dilated cardiomyopathy 1S

Summary

dilated cardiomyopathy 1S (MONDO:0013262) is a disease caused by MYH7 (GenCC Definitive), with 18 cohort genes. The dominant Reactome pathway is Striated Muscle Contraction (5 cohort genes).

At a glance

• Causal gene: MYH7 (GenCC Definitive)
• Cohort genes: 18
• ClinVar variants: 453

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	dilated cardiomyopathy 1S
Mondo ID	MONDO:0013262
MeSH	C563538
OMIM	613426
DOID	DOID:0110454
UMLS	C1834481
MedGen	371831
GARD	0012832
Is cancer (heuristic)	no

Also known as: cardiomyopathy, dilated, 1S · cardiomyopathy, dilated, type 1S · CMD1S · dilated cardiomyopathy type 1S · dilated cardiomyopathy-1S · familial isolated dilated cardiomyopathy caused by mutation in MYH7 · left ventricular noncompaction 5 · MYH7 familial isolated dilated cardiomyopathy

Data availability: 453 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › intrinsic cardiomyopathy › left ventricular noncompaction › dilated cardiomyopathy 1S

Related subtypes (12): dilated cardiomyopathy 1C, dilated cardiomyopathy 1D, left ventricular noncompaction 1, left ventricular noncompaction 2, dilated cardiomyopathy 1Y, dilated cardiomyopathy 1R, left ventricular noncompaction 7, left ventricular noncompaction 8, left ventricular noncompaction 10, left ventricular noncompaction 9, left ventricular noncompaction 4, left ventricular noncompaction 5

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

453 retrieved; paginated sample, class counts are floors:

210 uncertain significance, 104 conflicting classifications of pathogenicity, 33 likely pathogenic, 27 pathogenic, 23 benign, 22 likely benign, 21 pathogenic/likely pathogenic, 13 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
265817	NM_001927.4(DES):c.493_520delinsGCGT (p.Gln165_Ala174delinsAlaSer)	DES	Pathogenic	no assertion criteria provided
66908	NM_170707.4(LMNA):c.568C>T (p.Arg190Trp)	LMNA	Pathogenic	criteria provided, multiple submitters, no conflicts
66955	NM_170707.4(LMNA):c.908_909del (p.Ser303fs)	LMNA	Pathogenic	criteria provided, multiple submitters, no conflicts
36642	NM_000257.4(MYH7):c.5135G>A (p.Arg1712Gln)	LOC126861897	Pathogenic	reviewed by expert panel
14109	NM_000257.4(MYH7):c.2292C>G (p.Phe764Leu)	LOC126861898	Pathogenic	criteria provided, single submitter
14120	NM_000257.4(MYH7):c.2609G>A (p.Arg870His)	LOC126861898	Pathogenic	reviewed by expert panel
164324	NM_000257.4(MYH7):c.2572C>T (p.Arg858Cys)	LOC126861898	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
42910	NM_000257.4(MYH7):c.2513C>T (p.Pro838Leu)	LOC126861898	Pathogenic	reviewed by expert panel
42921	NM_000257.4(MYH7):c.2644C>G (p.Gln882Glu)	LOC126861898	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
164284	NM_000257.4(MYH7):c.4498C>T (p.Arg1500Trp)	MHRT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2671917	NM_000257.4(MYH7):c.4309G>C (p.Ala1437Pro)	MHRT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
132914	NM_000257.4(MYH7):c.2163-1G>A	MYH7	Pathogenic	criteria provided, single submitter
132925	NM_000257.4(MYH7):c.1573G>A (p.Glu525Lys)	MYH7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14087	NM_000257.4(MYH7):c.1208G>A (p.Arg403Gln)	MYH7	Pathogenic	reviewed by expert panel
14088	NM_000257.4(MYH7):c.746G>A (p.Arg249Gln)	MYH7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14091	NM_000257.4(MYH7):c.1816G>A (p.Val606Met)	MYH7	Pathogenic	criteria provided, multiple submitters, no conflicts
14092	NM_000257.4(MYH7):c.2770G>A (p.Glu924Lys)	MYH7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14095	NM_000257.4(MYH7):c.2167C>T (p.Arg723Cys)	MYH7	Pathogenic	reviewed by expert panel
14098	NM_000257.4(MYH7):c.2221G>C (p.Gly741Arg)	MYH7	Pathogenic	reviewed by expert panel
14102	NM_000257.4(MYH7):c.1207C>T (p.Arg403Trp)	MYH7	Pathogenic	reviewed by expert panel
14104	NM_000257.4(MYH7):c.2155C>T (p.Arg719Trp)	MYH7	Pathogenic	reviewed by expert panel
14108	NM_000257.4(MYH7):c.1594T>C (p.Ser532Pro)	MYH7	Pathogenic	reviewed by expert panel
14124	NM_000257.4(MYH7):c.1491G>T (p.Glu497Asp)	MYH7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14125	NM_000257.4(MYH7):c.2717A>G (p.Asp906Gly)	MYH7	Pathogenic	reviewed by expert panel
14127	NM_000257.4(MYH7):c.732+1G>A	MYH7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143218	NM_000257.4(MYH7):c.5378_5380del (p.Leu1793del)	MYH7	Pathogenic	no assertion criteria provided
155814	NM_000257.4(MYH7):c.3158G>A (p.Arg1053Gln)	MYH7	Pathogenic	reviewed by expert panel
161328	NM_000257.4(MYH7):c.958G>A (p.Val320Met)	MYH7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
164294	NM_000257.4(MYH7):c.4066G>A (p.Glu1356Lys)	MYH7	Pathogenic	reviewed by expert panel
164312	NM_000257.4(MYH7):c.2788G>C (p.Glu930Gln)	MYH7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 20 · Orphanet: 72 · 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
MYH7	Definitive	Autosomal dominant	hypertrophic cardiomyopathy 1	20

