Familial hypertrophic cardiomyopathy

Summary

Familial hypertrophic cardiomyopathy (MONDO:0024573) is a disease (an umbrella term covering 40 Mondo subtypes) with 75 cohort genes and 2 clinical trials. The dominant Reactome pathway is Striated Muscle Contraction (13 cohort genes).

At a glance

• Umbrella term: 40 Mondo subtypes
• Cohort genes: 75
• ClinVar variants: 2,649
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial hypertrophic cardiomyopathy
Mondo ID	MONDO:0024573
MeSH	D024741
OMIM	192600
Orphanet	155
DOID	DOID:0080326
ICD-11	1408928442
NCIT	C84773
SNOMED CT	471885006
UMLS	C0949658
MedGen	183649
Is cancer (heuristic)	no

Also known as: cardiomyopathy, familial hypertrophic · familial hypertrophic cardiomyopathy · familila or idiopathic hypertrophic obstructive cardiomyopathy · hereditary hypertrophic cardiomyopathy · hypertrophic familial cardiomyopathy

Data availability: 2,649 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 40 Mondo subtypes.

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

Related subtypes (2): non-familial hypertrophic cardiomyopathy, progressive sensorineural hearing loss-hypertrophic cardiomyopathy syndrome

Subtypes (40): hypertrophic cardiomyopathy 2, 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:

251 uncertain significance, 212 likely benign, 69 conflicting classifications of pathogenicity, 21 pathogenic, 14 benign, 14 benign/likely benign, 11 pathogenic/likely pathogenic, 8 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
162727	NM_001103.4(ACTN2):c.355G>A (p.Ala119Thr)	ACTN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1342709	NM_020778.5(ALPK3):c.297del (p.Ile99fs)	ALPK3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
10715	NM_000169.3(GLA):c.902G>A (p.Arg301Gln)	GLA	Pathogenic	criteria provided, multiple submitters, no conflicts
155800	NM_020433.5(JPH2):c.482C>A (p.Thr161Lys)	JPH2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14120	NM_000257.4(MYH7):c.2609G>A (p.Arg870His)	LOC126861898	Pathogenic	reviewed by expert panel
164337	NM_000257.4(MYH7):c.2302G>A (p.Gly768Arg)	LOC126861898	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
155808	NM_000256.3(MYBPC3):c.3190+5G>A	MYBPC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
164042	NC_000011.10:g.47333236del	MYBPC3	Pathogenic	criteria provided, multiple submitters, no conflicts
164109	NM_000256.3(MYBPC3):c.1591G>A (p.Gly531Arg)	MYBPC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
164119	NM_000256.3(MYBPC3):c.1351+1G>A	MYBPC3	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
14089	NM_000257.4(MYH7):c.1357C>T (p.Arg453Cys)	MYH7	Pathogenic	reviewed by expert panel
14091	NM_000257.4(MYH7):c.1816G>A (p.Val606Met)	MYH7	Pathogenic	criteria provided, multiple submitters, no conflicts
14095	NM_000257.4(MYH7):c.2167C>T (p.Arg723Cys)	MYH7	Pathogenic	reviewed by expert panel
14097	NM_000257.4(MYH7):c.2722C>G (p.Leu908Val)	MYH7	Pathogenic	reviewed by expert panel
14104	NM_000257.4(MYH7):c.2155C>T (p.Arg719Trp)	MYH7	Pathogenic	reviewed by expert panel
14125	NM_000257.4(MYH7):c.2717A>G (p.Asp906Gly)	MYH7	Pathogenic	reviewed by expert panel
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
164342	NM_000257.4(MYH7):c.2207T>C (p.Ile736Thr)	MYH7	Pathogenic	reviewed by expert panel
164401	NM_000257.4(MYH7):c.427C>T (p.Arg143Trp)	MYH7	Pathogenic	reviewed by expert panel
177626	NM_000257.4(MYH7):c.1954A>G (p.Arg652Gly)	MYH7	Pathogenic	criteria provided, multiple submitters, no conflicts
14067	NM_000432.4(MYL2):c.173G>A (p.Arg58Gln)	MYL2	Pathogenic	criteria provided, multiple submitters, no conflicts
155818	NM_000432.4(MYL2):c.239C>A (p.Thr80Asn)	MYL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13958	NM_002880.4(RAF1):c.781C>T (p.Pro261Ser)	RAF1	Pathogenic	reviewed by expert panel
1055526	NM_003673.4(TCAP):c.110+5G>A	TCAP	Pathogenic	criteria provided, single submitter
1382475	NM_003673.4(TCAP):c.166C>T (p.Gln56Ter)	TCAP	Pathogenic	criteria provided, single submitter
1459213	NM_003673.4(TCAP):c.34del (p.Glu12fs)	TCAP	Pathogenic	criteria provided, single submitter
12422	NM_000363.5(TNNI3):c.586G>A (p.Asp196Asn)	TNNI3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12424	NM_000363.5(TNNI3):c.575G>A (p.Arg192His)	TNNI3	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 197 · 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
ANKRD1	Supportive	Autosomal dominant	familial isolated dilated cardiomyopathy	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ANKRD1	Orphanet:154	Familial isolated dilated cardiomyopathy
RYR2	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
RYR2	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
RYR2	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
RYR2	Orphanet:3286	Catecholaminergic polymorphic ventricular tachycardia
SCN5A	Orphanet:101016	Romano-Ward syndrome
SCN5A	Orphanet:130	Brugada syndrome
SCN5A	Orphanet:1344	Isolated atrial standstill
SCN5A	Orphanet:154	Familial isolated dilated cardiomyopathy
SCN5A	Orphanet:166282	Hereditary sick sinus syndrome
SCN5A	Orphanet:228140	Idiopathic ventricular fibrillation
SCN5A	Orphanet:334	Hereditary atrial fibrillation
SCN5A	Orphanet:871	Hereditary progressive cardiac conduction defect
SLC25A4	Orphanet:1369	Congenital cataract-hypertrophic cardiomyopathy-mitochondrial myopathy syndrome
SLC25A4	Orphanet:254892	Autosomal dominant progressive external ophthalmoplegia
BRCA2	Orphanet:1331	Familial prostate cancer
BRCA2	Orphanet:1333	Familial pancreatic carcinoma
BRCA2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
BRCA2	Orphanet:178	Chordoma
BRCA2	Orphanet:227535	Hereditary breast cancer
BRCA2	Orphanet:319462	Inherited cancer-predisposing syndrome due to biallelic BRCA2 mutations
BRCA2	Orphanet:440437	Familial colorectal cancer Type X
BRCA2	Orphanet:654	Nephroblastoma
BRCA2	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
BRCA2	Orphanet:694963	Inflammatory breast cancer
BRCA2	Orphanet:70567	Cholangiocarcinoma
BRCA2	Orphanet:84	Fanconi anemia
SOS1	Orphanet:2024	Hereditary gingival fibromatosis
SOS1	Orphanet:648	Noonan syndrome
TAFAZZIN	Orphanet:111	Barth syndrome
TAFAZZIN	Orphanet:154	Familial isolated dilated cardiomyopathy
TCAP	Orphanet:154	Familial isolated dilated cardiomyopathy
TCAP	Orphanet:34514	Telethonin-related limb-girdle muscular dystrophy R7
TMPO	Orphanet:154	Familial isolated dilated cardiomyopathy
TNNI3	Orphanet:154	Familial isolated dilated cardiomyopathy
TNNI3	Orphanet:75249	Familial isolated restrictive cardiomyopathy
TNNT2	Orphanet:154	Familial isolated dilated cardiomyopathy
TNNT2	Orphanet:54260	Left ventricular noncompaction
TNNT2	Orphanet:75249	Familial isolated restrictive cardiomyopathy
TPM1	Orphanet:154	Familial isolated dilated cardiomyopathy
TPM1	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

