Hypertrophic cardiomyopathy 4

Summary

Hypertrophic cardiomyopathy 4 (MONDO:0007268) is a disease caused by MYBPC3 (GenCC Definitive), with 10 cohort genes and 1 clinical trial. The dominant Reactome pathway is Striated Muscle Contraction (3 cohort genes).

At a glance

• Causal gene: MYBPC3 (GenCC Definitive)
• Cohort genes: 10
• ClinVar variants: 694
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypertrophic cardiomyopathy 4
Mondo ID	MONDO:0007268
MeSH	C566169
OMIM	115197
DOID	DOID:0110310
NCIT	C133725
UMLS	C1861862
MedGen	350526
GARD	0024542
Is cancer (heuristic)	no

Also known as: cardiomyopathy, familial hypertrophic, 4 · cardiomyopathy, familial hypertrophic, type 4 · cardiomyopathy, hypertrophic, 4 · CMH4 · familial hypertrophic cardiomyopathy type 4 · hypertrophic cardiomyopathy 4 · hypertrophic cardiomyopathy caused by mutation in MYBPC3 · hypertrophic cardiomyopathy type 4 · MYBPC3 hypertrophic cardiomyopathy

Data availability: 694 ClinVar variants · 4 GenCC gene-disease records · 42 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 4

Related subtypes (39): hypertrophic cardiomyopathy 2, hypertrophic cardiomyopathy 3, 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:

158 uncertain significance, 131 conflicting classifications of pathogenicity, 119 pathogenic, 76 pathogenic/likely pathogenic, 58 likely pathogenic, 37 benign/likely benign, 12 benign, 9 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
430737	NM_004333.6(BRAF):c.2128-4_2129del	BRAF	Pathogenic	criteria provided, single submitter
375467	NM_000265.3(NCF1):c.1351+1G>A	LOC106029312	Pathogenic	criteria provided, single submitter
2665104	NC_000011.10:g.(47329894_47331627)_(47335115_47335951)del	MADD	Pathogenic	no assertion criteria provided
1074339	NM_000256.3(MYBPC3):c.2164G>T (p.Glu722Ter)	MYBPC3	Pathogenic	criteria provided, multiple submitters, no conflicts
1301741	NM_000256.3(MYBPC3):c.2148+1G>A	MYBPC3	Pathogenic/Likely pathogenic	criteria provided, single submitter
1333262	NM_000256.3(MYBPC3):c.3313_3314insGG (p.Ala1105fs)	MYBPC3	Pathogenic	criteria provided, multiple submitters, no conflicts
1333356	NM_000256.3(MYBPC3):c.2149-2A>C	MYBPC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333510	NM_000256.3(MYBPC3):c.1609G>T (p.Glu537Ter)	MYBPC3	Pathogenic	criteria provided, multiple submitters, no conflicts
1333568	NM_000256.3(MYBPC3):c.86del (p.Phe29fs)	MYBPC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
138326	NM_000256.3(MYBPC3):c.1224-19G>A	MYBPC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1424922	NM_000256.3(MYBPC3):c.178G>T (p.Glu60Ter)	MYBPC3	Pathogenic	criteria provided, multiple submitters, no conflicts
1454685	NM_000256.3(MYBPC3):c.2578_2590dup (p.Phe864fs)	MYBPC3	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
162506	NM_000256.3(MYBPC3):c.3642G>A (p.Trp1214Ter)	MYBPC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
164021	NC_000011.10:g.47332110del	MYBPC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
164042	NC_000011.10:g.47333236del	MYBPC3	Pathogenic	criteria provided, multiple submitters, no conflicts
164091	NC_000011.10:g.47339718_47339719delinsC	MYBPC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
164098	NM_000256.3(MYBPC3):c.1790G>A (p.Arg597Gln)	MYBPC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
164107	NM_000256.3(MYBPC3):c.1624+2T>C	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
164118	NM_000256.3(MYBPC3):c.1357_1358del (p.Pro453fs)	MYBPC3	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
164140	NC_000011.10:g.47347670del	MYBPC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1687205	NM_000256.3(MYBPC3):c.1645C>T (p.Gln549Ter)	MYBPC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1687241	NM_000256.3(MYBPC3):c.3768_3771del (p.Asn1257fs)	MYBPC3	Pathogenic	criteria provided, single submitter
1687285	NM_000256.3(MYBPC3):c.3168del (p.Thr1057fs)	MYBPC3	Pathogenic	criteria provided, single submitter
1687419	NM_000256.3(MYBPC3):c.1526_1527del (p.Arg509fs)	MYBPC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1705335	NM_000256.3(MYBPC3):c.3805G>T (p.Glu1269Ter)	MYBPC3	Pathogenic	criteria provided, single submitter
1705378	NM_000256.3(MYBPC3):c.1595dup (p.Gln533fs)	MYBPC3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
177660	NM_000256.3(MYBPC3):c.2780_2781del (p.Thr927fs)	MYBPC3	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 40 · 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
MYBPC3	Definitive	Autosomal dominant	hypertrophic cardiomyopathy 4	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MYBPC3	Orphanet:154	Familial isolated dilated cardiomyopathy
MYBPC3	Orphanet:54260	Left ventricular noncompaction
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
BRAF	Orphanet:1340	Cardiofaciocutaneous syndrome
BRAF	Orphanet:146	Differentiated thyroid carcinoma
BRAF	Orphanet:251615	Pilomyxoid astrocytoma
BRAF	Orphanet:389	Langerhans cell histiocytosis
BRAF	Orphanet:500	Noonan syndrome with multiple lentigines
BRAF	Orphanet:54595	Craniopharyngioma
BRAF	Orphanet:58017	Classic hairy cell leukemia
BRAF	Orphanet:626	Large/giant congenital melanocytic nevus
BRAF	Orphanet:648	Noonan syndrome
BRAF	Orphanet:840	Syringocystadenoma papilliferum
BRAF	Orphanet:96253	Cushing disease
TCAP	Orphanet:154	Familial isolated dilated cardiomyopathy
TCAP	Orphanet:34514	Telethonin-related limb-girdle muscular dystrophy R7
TNNT2	Orphanet:154	Familial isolated dilated cardiomyopathy
TNNT2	Orphanet:54260	Left ventricular noncompaction
TNNT2	Orphanet:75249	Familial isolated restrictive cardiomyopathy
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
DNAAF3	Orphanet:244	Primary ciliary dyskinesia
ETFA	Orphanet:394529	Multiple acyl-CoA dehydrogenase deficiency, severe neonatal type
ETFA	Orphanet:394532	Multiple acyl-CoA dehydrogenase deficiency, mild type
MADD	Orphanet:528084	Non-specific syndromic intellectual disability
MADD	Orphanet:686495	MADD-related developmental delay-endocrine dysfunction-hypohemoglobinemia syndrome
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

Cohort genes → proteins

10 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MYBPC3	HGNC:7551	ENSG00000134571	Q14896	Myosin-binding protein C, cardiac-type	gencc,clinvar
RYR2	HGNC:10484	ENSG00000198626	Q92736	Ryanodine receptor 2	clinvar
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	clinvar
TCAP	HGNC:11610	ENSG00000173991	O15273	Telethonin	clinvar
TNNT2	HGNC:11949	ENSG00000118194	P45379	Troponin T, cardiac muscle	clinvar
LDB3	HGNC:15710	ENSG00000122367	O75112	LIM domain-binding protein 3	clinvar
DNAAF3	HGNC:30492	ENSG00000167646	Q8N9W5	Dynein axonemal assembly factor 3	clinvar
ETFA	HGNC:3481	ENSG00000140374	P13804	Electron transfer flavoprotein subunit alpha, mitochondrial	clinvar
MADD	HGNC:6766	ENSG00000110514	Q8WXG6	MAP kinase-activating death domain protein	clinvar
MYH7	HGNC:7577	ENSG00000092054	P12883	Myosin-7	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYBPC3	Myosin-binding protein C, cardiac-type	Thick filament-associated protein located in the crossbridge region of vertebrate striated muscle a bands.
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.
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
TCAP	Telethonin	Muscle assembly regulating factor.
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.
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.
DNAAF3	Dynein axonemal assembly factor 3	Required for the assembly of axonemal inner and outer dynein arms.
ETFA	Electron transfer flavoprotein subunit alpha, mitochondrial	Heterodimeric electron transfer flavoprotein that accepts electrons from several mitochondrial dehydrogenases, including acyl-CoA dehydrogenases, glutaryl-CoA and sarcosine dehydrogenase.
MADD	MAP kinase-activating death domain protein	Guanyl-nucleotide exchange factor that regulates small GTPases of the Rab family.
MYH7	Myosin-7	Myosins are actin-based motor molecules with ATPase activity essential for muscle contraction.