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MYH7	Orphanet:154	Familial isolated dilated cardiomyopathy
MYH7	Orphanet:1880	Ebstein malformation of the tricuspid valve
MYH7	Orphanet:324604	Classic multiminicore myopathy
MYH7	Orphanet:54260	Left ventricular noncompaction
MYH7	Orphanet:59135	Laing distal myopathy
MYH7	Orphanet:636965	Autosomal dominant myosin storage myopathy
MYH7	Orphanet:636970	Autosomal recessive myosin storage myopathy
TNNC1	Orphanet:154	Familial isolated dilated cardiomyopathy
TNNT2	Orphanet:154	Familial isolated dilated cardiomyopathy
TNNT2	Orphanet:54260	Left ventricular noncompaction
TNNT2	Orphanet:75249	Familial isolated restrictive cardiomyopathy
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
VCL	Orphanet:154	Familial isolated dilated cardiomyopathy
RBM20	Orphanet:154	Familial isolated dilated cardiomyopathy
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
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
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

Cohort genes → proteins

18 cohort genes, 14 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	18

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MYH7	HGNC:7577	ENSG00000092054	P12883	Myosin-7	gencc,clinvar
TNNC1	HGNC:11943	ENSG00000114854	P63316	Troponin C, slow skeletal and cardiac muscles	clinvar
TNNT2	HGNC:11949	ENSG00000118194	P45379	Troponin T, cardiac muscle	clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	clinvar
VCL	HGNC:12665	ENSG00000035403	P18206	Vinculin	clinvar
RBM20	HGNC:27424	ENSG00000203867	Q5T481	RNA-binding protein 20	clinvar
DES	HGNC:2770	ENSG00000175084	P17661	Desmin	clinvar
NEXN	HGNC:29557	ENSG00000162614	Q0ZGT2	Nexilin	clinvar
DSC2	HGNC:3036	ENSG00000134755	Q02487	Desmocollin-2	clinvar
DSC3	HGNC:3037	ENSG00000134762	Q14574	Desmocollin-3	clinvar
DSP	HGNC:3052	ENSG00000096696	P15924	Desmoplakin	clinvar
LAMA4-AS1	HGNC:40333	ENSG00000226440		LAMA4 antisense RNA 1	clinvar
TTN-AS1	HGNC:44124	ENSG00000237298		TTN antisense RNA 1	clinvar
MHRT	HGNC:51291			myosin heavy chain associated RNA transcript	clinvar
DSP-AS1	HGNC:56039	ENSG00000261189		DSP antisense RNA 1	clinvar
LMNA	HGNC:6636	ENSG00000160789	P02545	Prelamin-A/C	clinvar
MYL2	HGNC:7583	ENSG00000111245	P10916	Myosin regulatory light chain 2, ventricular/cardiac muscle isoform	clinvar
PKP2	HGNC:9024	ENSG00000057294	Q99959	Plakophilin-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYH7	Myosin-7	Myosins are actin-based motor molecules with ATPase activity essential for muscle contraction.
TNNC1	Troponin C, slow skeletal and cardiac muscles	Troponin is the central regulatory protein of striated muscle contraction.
TNNT2	Troponin T, cardiac muscle	Troponin T is the tropomyosin-binding subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
VCL	Vinculin	Actin filament (F-actin)-binding protein involved in cell-matrix adhesion and cell-cell adhesion.
RBM20	RNA-binding protein 20	RNA-binding protein that acts as a regulator of mRNA splicing of a subset of genes encoding key structural proteins involved in cardiac development, such as TTN (Titin), CACNA1C, CAMK2D or PDLIM5/ENH.
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.
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.
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.
MYL2	Myosin regulatory light chain 2, ventricular/cardiac muscle isoform	Contractile protein that plays a role in heart development and function.
PKP2	Plakophilin-2	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.

