Conduction system disorder
diseaseOn this page
Also known as conducting system of heart diseaseconducting system of heart disease or disorderdisease of conducting system of heartdisease or disorder of conducting system of heartdisorder of conducting system of heart
Summary
Conduction system disorder (MONDO:0005449) is a disease with 6 cohort genes (20 GWAS associations across 16 studies). The dominant Reactome pathway is Phase 0 - rapid depolarisation (3 cohort genes).
At a glance
- Cohort genes: 6
- GWAS associations: 20
- ClinVar variants: 14
Clinical features
No curated clinical features (Orphanet) for this disease.
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | conduction system disorder |
| Mondo ID | MONDO:0005449 |
| EFO | EFO:0005137 |
| UMLS | C2748542 |
| MedGen | 412576 |
| Anatomy (UBERON) | UBERON:0002350 |
| Is cancer (heuristic) | no |
Also known as: conducting system of heart disease · conducting system of heart disease or disorder · disease of conducting system of heart · disease or disorder of conducting system of heart · disorder of conducting system of heart
Data availability: 14 ClinVar variants · 20 GWAS associations (16 studies).
Disease family
An umbrella term covering 4 Mondo subtypes.
Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › conduction system disorder
Related subtypes (12): striated muscle rhabdoid tumor, septal myocardial infarction, tonsillar pillar cancer, atrophic muscular disease, cardiomyopathy, myalgic encephalomeyelitis/chronic fatigue syndrome, myostatin-related muscle hypertrophy, caveolinopathy, distal arthrogryposis, skeletal muscle disorder, myomatous neoplasm, Kocher-debre-Semelaigne syndrome
Subtypes (4): sinoatrial node disorder, atrioventricular node disorder, progressive familial heart block, type 1A, atrial conduction disease
Genetics & variants
GWAS landscape
20 GWAS associations across 16 studies. Top hits map to 1 distinct genes (as reported by GWAS).
Top associations by p-value
| rsID | p-value | Gene | Risk allele | Odds ratio |
|---|---|---|---|---|
| chr2:178975161 | 1e-14 | A | 0.29 | |
| chr4:23820705 | 1e-12 | A | 0.13 | |
| chr18:44848072 | 2e-11 | GGT | 0.11 | |
| rs140917642 | 3e-11 | TTC34 - ACTRT2 | C | 3.01 |
| rs547847532 | 3e-11 | ANK1 | G | 1.78 |
| chr1:85279692 | 2e-09 | T | 2.25 | |
| chr3:171271462 | 2e-09 | T | 0.1 | |
| chr5:4245885 | 6e-09 | C | 2.91 | |
| chr7:57201323 | 9e-09 | A | 3.37 | |
| chr6:151897627 | 2e-08 | C | 0.65 | |
| chrX:101522682 | 2e-08 | C | 1.98 | |
| chr16:604457 | 2e-08 | T | 2.73 | |
| chr4:109736968 | 3e-08 | C | 3.27 | |
| chr1:172985953 | 4e-08 | A | 2.65 | |
| chrX:103278860 | 4e-08 | T | 1.92 | |
| chr10:73263645 | 4e-08 | G | 2.69 | |
| chr11:89110961 | 4e-08 | G | 1.99 | |
| chr12:98616492 | 4e-08 | T | 1.82 | |
| chr7:56145458 | 5e-08 | T | 3.11 | |
| chr9:77703075 | 5e-08 | G | 2.45 |
Top studies (by case count)
| Study | Lead author | Year | Cases | Controls | Title |
|---|---|---|---|---|---|
| GCST90297581 | Auwerx C | 2024 | 43,312 | 179,146 | Rare copy-number variants as modulators of common disease susceptibility. |
| GCST90297635 | Auwerx C | 2024 | 43,312 | 179,146 | Rare copy-number variants as modulators of common disease susceptibility. |