Protein-family classification

Druggable: 3 · Difficult: 2 · Unknown: 5 · Druggable fraction: 0.3

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	1	11.2×	0.517
Antibody/Immunoglobulin	1	2.9×	0.615
Kinase	1	2.8×	0.615
Scaffold/PPI	1	1.7×	0.673
Other/Unknown	5	0.9×	0.756
Transcription factor	1	0.8×	0.756

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MYBPC3	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
RYR2	Ion channel	yes		RIH_dom, B30.2/SPRY, EF_hand_dom
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
TCAP	Other/Unknown	no		Telethonin, Titin-like_dom_sf
TNNT2	Other/Unknown	no		Troponin, TNNT, Troponin_sf
LDB3	Transcription factor	no		PDZ, Znf_LIM, Zasp-like_motif
DNAAF3	Other/Unknown	no		DUF4470, DNAAF3_C, DNAAF3
ETFA	Other/Unknown	no		ETF_a/FixB, Rossmann-like_a/b/a_fold, ETF_a/b_N
MADD	Other/Unknown	no		cDENN_dom, dDENN_dom, uDENN_dom
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.

10 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)	10
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	6
hindlimb stylopod muscle	3
cardiac atrium	2
right atrium auricular region	2
skeletal muscle tissue of biceps brachii	2
heart right ventricle	1
left ventricle myocardium	1
myocardium	1
buccal mucosa cell	1
calcaneal tendon	1
colonic epithelium	1
skeletal muscle tissue of rectus abdominis	1
right testis	1
right uterine tube	1
jejunal mucosa	1
oocyte	1
secondary oocyte	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYBPC3	149	tissue_specific	marker	apex of heart, right atrium auricular region, cardiac atrium
RYR2	210	broad	marker	heart right ventricle, left ventricle myocardium, myocardium
BRAF	265	ubiquitous	marker	buccal mucosa cell, colonic epithelium, calcaneal tendon
TCAP	213	tissue_specific	marker	apex of heart, hindlimb stylopod muscle, skeletal muscle tissue of rectus abdominis
TNNT2	154	broad	marker	apex of heart, right atrium auricular region, cardiac atrium
LDB3	247	broad	marker	skeletal muscle tissue of biceps brachii, hindlimb stylopod muscle, apex of heart
DNAAF3	158	broad	marker	apex of heart, right uterine tube, right testis
ETFA	297	ubiquitous	marker	oocyte, secondary oocyte, jejunal mucosa
MADD	280	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
MYH7	167	tissue_specific	marker	apex of heart, hindlimb stylopod muscle, skeletal muscle tissue of biceps brachii

Protein interactions among cohort

Intra-cohort edges: 9.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BRAF	7,394
ETFA	3,353
MYH7	2,744
RYR2	2,653
TNNT2	1,944
MYBPC3	1,800
TCAP	1,414
LDB3	1,275
MADD	1,021
DNAAF3	794

Intra-cohort edges

A	B	Sources
LDB3	MYBPC3	string_interaction
LDB3	MYH7	string_interaction
LDB3	TCAP	string_interaction
LDB3	TNNT2	string_interaction
MYBPC3	MYH7	intact, string_interaction
MYBPC3	TCAP	string_interaction
MYBPC3	TNNT2	string_interaction
MYH7	TCAP	string_interaction
MYH7	TNNT2	string_interaction