Cohort genes → proteins

75 cohort genes, 67 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	75

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ANKRD1	HGNC:15819	ENSG00000148677	Q15327	Ankyrin repeat domain-containing protein 1	gencc,clinvar
RYR2	HGNC:10484	ENSG00000198626	Q92736	Ryanodine receptor 2	clinvar
SCN5A	HGNC:10593	ENSG00000183873	Q14524	Sodium channel protein type 5 subunit alpha	clinvar
SLC25A4	HGNC:10990	ENSG00000151729	P12235	ADP/ATP translocase 1	clinvar
BRCA2	HGNC:1101	ENSG00000139618	P51587	Breast cancer type 2 susceptibility protein	clinvar
SOS1	HGNC:11187	ENSG00000115904	Q07889	Son of sevenless homolog 1	clinvar
TAF10	HGNC:11543	ENSG00000166337	Q12962	Transcription initiation factor TFIID subunit 10	clinvar
TAFAZZIN	HGNC:11577	ENSG00000102125	Q16635	Tafazzin	clinvar
TCAP	HGNC:11610	ENSG00000173991	O15273	Telethonin	clinvar
TMPO	HGNC:11875	ENSG00000120802	P42166	Lamina-associated polypeptide 2, isoform alpha	clinvar
TNNI3	HGNC:11947	ENSG00000129991	P19429	Troponin I, cardiac muscle	clinvar
TNNT2	HGNC:11949	ENSG00000118194	P45379	Troponin T, cardiac muscle	clinvar
TPM1	HGNC:12010	ENSG00000140416	P09493	Tropomyosin alpha-1 chain	clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	clinvar
TTR	HGNC:12405	ENSG00000118271	P02766	Transthyretin	clinvar
VCL	HGNC:12665	ENSG00000035403	P18206	Vinculin	clinvar
MYOZ2	HGNC:1330	ENSG00000172399	Q9NPC6	Myozenin-2	clinvar
PRDM16	HGNC:14000	ENSG00000142611	Q9HAZ2	Histone-lysine N-methyltransferase PRDM16	clinvar
JPH2	HGNC:14202	ENSG00000149596	Q9BR39	Junctophilin-2	clinvar
ACTC1	HGNC:143	ENSG00000159251	P68032	Actin, alpha cardiac muscle 1	clinvar
SHOC2	HGNC:15454	ENSG00000108061	Q9UQ13	Leucine-rich repeat protein SHOC-2	clinvar
LDB3	HGNC:15710	ENSG00000122367	O75112	LIM domain-binding protein 3	clinvar
TRIM63	HGNC:16007	ENSG00000158022	Q969Q1	E3 ubiquitin-protein ligase TRIM63	clinvar
MYLK2	HGNC:16243	ENSG00000101306	Q9H1R3	Myosin light chain kinase 2, skeletal/cardiac muscle	clinvar
ACTN2	HGNC:164	ENSG00000077522	P35609	Alpha-actinin-2	clinvar
FBXO32	HGNC:16731	ENSG00000156804	Q969P5	F-box only protein 32	clinvar
NEBL	HGNC:16932	ENSG00000078114	O76041	Nebulette	clinvar
ASTN2	HGNC:17021	ENSG00000148219	O75129	Astrotactin-2	clinvar
ALPK3	HGNC:17574	ENSG00000136383	Q96L96	Alpha-protein kinase 3	clinvar
TXNRD2	HGNC:18155	ENSG00000184470	Q9NNW7	Thioredoxin reductase 2, mitochondrial	clinvar
CALR3	HGNC:20407	ENSG00000269058	Q96L12	Calreticulin-3	clinvar
PDLIM3	HGNC:20767	ENSG00000154553	Q53GG5	PDZ and LIM domain protein 3	clinvar
MIB1	HGNC:21086	ENSG00000101752	Q86YT6	E3 ubiquitin-protein ligase MIB1	clinvar
COMT	HGNC:2228	ENSG00000093010	P21964	Catechol O-methyltransferase	clinvar
MYPN	HGNC:23246	ENSG00000138347	Q86TC9	Myopalladin	clinvar
GSDMB	HGNC:23690	ENSG00000073605	Q8TAX9	Gasdermin-B	clinvar
CRYAB	HGNC:2389	ENSG00000109846	P02511	Alpha-crystallin B chain	clinvar
CSRP3	HGNC:2472	ENSG00000129170	P50461	Cysteine and glycine-rich protein 3	clinvar
CTNNA3	HGNC:2511	ENSG00000183230	Q9UI47	Catenin alpha-3	clinvar
RBM20	HGNC:27424	ENSG00000203867	Q5T481	RNA-binding protein 20	clinvar
DES	HGNC:2770	ENSG00000175084	P17661	Desmin	clinvar
TMEM43	HGNC:28472	ENSG00000170876	Q9BTV4	Transmembrane protein 43	clinvar
GPD1L	HGNC:28956	ENSG00000152642	Q8N335	Glycerol-3-phosphate dehydrogenase 1-like protein	clinvar
DMD	HGNC:2928	ENSG00000198947	P11532	Dystrophin	clinvar
NEXN	HGNC:29557	ENSG00000162614	Q0ZGT2	Nexilin	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
DTNA	HGNC:3057	ENSG00000134769	Q9Y4J8	Dystrobrevin alpha	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ANKRD1	Ankyrin repeat domain-containing protein 1	May play an important role in endothelial cell activation.
RYR2	Ryanodine receptor 2	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering cardiac muscle contraction.
SCN5A	Sodium channel protein type 5 subunit alpha	Pore-forming subunit of Nav1.5, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
SLC25A4	ADP/ATP translocase 1	ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell.
BRCA2	Breast cancer type 2 susceptibility protein	Involved in double-strand break repair and/or homologous recombination.
SOS1	Son of sevenless homolog 1	Promotes the exchange of Ras-bound GDP by GTP.
TAF10	Transcription initiation factor TFIID subunit 10	The TFIID basal transcription factor complex plays a major role in the initiation of RNA polymerase II (Pol II)-dependent transcription.