| GCST90297687 | Auwerx C | 2024 | 43,312 | 179,146 | Rare copy-number variants as modulators of common disease susceptibility. |
| GCST90297731 | Auwerx C | 2024 | 43,312 | 179,146 | Rare copy-number variants as modulators of common disease susceptibility. |
| GCST90473565 | UK Biobank Whole-Genome Sequencing Consortium | 2025 | 8,175 | 450,265 | Whole-genome sequencing of 490,640 UK Biobank participants. |
| GCST90667959 | UK Biobank Whole-Genome Sequencing Consortium | 2025 | 8,175 | 450,265 | Whole-genome sequencing of 490,640 UK Biobank participants. |
| GCST90080007 | Backman JD | 2021 | 3,184 | 384,091 | Exome sequencing and analysis of 454,787 UK Biobank participants. |
| GCST90083993 | Backman JD | 2021 | 3,184 | 384,091 | Exome sequencing and analysis of 454,787 UK Biobank participants. |
| GCST90477912 | Verma A | 2024 | 1,717 | 447,263 | Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program. |
| GCST90726671 | Kim HI | 2026 | 757 | 43,269 | Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity. |
Variant details and genetic-evidence tiers
Tier distribution (top 50 variants)
| Tier | Variants |
|---|---|
| Tier 1: coding | 0 |
| Tier 2: splice/UTR | 0 |
| Tier 3: regulatory | 0 |
| Tier 4: intronic/intergenic | 20 |
MAF distribution
| Bucket | Variants |
|---|---|
| common (>=0.05) | 0 |
| low_freq (0.01-0.05) | 0 |
| rare (<0.01) | 2 |
| unknown | 18 |
Functional consequences
| Consequence | Count |
|---|---|
| unknown | 18 |
| intergenic_variant | 1 |
| intron_variant | 1 |
Top variants
| rsID | Chr | Pos | Alleles | MAF | Consequence | Gene | p-value | Tier |
|---|---|---|---|---|---|---|---|---|
| chr2:178975161 | 1e-14 | Tier 4: intronic/intergenic | ||||||
| chr4:23820705 | 1e-12 | Tier 4: intronic/intergenic | ||||||
| chr18:44848072 | 2e-11 | Tier 4: intronic/intergenic | ||||||
| rs140917642 | 1 | 2917891 | C>G,T | 0 | intergenic_variant | TTC34 - ACTRT2 | 3e-11 | Tier 4: intronic/intergenic |
| rs547847532 | 8 | 41786253 | G>T | 0.001 | intron_variant | ANK1 | 3e-11 | Tier 4: intronic/intergenic |
| chr1:85279692 | 2e-09 | Tier 4: intronic/intergenic | ||||||
| chr3:171271462 | 2e-09 | Tier 4: intronic/intergenic | ||||||
| chr5:4245885 | 6e-09 | Tier 4: intronic/intergenic | ||||||
| chr7:57201323 | 9e-09 | Tier 4: intronic/intergenic | ||||||
| chr6:151897627 | 2e-08 | Tier 4: intronic/intergenic | ||||||
| chrX:101522682 | 2e-08 | Tier 4: intronic/intergenic | ||||||
| chr16:604457 | 2e-08 | Tier 4: intronic/intergenic | ||||||
| chr4:109736968 | 3e-08 | Tier 4: intronic/intergenic | ||||||
| chr1:172985953 | 4e-08 | Tier 4: intronic/intergenic | ||||||
| chrX:103278860 | 4e-08 | Tier 4: intronic/intergenic | ||||||
| chr10:73263645 | 4e-08 | Tier 4: intronic/intergenic | ||||||
| chr11:89110961 | 4e-08 | Tier 4: intronic/intergenic | ||||||
| chr12:98616492 | 4e-08 | Tier 4: intronic/intergenic | ||||||
| chr7:56145458 | 5e-08 | Tier 4: intronic/intergenic | ||||||
| chr9:77703075 | 5e-08 | Tier 4: intronic/intergenic |
ClinVar germline variants
14 retrieved; paginated sample, class counts are floors:
6 uncertain significance, 3 conflicting classifications of pathogenicity, 3 pathogenic, 1 likely pathogenic, 1 pathogenic/likely pathogenic
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 9256 | NM_001037.5(SCN1B):c.448+89G>A | SCN1B | Pathogenic | no assertion criteria provided |
| 68032 | NM_000335.5(SCN5A):c.673C>T (p.Arg225Trp) | SCN5A | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 9386 | NM_000335.5(SCN5A):c.1540G>T (p.Gly514Cys) | SCN5A | Pathogenic | no assertion criteria provided |
| 9395 | NM_000335.5(SCN5A):c.4219G>A (p.Gly1407Arg) | SCN5A | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 222695 | NM_170707.4(LMNA):c.354_355delinsAG (p.Arg119Gly) | LMNA | Likely pathogenic | criteria provided, single submitter |
| 67931 | NM_000335.5(SCN5A):c.4856C>A (p.Thr1619Lys) | SCN5A | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 67939 | NM_000335.5(SCN5A):c.4892G>A (p.Arg1631His) | SCN5A | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 68036 | NM_000335.5(SCN5A):c.689T>C (p.Ile230Thr) | SCN5A | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 222519 | NM_201596.3(CACNB2):c.1399C>T (p.Pro467Ser) | CACNB2 | Uncertain significance | criteria provided, single submitter |
| 67773 | NM_000335.5(SCN5A):c.3022C>T (p.Pro1008Ser) | LOC110121269 | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 450490 | NM_002471.4(MYH6):c.1960C>T (p.Arg654Trp) | MYH6 | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 9255 | NM_001037.5(SCN1B):c.259G>C (p.Glu87Gln) | SCN1B | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 67665 | NM_000335.5(SCN5A):c.1535C>T (p.Thr512Ile) | SCN5A | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 222855 | NM_017636.4(TRPM4):c.3337C>G (p.Leu1113Val) | TRPM4 | Uncertain significance | criteria provided, multiple submitters, no conflicts |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 0 · Orphanet: 42 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0
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 |
| CACNB2 | Orphanet:130 | Brugada syndrome |
| TRPM4 | Orphanet:130 | Brugada syndrome |
| TRPM4 | Orphanet:316 | Progressive symmetric erythrokeratodermia |
| TRPM4 | Orphanet:871 | Hereditary progressive cardiac conduction defect |
| LMNA | Orphanet:154 | Familial isolated dilated cardiomyopathy |
| LMNA | Orphanet:157973 | Congenital muscular dystrophy due to LMNA mutation |
| LMNA | Orphanet:1662 | Restrictive dermopathy |
| LMNA | Orphanet:168796 | Heart-hand syndrome, Slovenian type |
| LMNA | Orphanet:2229 | Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome |
| LMNA | Orphanet:2348 | Familial partial lipodystrophy, Dunnigan type |
| LMNA | Orphanet:280365 | Autosomal semi-dominant severe lipodystrophic laminopathy |
| LMNA | Orphanet:293888 | Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant |
| LMNA | Orphanet:293899 | Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant |
| LMNA | Orphanet:293910 | Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant |
| LMNA | Orphanet:300751 | Familial dilated cardiomyopathy with conduction defect due to LMNA mutation |
| LMNA | Orphanet:363618 | LMNA-related cardiocutaneous progeria syndrome |
| LMNA | Orphanet:54260 | Left ventricular noncompaction |
