Hypertrophic cardiomyopathy 2

Summary

Hypertrophic cardiomyopathy 2 (MONDO:0007266) is a disease caused by TNNT2 (GenCC Definitive), with 17 cohort genes. The dominant Reactome pathway is Striated Muscle Contraction (4 cohort genes).

At a glance

• Causal gene: TNNT2 (GenCC Definitive)
• Cohort genes: 17
• ClinVar variants: 823

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypertrophic cardiomyopathy 2
Mondo ID	MONDO:0007266
MeSH	C566171
OMIM	115195
DOID	DOID:0110308
NCIT	C142892
UMLS	C1861864
MedGen	349383
GARD	0024540
Is cancer (heuristic)	no

Also known as: cardiomyopathy, familial hypertrophic, 2 · cardiomyopathy, familial hypertrophic, type 2 · cardiomyopathy, hypertrophic, 2 · CMH2 · familial hypertrophic cardiomyopathy type 2 · hypertrophic cardiomyopathy 2 · hypertrophic cardiomyopathy caused by mutation in TNNT2 · hypertrophic cardiomyopathy type 2 · TNNT2 hypertrophic cardiomyopathy

Data availability: 823 ClinVar variants · 3 GenCC gene-disease records · 6 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › cardiomyopathy › intrinsic cardiomyopathy › hypertrophic cardiomyopathy › familial hypertrophic cardiomyopathy › hypertrophic cardiomyopathy 2

Related subtypes (39): hypertrophic cardiomyopathy 3, hypertrophic cardiomyopathy 4, Beckwith-Wiedemann syndrome, myotonic dystrophy type 1, hypertrophic cardiomyopathy 1, very long chain acyl-CoA dehydrogenase deficiency, multiple acyl-CoA dehydrogenase deficiency, 46,XY complete gonadal dysgenesis, hypertrophic cardiomyopathy 6, dilated cardiomyopathy 1C, hypertrophic cardiomyopathy 25, hypertrophic cardiomyopathy 8, hypertrophic cardiomyopathy 10, long chain 3-hydroxyacyl-CoA dehydrogenase deficiency, cardiomyopathy-hypotonia-lactic acidosis syndrome, hypertrophic cardiomyopathy 11, hypertrophic cardiomyopathy 12, hypertrophic cardiomyopathy 13, hypertrophic cardiomyopathy 14, hypertrophic cardiomyopathy 15, hypertrophic cardiomyopathy 7, hypertrophic cardiomyopathy 9, hypertrophic cardiomyopathy 16, hypertrophic cardiomyopathy 17, hypertrophic cardiomyopathy 18, hypertrophic cardiomyopathy 19, hypertrophic cardiomyopathy 20, hypertrophic cardiomyopathy 21, dilated cardiomyopathy 1KK, hypertrophic cardiomyopathy 26, Noonan syndrome and Noonan-related syndrome, long chain acyl-CoA dehydrogenase deficiency, cardiomyopathy, familial hypertrophic, 28, cardiomyopathy, familial hypertrophic 27, cardiomyopathy, familial hypertrophic, 23, with or without ventricular noncompaction, cardiomyopathy, familial restrictive, 5, cardiomyopathy, familial hypertrophic, 29, with polyglucosan bodies, cardiomyopathy, familial hypertrophic, 30, atrial, cardiomyopathy, familial hypertrophic, 31

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:

234 uncertain significance, 184 likely benign, 74 conflicting classifications of pathogenicity, 34 benign/likely benign, 22 not provided, 18 pathogenic/likely pathogenic, 15 benign, 12 likely pathogenic, 7 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
12408	NM_001276345.2(TNNT2):c.266T>A (p.Ile89Asn)	TNNT2	Pathogenic	criteria provided, multiple submitters, no conflicts
12409	NM_001276345.2(TNNT2):c.305G>A (p.Arg102Gln)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12412	NM_001276345.2(TNNT2):c.358T>A (p.Phe120Ile)	TNNT2	Pathogenic	criteria provided, multiple submitters, no conflicts
12414	NM_001276345.2(TNNT2):c.451C>T (p.Arg151Trp)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12415	NM_001276345.2(TNNT2):c.421C>T (p.Arg141Trp)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
165533	NM_001276345.2(TNNT2):c.851+1G>T	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
165549	NM_001276345.2(TNNT2):c.310C>T (p.Arg104Cys)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
177634	NM_001276345.2(TNNT2):c.566C>T (p.Ser189Phe)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
177644	NM_001276345.2(TNNT2):c.274G>A (p.Gly92Arg)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
177807	NM_001276345.2(TNNT2):c.360T>G (p.Phe120Leu)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
181636	NM_001276345.2(TNNT2):c.891G>A (p.Trp297Ter)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
181649	NM_001276345.2(TNNT2):c.851+1G>C	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2100789	NM_001276345.2(TNNT2):c.321G>C (p.Lys107Asn)	TNNT2	Pathogenic	criteria provided, single submitter
228409	NM_001276345.2(TNNT2):c.547C>T (p.Arg183Trp)	TNNT2	Pathogenic	criteria provided, multiple submitters, no conflicts
2500774	NM_001276345.2(TNNT2):c.310C>A (p.Arg104Ser)	TNNT2	Pathogenic	criteria provided, single submitter
3753583	NM_001276345.2(TNNT2):c.291T>G (p.Phe97Leu)	TNNT2	Pathogenic	criteria provided, single submitter
43626	NM_001276345.2(TNNT2):c.287A>C (p.Asp96Ala)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43627	NM_001276345.2(TNNT2):c.304C>T (p.Arg102Trp)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43629	NM_001276345.2(TNNT2):c.311G>T (p.Arg104Leu)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43636	NM_001276345.2(TNNT2):c.418C>T (p.Arg140Cys)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43637	NM_001276345.2(TNNT2):c.422G>A (p.Arg141Gln)	TNNT2	Pathogenic	criteria provided, multiple submitters, no conflicts
43639	NM_001276345.2(TNNT2):c.430C>G (p.Arg144Gly)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43648	NM_001276345.2(TNNT2):c.508GAG[3] (p.Glu173del)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43649	NM_001276345.2(TNNT2):c.548G>A (p.Arg183Gln)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
43659	NM_001276345.2(TNNT2):c.650AGA[3] (p.Lys220del)	TNNT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1435754	NM_001276345.2(TNNT2):c.283G>A (p.Val95Met)	TNNT2	Likely pathogenic	criteria provided, single submitter
1699339	NM_001276345.2(TNNT2):c.299T>A (p.Ile100Asn)	TNNT2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
177636	NM_001276345.2(TNNT2):c.890G>A (p.Trp297Ter)	TNNT2	Likely pathogenic	reviewed by expert panel
2115456	NM_001276345.2(TNNT2):c.445C>G (p.Arg149Gly)	TNNT2	Likely pathogenic	criteria provided, single submitter
217496	NM_001276345.2(TNNT2):c.662T>C (p.Ile221Thr)	TNNT2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 80 · 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
TNNT2	Definitive	Autosomal dominant	hypertrophic cardiomyopathy 2	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
JPH2	Orphanet:154	Familial isolated dilated cardiomyopathy
ACTC1	Orphanet:154	Familial isolated dilated cardiomyopathy
ACTC1	Orphanet:54260	Left ventricular noncompaction
ACTC1	Orphanet:99103	Atrial septal defect, ostium secundum type
LDB3	Orphanet:154	Familial isolated dilated cardiomyopathy
LDB3	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
LDB3	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
LDB3	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
LDB3	Orphanet:54260	Left ventricular noncompaction
LDB3	Orphanet:98912	Late-onset distal myopathy, Markesbery-Griggs type
ANKRD1	Orphanet:154	Familial isolated dilated cardiomyopathy
MYPN	Orphanet:154	Familial isolated dilated cardiomyopathy
MYPN	Orphanet:171439	Childhood-onset nemaline myopathy
MYPN	Orphanet:171881	Cap myopathy
MYPN	Orphanet:75249	Familial isolated restrictive cardiomyopathy
NEXN	Orphanet:154	Familial isolated dilated cardiomyopathy
GATAD1	Orphanet:154	Familial isolated dilated cardiomyopathy
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
ABCC9	Orphanet:130	Brugada syndrome
ABCC9	Orphanet:1517	Cantú syndrome
ABCC9	Orphanet:154	Familial isolated dilated cardiomyopathy
ABCC9	Orphanet:334	Hereditary atrial fibrillation
LMNA	Orphanet:154	Familial isolated dilated cardiomyopathy

