Arrhythmogenic right ventricular dysplasia 9
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Also known as arrhythmogenic right ventricular cardiomyopathy 9arrhythmogenic right ventricular dysplasia type 9arrhythmogenic right ventricular dysplasia, familial, 9arrhythmogenic right ventricular dysplasia, familial, type 9ARVC9ARVD9familial isolated arrhythmogenic right ventricular dysplasia caused by mutation in PKP2PKP2 familial isolated arrhythmogenic right ventricular dysplasia
Summary
Arrhythmogenic right ventricular dysplasia 9 (MONDO:0012180) is a disease caused by PKP2 (GenCC Definitive), with 16 cohort genes. The dominant Reactome pathway is Formation of the cornified envelope (5 cohort genes).
At a glance
- Causal gene: PKP2 (GenCC Definitive)
- Cohort genes: 16
- ClinVar variants: 1,639
Clinical features
No curated clinical features (Orphanet) for this disease.
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | arrhythmogenic right ventricular dysplasia 9 |
| Mondo ID | MONDO:0012180 |
| MeSH | C563808 |
| OMIM | 609040 |
| DOID | DOID:0110077 |
| UMLS | C1836906 |
| MedGen | 373205 |
| GARD | 0024852 |
| Is cancer (heuristic) | no |
Also known as: arrhythmogenic right ventricular cardiomyopathy 9 · arrhythmogenic right ventricular dysplasia 9 · arrhythmogenic right ventricular dysplasia type 9 · arrhythmogenic right ventricular dysplasia, familial, 9 · arrhythmogenic right ventricular dysplasia, familial, type 9 · ARVC9 · ARVD9 · familial isolated arrhythmogenic right ventricular dysplasia caused by mutation in PKP2 · PKP2 familial isolated arrhythmogenic right ventricular dysplasia
Data availability: 1,639 ClinVar variants · 2 GenCC gene-disease records · 17 cell lines.
Disease family
Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › familial cardiomyopathy › familial isolated arrhythmogenic right ventricular dysplasia › arrhythmogenic right ventricular dysplasia 9
Related subtypes (15): arrhythmogenic right ventricular dysplasia 13, arrhythmogenic right ventricular dysplasia 1, arrhythmogenic right ventricular dysplasia 3, arrhythmogenic right ventricular dysplasia 4, arrhythmogenic right ventricular dysplasia 5, arrhythmogenic right ventricular dysplasia 6, catecholaminergic polymorphic ventricular tachycardia 1, arrhythmogenic right ventricular dysplasia 8, arrhythmogenic right ventricular dysplasia 10, arrhythmogenic right ventricular dysplasia 11, arrhythmogenic right ventricular dysplasia 12, familial isolated arrhythmogenic ventricular dysplasia, left dominant form, familial isolated arrhythmogenic ventricular dysplasia, biventricular form, familial isolated arrhythmogenic ventricular dysplasia, right dominant form, arrhythmogenic right ventricular dysplasia, familial, 14
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:
230 uncertain significance, 161 likely benign, 74 pathogenic, 72 conflicting classifications of pathogenicity, 25 likely pathogenic, 24 pathogenic/likely pathogenic, 9 benign/likely benign, 5 benign
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 16810 | NM_001943.5(DSG2):c.146G>A (p.Arg49His) | DSG2 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1068825 | NM_001005242.3(PKP2):c.1379-1992C>T | PKP2 | Pathogenic | criteria provided, single submitter |
| 1072271 | NM_001005242.3(PKP2):c.1616_1623dup (p.Val543fs) | PKP2 | Pathogenic | criteria provided, single submitter |
| 1073811 | NM_001005242.3(PKP2):c.379dup (p.Thr127fs) | PKP2 | Pathogenic | criteria provided, single submitter |