| LMNA | Orphanet:675396 | Epithelioid hemangioma |
| LMNA | Orphanet:740 | Hutchinson-Gilford progeria syndrome |
| LMNA | Orphanet:79084 | Familial partial lipodystrophy, Köbberling type |
| LMNA | Orphanet:79474 | Atypical Werner syndrome |
| LMNA | Orphanet:90153 | Mandibuloacral dysplasia with type A lipodystrophy |
| LMNA | Orphanet:98853 | Autosomal dominant Emery-Dreifuss muscular dystrophy |
| LMNA | Orphanet:98855 | Autosomal recessive Emery-Dreifuss muscular dystrophy |
| LMNA | Orphanet:98856 | Charcot-Marie-Tooth disease type 2B1 |
| MYH6 | Orphanet:154 | Familial isolated dilated cardiomyopathy |
| MYH6 | Orphanet:166282 | Hereditary sick sinus syndrome |
| MYH6 | Orphanet:99103 | Atrial septal defect, ostium secundum type |
Cohort genes → proteins
6 cohort genes, 6 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 6 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| SCN1B | HGNC:10586 | ENSG00000105711 | Q07699 | Sodium channel regulatory subunit beta-1 | clinvar |
| SCN5A | HGNC:10593 | ENSG00000183873 | Q14524 | Sodium channel protein type 5 subunit alpha | clinvar |
| CACNB2 | HGNC:1402 | ENSG00000165995 | Q08289 | Voltage-dependent L-type calcium channel subunit beta-2 | clinvar |
| TRPM4 | HGNC:17993 | ENSG00000130529 | Q8TD43 | Transient receptor potential cation channel subfamily M member 4 | clinvar |
| LMNA | HGNC:6636 | ENSG00000160789 | P02545 | Prelamin-A/C | clinvar |
| MYH6 | HGNC:7576 | ENSG00000197616 | P13533 | Myosin-6 | 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. |
| CACNB2 | Voltage-dependent L-type calcium channel subunit beta-2 | Beta subunit of voltage-dependent calcium channels which contributes to the function of the calcium channel by increasing peak calcium current. |
| TRPM4 | Transient receptor potential cation channel subfamily M member 4 | Calcium-activated selective cation channel that mediates membrane depolarization. |
| LMNA | Prelamin-A/C | Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane. |
| MYH6 | Myosin-6 | Muscle contraction. |
Protein-family classification
Druggable: 3 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.5
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 | 2 | 37.2× | 0.005 |
| Scaffold/PPI | 2 | 5.8× | 0.086 |
| Antibody/Immunoglobulin | 1 | 4.9× | 0.252 |
| Other/Unknown | 1 | 0.3× | 0.993 |
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 | |
| CACNB2 | Scaffold/PPI | no | VDCC_L_bsu, SH3_domain, VDCC_L_b2su | |
| TRPM4 | Ion channel | yes | Ion_trans_dom, TRPM_SLOG, TRPM | |
| LMNA | Other/Unknown | no | Lamin_tail_dom, IF_conserved, Lamin_tail_dom_sf | |
| MYH6 | Scaffold/PPI | no | Myosin_head_motor_dom-like, Myosin_tail, SH3_Myosin |
Expression context
Cohort genes with no expression data: 0.
4 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) | 6 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| apex of heart | 2 |
| mucosa of stomach | 2 |
| cerebellum | 1 |
| primary visual cortex | 1 |
| right hemisphere of cerebellum | 1 |
| cardiac ventricle | 1 |
| heart left ventricle | 1 |
| adrenal tissue | 1 |
| buccal mucosa cell | 1 |
| mucosa of transverse colon | 1 |
| rectum | 1 |
| nipple | 1 |
| skin of abdomen | 1 |
