short QT syndrome
diseaseOn this page
Also known as ventricular arrhythmia associated with short QT syndrome
Summary
short QT syndrome (MONDO:0000453) is a disease with 9 cohort genes and 1 clinical trial. The dominant Reactome pathway is Cardiac conduction (4 cohort genes).
At a glance
- Prevalence: Unknown (Worldwide) [Orphanet-validated]
- Cohort genes: 9
- ClinVar variants: 14
- Phenotypes (HPO): 9
- Clinical trials: 1
Clinical features
Epidemiology
Prevalence records
1 prevalence record(s), Orphanet:
| Type | Class | Value | Geography | Validation |
|---|---|---|---|---|
| Cases/families | 80 | Worldwide | Validated |
Signs & symptoms
Clinical features (HPO)
9 HPO clinical features (Orphanet curated; top 9 by frequency):
| HPO ID | Term | Frequency |
|---|---|---|
| HP:0012232 | Shortened QT interval | Obligate (100%) |
| HP:0001662 | Bradycardia | Very frequent (80-99%) |
| HP:0001962 | Palpitations | Frequent (30-79%) |
| HP:0005110 | Atrial fibrillation | Frequent (30-79%) |
| HP:0001279 | Syncope | Occasional (5-29%) |
| HP:0001645 | Sudden cardiac death | Occasional (5-29%) |
| HP:0001663 | Ventricular fibrillation | Occasional (5-29%) |
| HP:0001678 | Atrioventricular block | Occasional (5-29%) |
| HP:0004308 | Ventricular arrhythmia | Occasional (5-29%) |
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | short QT syndrome |
| Mondo ID | MONDO:0000453 |
| MeSH | C580439 |
| OMIM | 609620 |
| Orphanet | 51083 |
| DOID | DOID:0050793 |
| ICD-11 | 553392015 |
| NCIT | C71060 |
| SNOMED CT | 698272007 |
| UMLS | C2348199 |
| MedGen | 378835 |
| GARD | 0016650 |
| NORD | 2019 |
| Is cancer (heuristic) | no |
Also known as: short QT syndrome · ventricular arrhythmia associated with short QT syndrome
Data availability: 14 ClinVar variants · 10 GenCC gene-disease records · 5 cell lines.
Disease family
An umbrella term covering 4 Mondo subtypes.
Classification path: disease › human disease › disease by body system or component › cardiovascular disorder › heart disorder › heart conduction disease › short QT syndrome
Related subtypes (9): atrioventricular block, sinoatrial node disorder, Wolff-Parkinson-White syndrome, postural orthostatic tachycardia syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, progressive familial heart block, sinoatrial block, NKX2.5-related congenital, conduction and myopathic heart disease
Subtypes (4): short QT syndrome type 1, short QT syndrome type 2, short QT syndrome type 3, short QT syndrome 7
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
14 retrieved; paginated sample, class counts are floors:
7 uncertain significance, 2 conflicting classifications of pathogenicity, 2 pathogenic, 1 likely pathogenic, 1 pathogenic/likely pathogenic, 1 benign/likely benign
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 14437 | NM_000238.4(KCNH2):c.1764C>A (p.Asn588Lys) | KCNH2 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 67297 | NM_000238.4(KCNH2):c.1853C>T (p.Thr618Ile) | KCNH2 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 8927 | NM_000891.3(KCNJ2):c.514G>A (p.Asp172Asn) | KCNJ2 | Pathogenic | criteria provided, single submitter |
| 14436 | NM_000238.4(KCNH2):c.1764C>G (p.Asn588Lys) | KCNH2 | Likely pathogenic | criteria provided, single submitter |