| 1074817 | NM_001005242.3(PKP2):c.1217_1379-790inv | PKP2 | Pathogenic | criteria provided, single submitter |
| 1075513 | NC_000012.11:g.(?32949033)(32955500_?)del | PKP2 | Pathogenic | criteria provided, single submitter |
| 1075514 | NC_000012.11:g.(?33030760)(33031986_?)del | PKP2 | Pathogenic | criteria provided, single submitter |
| 1075515 | NC_000012.11:g.(?32945348)(32949242_?)del | PKP2 | Pathogenic | criteria provided, single submitter |
| 1075516 | NC_000012.11:g.(?33021851)(33031976_?)del | PKP2 | Pathogenic | criteria provided, single submitter |
| 1075965 | NM_001005242.3(PKP2):c.582T>A (p.Tyr194Ter) | PKP2 | Pathogenic | criteria provided, single submitter |
| 1076311 | NM_001005242.3(PKP2):c.1127del (p.Phe376fs) | PKP2 | Pathogenic | criteria provided, single submitter |
| 1187686 | NM_001005242.3(PKP2):c.1388G>A (p.Trp463Ter) | PKP2 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1205033 | NM_001005242.3(PKP2):c.1379-2A>G | PKP2 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1297006 | NM_001005242.3(PKP2):c.1368dup (p.Gln457fs) | PKP2 | Pathogenic | criteria provided, single submitter |
| 1321424 | NM_001005242.3(PKP2):c.2044C>T (p.Gln682Ter) | PKP2 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1342294 | NM_001005242.3(PKP2):c.962_965del (p.Val321fs) | PKP2 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 1344540 | NM_001005242.3(PKP2):c.336+1G>T | PKP2 | Pathogenic | criteria provided, single submitter |
| 1354302 | NM_001005242.3(PKP2):c.1738G>T (p.Glu580Ter) | PKP2 | Pathogenic | criteria provided, single submitter |
| 1358209 | NM_001005242.3(PKP2):c.329dup (p.Met110fs) | PKP2 | Pathogenic | criteria provided, single submitter |
| 1369432 | NM_001005242.3(PKP2):c.2408_2411del (p.Leu803fs) | PKP2 | Pathogenic | criteria provided, single submitter |
| 1372358 | NM_001005242.3(PKP2):c.472_473del (p.Arg158fs) | PKP2 | Pathogenic | criteria provided, single submitter |
| 1380244 | NM_001005242.3(PKP2):c.759_769del (p.Asn254fs) | PKP2 | Pathogenic | criteria provided, single submitter |
| 1394074 | NM_001005242.3(PKP2):c.464dup (p.Ser155fs) | PKP2 | Pathogenic | criteria provided, single submitter |
| 1400125 | NM_001005242.3(PKP2):c.253G>T (p.Glu85Ter) | PKP2 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1412205 | NM_001005242.3(PKP2):c.1750C>T (p.Gln584Ter) | PKP2 | Pathogenic | criteria provided, single submitter |
| 1443926 | NM_001005242.3(PKP2):c.1264_1265del (p.Leu422fs) | PKP2 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1452110 | NM_001005242.3(PKP2):c.1842dup (p.Tyr615fs) | PKP2 | Pathogenic | criteria provided, single submitter |
| 1453476 | NC_000012.11:g.(?33030760)(33049665_?)del | PKP2 | Pathogenic | criteria provided, single submitter |
| 1454572 | NM_001005242.3(PKP2):c.296_300dup (p.Arg101fs) | PKP2 | Pathogenic | criteria provided, single submitter |
| 1455995 | NC_000012.11:g.(?33003680)(33003927_?)del | PKP2 | Pathogenic | criteria provided, single submitter |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 6 · Orphanet: 78 · 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 |
|---|---|---|---|---|
| PKP2 | Definitive | Autosomal dominant | arrhythmogenic right ventricular dysplasia 9 | 6 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| 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 |
| TTN | Orphanet:140922 | Titin-related limb-girdle muscular dystrophy R10 |
| TTN | Orphanet:154 | Familial isolated dilated cardiomyopathy |