| cardiac atrium | 1 |
| cardiac muscle of right atrium | 1 |
| vena cava | 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 |
| CACNB2 | 237 | broad | marker | adrenal tissue, mucosa of stomach, buccal mucosa cell |
| TRPM4 | 201 | ubiquitous | marker | mucosa of transverse colon, rectum, apex of heart |
| LMNA | 295 | ubiquitous | marker | nipple, mucosa of stomach, skin of abdomen |
| MYH6 | 154 | tissue_specific | yes | cardiac muscle of right atrium, cardiac atrium, vena cava |
Protein interactions among cohort
Intra-cohort edges: 4.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| LMNA | 7,173 |
| MYH6 | 3,119 |
| SCN5A | 2,090 |
| CACNB2 | 1,425 |
| SCN1B | 1,328 |
| TRPM4 | 1,217 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| CACNB2 | SCN1B | string_interaction |
| CACNB2 | SCN5A | string_interaction |
| SCN1B | SCN5A | string_interaction |
| SCN5A | TRPM4 | string_interaction |
Structural data
PDB: 5 · AlphaFold-only: 1 · No structure: 0
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| SCN1B | Q07699 | 39 |
| TRPM4 | Q8TD43 | 29 |
| LMNA | P02545 | 28 |
| SCN5A | Q14524 | 16 |
| CACNB2 | Q08289 | 3 |
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| MYH6 | P13533 | 74.91 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 42. Enrichment computed across 6 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| Phase 0 - rapid depolarisation | 3 | 173.0× | 9e-06 | SCN1B, SCN5A, CACNB2 |
| Muscle contraction | 4 | 51.4× | 9e-06 | SCN1B, SCN5A, CACNB2, MYH6 |
| Cardiac conduction | 3 | 54.4× | 2e-04 | SCN1B, SCN5A, CACNB2 |
| Interaction between L1 and Ankyrins | 2 | 122.8× | 0.001 | SCN1B, SCN5A |
| Sensory perception of sweet, bitter, and umami (glutamate) taste | 2 | 92.8× | 0.001 | SCN1B, TRPM4 |
| Axon guidance | 3 | 22.6× | 0.001 | SCN1B, SCN5A, CACNB2 |
| Nervous system development | 3 | 21.5× | 0.001 | SCN1B, SCN5A, CACNB2 |
| L1CAM interactions | 2 | 40.1× | 0.005 | SCN1B, SCN5A |
| Breakdown of the nuclear lamina | 1 | 634.4× | 0.007 | LMNA |
| Sensory Perception | 2 | 31.7× | 0.007 | SCN1B, CACNB2 |
| Developmental Biology | 3 | 7.2× | 0.021 | SCN1B, SCN5A, CACNB2 |
| Presynaptic depolarization and calcium channel opening | 1 | 158.6× | 0.022 | CACNB2 |
| Depolymerization of the Nuclear Lamina | 1 | 126.9× | 0.024 | LMNA |
| Phase 2 - plateau phase | 1 | 126.9× | 0.024 | CACNB2 |
| Mechanical load activates signaling by PIEZO1 and integrins in osteocytes | 1 | 112.0× | 0.025 | CACNB2 |
| Initiation of Nuclear Envelope (NE) Reformation | 1 | 100.2× | 0.026 | LMNA |
| IRE1alpha activates chaperones | 1 | 86.5× | 0.027 | LMNA |
| Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models | 1 | 86.5× | 0.027 | LMNA |
| Nuclear Envelope Breakdown | 1 | 76.1× | 0.029 | LMNA |
| TRP channels | 1 | 68.0× | 0.029 | TRPM4 |
| Adrenaline,noradrenaline inhibits insulin secretion | 1 | 65.6× | 0.029 | CACNB2 |
| Cellular responses to stimuli | 2 | 10.5× | 0.029 | CACNB2, LMNA |
| Unfolded Protein Response (UPR) | 1 | 59.5× | 0.030 | LMNA |
| Sensory perception of taste | 1 | 56.0× | 0.031 | SCN1B |
| Striated Muscle Contraction | 1 | 51.4× | 0.031 | MYH6 |
| Sensory processing of sound | 1 | 51.4× | 0.031 | CACNB2 |