| 197406 | NM_000719.7(CACNA1C):c.4942G>A (p.Ala1648Thr) | CACNA1C | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 263722 | NM_000722.4(CACNA2D1):c.1141A>G (p.Lys381Glu) | CACNA2D1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 637981 | NM_000722.4(CACNA2D1):c.2721A>G (p.Ala907=) | CACNA2D1 | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 67211 | NM_000238.4(KCNH2):c.150G>T (p.Glu50Asp) | KCNH2 | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 67493 | NM_000238.4(KCNH2):c.3404G>A (p.Arg1135His) | KCNH2 | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 658326 | NM_000891.3(KCNJ2):c.1067G>T (p.Cys356Phe) | KCNJ2 | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 3148 | NM_000218.3(KCNQ1):c.919G>C (p.Val307Leu) | KCNQ1 | Uncertain significance | criteria provided, single submitter |
| 180561 | NM_017636.4(TRPM4):c.678C>G (p.Asp226Glu) | TRPM4 | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 2664945 | NM_014000.3(VCL):c.1177-3T>G | VCL | Uncertain significance | criteria provided, single submitter |
| 93419 | NM_000719.7(CACNA1C):c.5918G>A (p.Arg1973Gln) | CACNA1C | Benign/Likely benign | criteria provided, multiple submitters, no conflicts |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 71 · Orphanet: 24 · 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 |
|---|---|---|---|---|
| KCNH2 | Definitive | Autosomal dominant | short QT syndrome type 1 | 8 |
| KCNJ2 | Strong | Autosomal dominant | short QT syndrome type 3 | 15 |
| KCNQ1 | Strong | Autosomal dominant | short QT syndrome type 2 | 12 |
| SLC4A3 | Strong | Autosomal dominant | short QT syndrome 7 | 6 |
| CACNA2D1 | Supportive | Autosomal dominant | short QT syndrome | 8 |
| CACNA1C | Limited | Autosomal dominant | short QT syndrome | 13 |
| SLC22A5 | Disputed Evidence | Autosomal recessive | short QT syndrome | 9 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| CACNA1C | Orphanet:101016 | Romano-Ward syndrome |
| CACNA1C | Orphanet:130 | Brugada syndrome |
| CACNA1C | Orphanet:528084 | Non-specific syndromic intellectual disability |
| CACNA1C | Orphanet:595098 | Timothy syndrome type 1 |
| CACNA1C | Orphanet:595105 | Timothy syndrome type 2 |
| CACNA1C | Orphanet:595109 | Atypical Timothy syndrome |
| CACNA2D1 | Orphanet:130 | Brugada syndrome |
| CACNA2D1 | Orphanet:442835 | Non-specific early-onset epileptic encephalopathy |
| CACNA2D1 | Orphanet:51083 | Congenital short QT syndrome |
| KCNH2 | Orphanet:101016 | Romano-Ward syndrome |
| KCNH2 | Orphanet:51083 | Congenital short QT syndrome |
| KCNJ2 | Orphanet:334 | Hereditary atrial fibrillation |
| KCNJ2 | Orphanet:37553 | Andersen-Tawil syndrome |
| KCNJ2 | Orphanet:51083 | Congenital short QT syndrome |
| KCNQ1 | Orphanet:101016 | Romano-Ward syndrome |
| KCNQ1 | Orphanet:334 | Hereditary atrial fibrillation |
| KCNQ1 | Orphanet:51083 | Congenital short QT syndrome |
| KCNQ1 | Orphanet:90647 | Jervell and Lange-Nielsen syndrome |
| SLC22A5 | Orphanet:158 | Systemic primary carnitine deficiency |
| SLC4A3 | Orphanet:51083 | Congenital short QT syndrome |
| VCL | Orphanet:154 | Familial isolated dilated cardiomyopathy |
| TRPM4 | Orphanet:130 | Brugada syndrome |
| TRPM4 | Orphanet:316 | Progressive symmetric erythrokeratodermia |
| TRPM4 | Orphanet:871 | Hereditary progressive cardiac conduction defect |
Cohort genes → proteins
9 cohort genes, 9 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 9 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| CACNA1C | HGNC:1390 | ENSG00000151067 | Q13936 | Voltage-dependent L-type calcium channel subunit alpha-1C | gencc,clinvar |