TAFAZZIN	Tafazzin	Acyltransferase required to remodel newly synthesized phospholipid cardiolipin (1’,3’-bis-[1,2-diacyl-sn-glycero-3-phospho]-glycerol or CL), a key component of the mitochondrial inner membrane, with tissue specific acyl chains necessary fo…
TCAP	Telethonin	Muscle assembly regulating factor.
TMPO	Lamina-associated polypeptide 2, isoform alpha	May be involved in the structural organization of the nucleus and in the post-mitotic nuclear assembly.
TNNI3	Troponin I, cardiac muscle	Troponin I is the inhibitory subunit of troponin, the thin filament regulatory complex which confers calcium-sensitivity to striated muscle actomyosin ATPase activity.
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.
TPM1	Tropomyosin alpha-1 chain	Binds to actin filaments in muscle and non-muscle cells.
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
TTR	Transthyretin	Thyroid hormone-binding protein.
VCL	Vinculin	Actin filament (F-actin)-binding protein involved in cell-matrix adhesion and cell-cell adhesion.
MYOZ2	Myozenin-2	Myozenins may serve as intracellular binding proteins involved in linking Z line proteins such as alpha-actinin, gamma-filamin, TCAP/telethonin, LDB3/ZASP and localizing calcineurin signaling to the sarcomere.
PRDM16	Histone-lysine N-methyltransferase PRDM16	Transcription regulator that acts both as a histone methyltransferase or chromatin adapter, depending on the context.
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.
SHOC2	Leucine-rich repeat protein SHOC-2	Core component of the SHOC2-MRAS-PP1c (SMP) holophosphatase complex that regulates activation of the MAPK pathway.
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.
TRIM63	E3 ubiquitin-protein ligase TRIM63	E3 ubiquitin ligase.
MYLK2	Myosin light chain kinase 2, skeletal/cardiac muscle	Implicated in the level of global muscle contraction and cardiac function.
ACTN2	Alpha-actinin-2	F-actin cross-linking protein which is thought to anchor actin to a variety of intracellular structures.
FBXO32	F-box only protein 32	Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
NEBL	Nebulette	Binds to actin and plays an important role in the assembly of the Z-disk.
ASTN2	Astrotactin-2	Mediates recycling of the neuronal cell adhesion molecule ASTN1 to the anterior pole of the cell membrane in migrating neurons.
ALPK3	Alpha-protein kinase 3	Involved in cardiomyocyte differentiation.
TXNRD2	Thioredoxin reductase 2, mitochondrial	Involved in the control of reactive oxygen species levels and the regulation of mitochondrial redox homeostasis.
CALR3	Calreticulin-3	During spermatogenesis, may act as a lectin-independent chaperone for specific client proteins such as ADAM3.
PDLIM3	PDZ and LIM domain protein 3	May play a role in the organization of actin filament arrays within muscle cells.
MIB1	E3 ubiquitin-protein ligase MIB1	E3 ubiquitin-protein ligase that mediates ubiquitination of Delta receptors, which act as ligands of Notch proteins.
COMT	Catechol O-methyltransferase	Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones.
MYPN	Myopalladin	Component of the sarcomere that tethers together nebulin (skeletal muscle) and nebulette (cardiac muscle) to alpha-actinin, at the Z lines.
GSDMB	Gasdermin-B	Precursor of a pore-forming protein that acts as a downstream mediator of granzyme-mediated cell death.
CRYAB	Alpha-crystallin B chain	May contribute to the transparency and refractive index of the lens.
CSRP3	Cysteine and glycine-rich protein 3	Positive regulator of myogenesis.
CTNNA3	Catenin alpha-3	May be involved in formation of stretch-resistant cell-cell adhesion complexes.
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.
TMEM43	Transmembrane protein 43	May have an important role in maintaining nuclear envelope structure by organizing protein complexes at the inner nuclear membrane.
GPD1L	Glycerol-3-phosphate dehydrogenase 1-like protein	Plays a role in regulating cardiac sodium current; decreased enzymatic activity with resulting increased levels of glycerol 3-phosphate activating the DPD1L-dependent SCN5A phosphorylation pathway, may ultimately lead to decreased sodium c…
DMD	Dystrophin	Anchors the extracellular matrix to the cytoskeleton via F-actin.
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.
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.
DTNA	Dystrobrevin alpha	May be involved in the formation and stability of synapses as well as being involved in the clustering of nicotinic acetylcholine receptors.