| NCAM signaling for neurite out-growth | 1 | 45.3× | 0.034 | CACNB2 |
| Cellular responses to mechanical stimuli | 1 | 43.3× | 0.034 | CACNB2 |
| NCAM1 interactions | 1 | 41.4× | 0.034 | CACNB2 |
| Oncogenic MAPK signaling | 1 | 41.4× | 0.034 | LMNA |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| membrane depolarization during Purkinje myocyte cell action potential | 3 | 2808.7× | 3e-09 | SCN1B, SCN5A, TRPM4 |
| membrane depolarization during AV node cell action potential | 3 | 1685.2× | 2e-08 | SCN5A, CACNB2, TRPM4 |
| regulation of heart rate by cardiac conduction | 4 | 249.7× | 3e-08 | SCN1B, SCN5A, CACNB2, TRPM4 |
| membrane depolarization during bundle of His cell action potential | 2 | 1872.4× | 6e-06 | SCN5A, TRPM4 |
| membrane depolarization during atrial cardiac muscle cell action potential | 2 | 1872.4× | 6e-06 | SCN5A, CACNB2 |
| cardiac muscle contraction | 3 | 200.6× | 6e-06 | SCN1B, SCN5A, MYH6 |
| regulation of atrial cardiac muscle cell membrane depolarization | 2 | 624.1× | 7e-05 | SCN1B, SCN5A |
| membrane depolarization during action potential | 2 | 561.7× | 7e-05 | SCN1B, SCN5A |
| membrane depolarization during cardiac muscle cell action potential | 2 | 468.1× | 9e-05 | SCN1B, SCN5A |
| regulation of sodium ion transmembrane transport | 2 | 351.1× | 2e-04 | SCN1B, SCN5A |
| positive regulation of sodium ion transport | 2 | 280.9× | 2e-04 | SCN1B, SCN5A |
| regulation of ventricular cardiac muscle cell membrane repolarization | 2 | 280.9× | 2e-04 | SCN1B, SCN5A |
| cardiac muscle cell action potential involved in contraction | 2 | 234.1× | 3e-04 | SCN1B, SCN5A |
| membrane depolarization | 2 | 170.2× | 5e-04 | SCN1B, SCN5A |
| regulation of heart rate | 2 | 156.0× | 5e-04 | SCN5A, MYH6 |
| visceral muscle development | 1 | 2808.7× | 0.002 | MYH6 |
| corticospinal neuron axon guidance | 1 | 2808.7× | 0.002 | SCN1B |
| positive regulation of atrial cardiac muscle cell action potential | 1 | 2808.7× | 0.002 | TRPM4 |
| positive regulation of regulation of vascular associated smooth muscle cell membrane depolarization | 1 | 2808.7× | 0.002 | TRPM4 |
| calcium ion transmembrane transport | 2 | 70.2× | 0.002 | CACNB2, TRPM4 |
| sodium ion transmembrane transport | 2 | 67.7× | 0.002 | SCN1B, SCN5A |
| regulation of heart growth | 1 | 1404.3× | 0.003 | MYH6 |
| bundle of His cell action potential | 1 | 1404.3× | 0.003 | SCN5A |
| AV node cell to bundle of His cell communication | 1 | 1404.3× | 0.003 | SCN5A |
| positive regulation of calcium ion transmembrane transport via high voltage-gated calcium channel | 1 | 1404.3× | 0.003 | CACNB2 |
| positive regulation of voltage-gated sodium channel activity | 1 | 936.2× | 0.005 | SCN1B |
| DNA double-strand break attachment to nuclear envelope | 1 | 936.2× | 0.005 | LMNA |
| regulation of T cell cytokine production | 1 | 702.2× | 0.006 | TRPM4 |
| establishment or maintenance of microtubule cytoskeleton polarity | 1 | 702.2× | 0.006 | LMNA |
| AV node cell action potential | 1 | 702.2× | 0.006 | SCN5A |
Therapeutics
Drug target analysis
Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 4 · Undrugged: 2
Druggability breadth: 6 of 6 evidence-associated genes (100%) 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 |
