SCN5A Gene Complete Identifier and Functional Mapping Reference
Provide a comprehensive cross-database identifier and functional mapping reference for human SCN5A — a definitive lookup resource covering: ### Section 1: Gene identifiers For human gene SCN5A, list ALL gene-level database identifiers. Required: - HGNC ID and approved symbol - Ensembl gene ID (ENSG...) - NCBI Entrez Gene ID - OMIM gene/locus ID - Genomic location: chromosome, start position, end position, strand (GRCh38) ### Section 2: Transcript identifiers For human gene SCN5A, list ALL transcript-level identifiers. Required: - Ensembl transcripts: ALL ENST IDs with biotype. Total count. - RefSeq transcripts: ALL NM_ mRNA accessions. Mark which is MANE Select. - CCDS IDs. - For the CANONICAL/MANE SELECT transcript: ALL exon IDs (ENSE) with genomic coordinates and total exon count. ### Section 3: Protein identifiers For human gene SCN5A protein product(s), list ALL protein-level identifiers. Required: - UniProt accessions: ALL entries (reviewed and unreviewed). Mark the canonical reviewed entry. - RefSeq protein: ALL NP_ accessions. - Protein domains and families: list ALL annotated domains/families with identifiers, including name, type (domain/family/superfamily), and ID. - Antibody availability: known antibody resources for the protein. ### Section 4: Structure For human gene SCN5A protein, list ALL structural data. Required: - Experimental structures: ALL PDB IDs. For each: experimental method (X-ray/NMR/Cryo-EM) and resolution. Total count. - Predicted structures: AlphaFold model ID and confidence metrics (pLDDT). ### Section 5: Cross-species orthologs For human gene SCN5A, list orthologous genes in key model organisms. Organisms: - Mouse (Mus musculus): gene ID, symbol - Rat (Rattus norvegicus): gene ID, symbol - Zebrafish (Danio rerio): gene ID, symbol - Fruit fly (Drosophila melanogaster): gene ID, symbol - Worm (C. elegans): gene ID, symbol - Yeast (S. cerevisiae): gene ID, symbol ### Section 6: Clinical variants & AI predictions For human gene SCN5A, summarize clinical variants and AI predictions. Clinical variant annotations (ClinVar): - Total variant count (approximate is fine) - Breakdown by classification: Pathogenic, Likely Pathogenic, VUS, Likely Benign, Benign - TOP 30 pathogenic/likely pathogenic variants with: variant ID, HGVS notation, associated condition AI-based variant effect predictions: - Splice effect predictions: total count + TOP 30 with delta scores if known - Missense pathogenicity from AlphaMissense — total count + TOP 30 likely-pathogenic with am_pathogenicity scores. ### Section 7: Pathways & Gene Ontology For human gene SCN5A, list biological pathways and Gene Ontology annotations. Pathway membership: - ALL biological pathways this gene participates in, with pathway IDs and names - Total pathway count Gene Ontology: - Biological Process: count and TOP 20 terms with GO IDs - Molecular Function: count and TOP 20 terms with GO IDs - Cellular Component: count and TOP 20 terms with GO IDs ### Section 8: Protein interactions & networks For human gene SCN5A protein, summarize protein interactions and networks. Protein-protein interactions (STRING, IntAct, BioGRID, etc.): - Total interaction count (approximate) - TOP 30 highest-confidence interacting proteins with scores/evidence Protein similarity: - Structural/embedding similarity (e.g. Foldseek, ESM): TOP 20 similar proteins with scores - Sequence homology: TOP 20 homologous proteins with identity/similarity ### Section 9: Transcription factor regulatory data For human gene SCN5A, summarize transcription factor regulatory data. If SCN5A is a transcription factor: - Downstream targets: total count + TOP 30 with regulation type (activates/represses) and evidence - DNA binding motifs from JASPAR — all known motif IDs and motif family classification. Regardless: - Upstream regulators: TFs that regulate SCN5A — names with evidence type (ChIP-seq / predicted / experimentally validated) If SCN5A is not a transcription factor, say so briefly and skip the downstream/motif sections. ### Section 10: Drug & pharmacology data For human gene SCN5A protein as a drug target, summarize pharmacology data. If SCN5A is a known drug target: - Targeting molecules: total count in ChEMBL/DrugBank + TOP 30 by development phase (molecule ID, name, mechanism, highest phase) - Clinical trials: TOP 20 involving drugs targeting this gene — trial ID, phase, status, intervention - Pharmacogenomics: known drug-gene interactions affecting drug response + dosing guidelines if any If SCN5A is not currently a drug target, say so briefly. ### Section 11: Expression profiles For human gene SCN5A, summarize expression profiles. Tissue expression (GTEx, HPA, Bgee, etc.): - TOP 30 tissues with expression scores/levels (direction, units if known) - Note tissue-specific or tissue-enriched patterns Cell type expression (Tabula Sapiens, HCA, etc.): - TOP 30 cell types with expression scores - Note cell-type-specific patterns Single-cell expression: notable datasets or cell populations of interest for this gene. ### Section 12: Disease associations For human gene SCN5A, summarize disease associations. Mendelian / monogenic disease: - Diseases caused by mutations in SCN5A: disease name, disease ID (OMIM/Orphanet/Mondo), inheritance pattern, evidence level - Include all directly linked conditions Phenotype associations: - Clinical phenotypes associated with the gene (HPO terms where known) - TOP 30 phenotype terms with HPO IDs Complex-disease / GWAS: - Traits and diseases significantly associated via GWAS: trait name, variant, effect size, study where known - TOP 30 GWAS associations
Executive summary
SCN5A encodes Nav1.5, the principal voltage-gated sodium channel alpha subunit of the human heart, and is one of the most clinically significant cardiac ion channel genes known. It drives the rapid depolarization phase (Phase 0) of the cardiac action potential across all conduction-system compartments — SA node, AV node, bundle of His, and Purkinje fibers — making it indispensable for normal cardiac rhythm and conduction. Loss-of-function variants cause three definitively established Mendelian diseases: Brugada syndrome 1, Long QT syndrome 3, and dilated cardiomyopathy 1E, all autosomal dominant, with strong evidence additionally linking it to sick sinus syndrome and progressive familial heart block. The gene carries ~4,334 ClinVar variants, roughly 200 of which are classified pathogenic or likely pathogenic, and GWAS studies confirm genome-wide significant associations with PR interval (p = 1.0e-68), QRS duration, QT interval, P wave duration, and Brugada syndrome (p = 4.0e-57). Nav1.5 is designated a Very Important Pharmacogene (VIP) by PharmGKB, with 1,497 molecules recorded against it in ChEMBL; key clinical drugs include ranolazine (late sodium current inhibitor) and quinidine, with genotype-guided therapy now standard in LQT3 and Brugada syndrome management.
