Brugada syndrome 1
diseaseOn this page
Also known as BRGDA1Brugada syndrome caused by mutation in SCN5ABrugada syndrome type 1SCN5A Brugada syndrome
Summary
Brugada syndrome 1 (MONDO:0011001) is a disease caused by SCN5A (GenCC Definitive), with 18 cohort genes and 2 clinical trials. The dominant Reactome pathway is Cardiac conduction (8 cohort genes).
At a glance
- Causal gene: SCN5A (GenCC Definitive)
- Cohort genes: 18
- ClinVar variants: 666
- Clinical trials: 2
Clinical features
No curated clinical features (Orphanet) for this disease.
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | Brugada syndrome 1 |
| Mondo ID | MONDO:0011001 |
| OMIM | 601144 |
| DOID | DOID:0110218 |
| UMLS | C4551804 |
| MedGen | 1646402 |
| GARD | 0024766 |
| Is cancer (heuristic) | no |
Also known as: BRGDA1 · Brugada syndrome 1 · Brugada syndrome caused by mutation in SCN5A · Brugada syndrome type 1 · SCN5A Brugada syndrome
Data availability: 666 ClinVar variants · 13 GenCC gene-disease records.
Disease family
Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart conduction disease › Brugada syndrome › Brugada syndrome 1
Related subtypes (8): Brugada syndrome 2, Brugada syndrome 3, Brugada syndrome 4, Brugada syndrome 5, Brugada syndrome 6, Brugada syndrome 7, Brugada syndrome 8, Brugada syndrome 9
Genetics & variants
GWAS landscape
No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.
Variant details and genetic-evidence tiers
ClinVar germline variants
600 retrieved; paginated sample, class counts are floors:
270 uncertain significance, 198 conflicting classifications of pathogenicity, 47 benign/likely benign, 32 pathogenic/likely pathogenic, 22 likely pathogenic, 22 pathogenic, 8 likely benign, 1 benign
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 440848 | NM_198056.2(SCN5A):c.[3694C>T;4859C>T] | Pathogenic | no assertion criteria provided | |
| 440850 | NM_000335.4(SCN5A):c.[3919C>T;694G>A] | Pathogenic | no assertion criteria provided | |
| 264175 | NM_000138.5(FBN1):c.3G>T (p.Met1Ile) | FBN1 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 406434 | NM_000335.5(SCN5A):c.3282G>A (p.Trp1094Ter) | LOC110121269 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1327132 | NM_000335.5(SCN5A):c.4296+1del | SCN5A | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1527869 | NM_000335.5(SCN5A):c.2678G>T (p.Arg893Leu) | SCN5A | Pathogenic | criteria provided, single submitter |
| 1691761 | NM_000335.5(SCN5A):c.175C>T (p.Gln59Ter) | SCN5A | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 179829 | NM_000335.5(SCN5A):c.1936del (p.Gln646fs) | SCN5A | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1803812 | NM_000335.5(SCN5A):c.104dup (p.Ser36fs) | SCN5A | Pathogenic | no assertion criteria provided |
| 180520 | NM_000335.5(SCN5A):c.1140+1G>A | SCN5A | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 201427 | NM_000335.5(SCN5A):c.611+1G>A | SCN5A | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 201438 | NM_000335.5(SCN5A):c.664C>T (p.Arg222Ter) | SCN5A | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 201508 | NM_000335.5(SCN5A):c.4242+1G>C | SCN5A | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 201559 | NM_000335.5(SCN5A):c.2533del (p.Val845fs) | SCN5A | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 201560 | NM_000335.5(SCN5A):c.2550_2551dup (p.Phe851fs) | SCN5A | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 201566 | NM_000335.5(SCN5A):c.3488dup (p.Glu1164fs) | SCN5A | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 201572 | NM_000335.5(SCN5A):c.4844TCT[1] (p.Phe1616del) | SCN5A | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 2107170 | NM_000335.5(SCN5A):c.1947T>A (p.Cys649Ter) | SCN5A | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 222814 | NM_000335.5(SCN5A):c.4471AAG[1] (p.Lys1492del) | SCN5A | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 254156 | NM_000335.5(SCN5A):c.5353_5354del (p.Leu1785fs) | SCN5A | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 254157 | NM_198056.2(SCN5A):c.4813+3_4813+6dup | SCN5A | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 263423 | NM_000335.5(SCN5A):c.4716C>T (p.Gly1572=) | SCN5A | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 264039 | NM_000335.5(SCN5A):c.4420del (p.Gln1474fs) | SCN5A | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 264276 | NM_000335.5(SCN5A):c.4882C>T (p.Arg1628Ter) | SCN5A | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 3238947 | NM_000335.5(SCN5A):c.1551del (p.Thr518fs) | SCN5A | Pathogenic | criteria provided, single submitter |
| 3248566 | NM_000335.5(SCN5A):c.1978C>T (p.Gln660Ter) | SCN5A | Pathogenic | criteria provided, single submitter |
| 3438263 | NM_000335.5(SCN5A):c.1576del (p.Arg526fs) | SCN5A | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 3778738 | NM_000335.5(SCN5A):c.1036G>T (p.Glu346Ter) | SCN5A | Pathogenic | criteria provided, single submitter |
| 39444 | NM_000335.5(SCN5A):c.665G>A (p.Arg222Gln) | SCN5A | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 406415 | NM_000335.5(SCN5A):c.5414_5417del (p.Thr1805fs) | SCN5A | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 83 · Orphanet: 68 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0
GenCC gene–disease validity (cohort genes)
the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.