| TTN | Orphanet:169186 | Autosomal recessive centronuclear myopathy |
| TTN | Orphanet:178464 | Hereditary myopathy with early respiratory failure |
| TTN | Orphanet:289377 | Early-onset myopathy with fatal cardiomyopathy |
| TTN | Orphanet:293888 | Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant |
| TTN | Orphanet:293899 | Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant |
| TTN | Orphanet:293910 | Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant |
| TTN | Orphanet:324604 | Classic multiminicore myopathy |
| TTN | Orphanet:334 | Hereditary atrial fibrillation |
| TTN | Orphanet:466921 | Childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome |
| TTN | Orphanet:609 | Tibial muscular dystrophy |
| TTN | Orphanet:707983 | Early-onset autosomal recessive TTN-related distal myopathy |
| OBSCN | Orphanet:99845 | Genetic recurrent myoglobinuria |
| DES | Orphanet:154 | Familial isolated dilated cardiomyopathy |
| DES | Orphanet:85146 | Neurogenic scapuloperoneal syndrome, Kaeser type |
| DES | Orphanet:98909 | Desminopathy |
| NEXN | Orphanet:154 | Familial isolated dilated cardiomyopathy |
| DNM1L | Orphanet:330050 | DNM1L-related encephalopathy due to mitochondrial and peroxisomal fission defect |
| DNM1L | Orphanet:98673 | Autosomal dominant optic atrophy, classic form |
| DSC2 | Orphanet:293888 | Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant |
| DSC2 | Orphanet:293899 | Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant |
| DSC2 | Orphanet:293910 | Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant |
| DSC3 | Orphanet:217407 | Hereditary hypotrichosis with recurrent skin vesicles |
| DSG2 | Orphanet:154 | Familial isolated dilated cardiomyopathy |
| DSG2 | Orphanet:293888 | Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant |
| DSG2 | Orphanet:293899 | Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant |
| DSG2 | Orphanet:293910 | Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant |
| 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 |
| DSP | Orphanet:50942 | Striate palmoplantar keratoderma |
| DSP | Orphanet:65282 | Carvajal syndrome |
| 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 |
Cohort genes → proteins
16 cohort genes, 16 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 16 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| PKP2 | HGNC:9024 | ENSG00000057294 | Q99959 | Plakophilin-2 | gencc,clinvar |
| TTN | HGNC:12403 | ENSG00000155657 | Q8WZ42 | Titin | clinvar |
| OBSCN | HGNC:15719 | ENSG00000154358 | Q5VST9 | Obscurin | clinvar |
| DES | HGNC:2770 | ENSG00000175084 | P17661 | Desmin | clinvar |
| NEXN | HGNC:29557 | ENSG00000162614 | Q0ZGT2 | Nexilin | clinvar |
| DNM1L | HGNC:2973 | ENSG00000087470 | O00429 | Dynamin-1-like protein | clinvar |
| DSC2 | HGNC:3036 | ENSG00000134755 | Q02487 | Desmocollin-2 | clinvar |
| DSC3 | HGNC:3037 | ENSG00000134762 | Q14574 | Desmocollin-3 | clinvar |
| DSG2 | HGNC:3049 | ENSG00000046604 | Q14126 | Desmoglein-2 | clinvar |
| DSP | HGNC:3052 | ENSG00000096696 | P15924 | Desmoplakin | clinvar |
| LMNA | HGNC:6636 | ENSG00000160789 | P02545 | Prelamin-A/C | clinvar |
| MYH6 | HGNC:7576 | ENSG00000197616 | P13533 | Myosin-6 | clinvar |
| MYH7 | HGNC:7577 | ENSG00000092054 | P12883 | Myosin-7 | clinvar |
| PLN | HGNC:9080 | ENSG00000198523 | P26678 | Phospholamban | clinvar |
| PPP1R3A | HGNC:9291 | ENSG00000154415 | Q16821 | Protein phosphatase 1 regulatory subunit 3A | clinvar |