Protein-family classification

Druggable: 17 · Difficult: 15 · Unknown: 43 · Druggable fraction: 0.23

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	4	6.0×	0.037
Complement	1	3.6×	0.474
Antibody/Immunoglobulin	4	1.6×	0.474
Kinase	4	1.5×	0.474
Transcription factor	11	1.2×	0.474
Other/Unknown	43	1.0×	0.590
Scaffold/PPI	4	0.9×	0.728
Enzyme (other)	4	0.6×	0.881

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ANKRD1	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf
RYR2	Ion channel	yes		RIH_dom, B30.2/SPRY, EF_hand_dom
SCN5A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a5su
SLC25A4	Other/Unknown	no		MCP, ADT_euk_type, MCP_transmembrane
BRCA2	Other/Unknown	no		BRCA2_repeat, NA-bd_OB-fold, BRCA2_OB_1
SOS1	Scaffold/PPI	no		DH_dom, Ras-like_Gua-exchang_fac_N, PH_domain
TAF10	Other/Unknown	no		TAF10
TAFAZZIN	Other/Unknown	no		Tafazzin, Plipid/glycerol_acylTrfase
TCAP	Other/Unknown	no		Telethonin, Titin-like_dom_sf
TMPO	Other/Unknown	no		LEM_dom, LEM/LEM-like_dom_sf, LEM-like_dom
TNNI3	Other/Unknown	no		Troponin, Troponin-I_N, Troponin_sf
TNNT2	Other/Unknown	no		Troponin, TNNT, Troponin_sf
TPM1	Other/Unknown	no		Tropomyosin
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
TTR	Other/Unknown	no		Transthyretin/HIU_hydrolase, Transthyretin/HIU_hydrolase_d, Thyroxine_BS
VCL	Other/Unknown	no		Vinculin_CS, Vinculin/catenin, Vinculin
MYOZ2	Other/Unknown	no		MYOZ
PRDM16	Transcription factor	no	2.1.1.367	SET_dom, Znf_C2H2_type, Znf_C2H2_sf
JPH2	Other/Unknown	no		MORN, Junctophilin
ACTC1	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
SHOC2	Other/Unknown	no		Leu-rich_rpt, Leu-rich_rpt_typical-subtyp, LRR_dom_sf
LDB3	Transcription factor	no		PDZ, Znf_LIM, Zasp-like_motif
TRIM63	Transcription factor	no		Znf_B-box, Znf_RING, Znf_RING/FYVE/PHD
MYLK2	Kinase	yes	2.7.11.18	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
ACTN2	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
FBXO32	Other/Unknown	no		F-box-like_dom_sf, FBX25/32
NEBL	Scaffold/PPI	no		Nebulin_repeat, SH3_domain, Nebulette_SH3
ASTN2	Complement	yes		MACPF, Astrotactin, FN3_sf
ALPK3	Kinase	yes		Ig_sub2, Ig_sub, a-kinase_dom
TXNRD2	Enzyme (other)	yes	1.8.1.9	Pyr_nuc-diS_OxRdtase, Pyr_nucl-diS_OxRdtase_dimer, Thioredoxin/glutathione_Rdtase
CALR3	Other/Unknown	no		Calret/calnex, Calreticulin/calnexin_P_dom_sf, Calreticulin
PDLIM3	Transcription factor	no		PDZ, Znf_LIM, Zasp-like_motif
MIB1	Transcription factor	no		Znf_ZZ, Znf_RING, Ankyrin_rpt
COMT	Enzyme (other)	yes	2.1.1.6	SAM_O-MeTrfase, Catechol_O-MeTrfase_euk, SAM-dependent_MTases_sf
MYPN	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
GSDMB	Other/Unknown	no		Gasdermin, Gasdermin_pore, Gasdermin_PUB
CRYAB	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, Alpha-crystallin_N
CSRP3	Transcription factor	no		Znf_LIM
CTNNA3	Other/Unknown	no		Alpha_catenin, Vinculin/catenin, Alpha-catenin/vinculin-like_sf
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
TMEM43	Other/Unknown	no		TMEM43_fam
GPD1L	Other/Unknown	no		G3P_DH_NAD-dep_C, G3P_DH_NAD-dep, 6-PGluconate_DH-like_C_sf
DMD	Transcription factor	no		Znf_ZZ, WW_dom, Actinin_actin-bd_CS
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
DSG2	Other/Unknown	no		Cadherin-like_dom, Desmosomal_cadherin, Cadherin-like_sf
DSP	Scaffold/PPI	no		Plectin_repeat, SH3_domain, Spectrin/alpha-actinin
DTNA	Transcription factor	no		Znf_ZZ, EF-hand-dom_pair, EF-hand_dom_typ1

Expression context

Cohort genes with no expression data: 1.