| Gene | Classification | Inheritance | Disease | Records |
|---|---|---|---|---|
| SCN5A | Definitive | Autosomal dominant | Brugada syndrome 1 | 23 |
| HCN4 | Moderate | Autosomal dominant | Brugada syndrome 8 | 8 |
| SCN1B | Moderate | Autosomal dominant | Brugada syndrome 5 | 15 |
| SCN2B | Supportive | Autosomal dominant | Brugada syndrome | 7 |
| CACNA2D1 | Limited | Unknown | Brugada syndrome | 8 |
| GPD1L | Limited | Unknown | Brugada syndrome 2 | 3 |
| KCND3 | Limited | Autosomal dominant | Brugada syndrome 9 | 8 |
| KCNJ8 | Limited | Unknown | Brugada syndrome | 5 |
| PKP2 | Limited | Autosomal dominant | Brugada syndrome | 6 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| SCN1B | Orphanet:130 | Brugada syndrome |
| SCN1B | Orphanet:1934 | Early infantile developmental and epileptic encephalopathy |
| SCN1B | Orphanet:33069 | Dravet syndrome |
| SCN1B | Orphanet:334 | Hereditary atrial fibrillation |
| SCN1B | Orphanet:36387 | Genetic epilepsy with febrile seizure plus |
| SCN1B | Orphanet:871 | Hereditary progressive cardiac conduction defect |
| SCN5A | Orphanet:101016 | Romano-Ward syndrome |
| SCN5A | Orphanet:130 | Brugada syndrome |
| SCN5A | Orphanet:1344 | Isolated atrial standstill |
| SCN5A | Orphanet:154 | Familial isolated dilated cardiomyopathy |
| SCN5A | Orphanet:166282 | Hereditary sick sinus syndrome |
| SCN5A | Orphanet:228140 | Idiopathic ventricular fibrillation |
| SCN5A | Orphanet:334 | Hereditary atrial fibrillation |
| SCN5A | Orphanet:871 | Hereditary progressive cardiac conduction defect |
| CACNA2D1 | Orphanet:130 | Brugada syndrome |
| CACNA2D1 | Orphanet:442835 | Non-specific early-onset epileptic encephalopathy |
| CACNA2D1 | Orphanet:51083 | Congenital short QT syndrome |
| SCN2B | Orphanet:130 | Brugada syndrome |
| SCN2B | Orphanet:334 | Hereditary atrial fibrillation |
| HCN4 | Orphanet:130 | Brugada syndrome |
| HCN4 | Orphanet:166282 | Hereditary sick sinus syndrome |
| GPD1L | Orphanet:130 | Brugada syndrome |
| KCND3 | Orphanet:130 | Brugada syndrome |
| KCND3 | Orphanet:98772 | Spinocerebellar ataxia type 19/22 |
| KCNJ8 | Orphanet:130 | Brugada syndrome |
| KCNJ8 | Orphanet:1517 | Cantú syndrome |
| PKP2 | Orphanet:130 | Brugada syndrome |
| PKP2 | Orphanet:293888 | Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant |
| PKP2 | Orphanet:293899 | Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant |
| PKP2 | Orphanet:293910 | Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant |
| PKP2 | Orphanet:54260 | Left ventricular noncompaction |
| SCN10A | Orphanet:101016 | Romano-Ward syndrome |
| SCN10A | Orphanet:130 | Brugada syndrome |
| SCN10A | Orphanet:306577 | Hereditary sodium channelopathy-related small fibers neuropathy |
| SCN10A | Orphanet:46348 | Paroxysmal extreme pain disorder |
| SCN10A | Orphanet:88642 | Congenital insensitivity to pain-anosmia-neuropathic arthropathy |
| SCN10A | Orphanet:90026 | Primary erythromelalgia |
| SCNN1A | Orphanet:130 | Brugada syndrome |
| SCNN1A | Orphanet:171876 | Generalized pseudohypoaldosteronism type 1 |
| SCNN1A | Orphanet:526 | Liddle syndrome |
| SCNN1A | Orphanet:60033 | Idiopathic bronchiectasis |
| DSP | Orphanet:154 | Familial isolated dilated cardiomyopathy |
| DSP | Orphanet:158687 | Lethal acantholytic erosive disorder |
| DSP | Orphanet:2032 | Idiopathic pulmonary fibrosis |
| DSP | Orphanet:293165 | Skin fragility-woolly hair-palmoplantar keratoderma syndrome |
| DSP | Orphanet:293888 | Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant |
| DSP | Orphanet:293899 | Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant |
| DSP | Orphanet:293910 | Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant |
| DSP | Orphanet:369992 | Severe dermatitis-multiple allergies-metabolic wasting syndrome |
| DSP | Orphanet:476096 | Erythrokeratodermia-cardiomyopathy syndrome |
Cohort genes → proteins
18 cohort genes, 17 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 18 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| SCN1B | HGNC:10586 | ENSG00000105711 | Q07699 | Sodium channel regulatory subunit beta-1 | gencc,clinvar |
| SCN5A | HGNC:10593 | ENSG00000183873 | Q14524 | Sodium channel protein type 5 subunit alpha | gencc,clinvar |
| CACNA2D1 | HGNC:1399 | ENSG00000153956 | P54289 | Voltage-dependent calcium channel subunit alpha-2/delta-1 | gencc,clinvar |
| SCN2B | HGNC:10589 | ENSG00000149575 | O60939 | Sodium channel regulatory subunit beta-2 | gencc |