| CACNA2D1 | HGNC:1399 | ENSG00000153956 | P54289 | Voltage-dependent calcium channel subunit alpha-2/delta-1 | gencc,clinvar |
| KCNH2 | HGNC:6251 | ENSG00000055118 | Q12809 | Voltage-gated inwardly rectifying potassium channel KCNH2 | gencc,clinvar |
| KCNJ2 | HGNC:6263 | ENSG00000123700 | P63252 | Inward rectifier potassium channel 2 | gencc,clinvar |
| KCNQ1 | HGNC:6294 | ENSG00000053918 | P51787 | Potassium voltage-gated channel subfamily KQT member 1 | gencc,clinvar |
| SLC22A5 | HGNC:10969 | ENSG00000197375 | O76082 | Organic cation/carnitine transporter 2 | gencc |
| SLC4A3 | HGNC:11029 | ENSG00000114923 | P48751 | Anion exchange protein 3 | gencc |
| VCL | HGNC:12665 | ENSG00000035403 | P18206 | Vinculin | clinvar |
| TRPM4 | HGNC:17993 | ENSG00000130529 | Q8TD43 | Transient receptor potential cation channel subfamily M member 4 | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| CACNA1C | Voltage-dependent L-type calcium channel subunit alpha-1C | Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents. |
| 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. |
| KCNH2 | Voltage-gated inwardly rectifying potassium channel KCNH2 | Pore-forming (alpha) subunit of voltage-gated inwardly rectifying potassium channel. |
| KCNJ2 | Inward rectifier potassium channel 2 | Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. |
| KCNQ1 | Potassium voltage-gated channel subfamily KQT member 1 | Pore-forming subunit of the voltage-gated potassium (Kv) channel involved in the regulation of cardiomyocyte excitability and important in normal development and functions of myocardium, inner ear, stomach and colon. |
| SLC22A5 | Organic cation/carnitine transporter 2 | Sodium-ion dependent, high affinity carnitine transporter. |
| SLC4A3 | Anion exchange protein 3 | Sodium-independent anion exchanger which mediates the electroneutral exchange of chloride for bicarbonate ions across the cell membrane. |
| VCL | Vinculin | Actin filament (F-actin)-binding protein involved in cell-matrix adhesion and cell-cell adhesion. |
| TRPM4 | Transient receptor potential cation channel subfamily M member 4 | Calcium-activated selective cation channel that mediates membrane depolarization. |
Protein-family classification
Druggable: 6 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.67
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 | 5 | 62.0× | 2e-08 |
| Transporter | 1 | 8.6× | 0.165 |
| Other/Unknown | 3 | 0.6× | 0.955 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| CACNA1C | Ion channel | yes | VDCCAlpha1, VDCC_L_a1su, VDCC_L_a1csu | |
| CACNA2D1 | Other/Unknown | no | VWF_A, VWA_N, VDCC_a2/dsu | |
| KCNH2 | Ion channel | yes | PAS, cNMP-bd_dom, PAS-assoc_C | |
| KCNJ2 | Ion channel | yes | K_chnl_inward-rec_Kir2.1, K_chnl_inward-rec_Kir_cyto, K_chnl_inward-rec_Kir_N | |
| KCNQ1 | Ion channel | yes | K_chnl_volt-dep_KCNQ, Ion_trans_dom, K_chnl_volt-dep_KCQN1 | |
| SLC22A5 | Transporter | yes | Orgcat_transp/SVOP, MFS_sugar_transport-like, Sugar_transporter_CS | |
| SLC4A3 | Other/Unknown | no | Anion_exchange, Anion_exchange_3, HCO3_transpt_euk | |
| VCL | Other/Unknown | no | Vinculin_CS, Vinculin/catenin, Vinculin | |
| TRPM4 | Ion channel | yes | Ion_trans_dom, TRPM_SLOG, TRPM |
Expression context
Cohort genes with no expression data: 0.