Protein-family classification

Druggable: 2 · Difficult: 3 · Unknown: 13 · Druggable fraction: 0.11

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
Scaffold/PPI	2	1.9×	0.605
Antibody/Immunoglobulin	1	1.6×	0.605
Kinase	1	1.5×	0.605
Other/Unknown	13	1.3×	0.605
Transcription factor	1	0.5×	0.902

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MYH7	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail
TNNC1	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
TNNT2	Other/Unknown	no		Troponin, TNNT, Troponin_sf
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
VCL	Other/Unknown	no		Vinculin_CS, Vinculin/catenin, Vinculin
RBM20	Transcription factor	no		RRM_dom, Matrin/U1-C_Znf_C2H2, Matrin/U1-like-C_Znf_C2H2
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
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
DSP	Scaffold/PPI	no		Plectin_repeat, SH3_domain, Spectrin/alpha-actinin
LAMA4-AS1	Other/Unknown	no
TTN-AS1	Other/Unknown	no
MHRT	Other/Unknown	no
DSP-AS1	Other/Unknown	no
LMNA	Other/Unknown	no		Lamin_tail_dom, IF_conserved, Lamin_tail_dom_sf
MYL2	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
PKP2	Other/Unknown	no		Armadillo, ARM-like, ARM-type_fold

Expression context

Cohort genes with no expression data: 1.

16 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)	17
unknown	1

Top tissues across cohort

Tissue	Cohort genes
apex of heart	6
heart right ventricle	3
right atrium auricular region	3
left ventricle myocardium	3
hindlimb stylopod muscle	2
skeletal muscle tissue of biceps brachii	2
gluteal muscle	2
saphenous vein	2
myocardium	2
gastrocnemius	2
gingiva	2
gingival epithelium	2
upper leg skin	2
triceps brachii	1
cardiac atrium	1
biceps brachii	1
blood vessel layer	1
urethra	1
cardiac muscle of right atrium	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYH7	167	tissue_specific	marker	apex of heart, hindlimb stylopod muscle, skeletal muscle tissue of biceps brachii
TNNC1	207	broad	marker	triceps brachii, gluteal muscle, heart right ventricle
TNNT2	154	broad	marker	apex of heart, right atrium auricular region, cardiac atrium
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
VCL	300	ubiquitous	marker	saphenous vein, blood vessel layer, urethra
RBM20	191	broad	marker	left ventricle myocardium, cardiac muscle of right atrium, myocardium
DES	280	broad	marker	apex of heart, saphenous vein, gastrocnemius
NEXN	229	ubiquitous	marker	left ventricle myocardium, skeletal muscle tissue of rectus abdominis, myocardium
DSC2	256	ubiquitous	marker	gingival epithelium, gingiva, oral cavity
DSC3	177	broad	marker	upper leg skin, gingival epithelium, gingiva
DSP	253	ubiquitous	marker	skin of hip, upper leg skin, hair follicle
LAMA4-AS1	153		yes	lower esophagus muscularis layer, lower esophagus, esophagogastric junction muscularis propria
TTN-AS1	174	ubiquitous	marker	hindlimb stylopod muscle, gastrocnemius, right atrium auricular region
MHRT
DSP-AS1	162		marker	male germ line stem cell (sensu Vertebrata) in testis, apex of heart, right atrium auricular region
LMNA	295	ubiquitous	marker	nipple, mucosa of stomach, skin of abdomen
MYL2	179	tissue_specific	marker	heart right ventricle, diaphragm, apex of heart
PKP2	237	ubiquitous	marker	heart right ventricle, apex of heart, left ventricle myocardium