Cohort genes → proteins

17 cohort genes, 16 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	17

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TNNT2	HGNC:11949	ENSG00000118194	P45379	Troponin T, cardiac muscle	gencc,clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	clinvar
VCL	HGNC:12665	ENSG00000035403	P18206	Vinculin	clinvar
JPH2	HGNC:14202	ENSG00000149596	Q9BR39	Junctophilin-2	clinvar
ACTC1	HGNC:143	ENSG00000159251	P68032	Actin, alpha cardiac muscle 1	clinvar
LDB3	HGNC:15710	ENSG00000122367	O75112	LIM domain-binding protein 3	clinvar
ANKRD1	HGNC:15819	ENSG00000148677	Q15327	Ankyrin repeat domain-containing protein 1	clinvar
NEBL	HGNC:16932	ENSG00000078114	O76041	Nebulette	clinvar
MYPN	HGNC:23246	ENSG00000138347	Q86TC9	Myopalladin	clinvar
NEXN	HGNC:29557	ENSG00000162614	Q0ZGT2	Nexilin	clinvar
GATAD1	HGNC:29941	ENSG00000157259	Q8WUU5	GATA zinc finger domain-containing protein 1	clinvar
DSP	HGNC:3052	ENSG00000096696	P15924	Desmoplakin	clinvar
KCNJ8-AS1	HGNC:58193	ENSG00000256615		KCNJ8 antisense RNA 1	clinvar
ABCC9	HGNC:60	ENSG00000069431	O60706	ATP-binding cassette sub-family C member 9	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

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
JPH2	Junctophilin-2	Membrane-binding protein that provides a structural bridge between the plasma membrane and the sarcoplasmic reticulum and is required for normal excitation-contraction coupling in cardiomyocytes.
ACTC1	Actin, alpha cardiac muscle 1	Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.
LDB3	LIM domain-binding protein 3	May function as an adapter in striated muscle to couple protein kinase C-mediated signaling via its LIM domains to the cytoskeleton.
ANKRD1	Ankyrin repeat domain-containing protein 1	May play an important role in endothelial cell activation.
NEBL	Nebulette	Binds to actin and plays an important role in the assembly of the Z-disk.
MYPN	Myopalladin	Component of the sarcomere that tethers together nebulin (skeletal muscle) and nebulette (cardiac muscle) to alpha-actinin, at the Z lines.
NEXN	Nexilin	Involved in regulating cell migration through association with the actin cytoskeleton.
GATAD1	GATA zinc finger domain-containing protein 1	Component of some chromatin complex recruited to chromatin sites methylated ‘Lys-4’ of histone H3 (H3K4me), with a preference for trimethylated form (H3K4me3).
DSP	Desmoplakin	A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.
ABCC9	ATP-binding cassette sub-family C member 9	Subunit of ATP-sensitive potassium channels (KATP).
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.

Protein-family classification

Druggable: 4 · Difficult: 7 · Unknown: 6 · Druggable fraction: 0.24

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	5	5.1×	0.013
Antibody/Immunoglobulin	2	3.4×	0.341
Transporter	1	4.6×	0.395
Kinase	1	1.6×	0.697
Transcription factor	2	1.0×	0.753
Other/Unknown	6	0.6×	0.974

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
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
JPH2	Other/Unknown	no		MORN, Junctophilin
ACTC1	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
LDB3	Transcription factor	no		PDZ, Znf_LIM, Zasp-like_motif
ANKRD1	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf
NEBL	Scaffold/PPI	no		Nebulin_repeat, SH3_domain, Nebulette_SH3
MYPN	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
NEXN	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, Ig_I-set
GATAD1	Transcription factor	no		Znf_GATA, Znf_NHR/GATA, GATAD1
DSP	Scaffold/PPI	no		Plectin_repeat, SH3_domain, Spectrin/alpha-actinin
KCNJ8-AS1	Other/Unknown	no
ABCC9	Transporter	yes		ABCC8/9, ABCC9, ABC_transporter-like_ATP-bd
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

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)	17
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	4
hindlimb stylopod muscle	4
cardiac atrium	3
skeletal muscle tissue of biceps brachii	3
left ventricle myocardium	3
myocardium	3
right atrium auricular region	2
skeletal muscle tissue of rectus abdominis	2
heart right ventricle	2
gastrocnemius	2
biceps brachii	1
gluteal muscle	1
blood vessel layer	1
saphenous vein	1
urethra	1
tibialis anterior	1
cranial nerve II	1
vastus lateralis	1
inferior vagus X ganglion	1
left ovary	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
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
JPH2	173	broad	yes	left ventricle myocardium, skeletal muscle tissue of rectus abdominis, tibialis anterior
ACTC1	224	broad	marker	left ventricle myocardium, heart right ventricle, myocardium
LDB3	247	broad	marker	skeletal muscle tissue of biceps brachii, hindlimb stylopod muscle, apex of heart
ANKRD1	155	ubiquitous	marker	apex of heart, right atrium auricular region, cardiac atrium
NEBL	282	broad	marker	heart right ventricle, myocardium, cranial nerve II
MYPN	116	broad	marker	hindlimb stylopod muscle, gastrocnemius, vastus lateralis
NEXN	229	ubiquitous	marker	left ventricle myocardium, skeletal muscle tissue of rectus abdominis, myocardium
GATAD1	287	ubiquitous	marker	left ovary, right uterine tube, inferior vagus X ganglion
DSP	253	ubiquitous	marker	skin of hip, upper leg skin, hair follicle
KCNJ8-AS1	83		yes	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, small intestine
ABCC9	195	broad	marker	gastrocnemius, muscle of leg, hindlimb stylopod muscle
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