Gene identifiers
Symbol: SCN5A (sodium voltage-gated channel alpha subunit 5)
Database identifiers:
- HGNC: HGNC:10593
- Ensembl: ENSG00000183873
- NCBI Entrez: 6331
- OMIM: 600163
Genomic location (GRCh38):
- Chromosome: 3
- Start: 38,548,057
- End: 38,649,743
- Strand: − (reverse)
Transcript identifiers
Ensembl Transcripts (16 total)
| Transcript ID | Biotype |
|---|---|
| ENST00000327956 | protein_coding |
| ENST00000333535 | protein_coding |
| ENST00000413689 | protein_coding |
| ENST00000414099 | protein_coding |
| ENST00000423572 | protein_coding |
| ENST00000449557 | protein_coding |
| ENST00000450102 | protein_coding |
| ENST00000455624 | protein_coding |
| ENST00000464652 | protein_coding_CDS_not_defined |
| ENST00000476683 | retained_intron |
| ENST00000491944 | retained_intron |
| ENST00000713730 | nonsense_mediated_decay |
| ENST00000713731 | nonsense_mediated_decay |
| ENST00000718272 | retained_intron |
| ENST00000718273 | retained_intron |
| ENST00000970295 | protein_coding |
RefSeq mRNA Transcripts (9 total)
| Accession | Symbol | MANE Select |
|---|---|---|
| NM_000335 | SCN5A | ✓ |
| NM_001099404 | SCN5A | |
| NM_001099405 | SCN5A | |
| NM_001160160 | SCN5A | |
| NM_001160161 | SCN5A | |
| NM_001354701 | SCN5A | |
| NM_001407185 | SCN5A | |
| NM_001407186 | SCN5A | |
| NM_001407187 | SCN5A |
CCDS IDs (6 total)
- CCDS46796
- CCDS46797
- CCDS46798
- CCDS46799
- CCDS54569
- CCDS54570
MANE Select Transcript Exons (ENST00000423572 / NM_000335)
Total exons: 28
| Exon ID | Start | End | Strand | Chromosome |
|---|---|---|---|---|
| ENSE00004014129 | 38,548,062 | 38,551,558 | − | 3 |
| ENSE00003534979 | 38,554,279 | 38,554,549 | − | 3 |
| ENSE00001647919 | 38,555,656 | 38,555,760 | − | 3 |
| ENSE00001425187 | 38,556,441 | 38,556,578 | − | 3 |
| ENSE00004014126 | 38,557,231 | 38,557,284 | − | 3 |
| ENSE00001301918 | 38,560,147 | 38,560,428 | − | 3 |
| ENSE00001293012 | 38,562,415 | 38,562,537 | − | 3 |
| ENSE00001304836 | 38,566,409 | 38,566,582 | − | 3 |
| ENSE00001328382 | 38,575,297 | 38,575,451 | − | 3 |
| ENSE00001308928 | 38,576,661 | 38,576,781 | − | 3 |
| ENSE00004014128 | 38,579,334 | 38,579,492 | − | 3 |
| ENSE00001302724 | 38,580,931 | 38,581,371 | − | 3 |
| ENSE00001315108 | 38,585,691 | 38,586,041 | − | 3 |
| ENSE00001306185 | 38,587,400 | 38,587,573 | − | 3 |
| ENSE00001329449 | 38,597,729 | 38,597,967 | − | 3 |
| ENSE00001300049 | 38,598,918 | 38,599,050 | − | 3 |
| ENSE00003464330 | 38,620,843 | 38,620,971 | − | 3 |
| ENSE00003562400 | 38,622,400 | 38,622,489 | − | 3 |
| ENSE00004014127 | 38,613,743 | 38,613,834 | − | 3 |
| ENSE00001779170 | 38,633,035 | 38,633,359 | − | 3 |
| ENSE00003585523 | 38,630,311 | 38,630,429 | − | 3 |
| ENSE00001322079 | 38,603,712 | 38,604,083 | − | 3 |
| ENSE00001300791 | 38,604,729 | 38,604,908 | − | 3 |
| ENSE00001320962 | 38,605,951 | 38,606,148 | − | 3 |
| ENSE00001299736 | 38,606,669 | 38,606,810 | − | 3 |
| ENSE00001330780 | 38,608,151 | 38,608,214 | − | 3 |
| ENSE00001414724 | 38,609,734 | 38,609,964 | − | 3 |
| ENSE00004021056 | 38,649,531 | 38,649,687 | − | 3 |
Protein identifiers
UniProt Accessions
Reviewed (Canonical):
- Q14524 - Sodium channel protein type 5 subunit alpha (canonical reviewed entry; 2016 aa, 226.94 kDa)
Unreviewed isoforms/variants:
- A0A0A0MT39
- A0AAQ5BGT0
- A0AAQ5BGV8
- A3EY21
- E9PG18
- E9PHB6
- H9KVD2
- K4DIA1
RefSeq Protein Accessions (NP_)
MANE Select (canonical transcript):
- NP_000326
Additional RefSeq proteins:
- NP_001092874
- NP_001092875
- NP_001153632
- NP_001153633
- NP_001153634
- NP_001240789
- NP_001341630
- NP_001394114
- NP_001394115
- NP_001394116
- NP_037257
- NP_067519
- NP_179204
- NP_187663
- NP_932173
Protein Domains and Families
InterPro:
| ID | Name | Type |
|---|---|---|
| IPR001696 | Voltage gated sodium channel, alpha subunit | Family |
| IPR005821 | Ion transport domain | Domain |
| IPR008053 | Voltage gated sodium channel, alpha-5 subunit | Family |
| IPR010526 | Sodium ion transport-associated domain | Domain |
| IPR024583 | Voltage-gated Na+ ion channel, cytoplasmic domain | Domain |
| IPR027359 | Voltage-dependent channel domain superfamily | Homologous_superfamily |
| IPR043203 | Voltage-gated cation channel calcium and sodium | Family |
| IPR044564 | Voltage-gated sodium channel alpha subunit, inactivation gate | Domain |
| IPR058542 | SCN5A-like, C-terminal IQ motif | Domain |
Pfam:
- PF00520
- PF06512
- PF11933
- PF24609
Antibody Availability
No antibody resources are indexed in biobtree for SCN5A. Consult UniProt protein page (Q14524) for linked antibody provider information via external resources (e.g., commercial vendors, research catalogs).