Protein interactions among cohort

Intra-cohort edges: 19.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LMNA	7,173
VCL	4,495
TTN	4,237
MYL2	3,119
DSP	2,897
MYH7	2,744
DES	2,486
TNNT2	1,944
PKP2	1,861
DSC2	1,659

Intra-cohort edges

A	B	Sources
DES	DSP	string_interaction
DSC2	DSP	string_interaction
DSC2	LMNA	string_interaction
DSC2	PKP2	string_interaction
DSC3	DSP	string_interaction
DSC3	PKP2	string_interaction
DSP	PKP2	string_interaction
LMNA	PKP2	string_interaction
MYH7	MYL2	string_interaction
MYH7	NEXN	string_interaction
MYH7	RBM20	string_interaction
MYH7	TNNT2	string_interaction
MYH7	TTN	string_interaction
MYL2	TNNT2	string_interaction
NEXN	RBM20	string_interaction
NEXN	VCL	string_interaction
RBM20	TNNT2	string_interaction
RBM20	TTN	string_interaction
TNNC1	TNNT2	intact

Structural data

PDB: 10 · AlphaFold-only: 4 · No structure: 4

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTN	Q8WZ42	64
TNNC1	P63316	61
MYH7	P12883	43
VCL	P18206	37
LMNA	P02545	28
TNNT2	P45379	25
DSP	P15924	4
DSC2	Q02487	3
MYL2	P10916	3
PKP2	Q99959	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DES	P17661	77.73
DSC3	Q14574	75.53
NEXN	Q0ZGT2	70.78
RBM20	Q5T481	48.52