63 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)	74
unknown	1

Top tissues across cohort

Tissue	Cohort genes
apex of heart	15
left ventricle myocardium	12
hindlimb stylopod muscle	11
heart right ventricle	10
skeletal muscle tissue of rectus abdominis	8
right atrium auricular region	7
myocardium	7
skeletal muscle tissue of biceps brachii	7
gastrocnemius	7
sural nerve	5
cardiac atrium	4
biceps brachii	4
right lobe of liver	4
tibialis anterior	4
cardiac ventricle	3
gluteal muscle	3
trigeminal ganglion	3
heart left ventricle	2
male germ line stem cell (sensu Vertebrata) in testis	2
ventricular zone	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ANKRD1	155	ubiquitous	marker	apex of heart, right atrium auricular region, cardiac atrium
RYR2	210	broad	marker	heart right ventricle, left ventricle myocardium, myocardium
SCN5A	161	broad	yes	apex of heart, heart left ventricle, cardiac ventricle
SLC25A4	292	ubiquitous	marker	left ventricle myocardium, heart right ventricle, apex of heart
BRCA2	184	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, ventricular zone
SOS1	289	ubiquitous	marker	colonic epithelium, jejunal mucosa, tendon of biceps brachii
TAF10	166	ubiquitous	marker	right testis, left testis, granulocyte
TAFAZZIN	238	ubiquitous	marker	apex of heart, granulocyte, lower esophagus mucosa
TCAP	213	tissue_specific	marker	apex of heart, hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis
TMPO	287	ubiquitous	marker	ventricular zone, ganglionic eminence, embryo
TNNI3	169	broad	marker	apex of heart, left ventricle myocardium, right atrium auricular region
TNNT2	154	broad	marker	apex of heart, right atrium auricular region, cardiac atrium
TPM1	305	ubiquitous	marker	left ventricle myocardium, heart right ventricle, myocardium
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
TTR	185	broad	marker	choroid plexus epithelium, type B pancreatic cell, right lobe of liver
VCL	300	ubiquitous	marker	saphenous vein, blood vessel layer, urethra
MYOZ2	179	broad	marker	heart right ventricle, left ventricle myocardium, myocardium
PRDM16	202	broad	marker	sural nerve, pigmented layer of retina, ascending aorta
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
SHOC2	299	ubiquitous	marker	calcaneal tendon, sural nerve, bone marrow
LDB3	247	broad	marker	skeletal muscle tissue of biceps brachii, hindlimb stylopod muscle, apex of heart
TRIM63	169	tissue_specific	marker	gastrocnemius, tibialis anterior, hindlimb stylopod muscle
MYLK2	148	tissue_specific	yes	hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis, gastrocnemius
ACTN2	226	broad	marker	skeletal muscle tissue of rectus abdominis, skeletal muscle tissue of biceps brachii, hindlimb stylopod muscle
FBXO32	257	ubiquitous	marker	cardiac muscle of right atrium, deltoid, tibialis anterior
NEBL	282	broad	marker	heart right ventricle, myocardium, cranial nerve II
ASTN2	236	ubiquitous	marker	buccal mucosa cell, trigeminal ganglion, dorsal root ganglion
ALPK3	201	broad	yes	gastrocnemius, hindlimb stylopod muscle, gluteal muscle
TXNRD2	264	ubiquitous	marker	right lobe of liver, right adrenal gland cortex, apex of heart

Protein interactions among cohort

Intra-cohort edges: 187.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KRAS	14,509
LMNA	7,173
BRCA2	4,839
JUP	4,618
TTR	4,528
VCL	4,495
TTN	4,237
LAMP2	3,838
TXNRD2	3,712
SOS1	3,625

Intra-cohort edges

A	B	Sources
ACTC1	MYBPC3	intact
ACTN2	CSRP3	intact, string_interaction
ACTN2	LDB3	biogrid_interaction, intact, string_interaction
ACTN2	MYOZ2	biogrid_interaction, intact, string_interaction
ACTN2	MYPN	biogrid_interaction, string_interaction
ACTN2	NEBL	string_interaction
ACTN2	NEXN	string_interaction
ACTN2	PDLIM3	biogrid_interaction, intact, string_interaction
ACTN2	TCAP	string_interaction
ACTN2	TNNT2	string_interaction
ACTN2	TPM1	biogrid_interaction, string_interaction
ACTN2	TTN	string_interaction
ACTN2	VCL	string_interaction
ALPK3	MYBPC3	string_interaction
ALPK3	TNNT2	string_interaction
ANKRD1	CSRP3	string_interaction
ANKRD1	FHL2	string_interaction
ANKRD1	MYPN	biogrid_interaction, string_interaction
ANKRD1	NEBL	string_interaction
ANKRD1	TCAP	string_interaction
ANKRD1	TRIM63	biogrid_interaction
ANKRD1	TTN	biogrid_interaction, string_interaction
CALR3	CSRP3	string_interaction
CALR3	JPH2	string_interaction
CALR3	MYLK2	string_interaction
CALR3	MYOZ2	string_interaction
CALR3	MYPN	string_interaction
CALR3	RYR2	string_interaction
CALR3	TCAP	string_interaction
COMT	EMD	intact
COMT	TXNRD2	string_interaction
CRYAB	FLNC	string_interaction
CRYAB	LDB3	string_interaction
CRYAB	SCN5A	biogrid_interaction
CRYAB	TTN	string_interaction
CSRP3	EYA4	string_interaction
CSRP3	FHL1	intact
CSRP3	LDB3	string_interaction
CSRP3	MYBPC3	string_interaction
CSRP3	MYLK2	string_interaction
CSRP3	MYOZ2	string_interaction
CSRP3	MYPN	string_interaction
CSRP3	NEBL	string_interaction
CSRP3	NEXN	string_interaction
CSRP3	PDLIM3	string_interaction
CSRP3	RBM20	string_interaction
CSRP3	TCAP	intact, string_interaction
CSRP3	TNNI3	string_interaction
CSRP3	TNNT2	string_interaction
CSRP3	TPM1	string_interaction