9 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) | 9 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| apex of heart | 4 |
| skeletal muscle tissue of rectus abdominis | 2 |
| cardiac atrium | 2 |
| right atrium auricular region | 2 |
| mucosa of transverse colon | 2 |
| muscle layer of sigmoid colon | 1 |
| right coronary artery | 1 |
| biceps brachii | 1 |
| skeletal muscle tissue of biceps brachii | 1 |
| dorsal motor nucleus of vagus nerve | 1 |
| inferior vagus X ganglion | 1 |
| left adrenal gland | 1 |
| left adrenal gland cortex | 1 |
| right adrenal gland cortex | 1 |
| gastrocnemius | 1 |
| muscle of leg | 1 |
| blood vessel layer | 1 |
| saphenous vein | 1 |
| urethra | 1 |
| rectum | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| CACNA1C | 134 | broad | marker | apex of heart, right coronary artery, muscle layer of sigmoid colon |
| CACNA2D1 | 261 | ubiquitous | marker | biceps brachii, skeletal muscle tissue of biceps brachii, skeletal muscle tissue of rectus abdominis |
| KCNH2 | 211 | broad | marker | apex of heart, right atrium auricular region, cardiac atrium |
| KCNJ2 | 256 | ubiquitous | marker | inferior vagus X ganglion, skeletal muscle tissue of rectus abdominis, dorsal motor nucleus of vagus nerve |
| KCNQ1 | 132 | broad | marker | left adrenal gland cortex, left adrenal gland, right adrenal gland cortex |
| SLC22A5 | 235 | ubiquitous | marker | gastrocnemius, mucosa of transverse colon, muscle of leg |
| SLC4A3 | 203 | ubiquitous | marker | apex of heart, right atrium auricular region, cardiac atrium |
| VCL | 300 | ubiquitous | marker | saphenous vein, blood vessel layer, urethra |
| TRPM4 | 201 | ubiquitous | marker | mucosa of transverse colon, rectum, apex of heart |
Protein interactions among cohort
Intra-cohort edges: 3.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| VCL | 4,495 |
| KCNQ1 | 3,235 |
| CACNA1C | 3,145 |
| CACNA2D1 | 2,002 |
| KCNH2 | 1,932 |
| SLC22A5 | 1,492 |
| TRPM4 | 1,217 |
| SLC4A3 | 859 |
| KCNJ2 | 65 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| CACNA1C | CACNA2D1 | intact, string_interaction |
| CACNA1C | KCNH2 | string_interaction |
| KCNH2 | KCNQ1 | string_interaction |
Structural data
PDB: 9 · AlphaFold-only: 0 · No structure: 0
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| VCL | P18206 | 37 |
| CACNA1C | Q13936 | 33 |
| CACNA2D1 | P54289 | 30 |
| TRPM4 | Q8TD43 | 29 |
| KCNQ1 | P51787 | 28 |
| KCNH2 | Q12809 | 24 |
| SLC4A3 | P48751 | 4 |
| KCNJ2 | P63252 | 3 |
| SLC22A5 | O76082 | 3 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 65. Enrichment computed across 9 evidence-associated genes (9 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 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| Cardiac conduction | 4 | 48.3× | 5e-05 | CACNA1C, KCNH2, KCNJ2, KCNQ1 |
| Muscle contraction | 4 | 34.3× | 1e-04 | CACNA1C, KCNH2, KCNJ2, KCNQ1 |
| Phase 3 - rapid repolarisation | 2 | 253.8× | 5e-04 | KCNH2, KCNQ1 |
| Potassium Channels | 3 | 44.8× | 5e-04 | KCNH2, KCNJ2, KCNQ1 |