| PRKAG2 | HGNC:9386 | ENSG00000106617 | Q9UGJ0 | 5’-AMP-activated protein kinase subunit gamma-2 | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| PKP2 | Plakophilin-2 | A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion. |
| TTN | Titin | Key component in the assembly and functioning of vertebrate striated muscles. |
| OBSCN | Obscurin | Structural component of striated muscles which plays a role in myofibrillogenesis. |
| DES | Desmin | Muscle-specific type III intermediate filament essential for proper muscular structure and function. |
| NEXN | Nexilin | Involved in regulating cell migration through association with the actin cytoskeleton. |
| DNM1L | Dynamin-1-like protein | Functions in mitochondrial and peroxisomal division. |
| DSC2 | Desmocollin-2 | A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion. |
| DSC3 | Desmocollin-3 | A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion. |
| DSG2 | Desmoglein-2 | A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion. |
| DSP | Desmoplakin | A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion. |
| 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. |
| MYH7 | Myosin-7 | Myosins are actin-based motor molecules with ATPase activity essential for muscle contraction. |
| PLN | Phospholamban | Reversibly inhibits the activity of ATP2A2/SERCA2 in cardiac sarcoplasmic reticulum by decreasing the apparent affinity of the ATPase for Ca(2+). |
| PPP1R3A | Protein phosphatase 1 regulatory subunit 3A | Seems to act as a glycogen-targeting subunit for PP1. |
| PRKAG2 | 5’-AMP-activated protein kinase subunit gamma-2 | AMP/ATP-binding subunit of AMP-activated protein kinase (AMPK), an energy sensor protein kinase that plays a key role in regulating cellular energy metabolism. |
Protein-family classification
Druggable: 4 · Difficult: 3 · Unknown: 9 · Druggable fraction: 0.25
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 |
|---|---|---|---|
| Kinase | 2 | 3.5× | 0.279 |
| Scaffold/PPI | 3 | 3.2× | 0.279 |
| Antibody/Immunoglobulin | 1 | 1.8× | 0.713 |
| Other/Unknown | 9 | 1.0× | 0.736 |
| Enzyme (other) | 1 | 0.8× | 0.752 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| PKP2 | Other/Unknown | no | Armadillo, ARM-like, ARM-type_fold | |
| TTN | Kinase | yes | 2.7.11.1 | Prot_kinase_dom, Ig_sub2, Ig_sub |
| OBSCN | Kinase | yes | IQ_motif_EF-hand-BS, DH_dom, Prot_kinase_dom | |
| DES | Other/Unknown | no | Intermed_filament_DNA-bd, IF_conserved, IF_rod_dom | |
| NEXN | Antibody/Immunoglobulin | yes | Ig_sub, Ig-like_dom, Ig_I-set | |
| DNM1L | Enzyme (other) | yes | 3.6.5.5 | Dynamin_stalk, Dynamin_GTPase, GED |
| DSC2 | Other/Unknown | no | Cadherin_Y-type_LIR, Cadherin-like_dom, Desmosomal_cadherin | |
| DSC3 | Other/Unknown | no | Cadherin_Y-type_LIR, Cadherin-like_dom, Desmosomal_cadherin | |
| DSG2 | Other/Unknown | no | Cadherin-like_dom, Desmosomal_cadherin, Cadherin-like_sf | |
| DSP | Scaffold/PPI | no | Plectin_repeat, SH3_domain, Spectrin/alpha-actinin | |
| 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 | |
| MYH7 | Scaffold/PPI | no | IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail | |
| PLN | Other/Unknown | no | PLB | |
| PPP1R3A | Other/Unknown | no | CBM21_dom, CBM21_dom_sf, PP1_regulatory_subunit_3 | |
| PRKAG2 | Other/Unknown | no | CBS_dom, CBS_dom_sf, AMPK_gamma/SDS23_families |
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) | 16 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| apex of heart | 4 |