Structure
Experimental Structures
Total PDB Structures: 14
| PDB ID | Title | Method | Resolution |
|---|---|---|---|
| 2KBI | Solution NMR structure of the C-terminal EF-hand domain of human cardiac sodium channel NaV1.5 | NMR | — |
| 2L53 | Solution NMR Structure of apo-calmodulin in complex with the IQ motif of Human Cardiac Sodium Channel NaV1.5 | NMR | — |
| 4DCK | Crystal structure of the C-terminus of voltage-gated sodium channel in complex with FGF13 and CaM | X-ray | 2.2 Å |
| 4DJC | 1.35 A crystal structure of the NaV1.5 DIII-IV-Ca/CaM complex | X-ray | 1.35 Å |
| 4JQ0 | Voltage-gated sodium channel 1.5 C-terminal domain in complex with FGF12B and Ca2+/calmodulin | X-ray | 3.84 Å |
| 4OVN | Voltage-gated Sodium Channel 1.5 (Nav1.5) C-terminal domain in complex with Calmodulin poised for activation | X-ray | 2.8 Å |
| 5DBR | Ca2+ CaM with human cardiac Na+ channel (NaV1.5) inactivation gate | X-ray | 2.25 Å |
| 6LQA | Voltage-gated sodium channel Nav1.5 with quinidine | Cryo-EM | 3.3 Å |
| 6MUD | Voltage-gated sodium channel NaV1.5 C-terminal domain in complex with Ca2+/Calmodulin | X-ray | 2.69 Å |
| 7DTC | Voltage-gated sodium channel Nav1.5-E1784K | Cryo-EM | 3.3 Å |
| 7L83 | NMR solution structure of Nav1.5 DIV S3b-S4a paddle motif in DPC micelle | NMR | — |
| 8VYJ | Structure of full-length human cardiac sodium channel - Class-I | Cryo-EM | 3.6 Å |
| 8VYK | Structure of full-length human cardiac sodium channel - Class-II | Cryo-EM | 3.9 Å |
| 9ITH | Nav1.5 in complex with TTX | Cryo-EM | 3.4 Å |
Method Summary: 8 X-ray, 3 NMR, 5 Cryo-EM
Predicted Structures
- AlphaFold Model ID: AF-Q14524-F1 (v4)
- Global pLDDT: 68.02
- Confidence breakdown:
- Very high (>90): 11.72%
- Confident (70-90): 48.79%
- Low (50-70): 14.34%
- Very low (<50): 25.15%
- Predicted Aligned Error (PAE): mean 20.23, max 31.75
Cross-species orthologs
| Organism | Gene ID | Symbol |
|---|---|---|
| Mouse (Mus musculus) | ENSMUSG00000032511 | Scn5a |
| Rat (Rattus norvegicus) | ENSRNOG00000015049 | Scn5a |
| Zebrafish (Danio rerio) | none | none |
| Fruit fly (Drosophila melanogaster) | none | none |
| Worm (C. elegans) | none | none |
| Yeast (S. cerevisiae) | none | none |
Clinical variants & AI predictions
ClinVar Variants
Total variants: ~4,334
Classification breakdown:
| Classification | Count |
|---|---|
| Pathogenic | ~100 |
| Likely Pathogenic | ~100 |
| Uncertain significance | ~2,000+ |
| Likely Benign | ~1,500+ |
| Benign | 71 |
TOP 30 pathogenic/likely pathogenic variants:
| ClinVar ID | HGVS Notation | Condition/Context |
|---|---|---|
| 1072446 | c.2618C>G (p.Ser873Ter) | Stop codon - Long QT/Brugada |
| 1072847 | c.934+1G>A | Splice site loss - cardiac arrhythmia |
| 1073629 | c.4320dup (p.Tyr1441fs) | Frameshift - inherited arrhythmia |
| 1073809 | c.4085del (p.Cys1362fs) | Frameshift deletion |
| 1075437 | c.4837A>T (p.Lys1613Ter) | Stop codon |
| 1076513 | c.901del (p.Trp301fs) | Frameshift deletion |
| 1076635 | c.3394G>T (p.Glu1132Ter) | Stop codon |
| 201427 | c.611+1G>A | Splice site loss |
| 201438 | c.664C>T (p.Arg222Ter) | Stop codon |
| 201443 | c.1080G>A (p.Trp360Ter) | Stop codon |
| 201447 | c.1134T>A (p.Tyr378Ter) | Stop codon |
| 201448 | c.1167C>A (p.Tyr389Ter) | Stop codon |
| 201488 | c.3550C>T (p.Gln1184Ter) | Stop codon |
| 201500 | c.3820G>T (p.Asp1274Tyr) | Missense - voltage gating defect |
| 201502 | c.3991C>T (p.Pro1331Ser) | Missense |
| 1067586 | c.2024-1G>A | Splice site loss - likely pathogenic |
| 1068181 | c.4296+1G>T | Splice site loss - likely pathogenic |
| 1066010 | c.3961G>T (p.Val1321Leu) | Missense - likely pathogenic |
| 201503 | c.3992C>G (p.Pro1331Arg) | Missense - likely pathogenic |
| 201516 | c.4421A>T (p.Gln1474Leu) | Missense - likely pathogenic |
| 201522 | c.4948A>G (p.Met1650Val) | Missense - likely pathogenic |
| 201525 | c.5023A>G (p.Met1675Val) | Missense - likely pathogenic |
| 201528 | c.5105G>A (p.Cys1702Tyr) | Missense - likely pathogenic |
| 201533 | c.5228G>T (p.Ser1743Ile) | Missense - likely pathogenic |
| 201542 | c.5623G>A (p.Glu1875Lys) | Missense - likely pathogenic |
| 392337 | c.273+1G>A | Splice site loss - likely pathogenic |
| 406420 | c.2787+1G>T | Splice site loss - likely pathogenic |
| 222803 | c.784A>C (p.Ser262Arg) | Missense - likely pathogenic |
| 222805 | c.1252G>T (p.Glu418Ter) | Stop codon - likely pathogenic |
| 217838 | c.4769G>A (p.Trp1590Ter) | Stop codon - likely pathogenic |
AI-Based Variant Effect Predictions
SpliceAI predictions
- Total variants: 5,420
- High effect scores (>0.8): ~50 variants
- TOP 30 high-scoring splice variants:
| Variant | Effect Type | Delta Score |
|---|---|---|
| 3:38551555:GTGC:G | acceptor_gain | 0.97 |
| 3:38551556:TGCC:T | acceptor_loss | 0.99 |
| 3:38551557:GCCT:G | acceptor_loss | 0.99 |
| 3:38551558:CCT:C | acceptor_loss | 0.99 |
| 3:38551554:AGTGC:A | acceptor_gain | 0.95 |
| 3:38551557:GC:G | acceptor_gain | 0.95 |
| 3:38551558:CC:C | acceptor_gain | 0.95 |
| 3:38551556:TGC:T | acceptor_gain | 0.98 |
| 3:38548533:GGACT:G | acceptor_gain | 0.67 |
| 3:38548535:ACTC:A | acceptor_gain | 0.65 |
| 3:38548537:T:TG | acceptor_gain | 0.61 |
| 3:38548223:C:T | acceptor_gain | 0.61 |
| 3:38548228:C:T | acceptor_gain | 0.60 |
| 3:38548534:GACTC:G | acceptor_gain | 0.53 |
| 3:38548538:C:G | acceptor_gain | 0.42 |
| 3:38548472:A:T | donor_gain | 0.44 |
| 3:38548217:T:A | acceptor_gain | 0.36 |
| 3:38548200:T:TC | acceptor_gain | 0.39 |
| 3:38548199:T:TA | acceptor_gain | 0.37 |
| 3:38548219:A:AT | acceptor_gain | 0.30 |
| 3:38548197:AGT:A | acceptor_gain | 0.28 |
| 3:38548538:C:CT | acceptor_gain | 0.33 |
| 3:38548551:C:CT | acceptor_gain | 0.28 |
| 3:38548225:AGGC:A | acceptor_gain | 0.29 |
| 3:38548226:GGC:G | acceptor_gain | 0.33 |
| 3:38548227:GC:G | acceptor_gain | 0.31 |
| 3:38548214:AGGT:A | acceptor_gain | 0.22 |
| 3:38548215:GGTG:G | acceptor_gain | 0.22 |
| 3:38548216:G:A | acceptor_gain | 0.25 |
| 3:38548529:CA:C | acceptor_gain | 0.22 |
AlphaMissense predictions (missense pathogenicity)
- Total variants: ~2,500+
- Likely pathogenic: 100+
- TOP 30 likely-pathogenic predictions (am_pathogenicity score):
| Genomic Variant | Protein Change | am_pathogenicity |
|---|---|---|
| 3:38550443:A:T | Y1977N | 0.966 |
| 3:38550443:A:G | Y1977H | 0.981 |
| 3:38550443:A:C | Y1977D | 0.983 |
| 3:38550616:C:G | R1919P | 0.992 |
| 3:38550601:G:T | A1924D | 0.976 |
| 3:38550602:C:G | A1924P | 0.977 |
| 3:38550536:C:G | G1946R | 0.972 |
| 3:38550433:A:T | V1980D | 0.979 |
| 3:38550448:G:C | P1975R | 0.944 |
| 3:38550449:G:T | P1975T | 0.943 |
| 3:38550435:A:C | S1979R | 0.939 |
| 3:38550435:A:T | S1979R | 0.939 |
| 3:38550445:G:A | S1976F | 0.939 |
| 3:38550445:G:T | S1976Y | 0.914 |
| 3:38550433:A:G | V1980A | 0.893 |
| 3:38550433:A:C | V1980G | 0.918 |
| 3:38550536:C:A | G1946C | 0.895 |
| 3:38550599:A:G | S1925P | 0.895 |
| 3:38550529:A:T | I1948N | 0.915 |
| 3:38550535:C:A | G1946V | 0.900 |
| 3:38550449:G:A | P1975S | 0.941 |
| 3:38550448:G:T | P1975H | 0.962 |
| 3:38550534:C:A | G1946S | 0.654 |
| 3:38550587:A:G | F1928L | 0.809 |
| 3:38550594:G:C | F1926L | 0.933 |
| 3:38550594:G:T | F1926L | 0.933 |
| 3:38550595:A:G | F1926S | 0.751 |
| 3:38550542:T:G | Y1977C | 0.924 |
| 3:38550542:T:C | Y1977C | 0.924 |
| 3:38550442:T:G | Y1977S | 0.935 |
Pathways & Gene Ontology
Biological Pathways
Reactome Pathways (2 total)
| Pathway ID | Pathway Name |
|---|---|
| R-HSA-445095 | Interaction between L1 and Ankyrins |
| R-HSA-5576892 | Phase 0 - rapid depolarisation |
MSigDB Gene Sets (100 total)
SCN5A participates in 100 MSigDB gene sets, including:
- Canonical Pathways: Cardiac conduction (M27454), Phase 0 rapid depolarisation (M27455), Nervous system development (M29853)
- Gene Ontology Collections (C5): Voltage-gated sodium channel activity, cardiac muscle contraction, regulation of heart rate, and 40+ additional GO-derived sets
- Transcription Factor Targets (C3): Binding sites for MYB, SP3, TAL1, AP1, and others
- microRNA Targets (C3): Predicted targets of miR-520d, miR-374, miR-429, miR-200b/c, and others
- Human Phenotype (C5): Associated with congestive heart failure, dilated cardiomyopathy, ventricular fibrillation, torsade de pointes, and cardiac conduction abnormalities
Gene Ontology Annotations
Biological Process (35 terms)
| Term ID | Term Name |
|---|---|
| GO:0002027 | Regulation of heart rate |
| GO:0003161 | Cardiac conduction system development |
| GO:0003231 | Cardiac ventricle development |
| GO:0003360 | Brainstem development |
| GO:0006814 | Sodium ion transport |
| GO:0010765 | Positive regulation of sodium ion transport |
| GO:0014894 | Response to denervation involved in regulation of muscle adaptation |
| GO:0021537 | Telencephalon development |
| GO:0021549 | Cerebellum development |
| GO:0042475 | Odontogenesis of dentin-containing tooth |
| GO:0045760 | Positive regulation of action potential |
| GO:0050679 | Positive regulation of epithelial cell proliferation |
| GO:0051899 | Membrane depolarization |
| GO:0060048 | Cardiac muscle contraction |
| GO:0060307 | Regulation of ventricular cardiac muscle cell membrane repolarization |
| GO:0060371 | Regulation of atrial cardiac muscle cell membrane depolarization |
| GO:0060372 | Regulation of atrial cardiac muscle cell membrane repolarization |
| GO:0060373 | Regulation of ventricular cardiac muscle cell membrane depolarization |
| GO:0071277 | Cellular response to calcium ion |
| GO:0086002 | Cardiac muscle cell action potential involved in contraction |
| GO:0086004 | Regulation of cardiac muscle cell contraction |
| GO:0086005 | Ventricular cardiac muscle cell action potential |
| GO:0086010 | Membrane depolarization during action potential |
| GO:0086012 | Membrane depolarization during cardiac muscle cell action potential |
| GO:0086014 | Atrial cardiac muscle cell action potential |
| GO:0086015 | SA node cell action potential |
| GO:0086016 | AV node cell action potential |
| GO:0086043 | Bundle of His cell action potential |
| GO:0086045 | Membrane depolarization during AV node cell action potential |
| GO:0086046 | Membrane depolarization during SA node cell action potential |
| GO:0086047 | Membrane depolarization during Purkinje myocyte cell action potential |
| GO:0086048 | Membrane depolarization during bundle of His cell action potential |
| GO:0086091 | Regulation of heart rate by cardiac conduction |
| GO:0098912 | Membrane depolarization during atrial cardiac muscle cell action potential |
| GO:1902305 | Regulation of sodium ion transmembrane transport |
Molecular Function (16 terms)
| Term ID | Term Name |
|---|---|
| GO:0005248 | Voltage-gated sodium channel activity |
| GO:0005516 | Calmodulin binding |
| GO:0017134 | Fibroblast growth factor binding |
| GO:0019899 | Enzyme binding |
| GO:0019901 | Protein kinase binding |
| GO:0019904 | Protein domain specific binding |
| GO:0030506 | Ankyrin binding |
| GO:0031625 | Ubiquitin protein ligase binding |
| GO:0044325 | Transmembrane transporter binding |
| GO:0050998 | Nitric-oxide synthase binding |
| GO:0086006 | Voltage-gated sodium channel activity involved in cardiac muscle cell action potential |
| GO:0086060 | Voltage-gated sodium channel activity involved in AV node cell action potential |
| GO:0086061 | Voltage-gated sodium channel activity involved in bundle of His cell action potential |
| GO:0086062 | Voltage-gated sodium channel activity involved in Purkinje myocyte action potential |
| GO:0086063 | Voltage-gated sodium channel activity involved in SA node cell action potential |
| GO:0097110 | Scaffold protein binding |
Cellular Component (14 terms)
| Term ID | Term Name |
|---|---|
| GO:0001518 | Voltage-gated sodium channel complex |
| GO:0005654 | Nucleoplasm |
| GO:0005730 | Nucleolus |
| GO:0005783 | Endoplasmic reticulum |
| GO:0005886 | Plasma membrane |
| GO:0005901 | Caveola |
| GO:0009986 | Cell surface |
| GO:0014704 | Intercalated disc |
| GO:0016020 | Membrane |
| GO:0016328 | Lateral plasma membrane |
| GO:0030018 | Z disc |
| GO:0030315 | T-tubule |
| GO:0042383 | Sarcolemma |
| GO:0048471 | Perinuclear region of cytoplasm |
Protein interactions & networks
Total interaction count
- STRING: ~1,878 high-confidence interactions
- IntAct: ~172 interactions (with confidence scores)
- BioGRID: 40 manually curated interactions
- Combined estimate: ~2,090 protein-protein interactions
TOP 30 highest-confidence protein interacting partners (STRING, sorted by score)
| Rank | UniProt | Gene | Protein Name | STRING Score |
|---|---|---|---|---|
| 1 | P02593 | CALM1 | Calmodulin-1/2/3 | 987 |
| 2 | Q12955 | ANK3 | Ankyrin-3 | 982 |
| 3 | Q12809 | KCNH2 | Voltage-gated potassium channel H2 | 978 |
| 4 | P15382 | KCNE1 | Potassium channel regulatory subunit | 977 |
| 5 | Q9Y6J6 | KCNE2 | Potassium channel regulatory subunit | 977 |
| 6 | Q99959 | PKP2 | Plakophilin-2 | 976 |
| 7 | P51787 | KCNQ1 | Potassium voltage-gated channel | 973 |
| 8 | Q07699 | SCN1B | Sodium channel regulatory beta-1 | 967 |
| 9 | P27482 | CALML3 | Calmodulin-like protein 3 | 965 |
| 10 | Q8N335 | GPD1L | Glycerol-3-phosphate dehydrogenase 1-like | 965 |
| 11 | Q9NZT1 | CALML5 | Calmodulin-like protein 5 | 965 |
| 12 | Q8TD86 | CALML6 | Calmodulin-like protein 6 | 964 |
| 13 | Q96GE6 | CALML4 | Calmodulin-like protein 4 | 964 |
| 14 | Q8IWT1 | SCN4B | Sodium channel regulatory beta-4 | 950 |
| 15 | Q9Y3Q4 | HCN4 | Potassium/sodium hyperpolarization-activated channel | 950 |
| 16 | Q92913 | FGF13 | Fibroblast growth factor 13 | 949 |
| 17 | O60258 | FGF17 | Fibroblast growth factor 17 | 928 |
| 18 | Q13424 | SNTA1 | Alpha-1-syntrophin | 927 |
| 19 | P42658 | DPP6 | Dipeptidyl peptidase-like 6 | 909 |
| 20 | P56539 | CAV3 | Caveolin-3 | 897 |
| 21 | Q9Y6H6 | KCNE3 | Potassium channel regulatory subunit | 892 |
| 22 | Q9NY72 | SCN3B | Sodium channel regulatory beta-3 | 891 |
| 23 | Q12959 | DLG1 | Disks large homolog 1 (SAP90) | 890 |
| 24 | P48049 | KCNJ2 | Inward rectifier potassium channel 2 | 886 |
| 25 | P36382 | GJA5 | Gap junction alpha-5 protein (Connexin-40) | 879 |
| 26 | Q92736 | RYR2 | Ryanodine receptor 2 (calcium channel) | 873 |
| 27 | Q08289 | CACNB2 | L-type calcium channel beta-2 subunit | 869 |
| 28 | P17302 | GJA1 | Gap junction alpha-1 protein (Connexin-43) | 868 |
| 29 | Q9HD47 | (unknown) | (additional interaction) | 837 |
| 30 | P22460 | (unknown) | (additional interaction) | 827 |
Key interaction classes: voltage-gated ion channels (K+, Ca2+, Na+), calmodulin/regulatory proteins, adaptor proteins (syndrophin, MAGUK), gap junction proteins, and regulatory ubiquitin ligases (NEDD4/NEDD4L).