| Phase 2 - plateau phase | 2 | 169.2× | 7e-04 | CACNA1C, KCNQ1 |
| Voltage gated Potassium channels | 2 | 54.0× | 0.006 | KCNH2, KCNQ1 |
| Neuronal System | 3 | 14.8× | 0.008 | KCNH2, KCNJ2, KCNQ1 |
| Defective SLC22A5 causes systemic primary carnitine deficiency (CDSP) | 1 | 634.4× | 0.011 | SLC22A5 |
| Sensory perception of sour taste | 1 | 634.4× | 0.011 | KCNJ2 |
| Classical Kir channels | 1 | 317.2× | 0.020 | KCNJ2 |
| G protein gated Potassium channels | 1 | 126.9× | 0.043 | KCNJ2 |
| Bicarbonate transporters | 1 | 126.9× | 0.043 | SLC4A3 |
| Regulation of CDH1 Function | 1 | 105.7× | 0.044 | VCL |
| SLC-mediated transmembrane transport | 2 | 13.2× | 0.044 | SLC22A5, SLC4A3 |
| Carnitine shuttle | 1 | 84.6× | 0.045 | SLC22A5 |
| SLC-mediated transport of organic cations | 1 | 84.6× | 0.045 | SLC22A5 |
| R-HSA-549132 | 1 | 84.6× | 0.045 | SLC22A5 |
| Inwardly rectifying K+ channels | 1 | 79.3× | 0.045 | KCNJ2 |
| Mechanical load activates signaling by PIEZO1 and integrins in osteocytes | 1 | 74.6× | 0.046 | CACNA2D1 |
| Phase 4 - resting membrane potential | 1 | 66.8× | 0.046 | KCNJ2 |
| Activation of GABAB receptors | 1 | 66.8× | 0.046 | KCNJ2 |
| GABA B receptor activation | 1 | 60.4× | 0.049 | KCNJ2 |
| TRP channels | 1 | 45.3× | 0.057 | TRPM4 |
| Activation of G protein gated Potassium channels | 1 | 43.8× | 0.057 | KCNJ2 |
| Adrenaline,noradrenaline inhibits insulin secretion | 1 | 43.8× | 0.057 | CACNA1C |
| Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits | 1 | 43.8× | 0.057 | KCNJ2 |
| Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells | 1 | 39.6× | 0.057 | VCL |
| Phase 0 - rapid depolarisation | 1 | 38.5× | 0.057 | CACNA1C |
| Sensory perception of taste | 1 | 37.3× | 0.057 | KCNJ2 |
| Signaling by high-kinase activity BRAF mutants | 1 | 35.2× | 0.057 | VCL |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 9 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 | 6 | 249.7× | 3e-12 | CACNA1C, CACNA2D1, KCNH2, KCNJ2, KCNQ1, TRPM4 |
| membrane repolarization during action potential | 3 | 561.7× | 6e-07 | KCNH2, KCNJ2, KCNQ1 |
| membrane repolarization during cardiac muscle cell action potential | 3 | 561.7× | 6e-07 | KCNH2, KCNJ2, KCNQ1 |
| regulation of membrane repolarization | 3 | 432.1× | 1e-06 | KCNH2, KCNJ2, KCNQ1 |
| positive regulation of potassium ion transmembrane transport | 3 | 330.4× | 2e-06 | KCNH2, KCNJ2, KCNQ1 |
| regulation of ventricular cardiac muscle cell membrane repolarization | 3 | 280.9× | 3e-06 | CACNA2D1, KCNH2, KCNQ1 |
| cardiac muscle cell action potential involved in contraction | 3 | 234.1× | 4e-06 | CACNA1C, CACNA2D1, KCNJ2 |
| calcium ion transmembrane transport via high voltage-gated calcium channel | 2 | 1248.3× | 1e-05 | CACNA1C, CACNA2D1 |
| membrane depolarization during bundle of His cell action potential | 2 | 1248.3× | 1e-05 | CACNA2D1, TRPM4 |
| potassium ion import across plasma membrane | 3 | 122.1× | 2e-05 | KCNH2, KCNJ2, KCNQ1 |
| membrane depolarization during AV node cell action potential | 2 | 749.0× | 3e-05 | CACNA1C, TRPM4 |
