiomyopathy (MONDO:0016333), sinoatrial node disorder (MONDO:0000469)

Orphanet (23): Romano-Ward syndrome (Orphanet:101016), Brugada syndrome (Orphanet:130), Familial isolated dilated cardiomyopathy (Orphanet:154), Hereditary sick sinus syndrome (Orphanet:166282), Idiopathic ventricular fibrillation (Orphanet:228140), Congenital long QT syndrome (Orphanet:768), Hereditary progressive cardiac conduction defect (Orphanet:871), Rare cardiomyopathy (Orphanet:167848), Dilated cardiomyopathy (Orphanet:217604), Inherited arrhythmogenic cardiomyopathy (Orphanet:247), Familial dilated cardiomyopathy (Orphanet:217607), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), Catecholaminergic polymorphic ventricular tachycardia (Orphanet:3286), Arthrogryposis multiplex congenita (Orphanet:1037), Fetal akinesia deformation sequence (Orphanet:994)

HPO phenotypes

105 total (30 of 105 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000969	Edema
HP:0001197	Abnormality of prenatal development or birth
HP:0001250	Seizure
HP:0001260	Dysarthria
HP:0001279	Syncope
HP:0001297	Stroke
HP:0001371	Flexion contracture
HP:0001426	Non-Mendelian inheritance
HP:0001627	Abnormal heart morphology
HP:0001635	Congestive heart failure
HP:0001638	Cardiomyopathy
HP:0001644	Dilated cardiomyopathy
HP:0001645	Sudden cardiac death
HP:0001649	Tachycardia
HP:0001657	Prolonged QT interval
HP:0001658	Myocardial infarction
HP:0001662	Bradycardia
HP:0001663	Ventricular fibrillation
HP:0001664	Torsade de pointes
HP:0001678	Atrioventricular block
HP:0001688	Sinus bradycardia
HP:0001695	Cardiac arrest
HP:0001699	Sudden death
HP:0001712	Left ventricular hypertrophy
HP:0001727	Thromboembolic stroke
HP:0001789	Hydrops fetalis

GWAS associations

193 associations (top):

Study	Trait	p-value
GCST000344_2	Electrocardiographic conduction measures	2.000000e-06
GCST000344_5	Electrocardiographic conduction measures	4.000000e-06
GCST000363_3	QT interval	1.000000e-14
GCST000364_7	QT interval	5.000000e-14
GCST000561_14	Electrocardiographic traits	1.000000e-07
GCST000561_9	Electrocardiographic traits	5.000000e-10
GCST000562_8	PR interval	6.000000e-26
GCST000872_12	QRS duration	1.000000e-16
GCST000872_7	QRS duration	2.000000e-20
GCST000872_8	QRS duration	6.000000e-22
GCST000971_1	PR interval	3.000000e-23
GCST000971_5	PR interval	2.000000e-08
GCST001735_1	PR interval	4.000000e-12
GCST001735_5	PR interval	5.000000e-43
GCST001893_2	Electrocardiographic conduction measures	3.000000e-20
GCST002098_1	Brugada syndrome	1.000000e-14
GCST002456_3	PR segment duration	7.000000e-41
GCST002457_2	P wave duration	8.000000e-27
GCST002500_21	QT interval	2.000000e-11
GCST002500_22	QT interval	1.000000e-10
GCST002500_32	QT interval	4.000000e-27
GCST002500_33	QT interval	2.000000e-11
GCST002500_34	QT interval	1.000000e-13
GCST002533_6	QRS duration	2.000000e-06
GCST002535_3	PR interval	1.000000e-14
GCST003598_22	QRS duration	4.000000e-14
GCST003598_23	QRS duration	2.000000e-13
GCST003598_25	QRS duration	7.000000e-06
GCST003818_62	Resting heart rate	1.000000e-11
GCST004826_11	P wave duration	3.000000e-14

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004327	electrocardiography
EFO:0004462	PR interval
EFO:0004682	QT interval
EFO:0005095	PR segment
EFO:0005094	P wave duration
EFO:0009277	supraventricular ectopy
EFO:0008398	T wave morphology measurement
EFO:0004644	TPE interval measurement

MeSH disease descriptors (29)

Descriptor	Name	Tree numbers
D019571	Arrhythmogenic Right Ventricular Dysplasia	C14.240.400.145; C14.280.238.028; C14.280.400.145; C16.131.240.400.145
D001281	Atrial Fibrillation	C14.280.067.198; C23.550.073.198
D054537	Atrioventricular Block	C14.280.067.558.230; C14.280.123.500.230; C23.550.073.425.062
D001321	Autistic Disorder	F03.625.164.113.500
D053840	Brugada Syndrome	C14.280.067.322; C14.280.123.250; C16.320.100
D002037	Bundle-Branch Block	C14.280.067.558.323; C14.280.123.500.323; C23.550.073.425.100
D009202	Cardiomyopathies	C14.280.238
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D006323	Heart Arrest	C14.280.383
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D006333	Heart Failure	C14.280.434
D006429	Hemiplegia	C10.597.622.295; C23.888.592.636.312
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D008881	Migraine Disorders	C10.228.140.546.399.750
D012804	Sick Sinus Syndrome	C14.280.067.093.249; C14.280.067.558.536; C14.280.123.500.536; C23.550.073.093.249; C23.550.073.425.440
D017180	Tachycardia, Ventricular	C14.280.067.845.940; C14.280.123.875.940; C23.550.073.845.940
D016171	Torsades de Pointes	C14.280.067.845.940.700; C14.280.123.875.940.700; C23.550.073.845.940.700
D014693	Ventricular Fibrillation	C14.280.067.922; C23.550.073.922
D014927	Wolff-Parkinson-White Syndrome	C14.280.067.780.977; C14.280.123.750.977; C16.131.240.400.980
C563409	Arrhythmogenic Right Ventricular Dysplasia, Familial, 2 (supp.)
C563984	Atrial Standstill (supp.)
C563384	Cardiomyopathy, Dilated, 1E (supp.)
C563614	Long Qt Syndrome 2 (supp.)
C565840	Long Qt Syndrome 3 (supp.)
C563907	Sick Sinus Syndrome 1, Autosomal Recessive (supp.)
C567851	Ventricular Fibrillation, Paroxysmal Familial, 1 (supp.)
C536231	familial dilated cardiomyopathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL1980 (SINGLE PROTEIN), CHEMBL2331043 (PROTEIN FAMILY), CHEMBL4523669 (PROTEIN COMPLEX), CHEMBL4630763 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

108 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 354,548 (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
CHEMBL1008	BEPRIDIL	4	11,776
CHEMBL1014	CANDESARTAN CILEXETIL	4	11,194
CHEMBL1017	TELMISARTAN	4	27,457
CHEMBL108	CARBAMAZEPINE	4	53,528
CHEMBL1086	DIBUCAINE	4	17,231
CHEMBL11	IMIPRAMINE	4	48,893
CHEMBL1108	DROPERIDOL	4	16,888
CHEMBL1171837	PONATINIB	4	8,955
CHEMBL1175	DULOXETINE	4	28,527
CHEMBL1189679	PALONOSETRON	4	9,399
CHEMBL1198857	VILANTEROL	4	2,552
CHEMBL1200606	MEXILETINE HYDROCHLORIDE	4	4,087
CHEMBL1200661	UNOPROSTONE ISOPROPYL	4	2,396
CHEMBL1237021	LURASIDONE	4	2,517
CHEMBL1241951	LETERMOVIR	4	1,026
CHEMBL12713	SERTINDOLE	4	8,984
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1294	QUINIDINE	4	71,943
CHEMBL1323	DARUNAVIR	4	15,382
CHEMBL1346	DARIFENACIN	4	8,259
CHEMBL1374379	BENZONATATE	4
CHEMBL1382	TOLTERODINE	4
CHEMBL1404	RANOLAZINE	4
CHEMBL1423	PIMOZIDE	4
CHEMBL1428	NIMODIPINE	4
CHEMBL1480	FELODIPINE	4
CHEMBL1484	NICARDIPINE	4
CHEMBL1491	AMLODIPINE	4
CHEMBL16	PHENYTOIN	4
CHEMBL1621	PALIPERIDONE	4

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

PharmGKB variants

10 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1805124	SCN5A		0.00	0
rs1805125	SCN5A		0.00	0
rs6791924	SCN5A		0.00	0
rs7626962	SCN5A		0.00	0
rs41313691	SCN5A		0.00	0
rs41315493	SCN5A		0.00	0
rs200034939	SCN5A		0.00	0
rs79299226	SCN5A		0.00	0
rs41261344	SCN5A		0.00	0
rs137854601	SCN5A		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 (23 total), top 23:

Ligand	Action	Affinity	Parameter
α-scorpion toxin 2	Slows inactivation	7.7	pKd
batrachotoxin	Full agonist	7.6	pKd
saxitoxin	Pore blocker	7.4	pKd
ATX-II	Slows inactivation	7.3	pEC50
AFT-II	Slows inactivation	7.2	pEC50
funapide	Inhibition	7.08	pIC50
GNE-131	Inhibition	6.96	pIC50
GS-458967	Inhibition	6.89	pIC50
relutrigine	Inhibition	6.76	pIC50
jingzhaotoxin-III	Voltage-dependent inhibition	6.5	pKi
Bc-III	Slows inactivation	6.5	pEC50
protoxin II	Voltage-dependent inhibition	6.5	pKi
veratridine	Partial agonist	6.3	pEC50
GNE-616	Inhibition	6.0	pKd
tetrodotoxin	Pore blocker	5.8	pKd
amiodarone	Pore blocker	5.7	pIC50
μ-conotoxin SmIIIA	Pore blocker	5.5	pKi
cannabidiol	Channel blocker	5.42	pIC50
AM-6120	Inhibition	5.18	pIC50
quinidine	Pore blocker	5.0	pIC50
lidocaine	Pore blocker	4.8	pKd
bupivacaine	Pore blocker	4.16	pIC50
ropivacaine	Pore blocker	3.49	pIC50

Binding affinities (BindingDB)

1172 measured of 2059 human assays (2059 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-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	IC50	1 nM	US-8952169: N-substituted benzamides and methods of use thereof
4-(1-adamantylmethoxy)-5-cyclopropyl-N-cyclopropylsulfonyl-2-fluorobenzamide	IC50	1 nM	US-8952169: N-substituted benzamides and methods of use thereof
4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-(3-fluoroazetidin-1-yl)sulfonylbenzamide	IC50	1 nM	US-8952169: N-substituted benzamides and methods of use thereof
5-cyclopropyl-4-[(4,4-difluoro-1-adamantyl)methoxy]-2-fluoro-N-methylsulfonylbenzamide	IC50	1 nM	US-8952169: N-substituted benzamides and methods of use thereof
4-(2-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluorobenzamide	IC50	1 nM	US-8952169: N-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
CHEMBL4753470	EC50	1.9 nM
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
4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluorobenzamide	IC50	2 nM	US-8952169: N-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
(R)-5-cyclopropyl-N-(cyclopropylsulfonyl)-4-((1-(3,5-dichlorophenyl)piperidin-3-yl)oxy)-2-fluorobenzamide	IC50	2.1 nM	US-9546164: Substituted benzamides and methods of use thereof
(5-cyclopropyl-4-(((R)-1-((R)-1-(3,5-dichlorophenyl)ethyl)piperidin-3-yl)oxy)-2-fluoro-N-(methylsulfonyl)benzamide	IC50	2.1 nM	US-9546164: 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
4-(((1R,3r,5S)-3-(3-chloro-5-(trifluoromethoxy)phenoxy)-8-azabicyclo[3.2.1]octan-8-yl)methyl)-5-cyclopropyl-N-(cyclopropylsulfonyl)-2-fluorobenzamide, trifluoroacetic acid salt	IC50	2.2 nM	US-9546164: 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

ChEMBL bioactivities

1067 potent at pChembl≥5 of 1745 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.55	IC50	0.28	nM	CHEMBL3617050
8.72	EC50	1.9	nM	CHEMBL4753470
8.66	IC50	2.2	nM	CHEMBL4061793
8.49	IC50	3.2	nM	CHEMBL4444707
7.96	IC50	11	nM	PF-05089771
7.85	IC50	14	nM	CHEMBL3657939
7.80	IC50	15.8	nM	CHEMBL4854735
7.75	IC50	18	nM	CHEMBL4079509
7.75	IC50	17.7	nM	CHEMBL4854735
7.70	IC50	20	nM	CHEMBL2012259
7.70	IC50	20	nM	CHEMBL2012299
7.66	IC50	22	nM	CHEMBL3657952
7.58	IC50	26	nM	CHEMBL3657932
7.56	EC50	27.8	nM	CHEMBL5077579
7.52	IC50	30	nM	CHEMBL2012180
7.52	IC50	30	nM	CHEMBL2012298
7.52	IC50	30	nM	CHEMBL3677849
7.51	IC50	31	nM	CHEMBL4864812
7.43	IC50	37	nM	CHEMBL4075332
7.41	IC50	39	nM	CHEMBL4854735
7.40	IC50	40	nM	CHEMBL2012273
7.40	IC50	40	nM	CHEMBL2012274
7.40	IC50	40	nM	CHEMBL2012292
7.40	IC50	40	nM	CHEMBL3662238
7.36	IC50	44	nM	CHEMBL4854735
7.31	IC50	49	nM	CHEMBL3657855
7.30	IC50	50	nM	CHEMBL2012179
7.30	IC50	50	nM	CHEMBL2012272
7.30	IC50	50	nM	CHEMBL4094490
7.30	IC50	50	nM	CHEMBL3662190
7.29	IC50	51.5	nM	CHEMBL3657855
7.29	IC50	51	nM	CHEMBL3657855
7.28	IC50	52	nM	CHEMBL4102624
7.27	IC50	54	nM	PIMOZIDE
7.23	IC50	59	nM	CHEMBL3810248
7.22	IC50	60	nM	CHEMBL2012266
7.22	IC50	60	nM	CHEMBL2012291
7.22	IC50	60.6	nM	CHEMBL3657838
7.19	IC50	65	nM	CHEMBL4854735
7.16	IC50	70	nM	CHEMBL2012271
7.13	IC50	74	nM	CHEMBL4087220
7.12	IC50	76	nM	CHEMBL4072883
7.11	IC50	77	nM	CHEMBL4102233
7.10	IC50	80	nM	CHEMBL2012181
7.10	IC50	80	nM	CHEMBL2012285
7.10	IC50	80	nM	CHEMBL2012300
7.10	IC50	79	nM	CHEMBL4224739
7.08	IC50	84	nM	FUNAPIDE
7.05	IC50	90	nM	CHEMBL2012290
7.05	IC50	90	nM	CHEMBL2012296

PubChem BioAssay actives

705 with measured affinity, of 2861 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
[(3R,5S,6S,11R,12S,16S)-14,17-diamino-19,19-dihydroxy-6-(hydroxymethyl)-10-oxo-3-sulfooxy-8-oxa-1,9,13,15,18-pentazapentacyclo[9.5.2.13,16.05,9.012,16]nonadeca-14,17-dien-13-yl]methyl N-hydroxycarbamate	1246044: Inhibition of NaV1.5 channel (unknown origin) expressed in Xenopus laevis oocytes by two-electrode oocyte voltage-clamp method	ic50	0.0003	uM
(5R,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	1676149: Inhibition of NaV1.5 (unknown origin)	ec50	0.0019	uM
5-chloro-2-fluoro-4-(1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethylamino)-N-(1,3-thiazol-2-yl)benzenesulfonamide	1463696: Inhibition of human Nav1.5 inactivated state form expressed in HEK293 cells at -60 mV holding potential by by automated patch clamp electrophysiology assay	ic50	0.0022	uM
4-[[1-[[2-chloro-5-(trifluoromethyl)phenyl]methyl]piperidin-4-yl]methoxy]-5-cyclopropyl-2-fluoro-N-methylsulfonylbenzamide	1922057: Inhibition of human Nav1.5 at -60 mV holding potential by manual patch-clamp assay	ic50	0.0032	uM
4-[2-(5-amino-1H-pyrazol-4-yl)-4-chlorophenoxy]-5-chloro-2-fluoro-N-(1,3-thiazol-4-yl)benzenesulfonamide	1466767: Inhibition of 50% inactivated human Nav1.5alpha expressed in HEK293 cells measured after 5 to 10 mins post compound washout by PatchXpress automated electrophysiology method	ic50	0.0110	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	1754524: Inhibition of human Nav1.5 expressed in HEK293 cells assessed as inhibition of late channel current at holding potential of -95 mV	ic50	0.0158	uM
3-[3-(difluoromethoxy)-2-pyridinyl]-N-[2-pyridin-2-yl-3-(trifluoromethyl)phenyl]benzamide	1487519: Inhibition of human NaV1.5 expressed in HEK293 cells at -50 mV holding potential after 3 to 5 mins by PatchXpress automated electrophysiology method	ic50	0.0180	uM
4-[[4-[7-[(2-fluorophenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]oxypiperidin-1-yl]methyl]-1,3-thiazole	655061: Antagonist activity at human NaV1.5 channel by patchXpress assay	ic50	0.0200	uM
7-[(2,3-difluorophenyl)methyl]-4-[1-(pyridin-2-ylmethyl)piperidin-4-yl]oxypyrrolo[2,3-d]pyrimidine	655061: Antagonist activity at human NaV1.5 channel by patchXpress assay	ic50	0.0200	uM
(2S)-5-amino-2-[[(2S)-4-amino-2-[[(2S,4S)-1-[(2S,4S)-1-[(2S)-4-amino-2-[[(1R,4S,7S,10S,13S,19R,24R,27S,30S,33S,36S,42R,45S,48S,51S,54R,59R,62S,65S,68S,74S,77S)-59-[(2-aminoacetyl)amino]-13,27,48-tris(4-aminobutyl)-33,45-bis(2-amino-2-oxoethyl)-30,77-dibenzyl-62-[(2S)-butan-2-yl]-4,51,68-tris[(1R)-1-hydroxyethyl]-10,65,74-tris(hydroxymethyl)-36-(1H-indol-3-ylmethyl)-7-(2-methylpropyl)-2,5,8,11,14,17,26,29,32,35,38,41,44,47,50,53,60,63,66,69,72,75,78,85-tetracosaoxo-21,22,56,57,81,82-hexathia-3,6,9,12,15,18,25,28,31,34,37,40,43,46,49,52,61,64,67,70,73,76,79,84-tetracosazatricyclo[40.37.4.219,54]pentaoctacontane-24-carbonyl]amino]-4-oxobutanoyl]-4-hydroxypyrrolidine-2-carbonyl]-4-hydroxypyrrolidine-2-carbonyl]amino]-4-oxobutanoyl]amino]-5-oxopentanoic acid	1815034: Modulator activity at human Nav1.5 expressed in Xenopus laevis oocytes assessed as elicitation in sodium current measured after 1 to 4 days by two-electrode voltage clamp assay	ec50	0.0278	uM
4-[[4-(7-benzyl-5-fluoropyrrolo[2,3-d]pyrimidin-4-yl)oxypiperidin-1-yl]methyl]-1,3-thiazole	655061: Antagonist activity at human NaV1.5 channel by patchXpress assay	ic50	0.0300	uM
7-[(2-fluorophenyl)methyl]-4-[1-(pyridin-2-ylmethyl)piperidin-4-yl]oxypyrrolo[2,3-d]pyrimidine	655061: Antagonist activity at human NaV1.5 channel by patchXpress assay	ic50	0.0300	uM
4-[(3S,4S)-3-(3,4-difluorophenyl)-1-(2,2,2-trifluoroethyl)piperidin-4-yl]oxy-2,3,5-trifluoro-N-(6-fluoro-2-pyridinyl)benzenesulfonamide	1754460: Inhibition of human Nav1.5 by automated voltage clamp electrophysiology	ic50	0.0310	uM
5-chloro-4-[2-(1,1-dioxothian-4-yl)ethylamino]-2-fluoro-N-(1,3-thiazol-2-yl)benzenesulfonamide	1463696: Inhibition of human Nav1.5 inactivated state form expressed in HEK293 cells at -60 mV holding potential by by automated patch clamp electrophysiology assay	ic50	0.0370	uM
4-[[4-[7-[[2-fluoro-3-(trifluoromethyl)phenyl]methyl]pyrrolo[2,3-d]pyrimidin-4-yl]oxypiperidin-1-yl]methyl]-1,3-thiazole	655061: Antagonist activity at human NaV1.5 channel by patchXpress assay	ic50	0.0400	uM
4-[[4-[7-[(2,6-difluorophenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]oxypiperidin-1-yl]methyl]-1,3-thiazole	655061: Antagonist activity at human NaV1.5 channel by patchXpress assay	ic50	0.0400	uM
7-benzyl-4-[1-[(4-methyl-2-pyridinyl)methyl]piperidin-4-yl]oxypyrrolo[2,3-d]pyrimidine	655061: Antagonist activity at human NaV1.5 channel by patchXpress assay	ic50	0.0400	uM
4-(1-adamantylmethoxy)-N-(azetidin-1-ylsulfonyl)-5-cyclopropyl-2-fluorobenzamide	1525392: Inhibition of human Nav1.5 expressed in HEK293 cells by electrophysiology assay	ic50	0.0490	uM
5-chloro-2-fluoro-4-[2-(oxan-3-yl)ethylamino]-N-(1,3-thiazol-2-yl)benzenesulfonamide	1463696: Inhibition of human Nav1.5 inactivated state form expressed in HEK293 cells at -60 mV holding potential by by automated patch clamp electrophysiology assay	ic50	0.0500	uM
4-[[4-[7-[(3-chloro-2-fluorophenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]oxypiperidin-1-yl]methyl]-1,3-thiazole	655061: Antagonist activity at human NaV1.5 channel by patchXpress assay	ic50	0.0500	uM
4-[[4-(7-benzyl-5-methylpyrrolo[2,3-d]pyrimidin-4-yl)oxypiperidin-1-yl]methyl]-1,3-thiazole	655061: Antagonist activity at human NaV1.5 channel by patchXpress assay	ic50	0.0500	uM
5-cyclopropyl-N-cyclopropylsulfonyl-2-fluoro-4-[(6-methylspiro[2.5]octan-6-yl)methoxy]benzamide	1525392: Inhibition of human Nav1.5 expressed in HEK293 cells by electrophysiology assay	ic50	0.0500	uM
5-chloro-2-fluoro-4-[(3-oxocyclohexyl)methylamino]-N-(1,3-thiazol-2-yl)benzenesulfonamide	1463696: Inhibition of human Nav1.5 inactivated state form expressed in HEK293 cells at -60 mV holding potential by by automated patch clamp electrophysiology assay	ic50	0.0520	uM
Pimozide	1207165: Inhibition of Na channel (species unknown)	ic50	0.0540	uM
trimethyl-[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl]phenyl]silane	1302433: Inhibition of Nav 1.5 (unknown origin) assessed as reduction in late channel current	ic50	0.0590	uM
7-benzyl-4-[1-[(5-methyl-2-pyridinyl)methyl]piperidin-4-yl]oxypyrrolo[2,3-d]pyrimidine	655061: Antagonist activity at human NaV1.5 channel by patchXpress assay	ic50	0.0600	uM
4-[[4-[7-[(3-methylphenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]oxypiperidin-1-yl]methyl]-1,3-thiazole	655061: Antagonist activity at human NaV1.5 channel by patchXpress assay	ic50	0.0600	uM
4-[[4-[7-[(2,3-difluorophenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]oxypiperidin-1-yl]methyl]-1,3-thiazole	655061: Antagonist activity at human NaV1.5 channel by patchXpress assay	ic50	0.0700	uM
5-chloro-4-(1,4-dioxan-2-ylmethylamino)-2-fluoro-N-(1,3-thiazol-2-yl)benzenesulfonamide	1463696: Inhibition of human Nav1.5 inactivated state form expressed in HEK293 cells at -60 mV holding potential by by automated patch clamp electrophysiology assay	ic50	0.0740	uM
5-chloro-2-fluoro-4-[[(3R)-oxan-3-yl]methylamino]-N-(1,3-thiazol-2-yl)benzenesulfonamide	1463696: Inhibition of human Nav1.5 inactivated state form expressed in HEK293 cells at -60 mV holding potential by by automated patch clamp electrophysiology assay	ic50	0.0760	uM
5-chloro-2-fluoro-4-[[(2S,3R)-2-phenyloxan-3-yl]methylamino]-N-(1,3-thiazol-2-yl)benzenesulfonamide	1463696: Inhibition of human Nav1.5 inactivated state form expressed in HEK293 cells at -60 mV holding potential by by automated patch clamp electrophysiology assay	ic50	0.0770	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	1388448: Inhibition of Nav1.5 (unknown origin) expressed in xenopus oocytes at -80 mV holding potential by two-electrode voltage-clamp method	ic50	0.0790	uM
4-[[4-(7-benzyl-5-chloropyrrolo[2,3-d]pyrimidin-4-yl)oxypiperidin-1-yl]methyl]-1,3-thiazole	655061: Antagonist activity at human NaV1.5 channel by patchXpress assay	ic50	0.0800	uM
4-[[4-(7-benzylpyrrolo[2,3-d]pyrimidin-4-yl)oxypiperidin-1-yl]methyl]-2-methyl-1,3-thiazole	655061: Antagonist activity at human NaV1.5 channel by patchXpress assay	ic50	0.0800	uM
7-[(3-chloro-2-fluorophenyl)methyl]-4-[1-(pyridin-2-ylmethyl)piperidin-4-yl]oxypyrrolo[2,3-d]pyrimidine	655061: Antagonist activity at human NaV1.5 channel by patchXpress assay	ic50	0.0800	uM
(7S)-1’-[[5-(trifluoromethyl)furan-2-yl]methyl]spiro[6H-furo[2,3-f][1,3]benzodioxole-7,3’-indole]-2’-one	1525392: Inhibition of human Nav1.5 expressed in HEK293 cells by electrophysiology assay	ic50	0.0840	uM
7-benzyl-4-[1-[(3-fluoro-2-pyridinyl)methyl]piperidin-4-yl]oxypyrrolo[2,3-d]pyrimidine	655061: Antagonist activity at human NaV1.5 channel by patchXpress assay	ic50	0.0900	uM
7-benzyl-4-[1-[(6-methyl-2-pyridinyl)methyl]piperidin-4-yl]oxypyrrolo[2,3-d]pyrimidine	655061: Antagonist activity at human NaV1.5 channel by patchXpress assay	ic50	0.0900	uM
5-chloro-2-fluoro-4-[(4-methoxyiminocyclohexyl)methylamino]-N-(1,3-thiazol-2-yl)benzenesulfonamide	1463696: Inhibition of human Nav1.5 inactivated state form expressed in HEK293 cells at -60 mV holding potential by by automated patch clamp electrophysiology assay	ic50	0.0940	uM
[5-(4-tert-butylphenyl)furan-2-yl]-(4-cyclohexylpiperazin-1-yl)methanone	404536: Inhibition of human recombinant Nav1.5 channel expressed in HEK293 cells by whole cell voltage clamp technique	ic50	0.1000	uM
4-(pyrimidin-2-ylmethyl)-7-[4-(trifluoromethoxy)phenyl]-2,3-dihydro-1,4-benzoxazepin-5-one	1734578: Inhibition of NaV1.5 expressed in human HEK293 cells assessed as inhibition of late sodium current at -80 mV resting membrane potential by electrophysiology assay	ic50	0.1000	uM
6-[4-(trifluoromethoxy)phenyl]-3-(trifluoromethyl)imidazo[1,5-a]pyridine	1302433: Inhibition of Nav 1.5 (unknown origin) assessed as reduction in late channel current	ic50	0.1020	uM
4-(3,4,5,6a-tetrahydro-2H-furo[2,3-b]furan-3a-ylmethylamino)-5-chloro-2-fluoro-N-(1,3-thiazol-2-yl)benzenesulfonamide	1463696: Inhibition of human Nav1.5 inactivated state form expressed in HEK293 cells at -60 mV holding potential by by automated patch clamp electrophysiology assay	ic50	0.1080	uM
(2S)-5-amino-2-[[(2S)-4-amino-2-[[(2S,4S)-1-[(2S,4S)-1-[(2S)-4-amino-2-[[(1R,4S,7S,10S,13S,19R,24R,27S,30S,33S,36S,42R,45S,48S,51S,54R,59R,62S,65S,68S,74S)-59-[(2-aminoacetyl)amino]-13,27,48,65-tetrakis(4-aminobutyl)-33,45-bis(2-amino-2-oxoethyl)-30-benzyl-62-[(2S)-butan-2-yl]-4,51,68-tris[(1R)-1-hydroxyethyl]-10,74-bis(hydroxymethyl)-36-(1H-indol-3-ylmethyl)-7-(2-methylpropyl)-2,5,8,11,14,17,26,29,32,35,38,41,44,47,50,53,60,63,66,69,72,75,78,85-tetracosaoxo-21,22,56,57,81,82-hexathia-3,6,9,12,15,18,25,28,31,34,37,40,43,46,49,52,61,64,67,70,73,76,79,84-tetracosazatricyclo[40.37.4.219,54]pentaoctacontane-24-carbonyl]amino]-4-oxobutanoyl]-4-hydroxypyrrolidine-2-carbonyl]-4-hydroxypyrrolidine-2-carbonyl]amino]-4-oxobutanoyl]amino]-5-oxopentanoic acid	1815034: Modulator activity at human Nav1.5 expressed in Xenopus laevis oocytes assessed as elicitation in sodium current measured after 1 to 4 days by two-electrode voltage clamp assay	ec50	0.1084	uM
4-[[4-[7-[(2-chlorophenyl)methyl]pyrrolo[2,3-d]pyrimidin-4-yl]oxypiperidin-1-yl]methyl]-1,3-thiazole	655061: Antagonist activity at human NaV1.5 channel by patchXpress assay	ic50	0.1100	uM
7-benzyl-4-[1-[(5-fluoro-2-pyridinyl)methyl]piperidin-4-yl]oxypyrrolo[2,3-d]pyrimidine	655061: Antagonist activity at human NaV1.5 channel by patchXpress assay	ic50	0.1100	uM
N-[7-(1-adamantylmethoxy)-6-cyclopropyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl]cyclopropanesulfonamide	1410605: Inhibition of inactivated state of recombinant human NaV1.5 expressed in HEK293 cell membranes coexpressing Nav beta1 subunit assessed as decrease in sodium current amplitude at -60 mV holding potential by PX automated voltage clamp method	ic50	0.1100	uM
4-(1-adamantylmethoxy)-5-cyclopropyl-2-fluoro-N-morpholin-4-ylsulfonylbenzamide	1831642: Inhibition of human Nav1.5 expressed in HEK293 cells incubated for 1 hr in presence of veratridine and anthropleurin-C by sodium influx assay	ic50	0.1100	uM
(4-methoxy-3-pyrrolidin-1-ylphenyl)-(7-methoxyspiro[5H-pyrrolo[1,2-a]quinoxaline-4,4’-piperidine]-1’-yl)methanone	1167923: Inhibition of human Nav1.5 expressed in HEK293 cells after 60 mins by FLIPR assay	ic50	0.1180	uM
5-chloro-2-fluoro-4-[2-(oxan-4-yl)ethylamino]-N-(1,3-thiazol-2-yl)benzenesulfonamide	1463696: Inhibition of human Nav1.5 inactivated state form expressed in HEK293 cells at -60 mV holding potential by by automated patch clamp electrophysiology assay	ic50	0.1200	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Doxorubicin	decreases expression	3
Sunitinib	decreases activity	2
Ajmaline	affects response to substance	2
Daunorubicin	decreases expression	2
Mitoxantrone	decreases expression	2
bisphenol A	affects binding, decreases activity	1
nimesulide	decreases activity	1
tris(2-butoxyethyl) phosphate	affects expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
aflatoxin B2	decreases methylation	1
pentanal	increases expression	1
nefazodone	affects activity	1
wilforlide A	decreases activity	1
9-phenanthrol	decreases activity	1
ezogabine	affects activity	1
18-methoxycoronaridine	decreases activity	1
1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene	increases expression, affects cotreatment	1
K 7174	increases expression	1
icajine	affects binding, decreases activity	1
2,3,5,6-tetrafluoro-4-methylbenzyl (Z)-(1RS)-cis-3-(2-chloro-3,3,3-trifluoroprop-1-enyl)-2,2-dimethylcyclopropanecarboxylate	increases activity, decreases reaction	1
1-oleoyl-2-acetoyl-sn-glycerol	decreases activity	1
incobotulinumtoxinA	decreases expression	1
Ranolazine	decreases reaction, increases activity	1
Resveratrol	affects cotreatment, decreases expression	1
Limonene	decreases reaction, increases activity	1
Meloxicam	decreases activity	1
Telmisartan	increases activity	1
Crizotinib	decreases activity	1
Amiodarone	affects response to substance	1

ChEMBL screening assays

594 unique, capped per target: 380 binding, 98 functional, 72 admet, 43 toxicity, 1 unclassified

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1001516	Binding	Inhibition of Voltage-gated sodium channel subunit alpha Nav1.5	Discovery of spirocyclic secondary amine-derived tertiary ureas as highly potent, selective and bioavailable soluble epoxide hydrolase inhibitors. — Bioorg Med Chem Lett
CHEMBL1942853	Functional	Antagonist activity at partially inactivated human sodium channel Nav1.5 expressed in human HEK293 cells by patch-clamp electrophysiological assay	Discovery and optimization of aminopyrimidinones as potent and state-dependent Nav1.7 antagonists. — Bioorg Med Chem Lett
CHEMBL3370463	ADMET	Inhibition of human Nav1.5 channel expressed in HEK293 cells assessed as membrane potential after 60 mins by FLIPR assay	Discovery of pyrrolo-benzo-1,4-diazines as potent Na(v)1.7 sodium channel blockers. — Bioorg Med Chem Lett

Cellosaurus cell lines

36 cell lines: 29 induced pluripotent stem cell, 5 transformed cell line, 1 embryonic stem cell, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1N93	GM25267	Induced pluripotent stem cell	Female
CVCL_9S60	UKKi008-A	Induced pluripotent stem cell	Male
CVCL_A4LH	iSCN5A	Induced pluripotent stem cell
CVCL_A4TZ	WAe009-A-48	Embryonic stem cell	Female
CVCL_B3NL	BBANTWi006-A	Induced pluripotent stem cell	Male
CVCL_B3NM	BBANTWi007-A	Induced pluripotent stem cell	Female
CVCL_B5EZ	ICANi002-A-2	Induced pluripotent stem cell	Male
CVCL_B5FM	SCVIi026-A	Induced pluripotent stem cell	Female
CVCL_B5FN	SCVIi027-A	Induced pluripotent stem cell	Male
CVCL_B5GQ	ZJYYPHi001-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT02201914	PHASE4	UNKNOWN	Clomiphene Citrate Plus Gonadotropins and GnRH Antagonist Versus Flexible GnRH Antagonist Protocol Versus Microdose GnRH Agonist Protocol in Poor Responders Undergoing IVF
NCT02651285	PHASE4	UNKNOWN	Use of G-CSF Supplemented IVF Medium in Patients Undergoing IVF
NCT04002635	PHASE4	WITHDRAWN	Letrozole for Frozen Embryo Transfer (FET) in Patients With Polycystic Ovary Syndrome (PCOS)
NCT04385342	PHASE4	UNKNOWN	FSH Followed by HMG vs FSH Plus HMG in IVF
NCT04487925	PHASE4	RECRUITING	Controlled Ovarian Stimulation Versus Modified Natural Cycles in Poor Responders
NCT04654741	PHASE4	UNKNOWN	The Rate of Embryo Euploidy in Progestin-primed Ovarian Stimulation Cycles
NCT04728659	PHASE4	UNKNOWN	Desogestrel Versus GnRH Antagonist in IVF/ICSI
NCT04993924	PHASE4	UNKNOWN	GnRH Antagonist Pre-treatment in the Early Follicular Phase for Resolution of a Baseline Functional Ovarian Cyst
NCT05071339	PHASE4	UNKNOWN	GnRH Antagonist Pre-treatment for the Prevention of Asynchronous Follicular Growth
NCT05321511	PHASE4	UNKNOWN	Comparison of Triggers in Double Ovarian Stimulation (DuoStim).
NCT05954962	PHASE4	COMPLETED	Efficacy of Micronized Natural Progesterone vs GnRH Antagonist in the Prevention of LH Peak During Ovarian Stimulation.
NCT06181305	PHASE4	UNKNOWN	Endometrial Preparation in Frozen Embryo Transfer Cycles
NCT06396390	PHASE4	NOT_YET_RECRUITING	Comparison of Progestin Primed Ovarian Stimulation (PPOS) vs.GnRH Antagonist Methods on IVF Outcomes
NCT07499804	PHASE4	RECRUITING	Effect of Tadalafil on Endometrial Thickness and Frozen Embryo Transfer Outcomes
NCT00146822	PHASE4	COMPLETED	REFLEx Study (ENDOTAK RELIANCE G Evaluation of Handling and Electrical Performance
NCT00187239	PHASE4	COMPLETED	Reduce Ventricular Pacing in Dual Chamber Implantable Cardioverter Defibrillators Using AutoIntrinsic Conduction Search Study
NCT00247533	PHASE4	UNKNOWN	Cerebral Artery Stenosis, Coronary Artery Disease and Arrhythmia
NCT00282620	PHASE4	UNKNOWN	Magnesium to Reduce Implantable Cardioverter Defibrillator (ICD) Shocks and Improve Patient’s Quality of Life.
NCT00290056	PHASE4	UNKNOWN	Effect of Supplemental Intake of Omega-3 Polyunsaturated Fatty Acids on the Rate and Complexity of Spontaneously Occurring Ventricular and Supraventricular Arrhythmias in Patients With Implantable Cardioverter Defibrillator (ICD) - A Randomized Clinical Trial
NCT00313443	PHASE4	COMPLETED	Concentrations of Amiodarone in Fat Tissue During Chronic Treatment
NCT00457340	PHASE4	COMPLETED	Atorvastatin For The Reduction Of Ventricular Arrhythmias
NCT00507390	PHASE4	WITHDRAWN	Omega 3 Polyunsaturated Fatty Acid Supplements (PUFAs) and Microvolt T Wave Alternans (TWA) in Patients With Ventricular Arrhythmia
NCT00575523	PHASE4	COMPLETED	Atropine for Prevention of Dysrhythmias Caused by Percutaneous Ethanol Instillation for Hepatoma Therapy
NCT00579098	PHASE4	COMPLETED	The Use of Statins Following a Left Atrial Catheter Ablation Procedure to Prevent Atrial Fibrillation
NCT01613092	PHASE4	COMPLETED	Prevention of Arrhythmia Device Infection Trial (PADIT)
NCT01628666	PHASE4	COMPLETED	Prevention of Arrhythmia Device Infection Trial (PADIT)
NCT01717469	PHASE4	UNKNOWN	Safety and the Effects of Isolated Left Ventricular Pacing in Patients With Bradyarrhythmias
NCT01819064	PHASE4	COMPLETED	Heart Rate Response to Atropine Doses Less Than 0.1mg IV to Anesthetized Infants