TOP 20 structurally/embedding similar proteins (ESM2 embeddings, sorted by top similarity)
| Rank | UniProt | Organism/Type | Top ESM2 Similarity | Avg Similarity |
|---|---|---|---|---|
| 1 | A2APX8 | Sodium channel ortholog | 1.0000 | 0.9927 |
| 2 | B1AWN6 | Sodium channel ortholog | 0.9999 | 0.9936 |
| 3 | A2ASI5 | Sodium channel ortholog | 0.9999 | 0.9932 |
| 4 | O88420 | Sodium channel ortholog | 1.0000 | 0.9935 |
| 5 | P04774 | Sodium channel ortholog | 1.0000 | 0.9927 |
| 6 | Q9WTU3 | Sodium channel ortholog | 1.0000 | 0.9934 |
| 7 | O08562 | Sodium channel ortholog | 0.9999 | 0.9934 |
| 8 | Q99250 | Sodium channel ortholog | 0.9998 | 0.9933 |
| 9 | O60840 | Sodium channel ortholog | 0.9995 | 0.9864 |
| 10 | P04775 | Sodium channel ortholog | 0.9999 | 0.9936 |
| 11 | P08104 | Sodium channel ortholog | 0.9999 | 0.9931 |
| 12 | Q28644 | Sodium channel ortholog | 0.9997 | 0.9932 |
| 13 | P35498 | Sodium channel ortholog | 0.9999 | 0.9926 |
| 14 | Q62205 | Sodium channel ortholog | 0.9999 | 0.9937 |
| 15 | O46669 | Sodium channel ortholog | 0.9989 | 0.9930 |
| 16 | Q15858 | Sodium channel ortholog | 0.9997 | 0.9933 |
| 17 | Q6QIY3 | Sodium channel ortholog | 0.9996 | 0.9929 |
| 18 | P15390 | Sodium channel ortholog | 0.9996 | 0.9914 |
| 19 | P15389 | Sodium channel ortholog | 0.9996 | 0.9914 |
| 20 | O43497 | Sodium channel ortholog | 0.9996 | 0.9874 |
TOP 20 sequence homologous proteins (DIAMOND similarity, sorted by identity %)
| Rank | UniProt | Identity % | Bitscore | Classification |
|---|---|---|---|---|
| 1 | P04775 | 99.60% | 3630 | Sodium channel alpha (ortholog) |
| 2 | B1AWN6 | 99.60% | 3629 | Sodium channel alpha (ortholog) |
| 3 | P04774 | 99.40% | 3652 | Sodium channel alpha (ortholog) |
| 4 | A2APX8 | 99.40% | 3653 | Sodium channel alpha (ortholog) |
| 5 | O88420 | 99.10% | 3636 | Sodium channel alpha (ortholog) |
| 6 | Q9WTU3 | 99.10% | 3640 | Sodium channel alpha (ortholog) |
| 7 | A2ASI5 | 98.80% | 3509 | Sodium channel alpha (ortholog) |
| 8 | P08104 | 98.80% | 3503 | Sodium channel alpha (ortholog) |
| 9 | Q07652 | 98.20% | 3944 | Sodium channel alpha (ortholog) |
| 10 | Q61290 | 98.20% | 3953 | Sodium channel alpha (ortholog) |
| 11 | P15389 | 97.50% | 3729 | Sodium channel alpha (ortholog) |
| 12 | Q9JJV9 | 97.50% | 3736 | Sodium channel alpha (ortholog) |
| 13 | P35498 | 96.70% | 3605 | Sodium channel alpha (ortholog) |
| 14 | P15390 | 95.80% | 3269 | Sodium channel alpha (ortholog) |
| 15 | Q9ER60 | 95.80% | 3275 | Sodium channel alpha (ortholog) |
| 16 | Q15878 | 94.10% | 3872 | Sodium channel alpha (ortholog) |
| 17 | Q62968 | 93.70% | 3523 | Sodium channel alpha (ortholog) |
| 18 | Q6QIY3 | 93.70% | 3532 | Sodium channel alpha (ortholog) |
| 19 | Q28644 | 93.20% | 3407 | Sodium channel alpha (ortholog) |
| 20 | Q15858 | 93.20% | 3417 | Sodium channel alpha (ortholog) |
Note: Most homologous proteins are SCN5A orthologs from other organisms (mouse, rat, zebrafish, etc.), reflecting the high sequence conservation of voltage-gated sodium channels across species. Some divergent similarity hits include distantly related sodium channels (SCN1-4) and ion channel-related proteins.
Transcription factor regulatory data
SCN5A classification: Not a transcription factor. SCN5A encodes sodium voltage-gated channel alpha subunit 5 (Nav1.5), a voltage-gated ion channel protein, not a DNA-binding transcription factor. Therefore, downstream targets and JASPAR motif data sections are not applicable.
Upstream regulators of SCN5A
Total upstream regulators: 20 transcription factors and regulatory proteins identified in CollecTRI database.
| Regulator | Full Name | Evidence Type | Regulation | Confidence |
|---|---|---|---|---|
| TBX5 | T-box transcription factor 5 | GOA | Activation | — |
| FOXO1 | Forkhead box O1 | ExTRI, NTNU Curated | Activation | High |
| ANK3 | Ankyrin 3 | GOA | Activation | — |
| TNF | Tumor necrosis factor | SIGNOR | Activation | — |
| MYOG | Myogenin | GEREDB | Activation | — |
| SP1 | Sp1 transcription factor | ExTRI | — | High |
| ESR1 | Estrogen receptor 1 | SIGNOR | Repression | — |
| FOXK1 | Forkhead box K1 | ExTRI, NTNU Curated | Repression | High |
| IL10 | Interleukin 10 | SIGNOR | Repression | — |
| CTNNB1 | Catenin beta 1 | Pavlidis2021 | Repression | — |
| TCF7L2 | Transcription factor 7 like 2 | Pavlidis2021 | Repression | — |
| GTF3A | General transcription factor IIIA | ExTRI | — | Low |
| ESR2 | Estrogen receptor 2 | ExTRI | — | Low |
| IRF6 | Interferon regulatory factor 6 | ExTRI | — | High |
| PARP1 | Poly(ADP-ribose) polymerase 1 | ExTRI | — | Low |
| NFKBIA | NFKB inhibitor alpha | ExTRI | — | Low |
| MAFB | MAF bZIP transcription factor B | ExTRI | — | Low |
| USF1 | Upstream transcription factor 1 | ExTRI | — | Low |
| VSX2 | Visual system homeobox 2 | ExTRI | — | Low |
| THRA | Thyroid hormone receptor alpha | ExTRI | — | Low |
Evidence sources: ExTRI (predicted TF-target interactions), SIGNOR (curated signaling database), NTNU Curated (manually curated regulatory relationships), GOA (Gene Ontology annotations), GEREDB (gene regulatory network database), Pavlidis2021 (published systematic analysis of TF-gene regulation).
Drug & pharmacology data
SCN5A is a well-established drug target with substantial clinical development and therapeutic applications.
Targeting Molecules
Total count: 1,497 molecules in ChEMBL target CHEMBL1980 (sodium channel protein type 5 subunit alpha)
Top 30+ approved drugs (Phase 4) by mechanism:
| Molecule ID | Name | Mechanism | Phase | Clinical Trials |
|---|---|---|---|---|
| CHEMBL108 | Carbamazepine | Sodium channel blocker | 4 | 96 |
| CHEMBL1404 | Ranolazine | Late sodium current inhibitor | 4 | 81 |
| CHEMBL1294 | Quinidine | Class IA antiarrhythmic | 4 | 22 |
| CHEMBL1008 | Bepridil | Calcium channel antagonist | 4 | — |
| CHEMBL1491 | Amlodipine | Calcium channel blocker | 4 | — |
| CHEMBL193 | Nifedipine | Calcium channel blocker | 4 | — |
| CHEMBL1480 | Felodipine | Calcium channel blocker | 4 | — |
| CHEMBL1484 | Nicardipine | Calcium channel blocker | 4 | — |
| CHEMBL1428 | Nimodipine | Calcium channel blocker | 4 | — |
| CHEMBL11 | Imipramine | Tricyclic antidepressant | 4 | — |
| CHEMBL16 | Phenytoin | Anticonvulsant | 4 | — |
| CHEMBL1726 | Nisoldipine | Calcium channel blocker | 4 | — |
| CHEMBL1648 | Isradipine | Calcium channel blocker | 4 | — |
| CHEMBL2107383 | Vernakalant | Antiarrhythmic | 4 | — |
| CHEMBL1200606 | Mexiletine | Antiarrhythmic | 4 | — |
| CHEMBL1086 | Dibucaine | Local anesthetic | 4 | — |
| CHEMBL127810 | Meprylcaine | Local anesthetic | 2 | — |
Clinical Trials
Top trials involving SCN5A-targeting drugs (ranolazine):
| Trial ID | Phase | Status | Indication |
|---|---|---|---|
| NCT00644332 | Phase 4 | Completed | Chronic angina in women |
| NCT01648205 | Phase 2 | Completed | Long QT Syndrome Type III (LQT3) |
| NCT01728025 | Phase 2 | Active | Long-term prophylactic therapy for congenital LQT3 |
| NCT01221272 | Phase 4 | Completed | Myocardial perfusion/exercise tolerance |
| NCT01345188 | Phase 4 | Completed | Ischemic cardiomyopathy |
| NCT01425359 | Phase 4 | Completed | Type 2 diabetes with stable angina |
| NCT01163734 | Phase 2 | Completed | Diastolic heart failure |
| NCT02133352 | Phase 4 | Completed | Pulmonary hypertension with diastolic dysfunction |
| NCT01534962 | Phase 2 | Completed | Atrial fibrillation post-cardioversion |
| NCT03472950 | Phase 2 | Completed | Amyotrophic lateral sclerosis (ALS) |
| NCT06527222 | Phase 2 | Recruiting | ALS |
| NCT00998218 | Phase 3 | Completed | LV dysfunction arrhythmias |
| NCT01215253 | Phase 3 | Completed | ICD outcomes |
| NCT07380919 | Phase 2/3 | Not yet recruiting | ST-elevation MI with multivessel disease |
Pharmacogenomics
PharmGKB Status: SCN5A (PA304) is designated a VIP (Very Important Pharmacogene) with variant annotations
Disease associations:
- Long QT Syndrome 3 (LQT3) – Loss-of-function mutations; treated with sodium channel blockers
- Brugada Syndrome – Loss-of-function variants
- Dilated Cardiomyopathy 1E (CMD1E) – Loss-of-function mutations
- Progressive familial heart block 1A – Conduction delay/block
Known pharmacogenomic interactions:
- SCN5A variants affect response to antiarrhythmics (quinidine, mexiletine, flecainide) and sodium channel blockers (ranolazine, carbamazepine)
- Genotype-guided dosing recommended for antiarrhythmic therapy in LQT3 patients
- Loss-of-function variants benefit from sodium channel blockade; gain-of-function variants may worsen with blockers
Clinical application: Genetic testing for SCN5A mutations is standard for diagnosis and risk stratification in long QT syndrome and Brugada syndrome; guides drug selection and dosing.
Expression profiles
Based on biobtree indexing, detailed tissue and cell-type expression profiles for SCN5A are not fully enumerated in the available databases. However, the following information is available:
Tissue Expression Summary
| Dataset | Expression Pattern | Score/Details |
|---|---|---|
| Bgee | Ubiquitous | Max score: 95.49; 161 present calls across tissues |
Known tissue specificity (from gene function context):
- Heart (cardiac muscle): Primary tissue; essential for cardiac action potential generation
- Skeletal muscle: Secondary expression
- Smooth muscle: Present
- Brain: Moderate expression (neural isoforms exist)
- Other tissues: Limited/low expression based on tissue-specific roles
Single-Cell Expression
| Dataset | Details |
|---|---|
| Single Cell Expression Atlas (SCXA) | 141 cell clusters across 1 marker experiment; max mean expression: 3.87 |
Cell types of interest (inferred from function):
- Cardiomyocytes: Highest expression — essential for ventricular/atrial action potential initiation
- Cardiac conduction cells: SA node, AV node, Purkinje fibers
- Neurons: Nav1.5 isoforms in CNS and peripheral nervous system
Data Limitations
Biobtree’s indexed expression data for SCN5A is sparse. Complete tissue/cell-type rankings with quantitative scores from GTEx, HPA, and Tabula Sapiens would require direct query of those databases’ primary sources, which are not fully represented in biobtree’s current schema.
Disease associations
Mendelian / Monogenic Diseases
Definitive Evidence (Gold Standard):
| Disease | Disease ID | Inheritance | Classification |
|---|---|---|---|
| Brugada syndrome 1 | OMIM:601144, MONDO:0011001, Orphanet:130 | Autosomal dominant | Definitive |
| Long QT syndrome 3 | OMIM:603830, MONDO:0011377 | Autosomal dominant | Definitive |
| Dilated cardiomyopathy 1E | OMIM:601154, MONDO:0011003, Orphanet:154 | Autosomal dominant | Definitive |
Strong Evidence:
| Disease | Disease ID | Inheritance | Classification |
|---|---|---|---|
| Progressive familial heart block, type 1A | OMIM:113900, MONDO:0007240, Orphanet:871 | Autosomal dominant | Strong |
| Sick sinus syndrome 1 | OMIM:608567, MONDO:0024562, Orphanet:166282 | Autosomal dominant/recessive | Strong |
Additional Supportive Evidence (Orphanet):
| Disease | Orphanet ID | Inheritance |
|---|---|---|
| Romano-Ward syndrome | 101016 | Autosomal dominant |
| Atrial standstill | 1344 | Autosomal dominant |
| Familial atrial fibrillation | 334 | Autosomal dominant |
| Idiopathic ventricular fibrillation | 228140 | Autosomal dominant |
Phenotype Associations (Top 30 HPO Terms)
- HP:0000006 – Autosomal dominant inheritance
- HP:0001645 – Sudden cardiac death
- HP:0001663 – Ventricular fibrillation
- HP:0001657 – Prolonged QT interval
- HP:0001644 – Dilated cardiomyopathy
- HP:0005110 – Atrial fibrillation
- HP:0001662 – Bradycardia
- HP:0011704 – Sick sinus syndrome
- HP:0004756 – Ventricular tachycardia
- HP:0001678 – Atrioventricular block
- HP:0001649 – Tachycardia
- HP:0001638 – Cardiomyopathy
- HP:0001695 – Cardiac arrest
- HP:0012722 – Heart block
- HP:0005184 – Prolonged QTc interval
- HP:0001664 – Torsade de pointes
- HP:0011675 – Arrhythmia
- HP:0001635 – Congestive heart failure
- HP:0001279 – Syncope
- HP:0031546 – Cardiac conduction abnormality
- HP:0012664 – Reduced left ventricular ejection fraction
- HP:0025478 – Atrial standstill
- HP:0030682 – Left ventricular noncompaction
- HP:0001688 – Sinus bradycardia
- HP:0011705 – First degree atrioventricular block
- HP:0011707 – Mobitz I atrioventricular block
- HP:0011710 – Bundle branch block
- HP:0004751 – Paroxysmal ventricular tachycardia
- HP:0004749 – Atrial flutter
- HP:0006682 – Premature ventricular contraction
Complex-Disease / GWAS Associations (Top 30)
| Trait/Disease | Most Significant P-value | Study ID | Gene Association |
|---|---|---|---|
| Brugada syndrome | 4.0e-57 | GCST90086158_3 | SCN5A |
| QT interval | 1.0e-14 | GCST000363_3 | SCN5A |
| PR interval | 1.0e-68 | GCST007045_3 | SCN5A |
| QRS duration | 2.0e-31 | GCST008054_26 | SCN5A |
| P wave duration | 2.0e-40 | GCST004826_15 | SCN5A |
| Electrocardiographic conduction measures | 2.0e-06 | GCST000344_2 | SCN5A |
| Electrocardiographic traits | 5.0e-10 | GCST000561_9 | SCN5A |
| Atrial fibrillation | 7.0e-12 | GCST006414_122 | SCN5A |
| Resting heart rate | 1.0e-11 | GCST003818_26 | SCN5A |
| Electrocardiogram morphology (temporal datapoints) | 1.0e-52 | GCST010796_3929 | SCN5A - SCN10A |
| T wave morphology restitution during exercise | 6.0e-13 | GCST009017_1 | SCN5A - SCN10A |
| T wave morphology restitution during recovery | 2.0e-11 | GCST009069_3 | SCN5A - SCN10A |
| Global electrical heterogeneity phenotypes | 3.0e-11 | GCST005905_11 | SCN5A |
| Supraventricular ectopy | 2.0e-07 | GCST005936_1 | SCN5A |
| PR segment duration | 7.0e-41 | GCST002456_3 | SCN10A |
| QT interval (multi-study) | 4.0e-27 | GCST002500_20 | SCN5A |
| QRS duration (multi-study) | 4.0e-14 | GCST003598_24 | SCN5A |
| Electrocardiogram morphology multiple timepoints | 6.0e-46 | GCST010796_5079 | SCN5A |
| Brugada syndrome (replication) | 3.0e-08 | GCST90086158_1 | SCN5A |
| PR interval (replication) | 5.0e-43 | GCST001735_5 | SCN5A |
Summary: SCN5A shows extremely strong GWAS associations with electrocardiographic traits (particularly QT, PR, and QRS intervals) and direct disease associations with cardiac arrhythmias and conduction disorders. All primary disease associations are autosomal dominant cardiac channelopathies affecting electrical function.