| cardiac conduction | 2 | 374.5× | 1e-04 | CACNA1C, SLC4A3 |
| membrane repolarization during ventricular cardiac muscle cell action potential | 2 | 374.5× | 1e-04 | KCNH2, KCNQ1 |
| membrane depolarization during cardiac muscle cell action potential | 2 | 312.1× | 2e-04 | CACNA1C, KCNJ2 |
| regulation of ventricular cardiac muscle cell action potential | 2 | 312.1× | 2e-04 | CACNA1C, TRPM4 |
| calcium ion transport into cytosol | 2 | 267.5× | 2e-04 | CACNA1C, CACNA2D1 |
| potassium ion export across plasma membrane | 2 | 234.1× | 3e-04 | KCNH2, KCNQ1 |
| potassium ion transmembrane transport | 3 | 45.3× | 3e-04 | KCNH2, KCNJ2, KCNQ1 |
| ventricular cardiac muscle cell action potential | 2 | 220.3× | 3e-04 | KCNH2, KCNQ1 |
| potassium ion homeostasis | 2 | 170.2× | 4e-04 | KCNH2, KCNQ1 |
| positive regulation of heart rate | 2 | 156.0× | 5e-04 | KCNQ1, TRPM4 |
| calcium ion import across plasma membrane | 2 | 120.8× | 8e-04 | CACNA1C, CACNA2D1 |
| cardiac muscle contraction | 2 | 89.2× | 0.001 | KCNH2, KCNQ1 |
| gastrin-induced gastric acid secretion | 1 | 1872.4× | 0.003 | KCNQ1 |
| regulation of skeletal muscle contraction via regulation of action potential | 1 | 1872.4× | 0.003 | KCNJ2 |
| negative regulation of voltage-gated potassium channel activity | 1 | 1872.4× | 0.003 | KCNQ1 |
| positive regulation of atrial cardiac muscle cell action potential | 1 | 1872.4× | 0.003 | TRPM4 |
| positive regulation of regulation of vascular associated smooth muscle cell membrane depolarization | 1 | 1872.4× | 0.003 | TRPM4 |
| regulation of protein localization to adherens junction | 1 | 1872.4× | 0.003 | VCL |
| cellular response to xenobiotic stimulus | 2 | 53.5× | 0.003 | KCNH2, KCNQ1 |
Therapeutics
Drug target analysis
Approved (phase 4): 4 · Phase ≥3: 4 · Phased (≥1): 4 · Undrugged: 5
Druggability breadth: 8 of 9 evidence-associated genes (89%) 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 |
|---|---|
| CACNA1C | REMIFENTANIL |
| CACNA2D1 | PREGABALIN |
| KCNH2 | CETIRIZINE |
| KCNQ1 | AMBRISENTAN |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| KCNH2 | 706 | 4 |
| CACNA1C | 85 | 4 |
| KCNQ1 | 15 | 4 |
| CACNA2D1 | 5 | 4 |
| KCNJ2 | 0 | 0 |
| SLC22A5 | 0 | 0 |
| SLC4A3 | 0 | 0 |
| VCL | 0 | 0 |
| TRPM4 | 0 | 0 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| REMIFENTANIL | 4 | CACNA1C |
| BEPRIDIL | 4 | CACNA1C, KCNH2 |
| CLOTRIMAZOLE | 4 | CACNA1C, KCNH2 |
| PROPIVERINE | 4 | CACNA1C, KCNH2 |
| DIBUCAINE | 4 | CACNA1C, KCNH2 |
| IMIPRAMINE | 4 | CACNA1C, KCNH2 |
| DULOXETINE | 4 | CACNA1C, KCNH2, KCNQ1 |
| QUINIDINE | 4 | CACNA1C, KCNH2 |
| ESTRADIOL | 4 | CACNA1C |
| TOLTERODINE | 4 | CACNA1C, KCNH2, KCNQ1 |
| PIMOZIDE | 4 | CACNA1C, KCNH2 |
| NIMODIPINE | 4 | CACNA1C, CACNA2D1 |
| NICARDIPINE | 4 | CACNA1C, KCNH2 |
| AMLODIPINE | 4 | CACNA1C, KCNH2 |
| VARDENAFIL | 4 | CACNA1C, KCNH2 |
| CLEMASTINE | 4 | CACNA1C, KCNH2 |
| ISRADIPINE | 4 | CACNA1C, KCNH2 |
| TERFENADINE | 4 | CACNA1C, KCNH2 |
| NISOLDIPINE | 4 | CACNA1C, KCNH2 |