Structural data

PDB: 49 · AlphaFold-only: 18 · No structure: 8

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KRAS	P01116	511
TTR	P02766	462
SOS1	Q07889	91
TTN	Q8WZ42	64
TAF10	Q12962	48
TNNI3	P19429	39
VCL	P18206	37
GLA	P06280	31
LMNA	P02545	28
RYR2	Q92736	26
TNNT2	P45379	25
KCNH2	Q12809	24
CRYAB	P02511	21
F5	P12259	18
ILK	Q13418	17
MYBPC3	Q14896	17
SCN5A	Q14524	16
ACTC1	P68032	16
ACTN2	P35609	16
BRCA2	P51587	14
TMPO	P42166	14
TPM1	P09493	14
FLNC	Q14315	14
SHOC2	Q9UQ13	13
COMT	P21964	12
DSG2	Q14126	12
GSDMB	Q8TAX9	11
MIB1	Q86YT6	6
DMD	P11532	6
EMD	P50402	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TAFAZZIN	Q16635	94.87
SLC25A4	P12235	92.07
TMEM43	Q9BTV4	89.92
ANKRD1	Q15327	82.64
CTNNA3	Q9UI47	81.65
FBXO32	Q969P5	80.15
DES	P17661	77.73
CALR3	Q96L12	77.43
DSC3	Q14574	75.53
LAMA4	Q16363	73.75
NEXN	Q0ZGT2	70.78
PDLIM3	Q53GG5	66.98
MYOZ2	Q9NPC6	65.51
EYA4	O95677	63.79
MYPN	Q86TC9	52.71
ALPK3	Q96L96	49.15
RBM20	Q5T481	48.52
TXNRD2	Q9NNW7