Structural data

PDB: 8 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BRAF	P15056	131
MYH7	P12883	43
RYR2	Q92736	26
TNNT2	P45379	25
MYBPC3	Q14896	17
ETFA	P13804	4
TCAP	O15273	2
LDB3	O75112	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNAAF3	Q8N9W5	81.06
MADD	Q8WXG6	64.59

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 49. Enrichment computed across 10 evidence-associated genes (7 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 7 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	3	132.3×	5e-05	MYBPC3, TCAP, TNNT2
Muscle contraction	3	33.1×	0.002	MYBPC3, RYR2, TCAP
Signaling by MRAS-complex mutants	1	407.9×	0.027	BRAF
Signalling to p38 via RIT and RIN	1	326.3×	0.027	BRAF
Negative feedback regulation of MAPK pathway	1	271.9×	0.027	BRAF
ARMS-mediated activation	1	233.1×	0.027	BRAF
Prolonged ERK activation events	1	203.9×	0.027	BRAF
SHOC2 M1731 mutant abolishes MRAS complex function	1	203.9×	0.027	BRAF
Gain-of-function MRAS complexes activate RAF signaling	1	203.9×	0.027	BRAF
Signaling by FGFR3	1	163.1×	0.030	BRAF
Signaling by FGFR4	1	148.3×	0.030	BRAF
Frs2-mediated activation	1	135.9×	0.030	BRAF
Signaling by FGFR1	1	116.5×	0.032	BRAF
Spry regulation of FGF signaling	1	102.0×	0.034	BRAF
Signalling to ERKs	1	85.9×	0.038	BRAF
Negative regulation of FGFR3 signaling	1	62.8×	0.044	BRAF
Signaling by RAS mutants	1	60.4×	0.044	BRAF
Negative regulation of FGFR4 signaling	1	58.3×	0.044	BRAF
Signaling by FGFR2	1	58.3×	0.044	BRAF
Negative regulation of FGFR1 signaling	1	52.6×	0.044	BRAF
Negative regulation of FGFR2 signaling	1	52.6×	0.044	BRAF
Signaling by FGFR	1	49.4×	0.044	BRAF
RAF activation	1	48.0×	0.044	BRAF
Signaling by high-kinase activity BRAF mutants	1	45.3×	0.044	BRAF
MAP2K and MAPK activation	1	40.8×	0.044	BRAF
Signaling by RAF1 mutants	1	39.8×	0.044	BRAF
Negative regulation of MAPK pathway	1	37.9×	0.044	BRAF
Signaling by moderate kinase activity BRAF mutants	1	36.2×	0.044	BRAF
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	36.2×	0.044	BRAF
Signaling downstream of RAS mutants	1	36.2×	0.044	BRAF