| left ventricle myocardium | 3 |
| skeletal muscle tissue of biceps brachii | 3 |
| hindlimb stylopod muscle | 3 |
| heart right ventricle | 2 |
| gastrocnemius | 2 |
| myocardium | 2 |
| skeletal muscle tissue of rectus abdominis | 2 |
| gingiva | 2 |
| gingival epithelium | 2 |
| upper leg skin | 2 |
| cardiac atrium | 2 |
| cardiac muscle of right atrium | 2 |
| biceps brachii | 1 |
| gluteal muscle | 1 |
| saphenous vein | 1 |
| lateral nuclear group of thalamus | 1 |
| sperm | 1 |
| substantia nigra pars compacta | 1 |
| oral cavity | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| PKP2 | 237 | ubiquitous | marker | heart right ventricle, apex of heart, left ventricle myocardium |
| TTN | 223 | broad | marker | biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii |
| OBSCN | 197 | ubiquitous | marker | hindlimb stylopod muscle, apex of heart, gastrocnemius |
| DES | 280 | broad | marker | apex of heart, saphenous vein, gastrocnemius |
| NEXN | 229 | ubiquitous | marker | left ventricle myocardium, skeletal muscle tissue of rectus abdominis, myocardium |
| DNM1L | 295 | ubiquitous | marker | lateral nuclear group of thalamus, substantia nigra pars compacta, sperm |
| DSC2 | 256 | ubiquitous | marker | gingival epithelium, gingiva, oral cavity |
| DSC3 | 177 | broad | marker | upper leg skin, gingival epithelium, gingiva |
| DSG2 | 238 | ubiquitous | marker | mucosa of sigmoid colon, colonic mucosa, jejunal mucosa |
| DSP | 253 | ubiquitous | marker | skin of hip, upper leg skin, hair follicle |
| 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 |
| MYH7 | 167 | tissue_specific | marker | apex of heart, hindlimb stylopod muscle, skeletal muscle tissue of biceps brachii |
| PLN | 243 | broad | marker | heart right ventricle, myocardium, left ventricle myocardium |
| PPP1R3A | 79 | tissue_specific | yes | skeletal muscle tissue of rectus abdominis, hindlimb stylopod muscle, skeletal muscle tissue of biceps brachii |
| PRKAG2 | 258 | ubiquitous | marker | right atrium auricular region, cardiac atrium, cardiac muscle of right atrium |
Protein interactions among cohort
Intra-cohort edges: 20.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| LMNA | 7,173 |
| DNM1L | 4,801 |
| TTN | 4,237 |
| PRKAG2 | 3,212 |
| MYH6 | 3,119 |
| DSP | 2,897 |
| MYH7 | 2,744 |
| DES | 2,486 |
| OBSCN | 2,042 |
| DSG2 | 2,033 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| DES | DSP | string_interaction |
| DSC2 | DSG2 | intact, string_interaction |
| DSC2 | DSP | string_interaction |
| DSC2 | LMNA | string_interaction |
| DSC2 | PKP2 | string_interaction |
| DSC3 | DSG2 | intact, string_interaction |
| DSC3 | DSP | string_interaction |
| DSC3 | PKP2 | string_interaction |
| DSC3 | PRKAG2 | intact |
| DSG2 | DSP | string_interaction |
| DSG2 | PKP2 | string_interaction |
| DSP | PKP2 | string_interaction |
| LMNA | PKP2 | string_interaction |
| MYH6 | PLN | string_interaction |
| MYH6 | PRKAG2 | intact |
| MYH6 | TTN | string_interaction |
| MYH7 | NEXN | string_interaction |
| MYH7 | PRKAG2 | intact, string_interaction |
| MYH7 | TTN | string_interaction |
| OBSCN | TTN | biogrid_interaction, intact, string_interaction |
Structural data
PDB: 11 · AlphaFold-only: 5 · No structure: 0
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| TTN | Q8WZ42 | 64 |
| MYH7 | P12883 | 43 |
| LMNA | P02545 | 28 |
| OBSCN | Q5VST9 | 25 |
| DSG2 | Q14126 | 12 |
| DNM1L | O00429 | 11 |
| PLN | P26678 | 7 |
| DSP | P15924 | 4 |
| DSC2 | Q02487 | 3 |