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 383. Enrichment computed across 87 evidence-associated genes (59 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 59 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	13	68.0×	6e-19	TCAP, TNNI3, TNNT2, TPM1, TTN, ACTC1, ACTN2, DES (+5 more)
Muscle contraction	11	14.4×	4e-08	RYR2, SCN5A, TCAP, ACTC1, ACTN2, KCNE2, KCNH2, MYBPC3 (+3 more)
Regulation of CDH1 Function	3	48.4×	0.004	VCL, ACTC1, JUP
Formation of the dystrophin-glycoprotein complex (DGC)	4	20.9×	0.004	ACTC1, DMD, DTNA, LAMA4
Depolymerization of the Nuclear Lamina	3	38.7×	0.004	TMPO, EMD, LMNA
Formation of the cornified envelope	6	8.9×	0.004	DSC2, DSC3, DSG2, DSP, JUP, PKP2
Initiation of Nuclear Envelope (NE) Reformation	3	30.6×	0.007	TMPO, EMD, LMNA
Nuclear Envelope Breakdown	3	23.2×	0.013	TMPO, EMD, LMNA
RAS signaling downstream of NF1 loss-of-function variants	2	55.3×	0.016	KRAS, NF1
SOS-mediated signalling	2	48.4×	0.016	SOS1, KRAS
SHOC2 M1731 mutant abolishes MRAS complex function	2	48.4×	0.016	SHOC2, RAF1
Gain-of-function MRAS complexes activate RAF signaling	2	48.4×	0.016	SHOC2, RAF1
RAF activation	3	17.1×	0.016	SHOC2, KRAS, RAF1
Signaling by BRAF and RAF1 fusions	4	11.6×	0.016	VCL, KRAS, LMNA, RAF1
Non-integrin membrane-ECM interactions	4	10.5×	0.016	TTR, ACTC1, DMD, LAMA4
Platelet degranulation	5	7.4×	0.016	TTN, VCL, ACTN2, F5, LAMP2
Keratinization	6	5.7×	0.016	DSC2, DSC3, DSG2, DSP, JUP, PKP2
Activated NTRK3 signals through RAS	2	43.0×	0.018	SOS1, KRAS
EGFR Transactivation by Gastrin	2	38.7×	0.018	SOS1, KRAS
SHC-related events triggered by IGF1R	2	38.7×	0.018	SOS1, KRAS
Phase 3 - rapid repolarisation	2	38.7×	0.018	KCNE2, KCNH2
Activated NTRK2 signals through RAS	2	38.7×	0.018	SOS1, KRAS
Signaling by high-kinase activity BRAF mutants	3	16.1×	0.018	VCL, KRAS, RAF1
MAP2K and MAPK activation	3	14.5×	0.018	VCL, KRAS, RAF1
MAPK1/MAPK3 signaling	4	8.9×	0.018	SOS1, SHOC2, ACTN2, NF1
Signaling by RAF1 mutants	3	14.2×	0.018	VCL, KRAS, RAF1
Apoptotic cleavage of cell adhesion proteins	2	35.2×	0.019	DSG2, DSP
MET activates RAS signaling	2	35.2×	0.019	SOS1, KRAS
Signaling by FGFR4 in disease	2	32.3×	0.019	SOS1, KRAS
Activated NTRK2 signals through FRS2 and FRS3	2	32.3×	0.019	SOS1, KRAS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 78 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cardiac muscle contraction	17	87.5×	5e-27	RYR2, SCN5A, TCAP, TNNI3, TNNT2, TPM1, TTN, ACTC1 (+9 more)
sarcomere organization	14	68.7×	2e-20	ANKRD1, TCAP, TNNT2, TPM1, TTN, MYOZ2, LDB3, ACTN2 (+6 more)
ventricular cardiac muscle tissue morphogenesis	9	81.0×	2e-13	TNNI3, TNNT2, TPM1, MYBPC3, MYH6, MYH7, MYL2, MYL3 (+1 more)
regulation of ventricular cardiac muscle cell action potential	7	126.0×	5e-12	RYR2, CTNNA3, DSC2, DSG2, DSP, JUP, PKP2
bundle of His cell-Purkinje myocyte adhesion involved in cell communication	6	185.2×	8e-12	CTNNA3, DSC2, DSG2, DSP, JUP, PKP2
muscle filament sliding	7	94.5×	5e-11	TCAP, TNNI3, TNNT2, TPM1, TTN, MYH6, MYH7
regulation of heart rate by cardiac conduction	9	43.2×	5e-11	SCN5A, CTNNA3, DSC2, DSG2, DSP, JUP, KCNE2, KCNH2 (+1 more)
ventricular cardiac muscle cell action potential	6	76.2×	9e-09	RYR2, SCN5A, GPD1L, KCNE2, KCNH2, PKP2
muscle contraction	9	24.0×	1e-08	TTN, TRIM63, CRYAB, DES, EMD, MYH6, MYH7, MYL3 (+1 more)
striated muscle contraction	6	64.8×	2e-08	RYR2, TTN, MYLK2, DTNA, MYH6, MYH7
cardiac muscle tissue morphogenesis	5	90.0×	1e-07	ANKRD1, TCAP, TTN, ACTC1, MYLK2
cardiac myofibril assembly	5	83.1×	1e-07	TCAP, TTN, ACTC1, CSRP3, MYL2
regulation of the force of heart contraction	5	63.5×	6e-07	CSRP3, MYH6, MYH7, MYL2, MYL3
regulation of heart rate	6	36.0×	7e-07	RYR2, SCN5A, GPD1L, DMD, MYH6, MYH7
response to muscle stretch	5	49.1×	2e-06	ANKRD1, RYR2, TCAP, DMD, RAF1
cardiac muscle hypertrophy	4	86.4×	4e-06	RYR2, TCAP, TTN, CSRP3
cardiac muscle cell development	5	40.0×	6e-06	TCAP, TTN, ACTN2, ALPK3, MYH6
skeletal muscle thin filament assembly	3	108.0×	8e-05	TCAP, TTN, ACTC1
detection of muscle stretch	3	92.6×	1e-04	TCAP, TTN, CSRP3
desmosome organization	3	81.0×	2e-04	DSG2, DSP, PKP2
regulation of striated muscle contraction	3	81.0×	2e-04	MYBPC3, MYL2, MYL3
muscle cell cellular homeostasis	4	33.2×	2e-04	CSRP3, DMD, LAMP2, BAG3
skeletal muscle tissue development	5	18.6×	2e-04	MYOZ2, CSRP3, DMD, MYL3, NF1
cell-cell adhesion	7	9.1×	4e-04	CTNNA3, DSC2, DSC3, DSG2, DSP, JUP, PKP2
skeletal muscle contraction	4	26.2×	5e-04	TCAP, TNNI3, TTN, MYH7
regulation of heart contraction	4	25.4×	5e-04	TNNT2, TPM1, DES, MYH6
regulation of muscle filament sliding	2	216.1×	6e-04	MYLK2, MYBPC3
regulation of cardiac muscle contraction by calcium ion signaling	3	49.9×	7e-04	RYR2, TNNI3, JPH2
adult heart development	3	46.3×	9e-04	TCAP, MYH6, MYH7
Schwann cell development	3	40.5×	0.001	SOS1, NF1, RAF1

Therapeutics

Drug target analysis

Approved (phase 4): 11 · Phase ≥3: 12 · Phased (≥1): 13 · Undrugged: 62

Druggability breadth: 41 of 87 evidence-associated genes (47%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SCN5A	BEPRIDIL
SOS1	IDARUBICIN
TTR	TRICLABENDAZOLE
MYLK2	FEDRATINIB
COMT	OPICAPONE
F5	EDOXABAN
GLA	CLOTRIMAZOLE
ILK	NILOTINIB
KCNH2	CETIRIZINE
KRAS	VEMURAFENIB
LMNA	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LMNA	823	4
KCNH2	706	4
SCN5A	108	4
GLA	62	4
TTR	29	4
MYLK2	19	4
KRAS	11	4
SOS1	5	4
ILK	4	4
TXNRD2	3	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	KCNH2, LMNA, SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	LMNA, SCN5A
DIBUCAINE	4	KCNH2, LMNA, SCN5A
IMIPRAMINE	4	KCNH2, LMNA, SCN5A
DROPERIDOL	4	KCNH2, LMNA, SCN5A
PONATINIB	4	KCNH2, SCN5A
DULOXETINE	4	KCNH2, SCN5A
PALONOSETRON	4	KCNH2, SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	LMNA, SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	KCNH2, SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	KCNH2, SCN5A
FEDRATINIB	4	KCNH2, MYLK2, SCN5A
QUINIDINE	4	KCNH2, SCN5A
DARUNAVIR	4	KCNH2, SCN5A
DARIFENACIN	4	KCNH2, SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	KCNH2, LMNA, SCN5A
RANOLAZINE	4	KCNH2, SCN5A
PIMOZIDE	4	KCNH2, LMNA, SCN5A
NIMODIPINE	4	LMNA, SCN5A
FELODIPINE	4	LMNA, SCN5A
NICARDIPINE	4	KCNH2, LMNA, SCN5A
AMLODIPINE	4	KCNH2, SCN5A
PHENYTOIN	4	KCNH2, SCN5A
PALIPERIDONE	4	KCNH2, SCN5A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 8.