| HCN4 | HGNC:16882 | ENSG00000138622 | Q9Y3Q4 | Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 | gencc |
| GPD1L | HGNC:28956 | ENSG00000152642 | Q8N335 | Glycerol-3-phosphate dehydrogenase 1-like protein | gencc |
| KCND3 | HGNC:6239 | ENSG00000171385 | Q9UK17 | A-type voltage-gated potassium channel KCND3 | gencc |
| KCNJ8 | HGNC:6269 | ENSG00000121361 | Q15842 | ATP-sensitive inward rectifier potassium channel 8 | gencc |
| PKP2 | HGNC:9024 | ENSG00000057294 | Q99959 | Plakophilin-2 | gencc |
| SCN10A | HGNC:10582 | ENSG00000185313 | Q9Y5Y9 | Sodium channel protein type 10 subunit alpha | clinvar |
| SCNN1A | HGNC:10599 | ENSG00000111319 | P37088 | Epithelial sodium channel subunit alpha | clinvar |
| DSP | HGNC:3052 | ENSG00000096696 | P15924 | Desmoplakin | clinvar |
| FBN1 | HGNC:3603 | ENSG00000166147 | P35555 | Fibrillin-1 | clinvar |
| AKAP9 | HGNC:379 | ENSG00000127914 | Q99996 | A-kinase anchor protein 9 | clinvar |
| KCNJ8-AS1 | HGNC:58193 | ENSG00000256615 | KCNJ8 antisense RNA 1 | clinvar | |
| KCNA5 | HGNC:6224 | ENSG00000130037 | P22460 | Potassium voltage-gated channel subfamily A member 5 | clinvar |
| KCNH2 | HGNC:6251 | ENSG00000055118 | Q12809 | Voltage-gated inwardly rectifying potassium channel KCNH2 | clinvar |
| KCNJ16 | HGNC:6262 | ENSG00000153822 | Q9NPI9 | Inward rectifier potassium channel 16 | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| SCN1B | Sodium channel regulatory subunit beta-1 | Regulatory subunit of multiple voltage-gated sodium (Nav) channels directly mediating the depolarization of excitable membranes. |
| SCN5A | Sodium channel protein type 5 subunit alpha | Pore-forming subunit of Nav1.5, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes. |
| CACNA2D1 | Voltage-dependent calcium channel subunit alpha-2/delta-1 | The alpha-2/delta subunit of voltage-dependent calcium channels regulates calcium current density and activation/inactivation kinetics of the calcium channel. |
| SCN2B | Sodium channel regulatory subunit beta-2 | Regulatory subunit of multiple voltage-gated sodium (Nav) channels directly mediating the depolarization of excitable membranes. |
| HCN4 | Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 | Hyperpolarization-activated ion channel that are permeable to Na(+) and K(+) ions with very slow activation and inactivation. |
| GPD1L | Glycerol-3-phosphate dehydrogenase 1-like protein | Plays a role in regulating cardiac sodium current; decreased enzymatic activity with resulting increased levels of glycerol 3-phosphate activating the DPD1L-dependent SCN5A phosphorylation pathway, may ultimately lead to decreased sodium c… |
| KCND3 | A-type voltage-gated potassium channel KCND3 | Pore-forming (alpha) subunit of voltage-gated A-type potassium channels that mediates transmembrane potassium transport in excitable membranes, in brain and heart. |
| KCNJ8 | ATP-sensitive inward rectifier potassium channel 8 | Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. |
| PKP2 | Plakophilin-2 | A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion. |
| SCN10A | Sodium channel protein type 10 subunit alpha | Tetrodotoxin-resistant channel that mediates the voltage-dependent sodium ion permeability of excitable membranes. |
| SCNN1A | Epithelial sodium channel subunit alpha | This is one of the three pore-forming subunits of the heterotrimeric epithelial sodium channel (ENaC), a critical regulator of sodium balance and fluid homeostasis. |
| DSP | Desmoplakin | A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion. |
| FBN1 | Fibrillin-1 | Structural component of the 10-12 nm diameter microfibrils of the extracellular matrix, which conveys both structural and regulatory properties to load-bearing connective tissues. |
| AKAP9 | A-kinase anchor protein 9 | Scaffolding protein that assembles several protein kinases and phosphatases on the centrosome and Golgi apparatus. |
| KCNA5 | Potassium voltage-gated channel subfamily A member 5 | Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes. |
| KCNH2 | Voltage-gated inwardly rectifying potassium channel KCNH2 | Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. |
| KCNJ16 | Inward rectifier potassium channel 16 | Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. |
Protein-family classification
Druggable: 10 · Difficult: 1 · Unknown: 7 · Druggable fraction: 0.56
Family distribution
Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.
| Family | Genes | Fold | FDR |
|---|---|---|---|
| Ion channel | 8 | 49.6× | 6e-12 |
| Antibody/Immunoglobulin | 2 | 3.2× | 0.250 |
| Scaffold/PPI | 1 | 1.0× | 0.877 |
| Other/Unknown | 7 | 0.7× | 0.954 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| SCN1B | Antibody/Immunoglobulin | yes | Ig_V-set, Ig-like_fold, Na_channel_b1/b3 | |
| SCN5A | Ion channel | yes | Na_channel_asu, Ion_trans_dom, Na_channel_a5su | |
| CACNA2D1 | Other/Unknown | no | VWF_A, VWA_N, VDCC_a2/dsu | |
| SCN2B | Antibody/Immunoglobulin | yes | Myelin_P0-rel, Ig_sub, Ig-like_dom | |
| HCN4 | Ion channel | yes | cNMP-bd_dom, K_chnl_volt-dep_EAG/ELK/ERG, Ion_trans_dom | |
| GPD1L | Other/Unknown | no | G3P_DH_NAD-dep_C, G3P_DH_NAD-dep, 6-PGluconate_DH-like_C_sf | |
| KCND3 | Ion channel | yes | BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv | |
| KCNJ8 | Ion channel | yes | K_chnl_inward-rec_Kir6.1, K_chnl_inward-rec_Kir_cyto, Ig_E-set | |
| PKP2 | Other/Unknown | no | Armadillo, ARM-like, ARM-type_fold | |
| SCN10A | Ion channel | yes | Na_channel_asu, Ion_trans_dom, Na_trans_assoc_dom | |
| SCNN1A | Other/Unknown | no | ENaC, ENaC_chordates, ENaC_CS | |
| DSP | Scaffold/PPI | no | Plectin_repeat, SH3_domain, Spectrin/alpha-actinin | |
| FBN1 | Other/Unknown | no | EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom | |
| AKAP9 | Other/Unknown | no | ELK_dom, PACT_domain, AKAP9/Pericentrin | |
| KCNJ8-AS1 | Other/Unknown | no | ||
| KCNA5 | Ion channel | yes | BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv | |
| KCNH2 | Ion channel | yes | PAS, cNMP-bd_dom, PAS-assoc_C | |
| KCNJ16 | Ion channel | yes | K_chnl_inward-rec_Kir5, K_chnl_inward-rec_Kir_cyto, Ig_E-set |
Expression context
Cohort genes with no expression data: 0.
14 cohort genes are a single-cell marker in ≥1 SCXA experiment.
Breadth distribution (Bgee present_calls)
| Bucket | Genes |
|---|---|
| narrow (1-5 tissues) | 0 |
| moderate (6-20) | 0 |
| broad (>20) | 18 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| apex of heart | 3 |
| cardiac atrium | 3 |
| heart right ventricle | 3 |
| cardiac ventricle | 2 |
| biceps brachii | 2 |
| skeletal muscle tissue of biceps brachii | 2 |
| lateral nuclear group of thalamus | 2 |
| right atrium auricular region | 2 |
| left ventricle myocardium | 2 |
| skin of hip | 2 |
| cerebellum | 1 |
| primary visual cortex | 1 |
| right hemisphere of cerebellum | 1 |
| heart left ventricle | 1 |
| skeletal muscle tissue of rectus abdominis | 1 |
| cerebellar cortex | 1 |
| middle temporal gyrus | 1 |
| tibialis anterior | 1 |
| cerebellar vermis | 1 |
| substantia nigra pars reticulata | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| SCN1B | 133 | ubiquitous | marker | primary visual cortex, right hemisphere of cerebellum, cerebellum |
| SCN5A | 161 | broad | yes | apex of heart, heart left ventricle, cardiac ventricle |
| CACNA2D1 | 261 | ubiquitous | marker | biceps brachii, skeletal muscle tissue of biceps brachii, skeletal muscle tissue of rectus abdominis |
| SCN2B | 182 | broad | yes | middle temporal gyrus, lateral nuclear group of thalamus, cerebellar cortex |
| HCN4 | 86 | tissue_specific | yes | tibialis anterior, right atrium auricular region, cardiac atrium |
| GPD1L | 297 | ubiquitous | marker | biceps brachii, heart right ventricle, skeletal muscle tissue of biceps brachii |
| KCND3 | 262 | broad | marker | cerebellar vermis, substantia nigra pars reticulata, lateral nuclear group of thalamus |
| KCNJ8 | 233 | broad | marker | heart right ventricle, left ventricle myocardium, cardiac ventricle |
| PKP2 | 237 | ubiquitous | marker | heart right ventricle, apex of heart, left ventricle myocardium |
| SCN10A | 21 | marker | type B pancreatic cell, olfactory bulb, diaphragm | |
| SCNN1A | 283 | broad | marker | nasal cavity epithelium, metanephros cortex, right uterine tube |
| DSP | 253 | ubiquitous | marker | skin of hip, upper leg skin, hair follicle |
| FBN1 | 275 | ubiquitous | marker | synovial joint, skin of hip, decidua |
| AKAP9 | 292 | ubiquitous | marker | jejunal mucosa, bronchial epithelial cell, cortical plate |
| KCNJ8-AS1 | 83 | yes | primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, small intestine | |
| KCNA5 | 179 | broad | marker | cardiac muscle of right atrium, blood vessel layer, cardiac atrium |
| KCNH2 | 211 | broad | marker | apex of heart, right atrium auricular region, cardiac atrium |
| KCNJ16 | 212 | broad | marker | renal medulla, nephron tubule, caput epididymis |
Protein interactions among cohort
Intra-cohort edges: 30.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| FBN1 | 3,640 |
| AKAP9 | 3,537 |
| DSP | 2,897 |
| GPD1L | 2,618 |
| KCNA5 | 2,288 |
| KCND3 | 2,215 |
| SCN5A | 2,090 |
| CACNA2D1 | 2,002 |
| KCNH2 | 1,932 |
| PKP2 | 1,861 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| AKAP9 | KCNH2 | string_interaction |
| CACNA2D1 | KCNJ8 | string_interaction |
| CACNA2D1 | SCN5A | string_interaction |
| DSP | PKP2 | string_interaction |
| GPD1L | HCN4 | string_interaction |
| GPD1L | KCNJ8 | string_interaction |
| GPD1L | SCN10A | string_interaction |
| GPD1L | SCN1B | string_interaction |
| GPD1L | SCN2B | string_interaction |
| GPD1L | SCN5A | intact, string_interaction |
| HCN4 | SCN1B | string_interaction |
| HCN4 | SCN5A | string_interaction |
| KCNA5 | KCND3 | biogrid_interaction |
| KCNA5 | KCNH2 | string_interaction |
| KCNA5 | KCNJ8 | string_interaction |
| KCNA5 | SCN5A | string_interaction |
| KCND3 | KCNH2 | biogrid_interaction, string_interaction |
| KCND3 | KCNJ8 | string_interaction |
| KCND3 | SCN1B | biogrid_interaction, string_interaction |
| KCND3 | SCN2B | string_interaction |
| KCND3 | SCN5A | string_interaction |
| KCNH2 | SCN5A | string_interaction |
| KCNJ8 | SCN1B | string_interaction |
| KCNJ8 | SCN2B | string_interaction |
| KCNJ8 | SCN5A | string_interaction |
| PKP2 | SCN5A | string_interaction |
| SCN10A | SCN1B | string_interaction |
| SCN1B | SCN2B | intact, string_interaction |
| SCN1B | SCN5A | string_interaction |
| SCN2B | SCN5A | string_interaction |
Structural data
PDB: 14 · AlphaFold-only: 3 · No structure: 1
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| SCN1B | Q07699 | 39 |
| SCN2B | O60939 | 35 |
| CACNA2D1 | P54289 | 30 |
| KCNH2 | Q12809 | 24 |
| SCN5A | Q14524 | 16 |
| FBN1 | P35555 | 11 |
| HCN4 | Q9Y3Q4 | 8 |
| SCN10A | Q9Y5Y9 | 8 |
| KCND3 | Q9UK17 | 6 |
| DSP | P15924 | 4 |
| KCNJ16 | Q9NPI9 | 4 |
| SCNN1A | P37088 | 3 |
| GPD1L | Q8N335 | 1 |
| PKP2 | Q99959 | 1 |
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| KCNJ8 | Q15842 | 84.00 |
| KCNA5 | P22460 | 72.64 |
| AKAP9 | Q99996 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 70. Enrichment computed across 18 evidence-associated genes (17 with Reactome annotation).
Pathways by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 17 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| Cardiac conduction | 8 | 51.2× | 6e-11 | SCN1B, SCN5A, SCN10A, SCN2B, AKAP9, KCNA5, KCND3, KCNH2 |
| Muscle contraction | 8 | 36.3× | 5e-10 | SCN1B, SCN5A, SCN10A, SCN2B, AKAP9, KCNA5, KCND3, KCNH2 |
| Interaction between L1 and Ankyrins | 4 | 86.7× | 2e-06 | SCN1B, SCN5A, SCN10A, SCN2B |
| Phase 0 - rapid depolarisation | 4 | 81.4× | 2e-06 | SCN1B, SCN5A, SCN10A, SCN2B |
| Potassium Channels | 5 | 39.5× | 2e-06 | KCNA5, KCND3, KCNH2, KCNJ16, KCNJ8 |
| Phase 3 - rapid repolarisation | 3 | 201.5× | 4e-06 | AKAP9, KCNA5, KCNH2 |
| L1CAM interactions | 4 | 28.3× | 1e-04 | SCN1B, SCN5A, SCN10A, SCN2B |
| Sensory perception of taste | 3 | 59.3× | 1e-04 | SCN1B, SCN2B, SCNN1A |
| Neuronal System | 5 | 13.0× | 2e-04 | KCNA5, KCND3, KCNH2, KCNJ16, KCNJ8 |
| Voltage gated Potassium channels | 3 | 42.9× | 3e-04 | KCNA5, KCND3, KCNH2 |
| Inwardly rectifying K+ channels | 2 | 84.0× | 0.002 | KCNJ16, KCNJ8 |
| Axon guidance | 4 | 10.6× | 0.003 | SCN1B, SCN5A, SCN10A, SCN2B |
| Nervous system development | 4 | 10.1× | 0.003 | SCN1B, SCN5A, SCN10A, SCN2B |
| Sensory Perception | 3 | 16.8× | 0.003 | SCN1B, SCN2B, SCNN1A |
| Sensory perception of sweet, bitter, and umami (glutamate) taste | 2 | 32.8× | 0.008 | SCN1B, SCN2B |
| Potassium transport channels | 1 | 223.9× | 0.020 | KCNJ16 |
| ATP sensitive Potassium channels | 1 | 167.9× | 0.023 | KCNJ8 |
| HCN channels | 1 | 167.9× | 0.023 | HCN4 |
| Sensory perception of salty taste | 1 | 112.0× | 0.033 | SCNN1A |
| Phase 1 - inactivation of fast Na+ channels | 1 | 96.0× | 0.036 | KCND3 |
| G protein gated Potassium channels | 1 | 67.2× | 0.049 | KCNJ16 |
| Apoptotic cleavage of cell adhesion proteins | 1 | 61.1× | 0.049 | DSP |
| Formation of the cornified envelope | 2 | 10.3× | 0.049 | DSP, PKP2 |
| Phase 2 - plateau phase | 1 | 44.8× | 0.064 | AKAP9 |
| Mechanical load activates signaling by PIEZO1 and integrins in osteocytes | 1 | 39.5× | 0.070 | CACNA2D1 |
| Developmental Biology | 4 | 3.4× | 0.071 | SCN1B, SCN5A, SCN10A, SCN2B |
| Activation of GABAB receptors | 1 | 35.4× | 0.072 | KCNJ16 |
| GABA B receptor activation | 1 | 32.0× | 0.077 | KCNJ16 |
| Keratinization | 2 | 6.5× | 0.088 | DSP, PKP2 |
| Activation of G protein gated Potassium channels | 1 | 23.2× | 0.096 | KCNJ16 |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 17 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| regulation of heart rate by cardiac conduction | 11 | 242.3× | 3e-23 | SCN1B, SCN5A, CACNA2D1, SCN2B, HCN4, DSP, AKAP9, KCNA5 (+3 more) |
| cardiac muscle cell action potential involved in contraction | 6 | 247.8× | 5e-12 | SCN1B, SCN5A, CACNA2D1, SCN10A, SCN2B, PKP2 |
| membrane depolarization during action potential | 5 | 495.6× | 9e-12 | SCN1B, SCN5A, SCN10A, SCN2B, KCNH2 |
| positive regulation of sodium ion transport | 5 | 247.8× | 3e-10 | SCN1B, SCN5A, SCN2B, GPD1L, PKP2 |
| regulation of ventricular cardiac muscle cell membrane repolarization | 5 | 247.8× | 3e-10 | SCN1B, SCN5A, CACNA2D1, AKAP9, KCNH2 |
| regulation of atrial cardiac muscle cell membrane depolarization | 4 | 440.6× | 3e-09 | SCN1B, SCN5A, SCN10A, SCN2B |
| regulation of heart rate | 5 | 137.7× | 6e-09 | SCN5A, SCN10A, HCN4, GPD1L, KCNJ8 |
| membrane depolarization during cardiac muscle cell action potential | 4 | 330.4× | 9e-09 | SCN1B, SCN5A, SCN2B, HCN4 |
| ventricular cardiac muscle cell action potential | 4 | 233.2× | 3e-08 | SCN5A, GPD1L, KCNH2, PKP2 |
| potassium ion transmembrane transport | 6 | 48.0× | 3e-08 | HCN4, KCNA5, KCND3, KCNH2, KCNJ16, KCNJ8 |
| sodium ion transmembrane transport | 5 | 59.7× | 3e-07 | SCN1B, SCN5A, SCN10A, SCNN1A, HCN4 |
| potassium ion transport | 5 | 56.3× | 3e-07 | KCNA5, KCND3, KCNH2, KCNJ16, KCNJ8 |
| cardiac muscle contraction | 4 | 94.4× | 1e-06 | SCN1B, SCN5A, SCN2B, KCNH2 |
| membrane repolarization during ventricular cardiac muscle cell action potential | 3 | 297.4× | 1e-06 | KCND3, KCNH2, KCNJ8 |
| potassium ion import across plasma membrane | 4 | 86.2× | 2e-06 | HCN4, KCNH2, KCNJ16, KCNJ8 |
| potassium ion export across plasma membrane | 3 | 185.9× | 6e-06 | KCNA5, KCND3, KCNH2 |
| bundle of His cell action potential | 2 | 991.3× | 1e-05 | SCN5A, SCN10A |
| regulation of monoatomic ion transmembrane transport | 3 | 129.3× | 2e-05 | SCN10A, KCNJ16, KCNJ8 |
| membrane depolarization during Purkinje myocyte cell action potential | 2 | 660.9× | 3e-05 | SCN1B, SCN5A |
| membrane depolarization during bundle of His cell action potential | 2 | 660.9× | 3e-05 | SCN5A, CACNA2D1 |
| AV node cell action potential | 2 | 495.6× | 6e-05 | SCN5A, SCN10A |
| membrane depolarization during SA node cell action potential | 2 | 396.5× | 9e-05 | SCN5A, HCN4 |
| regulation of ventricular cardiac muscle cell membrane depolarization | 2 | 330.4× | 1e-04 | SCN5A, GPD1L |
| SA node cell action potential | 2 | 330.4× | 1e-04 | SCN5A, HCN4 |
| regulation of atrial cardiac muscle cell membrane repolarization | 2 | 283.2× | 2e-04 | SCN5A, KCNA5 |
| bundle of His cell-Purkinje myocyte adhesion involved in cell communication | 2 | 283.2× | 2e-04 | DSP, PKP2 |
| desmosome organization | 2 | 247.8× | 2e-04 | DSP, PKP2 |
| regulation of cardiac muscle cell action potential involved in regulation of contraction | 2 | 220.3× | 3e-04 | HCN4, AKAP9 |
| cardiac conduction | 2 | 198.3× | 3e-04 | SCN1B, SCN2B |
| membrane repolarization during cardiac muscle cell action potential | 2 | 198.3× | 3e-04 | KCND3, KCNH2 |
Therapeutics
Drug target analysis
Approved (phase 4): 8 · Phase ≥3: 8 · Phased (≥1): 11 · Undrugged: 7
Druggability breadth: 12 of 18 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).
Genes with an approved drug
The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.
| Symbol | Example approved molecule |
|---|---|
| SCN5A | BEPRIDIL |
| CACNA2D1 | PREGABALIN |
| HCN4 | IVABRADINE |
| KCND3 | DULOXETINE |
| SCN10A | IMIPRAMINE |
| SCNN1A | AMILORIDE |
| KCNA5 | DRONEDARONE HYDROCHLORIDE |
| KCNH2 | CETIRIZINE |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| KCNH2 | 706 | 4 |
| SCN5A | 108 | 4 |
| SCN10A | 21 | 4 |
| KCND3 | 10 | 4 |
| KCNA5 | 8 | 4 |
| CACNA2D1 | 5 | 4 |
| SCN1B | 2 | 2 |
| SCN2B | 2 | 2 |
| HCN4 | 2 | 4 |
| SCNN1A | 2 | 4 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| BEPRIDIL | 4 | KCNH2, SCN5A |
| CANDESARTAN CILEXETIL | 4 | SCN5A |
| TELMISARTAN | 4 | SCN5A |
| CARBAMAZEPINE | 4 | SCN5A |
| DIBUCAINE | 4 | KCNH2, SCN5A |
| IMIPRAMINE | 4 | KCNH2, SCN10A, SCN5A |
| DROPERIDOL | 4 | KCNH2, SCN5A |
| PONATINIB | 4 | KCNH2, SCN5A |
| DULOXETINE | 4 | KCND3, KCNH2, SCN5A |
| PALONOSETRON | 4 | KCNH2, SCN5A |
| VILANTEROL | 4 | SCN5A |
| MEXILETINE HYDROCHLORIDE | 4 | SCN5A |
| UNOPROSTONE ISOPROPYL | 4 | SCN5A |
| LURASIDONE | 4 | KCNH2, SCN5A |
| LETERMOVIR | 4 | SCN5A |
| SERTINDOLE | 4 | KCNA5, KCNH2, SCN10A, SCN5A |
| FEDRATINIB | 4 | KCNH2, SCN5A |
| QUINIDINE | 4 | KCNA5, KCNH2, SCN5A |
| DARUNAVIR | 4 | KCND3, KCNH2, SCN5A |
| DARIFENACIN | 4 | KCND3, KCNH2, SCN5A |
| BENZONATATE | 4 | SCN5A |
| TOLTERODINE | 4 | KCND3, KCNH2, SCN5A |
| RANOLAZINE | 4 | KCNH2, SCN5A |
| PIMOZIDE | 4 | KCNH2, SCN10A, SCN5A |
| NIMODIPINE | 4 | CACNA2D1, SCN5A |
| FELODIPINE | 4 | SCN5A |
| NICARDIPINE | 4 | KCNH2, SCN5A |
| AMLODIPINE | 4 | KCNH2, SCN5A |
| PHENYTOIN | 4 | KCNH2, SCN5A |
| PALIPERIDONE | 4 | KCND3, KCNH2, SCN5A |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 0.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| KCNH2 | 4,851 | Binding:3558, Toxicity:1071, Functional:169, ADMET:53 |
| SCN5A | 594 | Binding:380, Functional:98, ADMET:72, Toxicity:43, Unclassified:1 |
| KCNA5 | 152 | Binding:130, Functional:14, ADMET:5, Toxicity:3 |
| SCN10A | 144 | Binding:124, Functional:16, ADMET:4 |
| KCND3 | 118 | Binding:55, Functional:44, ADMET:12, Toxicity:7 |
| CACNA2D1 | 47 | Binding:45, ADMET:1, Toxicity:1 |
| KCNJ8 | 43 | Functional:38, Binding:5 |
| HCN4 | 30 | Binding:20, ADMET:5, Functional:4, Toxicity:1 |
| SCN1B | 15 | Binding:7, ADMET:6, Toxicity:2 |
| SCN2B | 9 | ADMET:4, Binding:3, Toxicity:2 |
| SCNN1A | 6 | Binding:4, ADMET:1, Functional:1 |
| DSP | 2 | Binding:2 |
Cohort genes with high screening signal
≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.