| PKP2 | Q99959 | 1 |
| PPP1R3A | Q16821 | 1 |
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| DES | P17661 | 77.73 |
| DSC3 | Q14574 | 75.53 |
| MYH6 | P13533 | 74.91 |
| NEXN | Q0ZGT2 | 70.78 |
| PRKAG2 | Q9UGJ0 | 67.24 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 67. Enrichment computed across 16 evidence-associated genes (13 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 13 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| Pathway | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| Formation of the cornified envelope | 5 | 33.8× | 1e-05 | PKP2, DSC2, DSC3, DSG2, DSP |
| Keratinization | 5 | 21.4× | 7e-05 | PKP2, DSC2, DSC3, DSG2, DSP |
| Striated Muscle Contraction | 3 | 71.2× | 2e-04 | TTN, DES, MYH6 |
| Apoptotic cleavage of cell adhesion proteins | 2 | 159.7× | 0.001 | DSG2, DSP |
| Breakdown of the nuclear lamina | 1 | 292.8× | 0.046 | LMNA |
| AMPK inhibits chREBP transcriptional activation activity | 1 | 109.8× | 0.095 | PRKAG2 |
| Lipophagy | 1 | 97.6× | 0.095 | PRKAG2 |
| Activation of PPARGC1A (PGC-1alpha) by phosphorylation | 1 | 87.8× | 0.095 | PRKAG2 |
| Carnitine shuttle | 1 | 58.6× | 0.114 | PRKAG2 |
| Depolymerization of the Nuclear Lamina | 1 | 58.6× | 0.114 | LMNA |
| Initiation of Nuclear Envelope (NE) Reformation | 1 | 46.2× | 0.126 | LMNA |
| IRE1alpha activates chaperones | 1 | 39.9× | 0.126 | LMNA |
| Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models | 1 | 39.9× | 0.126 | LMNA |
| Apoptotic execution phase | 1 | 36.6× | 0.126 | DNM1L |
| Nuclear Envelope Breakdown | 1 | 35.1× | 0.126 | LMNA |
| Energy dependent regulation of mTOR by LKB1-AMPK | 1 | 30.3× | 0.133 | PRKAG2 |
| Activation of AMPK downstream of NMDARs | 1 | 29.3× | 0.133 | PRKAG2 |
| Unfolded Protein Response (UPR) | 1 | 27.4× | 0.133 | LMNA |
| Selective autophagy | 1 | 21.4× | 0.147 | PRKAG2 |
| MTOR signalling | 1 | 20.4× | 0.147 | PRKAG2 |
| RND1 GTPase cycle | 1 | 20.4× | 0.147 | DSP |
| RND3 GTPase cycle | 1 | 20.0× | 0.147 | DSP |
| Oncogenic MAPK signaling | 1 | 19.1× | 0.147 | LMNA |
| XBP1(S) activates chaperone genes | 1 | 16.6× | 0.147 | LMNA |
| Ion transport by P-type ATPases | 1 | 16.0× | 0.147 | PLN |
| Post NMDA receptor activation events | 1 | 15.7× | 0.147 | PRKAG2 |
| Ion homeostasis | 1 | 15.7× | 0.147 | PLN |
| AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274) | 1 | 14.9× | 0.147 | PRKAG2 |
| NRAGE signals death through JNK | 1 | 14.2× | 0.147 | OBSCN |
| Activation of NMDA receptors and postsynaptic events | 1 | 14.2× | 0.147 | PRKAG2 |
GO biological processes by enrichment
Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 16 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| bundle of His cell-Purkinje myocyte adhesion involved in cell communication | 4 | 601.9× | 3e-09 | PKP2, DSC2, DSG2, DSP |
| regulation of ventricular cardiac muscle cell action potential | 4 | 351.1× | 2e-08 | PKP2, DSC2, DSG2, DSP |
| desmosome organization | 3 | 395.0× | 2e-06 | PKP2, DSG2, DSP |
| regulation of heart rate by cardiac conduction | 4 | 93.6× | 3e-06 | PKP2, DSC2, DSG2, DSP |
| muscle filament sliding | 3 | 197.5× | 1e-05 | TTN, MYH6, MYH7 |
| cell-cell adhesion | 5 | 31.7× | 1e-05 | PKP2, DSC2, DSC3, DSG2, DSP |
| regulation of the force of heart contraction | 3 | 185.9× | 1e-05 | MYH6, MYH7, PLN |
| striated muscle contraction | 3 | 158.0× | 2e-05 | TTN, MYH6, MYH7 |
| muscle contraction | 4 | 52.0× | 2e-05 | TTN, DES, MYH6, MYH7 |