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 10 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	5	200.6×	3e-09	MYBPC3, RYR2, TCAP, TNNT2, MYH7
sarcomere organization	4	153.2×	6e-07	MYBPC3, TCAP, TNNT2, LDB3
muscle filament sliding	3	316.0×	4e-06	TCAP, TNNT2, MYH7
ventricular cardiac muscle tissue morphogenesis	3	210.7×	1e-05	MYBPC3, TNNT2, MYH7
cardiac muscle hypertrophy	2	337.0×	4e-04	RYR2, TCAP
adult heart development	2	240.7×	7e-04	TCAP, MYH7
cardiac muscle hypertrophy in response to stress	2	210.7×	7e-04	TCAP, MYH7
striated muscle contraction	2	168.5×	0.001	RYR2, MYH7
response to muscle stretch	2	153.2×	0.001	RYR2, TCAP
skeletal muscle contraction	2	102.1×	0.002	TCAP, MYH7
regulation of heart rate	2	93.6×	0.002	RYR2, MYH7
establishment of protein localization to endoplasmic reticulum	1	1685.2×	0.007	RYR2
regulation of slow-twitch skeletal muscle fiber contraction	1	842.6×	0.011	MYH7
regulation of muscle filament sliding	1	842.6×	0.011	MYBPC3
Purkinje myocyte to ventricular cardiac muscle cell signaling	1	842.6×	0.011	RYR2
regulation of the force of skeletal muscle contraction	1	561.7×	0.011	MYH7
skeletal muscle myosin thick filament assembly	1	561.7×	0.011	TCAP
CD4-positive or CD8-positive, alpha-beta T cell lineage commitment	1	561.7×	0.011	BRAF
sarcomerogenesis	1	561.7×	0.011	TCAP
type B pancreatic cell apoptotic process	1	561.7×	0.011	RYR2
regulation of AV node cell action potential	1	561.7×	0.011	RYR2
regulation of atrial cardiac muscle cell action potential	1	561.7×	0.011	RYR2
left ventricular cardiac muscle tissue morphogenesis	1	421.3×	0.013	RYR2
obsolete positive regulation of sequestering of calcium ion	1	421.3×	0.013	RYR2
positive regulation of axon regeneration	1	337.0×	0.014	BRAF
sarcoplasmic reticulum calcium ion transport	1	337.0×	0.014	RYR2
positive regulation of the force of heart contraction	1	337.0×	0.014	RYR2
negative regulation of synaptic vesicle exocytosis	1	337.0×	0.014	BRAF
regulation of extrinsic apoptotic signaling pathway	1	337.0×	0.014	MADD
amino acid catabolic process	1	280.9×	0.014	ETFA

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 8

Druggability breadth: 5 of 10 evidence-associated genes (50%) 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
BRAF	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BRAF	48	4
RYR2	1	2
MYBPC3	0	0
TCAP	0	0
TNNT2	0	0
LDB3	0	0
DNAAF3	0	0
ETFA	0	0
MADD	0	0
MYH7	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	BRAF
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF
SORAFENIB	4	BRAF
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF
DASATINIB	4	BRAF
ERLOTINIB	4	BRAF
GEFITINIB	4	BRAF
IMATINIB	4	BRAF
MASITINIB	3	BRAF
AVUTOMETINIB	3	BRAF
NAPORAFENIB	3	BRAF
QUERCETIN	3	BRAF
MOTESANIB	3	BRAF
ALADORIAN	2	RYR2
DORAMAPIMOD	2	BRAF
FORETINIB	2	BRAF
REBASTINIB	2	BRAF
CEP-32496	2	BRAF

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
RYR2	15	Binding:15
TNNT2	2	Binding:2
ETFA	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
BRAF	1,442

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; 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)
VEMURAFENIB	4	BRAF
PONATINIB	4	BRAF
FEDRATINIB	4	BRAF
SORAFENIB	4	BRAF
DASATINIB ANHYDROUS	4	BRAF
RUXOLITINIB	4	BRAF
INFIGRATINIB PHOSPHATE	4	BRAF
INFIGRATINIB	4	BRAF
REGORAFENIB	4	BRAF
DABRAFENIB	4	BRAF
COBIMETINIB	4	BRAF
NILOTINIB	4	BRAF
ABEMACICLIB	4	BRAF
ENCORAFENIB	4	BRAF
TOVORAFENIB	4	BRAF
PAZOPANIB	4	BRAF
DASATINIB	4	BRAF
ERLOTINIB	4	BRAF
GEFITINIB	4	BRAF
IMATINIB	4	BRAF
MASITINIB	3	BRAF
AVUTOMETINIB	3	BRAF
NAPORAFENIB	3	BRAF
QUERCETIN	3	BRAF
MOTESANIB	3	BRAF
ALADORIAN	2	RYR2
DORAMAPIMOD	2	BRAF
FORETINIB	2	BRAF
REBASTINIB	2	BRAF
CEP-32496	2	BRAF

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	BRAF
B	Phased (≥1) drug, not yet approved	1	RYR2
C	Druggable family + PDB, no drug	1	MYBPC3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	7	TCAP, TNNT2, LDB3, DNAAF3, ETFA, MADD, MYH7

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MYBPC3	0	—
TCAP	0	—
TNNT2	2	—
LDB3	0	—
DNAAF3	0	—
ETFA	1	—
MADD	0	—
MYH7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening