SCN4B

Summary

SCN4B (sodium voltage-gated channel beta subunit 4, HGNC:10592) is a protein-coding gene on chromosome 11q23.3, encoding Sodium channel regulatory subunit beta-4 (Q8IWT1). Regulatory subunit of multiple voltage-gated sodium (Nav) channels directly mediating the depolarization of excitable membranes.

The protein encoded by this gene is one of several sodium channel beta subunits. These subunits interact with voltage-gated alpha subunits to change sodium channel kinetics. The encoded transmembrane protein forms interchain disulfide bonds with SCN2A. Defects in this gene are a cause of long QT syndrome type 10 (LQT10). Three protein-coding and one non-coding transcript variant have been found for this gene.

Source: NCBI Gene 6330 — RefSeq curated summary.

At a glance

• Gene–disease (curated): familial atrial fibrillation (Supportive, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 270 total — 2 pathogenic
• Phenotypes (HPO): 30
• MANE Select transcript: NM_174934

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10592
Approved symbol	SCN4B
Name	sodium voltage-gated channel beta subunit 4
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Aliases	LQT10
Ensembl gene	ENSG00000177098
Ensembl biotype	protein_coding
OMIM	608256
Entrez	6330

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 retained_intron, 2 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000324727, ENST00000415030, ENST00000423160, ENST00000529878, ENST00000531550, ENST00000532138

RefSeq mRNA: 3 — MANE Select: NM_174934 NM_001142348, NM_001142349, NM_174934

CCDS: CCDS44744, CCDS8389

Canonical transcript exons

ENST00000324727 — 5 exons

Exon	Start	End
ENSE00001286239	118145057	118145229
ENSE00002199292	118152613	118152823
ENSE00003496300	118141207	118141336
ENSE00003589136	118143833	118144061
ENSE00003624070	118133377	118137120

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 97.54.

FANTOM5 (CAGE): breadth broad, TPM avg 4.5873 / max 630.8494, expressed in 410 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122564	3.2975	382
122566	0.8232	155
122562	0.1814	48
122568	0.1416	52
122567	0.0666	36
122565	0.0570	33
122563	0.0200	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral globus pallidus	UBERON:0002476	97.54	gold quality
dorsal root ganglion	UBERON:0000044	96.74	gold quality
putamen	UBERON:0001874	95.79	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.79	gold quality
cerebellar hemisphere	UBERON:0002245	95.76	gold quality
cerebellar cortex	UBERON:0002129	95.69	gold quality
pons	UBERON:0000988	95.56	gold quality
cerebellum	UBERON:0002037	95.37	gold quality
caudate nucleus	UBERON:0001873	95.09	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.18	gold quality
primary visual cortex	UBERON:0002436	94.01	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.37	gold quality
trigeminal ganglion	UBERON:0001675	93.32	gold quality
cerebellar vermis	UBERON:0004720	92.96	gold quality
occipital lobe	UBERON:0002021	92.09	gold quality
middle temporal gyrus	UBERON:0002771	91.61	gold quality
apex of heart	UBERON:0002098	91.25	gold quality
endothelial cell	CL:0000115	90.59	gold quality
prefrontal cortex	UBERON:0000451	90.39	gold quality
nucleus accumbens	UBERON:0001882	90.13	gold quality
right frontal lobe	UBERON:0002810	90.12	gold quality
frontal cortex	UBERON:0001870	89.51	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	89.39	gold quality
parietal lobe	UBERON:0001872	89.24	gold quality
postcentral gyrus	UBERON:0002581	89.23	gold quality
Brodmann (1909) area 9	UBERON:0013540	88.92	gold quality
neocortex	UBERON:0001950	88.72	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.29	gold quality
anterior cingulate cortex	UBERON:0009835	87.96	gold quality
superior frontal gyrus	UBERON:0002661	87.67	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.64

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

201 targeting SCN4B, 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-4692	100.00	67.32	2066
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-5680	99.91	69.83	3421

Literature-anchored findings (GeneRIF, showing 23)

• molecular cloning and characterization of sodium channel beta4 (PMID:12930796)
• SCN4B is a long QT syndrome susceptibility gene. (PMID:17592081)
• Co-expression of the beta1 subunit impeded slow inactivation elicited by a 30-s depolarization, such that the voltage dependence was right shifted (depolarized) and recovery was hastened. (PMID:18941776)
• Loss of function mutations in sodium channel beta-subunits were identified in patients with atrial fibrillation and were associated with a distinctive ECG phenotype (PMID:19808477)
• The researchers found evidence of an association between SCN4B subunit mutations and sudden infant death syndrome pathogenesis. (PMID:20226894)
• The paroxysmal extreme pain disorder associated Nav1.7 missense mutations M1627K, T1464I and V1299F increase Navbeta4 peptide-mediated resurgent sodium currents, in contrast to the erythromelalgia associated I848T and L858H Nav1.7 missense mutations. (PMID:21115638)
• SCN5A-SCN4B were found to be essential for positive selection of CD4(+) T cells. (PMID:22842345)
• this is the first study to demonstrate an association of SCN4B mutations with AF, suggesting SCN4B as a novel AF susceptibility gene. (PMID:23604097)
• results suggest the presence of a docking site that is maintained by a cysteine bridge buried within the hydrophobic core of beta4. (PMID:24297919)
• The expression of a human-specific isoform of the voltage-gated sodium channel subunit SCN4B was significantly correlated to lifetime alcohol consumption (PMID:25450227)
• In a nonreferred nationwide Danish cohort of SIDS cases, up to 5/66 (7.5%) of SIDS cases can be explained by genetic variants in the sodium channel complex genes. (PMID:25757662)
• Contribution of Cardiac Sodium Channel beta-Subunit Variants to Brugada Syndrome. (PMID:26179811)
• 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)
• SCN4B overexpression reduces cancer cell invasiveness and tumour progression. (PMID:27917859)
• Data suggest that extracellular domains of SCN4B directly interact with each other in parallel homodimers that involve an intermolecular disulfide bond between unpaired Cys residues (Cys58) in loop connecting strands B and C and intermolecular hydrophobic and hydrogen-bonding interactions of N-terminal segments (Ser30-Val35); SCN4B homodimers appear to play role in cell-cell adhesion. (PMID:28655765)
• Preserved SCN4B expression is an independent indicator of favorable recurrence-free survival in classical papillary thyroid cancer. (PMID:29723302)
• this study reports the cryo-electron microscopy structure of the human Nav1.4-beta1 complex at 3.2-A resolution. (PMID:30190309)
• These data suggest that rare variant p.Gly8Ser of SCN4B confers a significant risk of AF, and SCN4B is a candidate susceptibility gene for AF. (PMID:30821358)
• Data identified one rare nonsynonymous heterozygous variant, p.Gly8Ser, in SCN4B that was significantly associated with a risk of ventricular tachycardia (VT) in two independent populations. (PMID:31020414)
• Silencing of microRNA-3175 represses cell proliferation and invasion in prostate cancer by targeting the potential tumor-suppressor SCN4B. (PMID:32833340)
• The Voltage-Gated Sodium Channel Beta4 Subunit Maintains Epithelial Phenotype in Mammary Cells. (PMID:34209614)
• SCN4B inhibits the progression of lung adenocarcinoma and is associated with better prognosis. (PMID:37826914)
• Anti-NSCLC role of SCN4B by negative regulation of the cGMP-PKG pathway: Integrated utilization of bioinformatics analysis and in vitro assay validation. (PMID:38678552)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	scn4bb	ENSDARG00000060319
danio_rerio	scn4ba	ENSDARG00000099031
mus_musculus	Scn4b	ENSMUSG00000046480
rattus_norvegicus	Scn4b	ENSRNOG00000026679

Paralogs (6): MPZL2 (ENSG00000149573), SCN2B (ENSG00000149575), MPZ (ENSG00000158887), MPZL3 (ENSG00000160588), JAML (ENSG00000160593), MPZL1 (ENSG00000197965)

Protein

Protein identifiers

Sodium channel regulatory subunit beta-4 — Q8IWT1 (reviewed: Q8IWT1)

All UniProt accessions (2): Q8IWT1, B0YJ93

UniProt curated annotations — full annotation on UniProt →

Function. Regulatory subunit of multiple voltage-gated sodium (Nav) channels directly mediating the depolarization of 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. The accessory beta subunits participate in localization and functional modulation of the Nav channels. Modulates the activity of SCN1A/Nav1.1. Modulates the activity of SCN2A/Nav1.2.

Subunit / interactions. A voltage-gated sodium (Nav) channel consists of an ion-conducting pore-forming alpha subunit functional on its own that is regulated by one or more beta subunits. The beta subunit SCN4B is disulfide-linked to the pore-forming alpha subunit. Interacts with SCN1A; regulatory subunit of SCN1A/Nav1.1. Interacts with SCN2A; regulatory subunit of SCN2A/Nav1.2.

Subcellular location. Cell membrane.

Tissue specificity. Expressed at a high level in dorsal root ganglia, at a lower level in brain, spinal cord, skeletal muscle and heart. Expressed in the atrium.

Post-translational modifications. Contains an interchain disulfide bond with SCN2A. N-glycosylated.

Disease relevance. Long QT syndrome 10 (LQT10) [MIM:611819] 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. Atrial fibrillation, familial, 17 (ATFB17) [MIM:611819] 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.

Similarity. Belongs to the sodium channel auxiliary subunit SCN4B (TC 8.A.17) family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8IWT1-1	1	yes
Q8IWT1-2	2
Q8IWT1-3	3

RefSeq proteins (3): NP_001135820, NP_001135821, NP_777594* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000920	Myelin_P0-rel	Family
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013106	Ig_V-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily

Pfam: PF07686

UniProt features (36 total): strand 11, glycosylation site 3, sequence variant 3, disulfide bond 2, splice variant 2, mutagenesis site 2, topological domain 2, helix 2, compositionally biased region 2, signal peptide 1, chain 1, sequence conflict 1, turn 1, transmembrane region 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
6VSV	X-RAY DIFFRACTION	1.62
4MZ2	X-RAY DIFFRACTION	1.72
4MZ3	X-RAY DIFFRACTION	1.74
5XAW	X-RAY DIFFRACTION	2.1
7DTD	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IWT1-F1	83.91	0.63

Functional residue map

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

Disulfide bonds (2): 53–131, 58

Glycosylation sites (3): 71, 113, 45

Mutagenesis-validated functional residues (2):

Position	Phenotype
58	abolishes regulation of channel activity.
131	decreases protein stability. causes conformation changes that impair interaction with the alpha subunit.

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-445095	Interaction between L1 and Ankyrins
R-HSA-5576892	Phase 0 - rapid depolarisation
R-HSA-9717207	Sensory perception of sweet, bitter, and umami (glutamate) taste
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
R-HSA-9709957	Sensory Perception
R-HSA-9717189	Sensory perception of taste

MSigDB gene sets: 256 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_MEMBRANE_DEPOLARIZATION, BENPORATH_ES_WITH_H3K27ME3, GOBP_CIRCULATORY_SYSTEM_PROCESS, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_MEMBRANE_DEPOLARIZATION_DURING_ACTION_POTENTIAL, GOBP_POSITIVE_REGULATION_OF_SODIUM_ION_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_REGULATION_OF_SODIUM_ION_TRANSPORT, GTGCCTT_MIR506, GOBP_REGULATION_OF_CARDIAC_MUSCLE_CELL_MEMBRANE_REPOLARIZATION, GOBP_MUSCLE_CONTRACTION, GOBP_POSITIVE_REGULATION_OF_MONOATOMIC_ION_TRANSPORT

GO Biological Process (14): sodium ion transport (GO:0006814), positive regulation of sodium ion transport (GO:0010765), neuronal action potential (GO:0019228), sodium ion transmembrane transport (GO:0035725), establishment of localization in cell (GO:0051649), cardiac muscle contraction (GO:0060048), regulation of ventricular cardiac muscle cell membrane repolarization (GO:0060307), cardiac conduction (GO:0061337), cardiac muscle cell action potential involved in contraction (GO:0086002), membrane depolarization during cardiac muscle cell action potential (GO:0086012), AV node cell action potential (GO:0086016), regulation of heart rate by cardiac conduction (GO:0086091), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220)

GO Molecular Function (5): voltage-gated sodium channel activity (GO:0005248), sodium channel regulator activity (GO:0017080), transmembrane transporter binding (GO:0044325), voltage-gated sodium channel activity involved in cardiac muscle cell action potential (GO:0086006), protein binding (GO:0005515)

GO Cellular Component (4): voltage-gated sodium channel complex (GO:0001518), plasma membrane (GO:0005886), intercalated disc (GO:0014704), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
L1CAM interactions	1
Cardiac conduction	1
Sensory perception of taste	1
Axon guidance	1
Nervous system development	1
Muscle contraction	1
Developmental Biology	1
Sensory Perception	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cardiac muscle cell action potential	3
sodium ion transport	2
sodium channel activity	2
metal ion transport	1
regulation of sodium ion transport	1
positive regulation of monoatomic ion transport	1
action potential	1
transmission of nerve impulse	1
monoatomic cation transmembrane transport	1
establishment of localization	1
cellular localization	1
striated muscle contraction	1
heart contraction	1
regulation of cardiac muscle cell membrane repolarization	1
ventricular cardiac muscle cell membrane repolarization	1
regulation of heart contraction	1
cardiac muscle cell contraction	1
membrane depolarization during action potential	1
AV node cell to bundle of His cell signaling	1
regulation of heart rate	1
cardiac conduction	1
transport	1
monoatomic ion transport	1
transmembrane transport	1
ion channel regulator activity	1
protein binding	1
voltage-gated sodium channel activity	1
membrane depolarization during cardiac muscle cell action potential	1
binding	1
sodium channel complex	1
plasma membrane protein complex	1
membrane	1
cell periphery	1
cell-cell contact zone	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1420 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SCN4B	SCN1B	Q07699	973
SCN4B	SCN5A	Q14524	950
SCN4B	SCN3B	Q9NY72	943
SCN4B	SCN11A	Q9UI33	903
SCN4B	SCN1A	P35498	892
SCN4B	KCNE2	Q9Y6J6	881
SCN4B	SNTA1	Q13424	871
SCN4B	SCN2A	Q99250	865
SCN4B	KCNE1	P15382	856
SCN4B	AKAP9	Q99996	856
SCN4B	KCNJ2	P48049	853
SCN4B	KCNJ5	P48544	841
SCN4B	CAV3	P56539	830
SCN4B	KCNH2	Q12809	827
SCN4B	SCN8A	Q9UQD0	822

IntAct

125 interactions, top by confidence:

A	B	Type	Score
YIF1A	SCN4B	psi-mi:“MI:0915”(physical association)	0.560
ANKH	FAM234B	psi-mi:“MI:0914”(association)	0.530
SCN4B	PICK1	psi-mi:“MI:0407”(direct interaction)	0.440
SCN4B	PATJ	psi-mi:“MI:0407”(direct interaction)	0.440
SCN4B	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
SCN4B	HTRA4	psi-mi:“MI:0407”(direct interaction)	0.440
APBA3	SCN4B	psi-mi:“MI:0407”(direct interaction)	0.440
SCN4B	WHRN	psi-mi:“MI:0407”(direct interaction)	0.440
SCN4B	PALS2	psi-mi:“MI:0407”(direct interaction)	0.440
LIN7C	SCN4B	psi-mi:“MI:0407”(direct interaction)	0.440
SCN4B	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
MPP2	SCN4B	psi-mi:“MI:0407”(direct interaction)	0.440
SCN4B	NHERF4	psi-mi:“MI:0407”(direct interaction)	0.440
LIN7B	SCN4B	psi-mi:“MI:0407”(direct interaction)	0.440
SCN4B	TAX1BP3	psi-mi:“MI:0407”(direct interaction)	0.440
SCN4B	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
SCN4B	ARHGAP21	psi-mi:“MI:0407”(direct interaction)	0.440
SCN4B	DLG3	psi-mi:“MI:0407”(direct interaction)	0.440
SCN4B	RAPGEF6	psi-mi:“MI:0407”(direct interaction)	0.440
SCN4B	TIAM2	psi-mi:“MI:0407”(direct interaction)	0.440
SCN4B	GRIP1	psi-mi:“MI:0407”(direct interaction)	0.440
SCN4B	TJP1	psi-mi:“MI:0407”(direct interaction)	0.440
SCN4B	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
SCN4B	FRMPD2	psi-mi:“MI:0407”(direct interaction)	0.440
SCN4B	GIPC2	psi-mi:“MI:0407”(direct interaction)	0.440
SCN4B	LNX2	psi-mi:“MI:0407”(direct interaction)	0.440
SCN4B	DLG5	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (6): SCN4B (Affinity Capture-Western), SCN4B (Two-hybrid), SCN4B (Affinity Capture-Western), SCN4B (Affinity Capture-Western), SCN4B (Affinity Capture-RNA), SCN4B (Affinity Capture-MS)

ESM2 similar proteins: A5D7H1, A8MXK1, O76036, P01134, P01135, P08887, P14745, P35790, P48030, P48061, P55244, P98135, Q01134, Q05078, Q06922, Q08334, Q08DW9, Q08E08, Q0V881, Q12841, Q28284, Q29423, Q2KI11, Q3SXP7, Q3UHH2, Q58D84, Q5M7U7, Q5R9Y1, Q5SQ64, Q62356, Q62632, Q6AZB0, Q6MG56, Q6UXG2, Q7M729, Q7M730, Q7TPB4, Q86XW9, Q8BHK2, Q8BZI6

Diamond homologs: A0JM41, A2VD98, A5D7C3, O60487, O60939, O70255, O95297, P06907, P10522, P20938, P25189, P27573, P37301, P54900, Q29RR6, Q32PI9, Q3TEW6, Q3V3F6, Q4KLY3, Q5EAB0, Q5R804, Q6AYT8, Q6UWV2, Q6WEB5, Q7M729, Q7M730, Q86XK7, Q8AVM3, Q8IWT1, Q9D2J4, Q9PWR4, Q08E08, P78310, P97792, Q56A07, Q5R764, Q864L3, Q86YT9, Q8WMV3, Q91664

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SCN4B	“form complex”	“Nax cation channel complex, SCN3B-SCN4B variant”	binding
SCN4B	“form complex”	“Nax cation channel complex, SCN1B-SCN4B variant”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 85 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×	1e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	49.4×	1e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	49.4×	1e-06
Assembly and cell surface presentation of NMDA receptors	10	46.1×	7e-13
Dopamine Neurotransmitter Release Cycle	5	45.1×	2e-06
Long-term potentiation	5	43.3×	2e-06
Neurexins and neuroligins	11	39.4×	4e-13
Protein-protein interactions at synapses	7	33.8×	7e-08

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	10	71.7×	3e-14
protein localization to synapse	6	56.7×	1e-07
receptor clustering	7	53.9×	9e-09
regulation of postsynaptic membrane neurotransmitter receptor levels	6	36.7×	1e-06
protein-containing complex assembly	9	12.7×	2e-06
cell-cell adhesion	10	12.5×	7e-07
regulation of small GTPase mediated signal transduction	5	8.9×	4e-03
chemical synaptic transmission	7	6.7×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	130
Likely benign	83
Benign	27

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
140600	NM_174934.4(SCN4B):c.485T>G (p.Val162Gly)	Pathogenic
140601	NM_174934.4(SCN4B):c.496A>C (p.Ile166Leu)	Pathogenic

SpliceAI

972 predictions. Top by Δscore:

Variant	Effect	Δscore
11:118137030:CA:C	donor_gain	1.0000
11:118137117:CTTC:C	acceptor_gain	1.0000
11:118137121:C:CC	acceptor_gain	1.0000
11:118137121:C:G	acceptor_loss	1.0000
11:118137122:T:A	acceptor_loss	1.0000
11:118141203:TCA:T	donor_loss	1.0000
11:118141204:CACT:C	donor_loss	1.0000
11:118141205:A:AC	donor_gain	1.0000
11:118141205:ACTT:A	donor_gain	1.0000
11:118141206:C:CG	donor_gain	1.0000
11:118141206:CTT:C	donor_gain	1.0000
11:118141206:CTTC:C	donor_gain	1.0000
11:118141208:T:TA	donor_gain	1.0000
11:118141334:CCA:C	acceptor_gain	1.0000
11:118141335:CAC:C	acceptor_gain	1.0000
11:118141336:AC:A	acceptor_loss	1.0000
11:118141337:C:CC	acceptor_gain	1.0000
11:118141339:G:C	acceptor_gain	1.0000
11:118141339:G:GC	acceptor_gain	1.0000
11:118141341:G:C	acceptor_gain	1.0000
11:118141346:CCGAG:C	acceptor_gain	1.0000
11:118141347:C:CT	acceptor_gain	1.0000
11:118141347:C:T	acceptor_gain	1.0000
11:118141348:G:T	acceptor_gain	1.0000
11:118141350:G:C	acceptor_gain	1.0000
11:118141350:G:GC	acceptor_gain	1.0000
11:118143824:A:AC	donor_gain	1.0000
11:118143825:C:CC	donor_gain	1.0000
11:118143831:A:AC	donor_gain	1.0000
11:118143832:C:CC	donor_gain	1.0000

AlphaMissense

1492 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:118143904:C:G	C131S	0.999
11:118143905:A:T	C131S	0.999
11:118145087:C:A	W68C	0.999
11:118145087:C:G	W68C	0.999
11:118145089:A:G	W68R	0.999
11:118145089:A:T	W68R	0.999
11:118143903:G:C	C131W	0.998
11:118143904:C:T	C131Y	0.998
11:118143905:A:G	C131R	0.998
11:118143910:T:G	Y129S	0.998
11:118143911:A:C	Y129D	0.998
11:118143910:T:C	Y129C	0.997
11:118143953:A:G	S115P	0.997
11:118145088:C:G	W68S	0.997
11:118145126:G:C	F55L	0.997
11:118145126:G:T	F55L	0.997
11:118145128:A:G	F55L	0.997
11:118145132:G:C	C53W	0.997
11:118145133:C:G	C53S	0.997
11:118145133:C:T	C53Y	0.997
11:118145134:A:G	C53R	0.997
11:118145134:A:T	C53S	0.997
11:118143891:G:C	N135K	0.996
11:118143891:G:T	N135K	0.996
11:118143917:C:A	G127C	0.996
11:118145094:A:G	F66S	0.996
11:118145120:G:C	S57R	0.996
11:118145120:G:T	S57R	0.996
11:118145122:T:G	S57R	0.996
11:118145127:A:C	F55C	0.996

dbSNP variants (sampled 300 via entrez): RS1000209850 (11:118151603 G>A), RS1000240178 (11:118143221 T>C), RS1000423869 (11:118145580 C>G,T), RS1000451268 (11:118149158 T>C,G), RS1000755231 (11:118144129 C>T), RS1000845711 (11:118141679 C>T), RS1001085548 (11:118154169 G>A,C), RS1001219641 (11:118137067 G>A,C), RS1001523987 (11:118152365 G>A), RS1001564419 (11:118153906 C>CTGGT), RS1001567765 (11:118137258 T>C,G), RS1001594807 (11:118145653 C>T), RS1001672431 (11:118132904 G>A), RS1001744001 (11:118139559 C>T), RS1001940603 (11:118154231 G>A)

Disease associations

OMIM: gene MIM:608256 | disease phenotypes: MIM:611819, MIM:600996, MIM:604772

GenCC curated gene-disease

Disease	Classification	Inheritance
familial atrial fibrillation	Supportive	Autosomal dominant
long QT syndrome 10	Limited	Unknown

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
long QT syndrome	Disputed	AD

Mondo (4): long QT syndrome 10 (MONDO:0012737), atrial fibrillation, familial, 17 (MONDO:0800345), catecholaminergic polymorphic ventricular tachycardia 1 (MONDO:0011484), familial atrial fibrillation (MONDO:0018054)

Orphanet (3): Romano-Ward syndrome (Orphanet:101016), Congenital long QT syndrome (Orphanet:768), Catecholaminergic polymorphic ventricular tachycardia (Orphanet:3286)

HPO phenotypes

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

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000365	Hearing impairment
HP:0001197	Abnormality of prenatal development or birth
HP:0001250	Seizure
HP:0001279	Syncope
HP:0001645	Sudden cardiac death
HP:0001657	Prolonged QT interval
HP:0001658	Myocardial infarction
HP:0001664	Torsade de pointes
HP:0001678	Atrioventricular block
HP:0001688	Sinus bradycardia
HP:0001727	Thromboembolic stroke
HP:0001907	Thromboembolism
HP:0001962	Palpitations
HP:0002094	Dyspnea
HP:0002321	Vertigo
HP:0002900	Hypokalemia
HP:0003546	Exercise intolerance
HP:0003581	Adult onset
HP:0003621	Juvenile onset
HP:0004308	Ventricular arrhythmia
HP:0005110	Atrial fibrillation
HP:0005135	Abnormal T-wave
HP:0005184	Prolonged QTc interval
HP:0011463	Childhood onset
HP:0012266	T-wave alternans
HP:0012332	Abnormal autonomic nervous system physiology
HP:0012378	Fatigue
HP:0100749	Chest pain
HP:0500018	Abnormal cardiac exercise stress test

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C563409	Arrhythmogenic Right Ventricular Dysplasia, Familial, 2 (supp.)
C567514	Long Qt Syndrome 10 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	6
trichostatin A	affects cotreatment, increases expression	3
Doxorubicin	increases expression	3
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Tretinoin	affects expression, increases expression	2
propionaldehyde	increases expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
pentanal	increases expression	1
tebuconazole	decreases expression	1
CGP 52608	affects binding, increases reaction	1
2,7-dihydroxynaphthalene	decreases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	decreases expression	1
Aldehydes	increases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Diethylhexyl Phthalate	decreases expression	1
Etoposide	increases expression	1
Methapyrilene	increases methylation	1
Nickel	decreases expression	1
Phenylmercuric Acetate	affects cotreatment, decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	affects expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05122975	PHASE2	TERMINATED	Treatment of an Inherited Ventricular Arrhythmia
NCT06005428	PHASE2	TERMINATED	Effectiveness of CRD-4730 in Participants With Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT)
NCT04075994	Not specified	COMPLETED	Atrial Fibrillation Health Literacy and Information Technology Trial
NCT04076020	Not specified	COMPLETED	Atrial Fibrillation Health Literacy and Information Technology Trial in Rural Pennsylvania Counties
NCT06661278	Not specified	RECRUITING	Evaluation of Exercise Testing and Physical Activity in Children and Adolescents Living With Inherited Arrhythmias