| ventricular cardiac muscle tissue morphogenesis | 3 | 131.7× | 2e-05 | PKP2, MYH6, MYH7 |
| regulation of heart contraction | 3 | 92.9× | 6e-05 | DES, MYH6, PLN |
| homophilic cell-cell adhesion | 4 | 35.1× | 6e-05 | NEXN, DSC2, DSC3, DSG2 |
| cardiac muscle contraction | 3 | 75.2× | 1e-04 | TTN, MYH6, MYH7 |
| sarcomere organization | 3 | 71.8× | 1e-04 | TTN, OBSCN, MYH6 |
| adult heart development | 2 | 150.5× | 9e-04 | MYH6, MYH7 |
| cardiac muscle hypertrophy in response to stress | 2 | 131.7× | 0.001 | MYH6, MYH7 |
| nuclear envelope organization | 2 | 123.9× | 0.001 | DES, LMNA |
| cardiac muscle cell development | 2 | 78.0× | 0.003 | TTN, MYH6 |
| glycogen metabolic process | 2 | 65.8× | 0.004 | PPP1R3A, PRKAG2 |
| skeletal muscle contraction | 2 | 63.8× | 0.004 | TTN, MYH7 |
| regulation of heart rate | 2 | 58.5× | 0.004 | MYH6, MYH7 |
| ATP metabolic process | 2 | 58.5× | 0.004 | MYH6, MYH7 |
| visceral muscle development | 1 | 1053.2× | 0.006 | MYH6 |
| circadian sleep/wake cycle, sleep | 1 | 1053.2× | 0.006 | PLN |
| adenylate cyclase-activating adrenergic receptor signaling pathway involved in heart process | 1 | 1053.2× | 0.006 | PLN |
| maintenance of protein localization at cell tip | 1 | 1053.2× | 0.006 | PKP2 |
| positive regulation of protein secretion | 2 | 43.0× | 0.006 | TTN, DNM1L |
| Purkinje myocyte development | 1 | 526.6× | 0.009 | DSG2 |
| regulation of slow-twitch skeletal muscle fiber contraction | 1 | 526.6× | 0.009 | MYH7 |
| protein localization to M-band | 1 | 526.6× | 0.009 | OBSCN |
Therapeutics
Drug target analysis
Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 14
Druggability breadth: 7 of 16 evidence-associated genes (44%) 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 |
|---|---|
| LMNA | BEPRIDIL |
| PRKAG2 | ADENOSINE PHOSPHATE |
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| LMNA | 823 | 4 |
| PRKAG2 | 19 | 4 |
| PKP2 | 0 | 0 |
| TTN | 0 | 0 |
| OBSCN | 0 | 0 |
| DES | 0 | 0 |
| NEXN | 0 | 0 |
| DNM1L | 0 | 0 |
| DSC2 | 0 | 0 |
| DSC3 | 0 | 0 |
Drugs targeting cohort genes (top 30)
| Molecule | Max phase | Targets in cohort |
|---|---|---|
| BEPRIDIL | 4 | LMNA |
| PHENYLBUTAZONE | 4 | LMNA |
| CEFOTAXIME SODIUM | 4 | LMNA |
| DIENESTROL | 4 | LMNA |
| IFOSFAMIDE | 4 | LMNA |
| PROGESTERONE | 4 | LMNA |
| CLOTRIMAZOLE | 4 | LMNA |
| DAPSONE | 4 | LMNA |
| AMINOCAPROIC ACID | 4 | LMNA |
| FLUCONAZOLE | 4 | LMNA |
| COLCHICINE | 4 | LMNA |
| NABUMETONE | 4 | LMNA |
| OXAPROZIN | 4 | LMNA |
| BUMETANIDE | 4 | LMNA |
| GLIPIZIDE | 4 | LMNA |
| BROMFENAC | 4 | LMNA |
| ROPIVACAINE | 4 | LMNA |
| TIZANIDINE | 4 | LMNA |
| METAXALONE | 4 | LMNA |
| CARBAMAZEPINE | 4 | LMNA |
| SALMETEROL XINAFOATE | 4 | LMNA |
| AMIODARONE HYDROCHLORIDE | 4 | LMNA |
| METHYL SALICYLATE | 4 | LMNA |
| DIBUCAINE | 4 | LMNA |
| PHENELZINE | 4 | LMNA |
| HYDROCORTISONE ACETATE | 4 | LMNA |
| BRETYLIUM TOSYLATE | 4 | LMNA |
| IMIPRAMINE | 4 | LMNA |
| FURAZOLIDONE | 4 | LMNA |
| DROPERIDOL | 4 | LMNA |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 2.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| PRKAG2 | 266 | Binding:265, Functional:1 |
| LMNA | 12 | Binding:9, Functional:3 |
| DNM1L | 4 | Binding:4 |
| DSP | 2 | Binding:2 |
| TTN | 1 | Binding:1 |
Cohort enzymes (BRENDA EC)
| Symbol | EC numbers | Names |
|---|---|---|
| TTN | 2.7.11.1 | non-specific serine/threonine protein kinase |
| DNM1L | 3.6.5.5 | dynamin GTPase |
Cohort genes with high screening signal
≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.