| CACNB2 | NIMODIPINE |
| LMNA | BEPRIDIL |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| LMNA | 823 | 4 |
| SCN5A | 108 | 4 |
| SCN1B | 2 | 2 |
| CACNB2 | 2 | 4 |
| TRPM4 | 0 | 0 |
| MYH6 | 0 | 0 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| BEPRIDIL | 4 | LMNA, SCN5A |
| CANDESARTAN CILEXETIL | 4 | SCN5A |
| TELMISARTAN | 4 | SCN5A |
| CARBAMAZEPINE | 4 | LMNA, SCN5A |
| DIBUCAINE | 4 | LMNA, SCN5A |
| IMIPRAMINE | 4 | LMNA, SCN5A |
| DROPERIDOL | 4 | LMNA, SCN5A |
| PONATINIB | 4 | SCN5A |
| DULOXETINE | 4 | SCN5A |
| PALONOSETRON | 4 | SCN5A |
| VILANTEROL | 4 | SCN5A |
| MEXILETINE HYDROCHLORIDE | 4 | LMNA, SCN5A |
| UNOPROSTONE ISOPROPYL | 4 | SCN5A |
| LURASIDONE | 4 | SCN5A |
| LETERMOVIR | 4 | SCN5A |
| SERTINDOLE | 4 | SCN5A |
| FEDRATINIB | 4 | SCN5A |
| QUINIDINE | 4 | SCN5A |
| DARUNAVIR | 4 | SCN5A |
| DARIFENACIN | 4 | SCN5A |
| BENZONATATE | 4 | SCN5A |
| TOLTERODINE | 4 | LMNA, SCN5A |
| RANOLAZINE | 4 | SCN5A |
| PIMOZIDE | 4 | LMNA, SCN5A |
| NIMODIPINE | 4 | CACNB2, LMNA, SCN5A |
| FELODIPINE | 4 | LMNA, SCN5A |
| NICARDIPINE | 4 | LMNA, SCN5A |
| AMLODIPINE | 4 | SCN5A |
| PHENYTOIN | 4 | SCN5A |
| PALIPERIDONE | 4 | 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 |
|---|---|---|
| SCN5A | 594 | Binding:380, Functional:98, ADMET:72, Toxicity:43, Unclassified:1 |
| CACNB2 | 22 | Binding:20, ADMET:1, Toxicity:1 |
| SCN1B | 15 | Binding:7, ADMET:6, Toxicity:2 |
| TRPM4 | 14 | Binding:13, Functional:1 |
| LMNA | 12 | Binding:9, Functional:3 |
Cohort genes with high screening signal
≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.
| Symbol | ChEMBL assays |
|---|---|
| SCN5A | 594 |
Pharmacogenomics
Cohort genes with a PharmGKB record: 6; 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 | LMNA, SCN5A |
| CANDESARTAN CILEXETIL | 4 | SCN5A |
| TELMISARTAN | 4 | SCN5A |
| CARBAMAZEPINE | 4 | LMNA, SCN5A |
| DIBUCAINE | 4 | LMNA, SCN5A |
| IMIPRAMINE | 4 | LMNA, SCN5A |
| DROPERIDOL | 4 | LMNA, SCN5A |
| PONATINIB | 4 | SCN5A |
| DULOXETINE | 4 | SCN5A |
| PALONOSETRON | 4 | SCN5A |
| VILANTEROL | 4 | SCN5A |
| MEXILETINE HYDROCHLORIDE | 4 | LMNA, SCN5A |
| UNOPROSTONE ISOPROPYL | 4 | SCN5A |
| LURASIDONE | 4 | SCN5A |
| LETERMOVIR | 4 | SCN5A |
| SERTINDOLE | 4 | SCN5A |
| FEDRATINIB | 4 | SCN5A |
| QUINIDINE | 4 | SCN5A |
| DARUNAVIR | 4 | SCN5A |
| DARIFENACIN | 4 | SCN5A |
| BENZONATATE | 4 | SCN5A |
| TOLTERODINE | 4 | LMNA, SCN5A |
| RANOLAZINE | 4 | SCN5A |
| PIMOZIDE | 4 | LMNA, SCN5A |
| NIMODIPINE | 4 | CACNB2, LMNA, SCN5A |
| FELODIPINE | 4 | LMNA, SCN5A |
| NICARDIPINE | 4 | LMNA, SCN5A |
| AMLODIPINE | 4 | SCN5A |
| PHENYTOIN | 4 | SCN5A |
| PALIPERIDONE | 4 | SCN5A |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 3 | SCN5A, CACNB2, LMNA |
| B | Phased (≥1) drug, not yet approved | 1 | SCN1B |
| C | Druggable family + PDB, no drug | 1 | TRPM4 |
| D | Druggable family + AlphaFold only, no drug | 0 | |
| E | Difficult family or no structure, no drug | 1 | MYH6 |
Undrugged target profiles
2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| TRPM4 | 14 | — |
| MYH6 | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 0.