| SOLIFENACIN | 4 | CACNA1C, KCNH2, KCNQ1 |
| PINAVERIUM | 4 | CACNA1C |
| SILDENAFIL | 4 | CACNA1C, KCNH2 |
| NIFEDIPINE | 4 | CACNA1C, KCNH2 |
| XANOMELINE | 4 | CACNA1C, KCNH2 |
| DILTIAZEM | 4 | CACNA1C, KCNH2 |
| PRENYLAMINE | 4 | CACNA1C, KCNH2 |
| OLICERIDINE | 4 | CACNA1C, KCNH2 |
| PROPRANOLOL | 4 | CACNA1C, KCNH2 |
| ALVIMOPAN | 4 | CACNA1C, KCNQ1 |
| ASTEMIZOLE | 4 | CACNA1C, KCNH2 |
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 |
| CACNA1C | 575 | Binding:319, Functional:211, Toxicity:26, ADMET:19 |
| KCNQ1 | 179 | Binding:96, Functional:64, ADMET:14, Toxicity:5 |
| SLC22A5 | 97 | Functional:79, ADMET:18 |
| CACNA2D1 | 47 | Binding:45, ADMET:1, Toxicity:1 |
| KCNJ2 | 31 | Binding:23, ADMET:8 |
| TRPM4 | 14 | Binding:13, Functional:1 |
| VCL | 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 |
|---|---|
| CACNA1C | 575 |
| KCNH2 | 4,851 |
| KCNQ1 | 179 |
Pharmacogenomics
Cohort genes with a PharmGKB record: 9; 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) |
|---|---|---|
| REMIFENTANIL | 4 | CACNA1C |
| BEPRIDIL | 4 | CACNA1C, KCNH2 |
| CLOTRIMAZOLE | 4 | CACNA1C, KCNH2 |
| PROPIVERINE | 4 | CACNA1C, KCNH2 |
| DIBUCAINE | 4 | CACNA1C, KCNH2 |
| IMIPRAMINE | 4 | CACNA1C, KCNH2 |
| DULOXETINE | 4 | CACNA1C, KCNH2, KCNQ1 |
| QUINIDINE | 4 | CACNA1C, KCNH2 |
| ESTRADIOL | 4 | CACNA1C |
| TOLTERODINE | 4 | CACNA1C, KCNH2, KCNQ1 |
| PIMOZIDE | 4 | CACNA1C, KCNH2 |
| NIMODIPINE | 4 | CACNA1C, CACNA2D1 |
| NICARDIPINE | 4 | CACNA1C, KCNH2 |
| AMLODIPINE | 4 | CACNA1C, KCNH2 |
| VARDENAFIL | 4 | CACNA1C, KCNH2 |
| CLEMASTINE | 4 | CACNA1C, KCNH2 |
| ISRADIPINE | 4 | CACNA1C, KCNH2 |
| TERFENADINE | 4 | CACNA1C, KCNH2 |
| NISOLDIPINE | 4 | CACNA1C, KCNH2 |
| SOLIFENACIN | 4 | CACNA1C, KCNH2, KCNQ1 |
| PINAVERIUM | 4 | CACNA1C |
| SILDENAFIL | 4 | CACNA1C, KCNH2 |
| NIFEDIPINE | 4 | CACNA1C, KCNH2 |
| XANOMELINE | 4 | CACNA1C, KCNH2 |
| DILTIAZEM | 4 | CACNA1C, KCNH2 |
| PRENYLAMINE | 4 | CACNA1C, KCNH2 |
| OLICERIDINE | 4 | CACNA1C, KCNH2 |
| PROPRANOLOL | 4 | CACNA1C, KCNH2 |
| ALVIMOPAN | 4 | CACNA1C, KCNQ1 |
| ASTEMIZOLE | 4 | CACNA1C, KCNH2 |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 4 | CACNA1C, CACNA2D1, KCNH2, KCNQ1 |
| B | Phased (≥1) drug, not yet approved | 0 | |
| C | Druggable family + PDB, no drug | 3 | KCNJ2, SLC22A5, TRPM4 |
| D | Druggable family + AlphaFold only, no drug | 0 | |
| E | Difficult family or no structure, no drug | 2 | SLC4A3, VCL |
Undrugged target profiles
5 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| KCNJ2 | 31 | — |
| SLC22A5 | 97 | — |
| SLC4A3 | 0 | — |
| VCL | 2 | — |
| TRPM4 | 14 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 1.
Phase distribution (across all retrieved trials)
| Phase | Trials |
|---|---|
| Not specified | 1 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT06546137 | Not specified | RECRUITING | National Network for Cardiovascular Genomics: Advancing Cardiovascular Healthcare for Hereditary Diseases in Brazil’s Unified Health System Through a Multicenter Registry |