| Symbol | ChEMBL assays |
|---|---|
| PRKAG2 | 266 |
Pharmacogenomics
Cohort genes with a PharmGKB record: 16; 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 |
| PHENYLBUTAZONE | 4 | LMNA |
| CEFOTAXIME SODIUM | 4 | LMNA |
| DIENESTROL | 4 | LMNA |
| IFOSFAMIDE | 4 | LMNA |
| PROGESTERONE | 4 | LMNA |
| CLOTRIMAZOLE | 4 | LMNA |
| DAPSONE | 4 | LMNA |
| AMINOCAPROIC ACID | 4 | LMNA |
| FLUCONAZOLE | 4 | LMNA |
| COLCHICINE | 4 | LMNA |
| NABUMETONE | 4 | LMNA |
| OXAPROZIN | 4 | LMNA |
| BUMETANIDE | 4 | LMNA |
| GLIPIZIDE | 4 | LMNA |
| BROMFENAC | 4 | LMNA |
| ROPIVACAINE | 4 | LMNA |
| TIZANIDINE | 4 | LMNA |
| METAXALONE | 4 | LMNA |
| CARBAMAZEPINE | 4 | LMNA |
| SALMETEROL XINAFOATE | 4 | LMNA |
| AMIODARONE HYDROCHLORIDE | 4 | LMNA |
| METHYL SALICYLATE | 4 | LMNA |
| DIBUCAINE | 4 | LMNA |
| PHENELZINE | 4 | LMNA |
| HYDROCORTISONE ACETATE | 4 | LMNA |
| BRETYLIUM TOSYLATE | 4 | LMNA |
| IMIPRAMINE | 4 | LMNA |
| FURAZOLIDONE | 4 | LMNA |
| DROPERIDOL | 4 | LMNA |
Druggability pyramid
Cohort genes binned by druggability tier (high → low):
| Tier | Definition | Genes | Symbols |
|---|---|---|---|
| A | Approved (phase 4 drug) | 2 | LMNA, PRKAG2 |
| B | Phased (≥1) drug, not yet approved | 0 | |
| C | Druggable family + PDB, no drug | 3 | TTN, OBSCN, DNM1L |
| D | Druggable family + AlphaFold only, no drug | 1 | NEXN |
| E | Difficult family or no structure, no drug | 10 | PKP2, DES, DSC2, DSC3, DSG2, DSP, MYH6, MYH7, PLN, PPP1R3A |
Undrugged target profiles
14 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).
| Symbol | ChEMBL assays | Drugged partners (top 3) |
|---|---|---|
| PKP2 | 0 | — |
| TTN | 1 | — |
| OBSCN | 0 | — |
| DES | 0 | — |
| NEXN | 0 | — |
| DNM1L | 4 | — |
| DSC2 | 0 | — |
| DSC3 | 0 | — |
| DSG2 | 0 | — |
| DSP | 2 | — |
| MYH6 | 0 | — |
| MYH7 | 0 | — |
| PLN | 0 | — |
| PPP1R3A | 0 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 0.