Protein interactions among cohort

Intra-cohort edges: 21.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LMNA	7,173
VCL	4,495
TTN	4,237
MYH6	3,119
DSP	2,897
MYH7	2,744
ANKRD1	2,441
TNNT2	1,944
MYPN	1,764
ABCC9	1,728

Intra-cohort edges

A	B	Sources
ABCC9	LDB3	string_interaction
ABCC9	NEXN	string_interaction
ANKRD1	MYPN	biogrid_interaction, string_interaction
ANKRD1	NEBL	string_interaction
ANKRD1	TTN	biogrid_interaction, string_interaction
GATAD1	MYPN	string_interaction
LDB3	MYH7	string_interaction
LDB3	MYPN	intact
LDB3	NEXN	string_interaction
LDB3	TNNT2	string_interaction
LDB3	TTN	string_interaction
MYH6	TNNT2	string_interaction
MYH6	TTN	string_interaction
MYH7	NEXN	string_interaction
MYH7	TNNT2	string_interaction
MYH7	TTN	string_interaction
MYPN	NEBL	biogrid_interaction, string_interaction
MYPN	TTN	biogrid_interaction, string_interaction
NEBL	TTN	string_interaction
NEBL	VCL	string_interaction
NEXN	VCL	string_interaction

Structural data

PDB: 11 · AlphaFold-only: 5 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TTN	Q8WZ42	64
MYH7	P12883	43
VCL	P18206	37
LMNA	P02545	28
TNNT2	P45379	25
ACTC1	P68032	16
DSP	P15924	4
JPH2	Q9BR39	2
LDB3	O75112	2
NEBL	O76041	1
GATAD1	Q8WUU5	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ANKRD1	Q15327	82.64
ABCC9	O60706	81.72
MYH6	P13533	74.91
NEXN	Q0ZGT2	70.78
MYPN	Q86TC9	52.71

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 60. Enrichment computed across 17 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
Striated Muscle Contraction	4	137.2×	7e-07	TNNT2, TTN, ACTC1, MYH6
Regulation of CDH1 Function	2	211.5×	0.001	VCL, ACTC1
Muscle contraction	3	25.7×	0.003	ACTC1, ABCC9, MYH6
Signaling by BRAF and RAF1 fusions	2	37.9×	0.016	VCL, LMNA
Activation of STAT3 by cadherin engagement	2	36.2×	0.016	VCL, ACTC1
Defective ABCC9 causes CMD10, ATFB12 and Cantu syndrome	1	634.4×	0.016	ABCC9
Breakdown of the nuclear lamina	1	423.0×	0.020	LMNA
ATP sensitive Potassium channels	1	317.2×	0.024	ABCC9
Platelet degranulation	2	19.5×	0.029	TTN, VCL
Apoptotic cleavage of cell adhesion proteins	1	115.3×	0.052	DSP
Depolymerization of the Nuclear Lamina	1	84.6×	0.063	LMNA
Inwardly rectifying K+ channels	1	79.3×	0.063	ABCC9
Initiation of Nuclear Envelope (NE) Reformation	1	66.8×	0.069	LMNA
IRE1alpha activates chaperones	1	57.7×	0.069	LMNA
Deregulated CDK5 triggers multiple neurodegenerative pathways in Alzheimer’s disease models	1	57.7×	0.069	LMNA
Nuclear Envelope Breakdown	1	50.8×	0.071	LMNA
ABC transporter disorders	1	48.8×	0.071	ABCC9
Unfolded Protein Response (UPR)	1	39.6×	0.071	LMNA
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	1	39.6×	0.071	VCL
Signaling by high-kinase activity BRAF mutants	1	35.2×	0.071	VCL
Formation of the dystrophin-glycoprotein complex (DGC)	1	34.3×	0.071	ACTC1
MAP2K and MAPK activation	1	31.7×	0.071	VCL
Signaling by RAF1 mutants	1	30.9×	0.071	VCL
Smooth Muscle Contraction	1	29.5×	0.071	VCL
RND1 GTPase cycle	1	29.5×	0.071	DSP
RND3 GTPase cycle	1	28.8×	0.071	DSP
Signaling by moderate kinase activity BRAF mutants	1	28.2×	0.071	VCL
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	28.2×	0.071	VCL
Signaling downstream of RAS mutants	1	28.2×	0.071	VCL
Oncogenic MAPK signaling	1	27.6×	0.071	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 16 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sarcomere organization	6	143.6×	3e-10	TNNT2, TTN, LDB3, ANKRD1, MYPN, MYH6
cardiac muscle contraction	5	125.4×	3e-08	TNNT2, TTN, ACTC1, MYH6, MYH7
muscle filament sliding	4	263.3×	6e-08	TNNT2, TTN, MYH6, MYH7
cardiac muscle tissue morphogenesis	3	263.3×	6e-06	TTN, ACTC1, ANKRD1
striated muscle contraction	3	158.0×	3e-05	TTN, MYH6, MYH7
ventricular cardiac muscle tissue morphogenesis	3	131.7×	4e-05	TNNT2, MYH6, MYH7
ATP metabolic process	3	87.8×	1e-04	ABCC9, MYH6, MYH7
skeletal muscle thin filament assembly	2	351.1×	3e-04	TTN, ACTC1
muscle contraction	3	39.0×	0.001	TTN, MYH6, MYH7
cardiac myofibril assembly	2	162.0×	0.001	TTN, ACTC1
adult heart development	2	150.5×	0.001	MYH6, MYH7
epithelial cell-cell adhesion	2	150.5×	0.001	VCL, DSP
cardiac muscle hypertrophy in response to stress	2	131.7×	0.001	MYH6, MYH7
dendrite self-avoidance	2	131.7×	0.001	MYPN, NEXN
regulation of the force of heart contraction	2	123.9×	0.001	MYH6, MYH7
cardiac muscle cell development	2	78.0×	0.003	TTN, MYH6
skeletal muscle contraction	2	63.8×	0.004	TTN, MYH7
regulation of heart contraction	2	62.0×	0.004	TNNT2, MYH6
regulation of heart rate	2	58.5×	0.005	MYH6, MYH7
visceral muscle development	1	1053.2×	0.007	MYH6
regulation of cardiac muscle tissue development	1	1053.2×	0.007	JPH2
obsolete positive regulation of ryanodine-sensitive calcium-release channel activity	1	1053.2×	0.007	JPH2
regulation of protein localization to adherens junction	1	1053.2×	0.007	VCL
positive regulation of protein secretion	2	43.0×	0.007	TTN, ANKRD1
response to calcium ion	2	39.8×	0.008	TNNT2, TTN
regulation of slow-twitch skeletal muscle fiber contraction	1	526.6×	0.011	MYH7
actin-myosin filament sliding	1	526.6×	0.011	ACTC1
regulation of heart growth	1	526.6×	0.011	MYH6
response to hydrogen sulfide	1	526.6×	0.011	ABCC9
cellular response to xenobiotic stimulus	2	30.1×	0.011	ANKRD1, ABCC9

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 15

Druggability breadth: 9 of 17 evidence-associated genes (53%) 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
ABCC9	PINACIDIL ANHYDROUS
LMNA	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LMNA	823	4
ABCC9	5	4
TNNT2	0	0
TTN	0	0
VCL	0	0
JPH2	0	0
ACTC1	0	0
LDB3	0	0
ANKRD1	0	0
NEBL	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PINACIDIL ANHYDROUS	4	ABCC9, LMNA
GLYBURIDE	4	ABCC9, LMNA
PROPAFENONE	4	ABCC9, LMNA
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

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ABCC9	61	Functional:46, Binding:15
LMNA	12	Binding:9, Functional:3
ACTC1	6	Binding:6
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: 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)
PINACIDIL ANHYDROUS	4	ABCC9, LMNA
GLYBURIDE	4	ABCC9, LMNA
PROPAFENONE	4	ABCC9, LMNA
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

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	ABCC9, LMNA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	TTN
D	Druggable family + AlphaFold only, no drug	2	MYPN, NEXN
E	Difficult family or no structure, no drug	12	TNNT2, VCL, JPH2, ACTC1, LDB3, ANKRD1, NEBL, GATAD1, DSP, KCNJ8-AS1 (+2 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TNNT2	2	—
TTN	1	—
VCL	2	—
JPH2	0	—
ACTC1	6	—
LDB3	0	—
ANKRD1	0	—
NEBL	0	—
MYPN	0	—
NEXN	0	—
GATAD1	0	—
DSP	2	—
KCNJ8-AS1	0	—
MYH6	0	—
MYH7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.