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
KRAS	861	Binding:829, Functional:32
SCN5A	594	Binding:380, Functional:98, ADMET:72, Toxicity:43, Unclassified:1
TTR	423	Binding:391, Functional:32
SOS1	421	Binding:409, Functional:12
MYLK2	196	Binding:196
GLA	114	Binding:104, Functional:10
TXNRD2	91	Binding:76, Functional:15
ILK	71	Binding:71
COMT	55	Binding:47, ADMET:8
RYR2	15	Binding:15
CRYAB	13	Binding:13
LMNA	12	Binding:9, Functional:3
ALPK3	10	Binding:10
F5	10	Binding:10
TMPO	7	Binding:7
ACTC1	6	Binding:6
TPM1	3	Binding:3
TNNI3	2	Binding:2
TNNT2	2	Binding:2
VCL	2	Binding:2
PRDM16	2	Binding:2
DSP	2	Binding:2
LAMP2	2	Binding:2
SLC25A4	1	Binding:1
TAFAZZIN	1	Binding:1
TTN	1	Binding:1
TMEM43	1	Binding:1
EMD	1	Binding:1
JUP	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TTN	2.7.11.1	non-specific serine/threonine protein kinase
PRDM16	2.1.1.367, 2.1.1.370	[histone H3]-lysine9 N-methyltransferase, [histone H3]-lysine4 N-dimethyltransferase
MYLK2	2.7.11.18	myosin-light-chain kinase
TXNRD2	1.8.1.9	thioredoxin-disulfide reductase (NADPH)
COMT	2.1.1.6	catechol O-methyltransferase
GLA	3.2.1.22	alpha-galactosidase
ILK	2.7.10.2	non-specific protein-tyrosine kinase
KRAS	3.6.5.2	small monomeric GTPase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SCN5A	594
SOS1	421
TTR	423
MYLK2	196
GLA	114
KCNH2	4,851
KRAS	861

Pharmacogenomics

Cohort genes with a PharmGKB record: 69; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
COMT	1

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	KCNH2, LMNA, SCN5A
CANDESARTAN CILEXETIL	4	SCN5A
TELMISARTAN	4	SCN5A
CARBAMAZEPINE	4	LMNA, SCN5A
DIBUCAINE	4	KCNH2, LMNA, SCN5A
IMIPRAMINE	4	KCNH2, LMNA, SCN5A
DROPERIDOL	4	KCNH2, LMNA, SCN5A
PONATINIB	4	KCNH2, SCN5A
DULOXETINE	4	KCNH2, SCN5A
PALONOSETRON	4	KCNH2, SCN5A
VILANTEROL	4	SCN5A
MEXILETINE HYDROCHLORIDE	4	LMNA, SCN5A
UNOPROSTONE ISOPROPYL	4	SCN5A
LURASIDONE	4	KCNH2, SCN5A
LETERMOVIR	4	SCN5A
SERTINDOLE	4	KCNH2, SCN5A
FEDRATINIB	4	KCNH2, MYLK2, SCN5A
QUINIDINE	4	KCNH2, SCN5A
DARUNAVIR	4	KCNH2, SCN5A
DARIFENACIN	4	KCNH2, SCN5A
BENZONATATE	4	SCN5A
TOLTERODINE	4	KCNH2, LMNA, SCN5A
RANOLAZINE	4	KCNH2, SCN5A
PIMOZIDE	4	KCNH2, LMNA, SCN5A
NIMODIPINE	4	LMNA, SCN5A
FELODIPINE	4	LMNA, SCN5A
NICARDIPINE	4	KCNH2, LMNA, SCN5A
AMLODIPINE	4	KCNH2, SCN5A
PHENYTOIN	4	KCNH2, SCN5A
PALIPERIDONE	4	KCNH2, SCN5A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	11	SCN5A, SOS1, TTR, MYLK2, COMT, F5, GLA, ILK, KCNH2, KRAS (+1 more)
B	Phased (≥1) drug, not yet approved	2	RYR2, TXNRD2
C	Druggable family + PDB, no drug	5	TTN, ASTN2, FLNC, KCNE2, MYBPC3
D	Druggable family + AlphaFold only, no drug	3	ALPK3, MYPN, NEXN
E	Difficult family or no structure, no drug	54	ANKRD1, SLC25A4, BRCA2, TAF10, TAFAZZIN, TCAP, TMPO, TNNI3, TNNT2, TPM1 (+44 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
JPH2	0	RYR2
SHOC2	0	SOS1
GPD1L	0	SCN5A
EMD	1	LMNA
KCNE2	0	KCNH2, SCN5A
ANKRD1	0	—
SLC25A4	1	—
BRCA2	0	—
TAF10	0	—
TAFAZZIN	1	—
TCAP	0	—
TMPO	7	—
TNNI3	2	—
TNNT2	2	—
TPM1	3	—
TTN	1	—
VCL	2	—
MYOZ2	0	—
PRDM16	2	—
ACTC1	6	—
LDB3	0	—
TRIM63	0	—
ACTN2	0	—
FBXO32	0	—
NEBL	0	—
ASTN2	0	—
ALPK3	10	—
CALR3	0	—
PDLIM3	0	—
MIB1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05100420	Not specified	ENROLLING_BY_INVITATION	Hypertrophic Cardiomyopathy Registry, Biobank and Imaging Data Repository
NCT01792960	Not specified	COMPLETED	Registry and Prevalence of Gene Mutation in Korean Patients With Familial Hypertrophic Cardiomyopathy