| Symbol | ChEMBL assays |
|---|---|
| SCN5A | 594 |
| KCND3 | 118 |
| SCN10A | 144 |
| KCNA5 | 152 |
| KCNH2 | 4,851 |
Pharmacogenomics
Cohort genes with a PharmGKB record: 17; with CPIC/DPWG dosing guidelines: 0.
No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).
Chemical tractability of cohort targets
30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.
| Compound | Max phase | Cohort target (bioactivity) |
|---|---|---|
| BEPRIDIL | 4 | KCNH2, SCN5A |
| CANDESARTAN CILEXETIL | 4 | SCN5A |
| TELMISARTAN | 4 | SCN5A |
| CARBAMAZEPINE | 4 | SCN5A |
| DIBUCAINE | 4 | KCNH2, SCN5A |
| IMIPRAMINE | 4 | KCNH2, SCN10A, SCN5A |
| DROPERIDOL | 4 | KCNH2, SCN5A |
| PONATINIB | 4 | KCNH2, SCN5A |
| DULOXETINE | 4 | KCND3, KCNH2, SCN5A |
| PALONOSETRON | 4 | KCNH2, SCN5A |
| VILANTEROL | 4 | SCN5A |
| MEXILETINE HYDROCHLORIDE | 4 | SCN5A |
| UNOPROSTONE ISOPROPYL | 4 | SCN5A |
| LURASIDONE | 4 | KCNH2, SCN5A |
| LETERMOVIR | 4 | SCN5A |
| SERTINDOLE | 4 | KCNA5, KCNH2, SCN10A, SCN5A |
| FEDRATINIB | 4 | KCNH2, SCN5A |
| QUINIDINE | 4 | KCNA5, KCNH2, SCN5A |
| DARUNAVIR | 4 | KCND3, KCNH2, SCN5A |
| DARIFENACIN | 4 | KCND3, KCNH2, SCN5A |
| BENZONATATE | 4 | SCN5A |
| TOLTERODINE | 4 | KCND3, KCNH2, SCN5A |
| RANOLAZINE | 4 | KCNH2, SCN5A |
| PIMOZIDE | 4 | KCNH2, SCN10A, SCN5A |
| NIMODIPINE | 4 | CACNA2D1, SCN5A |
| FELODIPINE | 4 | SCN5A |
| NICARDIPINE | 4 | KCNH2, SCN5A |
| AMLODIPINE | 4 | KCNH2, SCN5A |
| PHENYTOIN | 4 | KCNH2, SCN5A |
| PALIPERIDONE | 4 | KCND3, KCNH2, SCN5A |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 8 | SCN5A, CACNA2D1, HCN4, KCND3, SCN10A, SCNN1A, KCNA5, KCNH2 |
| B | Phased (≥1) drug, not yet approved | 3 | SCN1B, SCN2B, KCNJ8 |
| C | Druggable family + PDB, no drug | 1 | KCNJ16 |
| D | Druggable family + AlphaFold only, no drug | 0 | |
| E | Difficult family or no structure, no drug | 6 | GPD1L, PKP2, DSP, FBN1, AKAP9, KCNJ8-AS1 |
Undrugged target profiles
7 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| GPD1L | 0 | SCN5A, SCN1B |
| PKP2 | 0 | SCN5A |
| DSP | 2 | — |
| FBN1 | 0 | — |
| AKAP9 | 0 | — |
| KCNJ8-AS1 | 0 | — |
| KCNJ16 | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 2.
Phase distribution (across all retrieved trials)
| Phase | Trials |
|---|---|
| Not specified | 2 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT03572881 | Not specified | UNKNOWN | Rhythmic Risk of Type 1 Brugada Syndrome and Pulmonary Infundibulum Mapping |
| NCT04641585 | Not specified | UNKNOWN | Brugada Syndrome and Artificial Intelligence Applications to Diagnosis |