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 36. Enrichment computed across 18 evidence-associated genes (11 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 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Striated Muscle Contraction	5	140.3×	4e-09	TNNC1, TNNT2, TTN, DES, MYL2
Formation of the cornified envelope	4	31.9×	9e-05	DSC2, DSC3, DSP, PKP2
Keratinization	4	20.3×	4e-04	DSC2, DSC3, DSP, PKP2
Signaling by BRAF and RAF1 fusions	2	31.0×	0.016	VCL, LMNA
Breakdown of the nuclear lamina	1	346.1×	0.021	LMNA
Platelet degranulation	2	16.0×	0.040	TTN, VCL
Apoptotic cleavage of cell adhesion proteins	1	94.4×	0.052	DSP
Regulation of CDH1 Function	1	86.5×	0.052	VCL
Depolymerization of the Nuclear Lamina	1	69.2×	0.057	LMNA
Initiation of Nuclear Envelope (NE) Reformation	1	54.6×	0.063	LMNA
IRE1alpha activates chaperones	1	47.2×	0.063	LMNA
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	47.2×	0.063	LMNA
Nuclear Envelope Breakdown	1	41.5×	0.063	LMNA
Unfolded Protein Response (UPR)	1	32.4×	0.063	LMNA
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	32.4×	0.063	VCL
Signaling by high-kinase activity BRAF mutants	1	28.8×	0.063	VCL
MAP2K and MAPK activation	1	25.9×	0.063	VCL
Signaling by RAF1 mutants	1	25.3×	0.063	VCL
Smooth Muscle Contraction	1	24.1×	0.063	VCL
RND1 GTPase cycle	1	24.1×	0.063	DSP
RND3 GTPase cycle	1	23.6×	0.063	DSP
Signaling by moderate kinase activity BRAF mutants	1	23.1×	0.063	VCL
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	23.1×	0.063	VCL
Signaling downstream of RAS mutants	1	23.1×	0.063	VCL
Oncogenic MAPK signaling	1	22.6×	0.063	LMNA
XBP1(S) activates chaperone genes	1	19.6×	0.069	LMNA
Activation of STAT3 by cadherin engagement	1	14.8×	0.085	VCL
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	14.6×	0.085	VCL
Signaling by ALK fusions and activated point mutants	1	13.7×	0.088	VCL
Meiotic synapsis	1	12.8×	0.090	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 14 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ventricular cardiac muscle tissue morphogenesis	5	250.8×	9e-10	MYH7, TNNC1, TNNT2, MYL2, PKP2
cardiac muscle contraction	5	143.3×	9e-09	MYH7, TNNC1, TNNT2, TTN, MYL2
muscle filament sliding	4	300.9×	2e-08	MYH7, TNNC1, TNNT2, TTN
bundle of His cell-Purkinje myocyte adhesion involved in cell communication	3	515.9×	5e-07	DSC2, DSP, PKP2
regulation of ventricular cardiac muscle cell action potential	3	300.9×	3e-06	DSC2, DSP, PKP2
skeletal muscle contraction	3	109.4×	5e-05	MYH7, TNNC1, TTN
regulation of heart rate by cardiac conduction	3	80.2×	1e-04	DSC2, DSP, PKP2
cell-cell adhesion	4	29.0×	1e-04	DSC2, DSC3, DSP, PKP2
transition between fast and slow fiber	2	343.9×	2e-04	MYH7, TNNC1
desmosome organization	2	300.9×	2e-04	DSP, PKP2
regulation of muscle contraction	2	240.7×	3e-04	TNNC1, TNNT2
muscle contraction	3	44.6×	4e-04	MYH7, TTN, DES
cardiac myofibril assembly	2	185.2×	5e-04	TTN, MYL2
epithelial cell-cell adhesion	2	172.0×	5e-04	VCL, DSP
regulation of the force of heart contraction	2	141.6×	7e-04	MYH7, MYL2
nuclear envelope organization	2	141.6×	7e-04	DES, LMNA
striated muscle contraction	2	120.4×	9e-04	MYH7, TTN
homophilic cell-cell adhesion	3	30.1×	9e-04	NEXN, DSC2, DSC3
regulation of heart contraction	2	70.8×	0.002	TNNT2, DES
sarcomere organization	2	54.7×	0.004	TNNT2, TTN
regulation of muscle filament sliding speed	1	1203.7×	0.004	TNNC1
muscle cell fate specification	1	1203.7×	0.004	MYL2
maintenance of protein localization at cell tip	1	1203.7×	0.004	PKP2
regulation of protein localization to adherens junction	1	1203.7×	0.004	VCL
response to calcium ion	2	45.4×	0.004	TNNT2, TTN
intermediate filament organization	2	34.4×	0.007	DES, DSP
regulation of slow-twitch skeletal muscle fiber contraction	1	601.9×	0.008	MYH7
cardiac muscle cell-cardiac muscle cell adhesion	1	601.9×	0.008	DSC2
regulation of cell-substrate adhesion	1	401.2×	0.010	PKP2
regulation of the force of skeletal muscle contraction	1	401.2×	0.010	MYH7

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 16

Druggability breadth: 8 of 18 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
TNNC1	FINGOLIMOD
LMNA	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LMNA	823	4
TNNC1	2	4
MYH7	0	0
TNNT2	0	0
TTN	0	0
VCL	0	0
RBM20	0	0
DES	0	0
NEXN	0	0
DSC2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FINGOLIMOD	4	TNNC1
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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
LMNA	12	Binding:9, Functional:3
TNNC1	8	Binding:8
TNNT2	2	Binding:2
VCL	2	Binding:2
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

Pharmacogenomics

Cohort genes with a PharmGKB record: 14; 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)
FINGOLIMOD	4	TNNC1
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

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	TNNC1, LMNA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	TTN
D	Druggable family + AlphaFold only, no drug	1	NEXN
E	Difficult family or no structure, no drug	14	MYH7, TNNT2, VCL, RBM20, DES, DSC2, DSC3, DSP, LAMA4-AS1, TTN-AS1 (+4 more)

Undrugged target profiles

16 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MYH7	0	—
TNNT2	2	—
TTN	1	—
VCL	2	—
RBM20	0	—
DES	0	—
NEXN	0	—
DSC2	0	—
DSC3	0	—
DSP	2	—
LAMA4-AS1	0	—
TTN-AS1	0	—
MHRT	0	—
DSP-AS1	0	—
MYL2	0	—
PKP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.