JPH2

Summary

JPH2 (junctophilin 2, HGNC:14202) is a protein-coding gene on chromosome 20q13.12, encoding Junctophilin-2 (Q9BR39). 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.

Junctional complexes between the plasma membrane and endoplasmic/sarcoplasmic reticulum are a common feature of all excitable cell types and mediate cross talk between cell surface and intracellular ion channels. The protein encoded by this gene is a component of junctional complexes and is composed of a C-terminal hydrophobic segment spanning the endoplasmic/sarcoplasmic reticulum membrane and a remaining cytoplasmic domain that shows specific affinity for the plasma membrane. This gene is a member of the junctophilin gene family. Alternative splicing has been observed at this locus and two variants encoding distinct isoforms are described.

Source: NCBI Gene 57158 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cardiomyopathy, dilated, 2E (Strong, ClinGen) — +3 more curated relationships
• GWAS associations: 24
• Clinical variants (ClinVar): 1,129 total — 5 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 28
• MANE Select transcript: NM_020433

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14202
Approved symbol	JPH2
Name	junctophilin 2
Location	20q13.12
Locus type	gene with protein product
Status	Approved
Aliases	JP-2, JP2
Ensembl gene	ENSG00000149596
Ensembl biotype	protein_coding
OMIM	605267
Entrez	57158

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 14 protein_coding

ENST00000342272, ENST00000372980, ENST00000900328, ENST00000900329, ENST00000900330, ENST00000900331, ENST00000950203, ENST00000950204, ENST00000950205, ENST00000950206, ENST00000950207, ENST00000950208, ENST00000950209, ENST00000950210

RefSeq mRNA: 2 — MANE Select: NM_020433 NM_020433, NM_175913

CCDS: CCDS13325, CCDS13326

Canonical transcript exons

ENST00000372980 — 6 exons

Exon	Start	End
ENSE00000991558	44118505	44118623
ENSE00000991559	44115665	44116386
ENSE00001126824	44159618	44160407
ENSE00001230859	44114782	44114876
ENSE00001230862	44186327	44187188
ENSE00001459224	44106590	44113503

Expression profiles

Bgee: expression breadth ubiquitous, 173 present calls, max score 98.32.

FANTOM5 (CAGE): breadth broad, TPM avg 1.9792 / max 91.0322, expressed in 468 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
187314	1.5796	413
187313	0.1302	63
187315	0.1301	74
187312	0.1039	50
187316	0.0355	8

Top tissues by expression

249 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	98.32	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	96.60	gold quality
tibialis anterior	UBERON:0001385	96.40	gold quality
cardiac muscle of right atrium	UBERON:0003379	95.89	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.26	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.04	gold quality
biceps brachii	UBERON:0001507	94.70	gold quality
apex of heart	UBERON:0002098	94.59	gold quality
skeletal muscle tissue	UBERON:0001134	93.90	gold quality
quadriceps femoris	UBERON:0001377	93.74	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.61	gold quality
lower esophagus	UBERON:0013473	93.52	gold quality
vastus lateralis	UBERON:0001379	93.20	gold quality
muscle tissue	UBERON:0002385	93.15	gold quality
heart left ventricle	UBERON:0002084	92.86	gold quality
popliteal artery	UBERON:0002250	92.66	gold quality
cardiac ventricle	UBERON:0002082	92.64	gold quality
tibial artery	UBERON:0007610	92.64	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.32	gold quality
right coronary artery	UBERON:0001625	92.25	gold quality
aorta	UBERON:0000947	91.35	gold quality
gastrocnemius	UBERON:0001388	91.04	gold quality
deltoid	UBERON:0001476	91.04	gold quality
muscle of leg	UBERON:0001383	90.97	gold quality
heart	UBERON:0000948	90.69	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.56	gold quality
myocardium	UBERON:0002349	90.35	gold quality
smooth muscle tissue	UBERON:0001135	90.21	gold quality
thoracic aorta	UBERON:0001515	89.77	gold quality
ascending aorta	UBERON:0001496	89.69	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.73

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, MEF2A

miRNA regulators (miRDB)

78 targeting JPH2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6512-3P	99.65	66.07	1468

Literature-anchored findings (GeneRIF, showing 25)

• this is the first report on JPH2 mutation associated with hypertrophic cardiomyopathy (PMID:17476457)
• Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy. (PMID:17509612)
• S165F mutation of junctophilin 2 affects Ca2+ signalling in skeletal muscle. (PMID:20095964)
• JPH2 levels are reduced in patients with hypertrophic cardiomyopathy. Reduced JPH2 expression results in reduced excitation-contraction coupling gain as well as altered Ca(2+) homeostasis, which may be associated with prohypertrophic remodeling. (PMID:21216834)
• Loss-of-function mutations in JPH2 leads to cardiac-specific JPH2 deficiency and results in impaired cardiac contractility, causing heart failure and increased mortality. (PMID:21339484)
• JP1 and JP2 can facilitate the assembly of DHPR with other proteins of the excitation-contraction coupling machinery (PMID:22020936)
• Hypertrophy in skeletal myotubes induced by junctophilin-2 mutant, Y141H, involves an increase in store-operated Ca2+ entry via Orai1. (PMID:22389502)
• This study demonstrates that both JP1 and JP2 in skeletal muscle undergo Ca2+-dependent proteolysis by endogenous proteases when the intracellular Ca2+ is raised within the physiological range for a sustained period (PMID:23148318)
• The S101R mutation may have an effect upon the stability of the JP2 dyad organization with the potential to alter JP2-protein interactions regulating calcium cycling. (PMID:24001019)
• Our data identify a mechanistic link between microtubule densification and T-tubule remodeling and reveal microtubule-mediated JP2 redistribution as a novel mechanism for T-tubule disruption, loss of excitation-contraction coupling, and heart failure. (PMID:24519927)
• Junctophilin-2 is cleaved by calpain at multiple sites, resulting in dysfunctional junctophilin-2 truncations. (PMID:26063807)
• a novel mutation in JPH2 which suggests for the first time that JPH2 could cause dilated cardiomyopathy. (PMID:27471098)
• Junctophilin 2, as junctional membrane complex (JMC) protein, is an important regulator of the cardiac SK channels (PMID:29055091)
• the heterozygous JPH2 p.(Thr161Lys) variant is a new Finnish mutation causing atypical hypertrophic cardiomyopathy. (PMID:30235249)
• Junctophilin-2 expression rescues atrial dysfunction through polyadic junctional membrane complex biogenesis. (PMID:31217359)
• Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy. (PMID:31227780)
• The palmitoylatable Cys residues in JPH2 are conserved in other JPHs, suggesting that palmitoylation may also enhance ER/SR-PM tethering by these proteins. (PMID:31337710)
• Nuclear localization of a novel calpain-2 mediated junctophilin-2 C-terminal cleavage peptide promotes cardiomyocyte remodeling. (PMID:32592107)
• Interaction of the Joining Region in Junctophilin-2 With the L-Type Ca(2+) Channel Is Pivotal for Cardiac Dyad Assembly and Intracellular Ca(2+) Dynamics. (PMID:33092464)
• Sequence determinants of human junctophilin-2 protein nuclear localization and phase separation. (PMID:34062390)
• One gene, two modes of inheritance, four diseases: A systematic review of the cardiac manifestation of pathogenic variants in JPH2-encoded junctophilin-2. (PMID:34861382)
• Editorial commentary: Genomic and precision medicine provides deeper insights into the genetic basis of diverse JPH2-mediated phenotypes. (PMID:34965474)
• Junctophilins 1, 2, and 3 all support voltage-induced Ca2+ release despite considerable divergence. (PMID:35089322)
• Structures of the junctophilin/voltage-gated calcium channel interface reveal hot spot for cardiomyopathy mutations. (PMID:35238659)
• Junctophilin-2 is a double-stranded RNA-binding protein that regulates cardiomyocyte-autonomous innate immune response. (PMID:39317111)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	jph2	ENSDARG00000028625
mus_musculus	Jph2	ENSMUSG00000017817
rattus_norvegicus	Jph2	ENSRNOG00000008170
drosophila_melanogaster	jp	FBGN0032129
caenorhabditis_elegans	jph-1	WBGENE00002179

Paralogs (3): JPH4 (ENSG00000092051), JPH1 (ENSG00000104369), JPH3 (ENSG00000154118)

Protein

Protein identifiers

Junctophilin-2 — Q9BR39 (reviewed: Q9BR39)

Alternative names: Junctophilin type 2

All UniProt accessions (1): Q9BR39

UniProt curated annotations — full annotation on UniProt →

Function. 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. Provides a structural foundation for functional cross-talk between the cell surface and intracellular Ca(2+) release channels by maintaining the 12-15 nm gap between the sarcolemma and the sarcoplasmic reticulum membranes in the cardiac dyads. Necessary for proper intracellular Ca(2+) signaling in cardiac myocytes via its involvement in ryanodine receptor-mediated calcium ion release. Contributes to the construction of skeletal muscle triad junctions. Transcription repressor required to safeguard against the deleterious effects of cardiac stress. Generated following cleavage of the Junctophilin-2 chain by calpain in response to cardiac stress in cardiomyocytes. Following cleavage and release from the membrane, translocates to the nucleus, binds DNA and represses expression of genes implicated in cell growth and differentiation, hypertrophy, inflammation and fibrosis. Modifies the transcription profile and thereby attenuates pathological remodeling in response to cardiac stress. Probably acts by competing with MEF2 transcription factors and TATA-binding proteins.

Subunit / interactions. Interacts with TRPC3. Interacts with BAG5 and HSPA8; the interaction with HSPA8 is increased in the presence of BAG5. Interacts with MEF2C.

Subcellular location. Cell membrane. Sarcoplasmic reticulum membrane. Endoplasmic reticulum membrane Nucleus.

Tissue specificity. Specifically expressed in skeletal muscle and heart.

Post-translational modifications. Phosphorylation on Ser-165, probably by PKC, affects RYR1-mediated calcium ion release, interaction with TRPC3, and skeletal muscle myotubule development. Proteolytically cleaved by calpain in response to cardiac stress. The major cleavage site takes place at the C-terminus and leads to the release of the Junctophilin-2 N-terminal fragment chain (JP2NT).

Disease relevance. Cardiomyopathy, familial hypertrophic, 17 (CMH17) [MIM:613873] A hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death. The disease is caused by variants affecting the gene represented in this entry. Cardiomyopathy, dilated, 2E (CMD2E) [MIM:619492] A form of dilated cardiomyopathy, a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. CMD2E is an autosomal recessive form with neonatal or early childhood onset and rapid progression to cardiac failure. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The MORN (membrane occupation and recognition nexus) repeats contribute to the plasma membrane binding, by interacting with phospholipids. Has affinity for phosphatidylserine, and phosphorylated phosphatidylinositols including PtdIns3P, PtdIns4P, PtdIns5P, PtdIns(3,5)P2 and PtdIns(3,4,5)P3. The bipartite nuclear localization signal (bNLS) and Ala-rich (alanine-rich; ARR) regions are involved in DNA-binding.

Similarity. Belongs to the junctophilin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BR39-1	1	yes
Q9BR39-2	2

RefSeq proteins (2): NP_065166, NP_787109 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003409	MORN	Repeat
IPR017191	Junctophilin	Family

Pfam: PF02493

UniProt features (74 total): strand 19, modified residue 12, sequence variant 11, repeat 8, compositionally biased region 6, helix 4, region of interest 3, site 3, chain 2, short sequence motif 2, splice variant 2, topological domain 1, transmembrane region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7RXQ	X-RAY DIFFRACTION	2.03
7RXE	X-RAY DIFFRACTION	2.35

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BR39-F1	65.09	0.37

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 155–156 (cleavage; by calpain); 204–205 (cleavage; by calpain); 572–573 (cleavage; by calpain)

Post-translational modifications (12): 162, 165, 446, 448, 469, 477, 484, 486, 490, 534, 594, 598

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 205 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_REGULATION_OF_CARDIAC_MUSCLE_TISSUE_DEVELOPMENT, GOBP_CIRCULATORY_SYSTEM_PROCESS, TGACCTY_ERR1_Q2, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_REGULATION_OF_STRIATED_MUSCLE_CONTRACTION, SRF_C, GOBP_REGULATION_OF_MUSCLE_CONTRACTION, GOBP_MUSCLE_STRUCTURE_DEVELOPMENT, GOBP_MUSCLE_CONTRACTION, GOBP_REGULATION_OF_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_REGULATION_OF_CARDIAC_MUSCLE_CONTRACTION_BY_CALCIUM_ION_SIGNALING, GOBP_MAINTENANCE_OF_LOCATION

GO Biological Process (8): regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum (GO:0010880), regulation of cardiac muscle contraction by calcium ion signaling (GO:0010882), regulation of cardiac muscle tissue development (GO:0055024), calcium ion homeostasis (GO:0055074), obsolete positive regulation of ryanodine-sensitive calcium-release channel activity (GO:0060316), calcium ion transport into cytosol (GO:0060402), negative regulation of transcription by RNA polymerase II (GO:0000122), positive regulation of cytosolic calcium ion concentration (GO:0007204)

GO Molecular Function (11): DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), phosphatidylserine binding (GO:0001786), DNA binding (GO:0003677), phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), phosphatidylinositol-3,4,5-trisphosphate binding (GO:0005547), phosphatidylinositol-5-phosphate binding (GO:0010314), phosphatidylinositol-3-phosphate binding (GO:0032266), phosphatidylinositol-4-phosphate binding (GO:0070273), phosphatidic acid binding (GO:0070300), phosphatidylinositol-3,5-bisphosphate binding (GO:0080025), protein binding (GO:0005515)

GO Cellular Component (10): nucleus (GO:0005634), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), junctional sarcoplasmic reticulum membrane (GO:0014701), sarcoplasmic reticulum (GO:0016529), Z disc (GO:0030018), junctional membrane complex (GO:0030314), endoplasmic reticulum (GO:0005783), membrane (GO:0016020), sarcoplasmic reticulum membrane (GO:0033017)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
phosphatidylinositol phosphate binding	6
anion binding	5
phospholipid binding	2
phosphatidylinositol bisphosphate binding	2
intracellular membrane-bounded organelle	2
sarcoplasm	2
cellular anatomical structure	2
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1
regulation of release of sequestered calcium ion into cytosol	1
calcium-mediated signaling	1
regulation of cardiac muscle contraction	1
cardiac muscle contraction	1
regulation of striated muscle tissue development	1
cardiac muscle tissue development	1
monoatomic cation homeostasis	1
inorganic ion homeostasis	1
positive regulation of cytosolic calcium ion concentration	1
calcium ion transmembrane import into cytosol	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
regulation of biological quality	1
negative regulation of transcription by RNA polymerase II	1
RNA polymerase II transcription regulatory region sequence-specific DNA binding	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
modified amino acid binding	1
nucleic acid binding	1
binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
sarcoplasmic reticulum membrane	1
endoplasmic reticulum	1
I band	1
protein-containing complex	1
cytoplasm	1
endomembrane system	1

Protein interactions and networks

STRING

1216 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
JPH2	TRDN	Q13061	852
JPH2	CAV3	P56539	811
JPH2	RYR1	P21817	808
JPH2	SYPL2	Q5VXT5	757
JPH2	RYR2	Q92736	745
JPH2	ASPH	Q12797	742
JPH2	SPEG	Q15772	719
JPH2	CACNA1C	Q13936	694
JPH2	BIN1	O00499	680
JPH2	TRPC3	Q13507	670
JPH2	TCAP	O15273	662
JPH2	CASQ1	P31415	657
JPH2	CACNA1S	Q13698	647
JPH2	CALR3	Q96L12	620
JPH2	CASQ2	O14958	613

IntAct

17 interactions, top by confidence:

A	B	Type	Score
JPH2	H2AC14	psi-mi:“MI:0915”(physical association)	0.400
MTCL2	JPH2	psi-mi:“MI:0915”(physical association)	0.400
H4C16	JPH2	psi-mi:“MI:0915”(physical association)	0.400
CNOT10	JPH2	psi-mi:“MI:0915”(physical association)	0.400
JPH2	HMGA1	psi-mi:“MI:0915”(physical association)	0.400
JPH2	H2BC9	psi-mi:“MI:0915”(physical association)	0.400
JPH2	H2BC15	psi-mi:“MI:0915”(physical association)	0.400
JPH2	H2BC5	psi-mi:“MI:0915”(physical association)	0.400
JPH2	NPM1	psi-mi:“MI:0915”(physical association)	0.400
JPH2	H2BC20P	psi-mi:“MI:0915”(physical association)	0.400
JPH2	H2BC13	psi-mi:“MI:0915”(physical association)	0.400
H2BC21	JPH2	psi-mi:“MI:0915”(physical association)	0.400
H3-4	JPH2	psi-mi:“MI:0915”(physical association)	0.400
EMX2	JPH2	psi-mi:“MI:0915”(physical association)	0.400
TMTC1	JPH2	psi-mi:“MI:0915”(physical association)	0.400
JPH2	SDC2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (45): JPH2 (Affinity Capture-Western), JPH2 (Proximity Label-MS), JPH2 (Proximity Label-MS), JPH2 (Proximity Label-MS), JPH2 (Proximity Label-MS), JPH2 (Proximity Label-MS), JPH2 (Proximity Label-MS), JPH2 (Proximity Label-MS), JPH2 (Proximity Label-MS), JPH2 (Proximity Label-MS), CNOT10 (Proximity Label-MS), JPH2 (Proximity Label-MS), JPH2 (Proximity Label-MS), JPH2 (Proximity Label-MS), JPH2 (Proximity Label-MS)

ESM2 similar proteins: A0A8P0N4K0, A2AB59, B4F7F3, D3YZU1, D3ZD05, O35681, O75427, O95382, P22455, P22607, P40748, P55144, P70218, Q06418, Q14160, Q1LZH7, Q2PS20, Q32P44, Q495M9, Q4ACU6, Q4H4B6, Q505F5, Q5F488, Q61851, Q63ZY3, Q6P9K8, Q6TLK4, Q6ZUM4, Q7KRY7, Q80T11, Q80U72, Q8BH60, Q8BX02, Q8N1G4, Q8TE68, Q8VC03, Q8VHK1, Q8VHK2, Q8WXD9, Q8WXE0

Diamond homologs: Q2PS20, Q69FB3, Q80WT0, Q8WXH2, Q96JJ6, Q9BR39, Q9ET77, Q9ET78, Q9ET80, Q9GKY7, Q9GKY8, Q9HDC5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SPEG	“up-regulates activity”	JPH2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 16 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Packaging Of Telomere Ends	8	135.2×	1e-14
Recognition and association of DNA glycosylase with site containing an affected purine	8	125.5×	1e-14
Cleavage of the damaged purine	8	125.5×	1e-14
Replacement of protamines by nucleosomes in the male pronucleus	6	125.5×	1e-11
Recognition and association of DNA glycosylase with site containing an affected pyrimidine	8	113.3×	2e-14
Cleavage of the damaged pyrimidine	8	113.3×	2e-14
Inhibition of DNA recombination at telomere	8	103.3×	3e-14
DNA Damage/Telomere Stress Induced Senescence	8	100.4×	3e-14

GO biological processes:

GO term	Partners	Fold	FDR
nucleosome assembly	7	70.2×	2e-10

Disease & clinical

Clinical variants and AI predictions

ClinVar

1129 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	3
Uncertain significance	627
Likely benign	369
Benign	38

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
1205834	NM_020433.5(JPH2):c.1920dup (p.Glu641Ter)	Pathogenic
30455	NM_020433.5(JPH2):c.301A>C (p.Ser101Arg)	Pathogenic
30457	NM_020433.5(JPH2):c.494C>T (p.Ser165Phe)	Pathogenic
3768220	NM_020433.5(JPH2):c.54G>A (p.Trp18Ter)	Pathogenic
4813523	NM_020433.5(JPH2):c.107del (p.Gly36fs)	Pathogenic
4081465	NM_020433.5(JPH2):c.575C>A (p.Ser192Ter)	Likely pathogenic
4277386	NM_020433.5(JPH2):c.1836del (p.Glu613fs)	Likely pathogenic
829986	NM_020433.5(JPH2):c.191G>A (p.Trp64Ter)	Likely pathogenic

SpliceAI

1424 predictions. Top by Δscore:

Variant	Effect	Δscore
20:44113502:CT:C	acceptor_gain	1.0000
20:44113504:C:CA	acceptor_loss	1.0000
20:44113504:C:CC	acceptor_gain	1.0000
20:44113505:T:A	acceptor_loss	1.0000
20:44114776:CTGCA:C	donor_loss	1.0000
20:44114777:TGCAC:T	donor_loss	1.0000
20:44114778:GCAC:G	donor_loss	1.0000
20:44114779:CACCT:C	donor_loss	1.0000
20:44114780:AC:A	donor_loss	1.0000
20:44114781:CCTGG:C	donor_loss	1.0000
20:44114873:GGACC:G	acceptor_loss	1.0000
20:44114877:CTGG:C	acceptor_loss	1.0000
20:44114878:T:A	acceptor_loss	1.0000
20:44118501:CTACC:C	donor_loss	1.0000
20:44118502:TA:T	donor_loss	1.0000
20:44118504:C:CT	donor_loss	1.0000
20:44118504:CCTGG:C	donor_gain	1.0000
20:44118621:GTCC:G	acceptor_loss	1.0000
20:44118622:TC:T	acceptor_gain	1.0000
20:44118623:CC:C	acceptor_gain	1.0000
20:44118623:CCT:C	acceptor_loss	1.0000
20:44118624:C:CG	acceptor_loss	1.0000
20:44181466:T:A	donor_gain	1.0000
20:44114874:GAC:G	acceptor_gain	0.9900
20:44114877:C:CC	acceptor_gain	0.9900
20:44114884:C:CT	acceptor_gain	0.9900
20:44114885:A:T	acceptor_gain	0.9900
20:44115659:CCTCA:C	donor_loss	0.9900
20:44115660:CTCA:C	donor_loss	0.9900
20:44115662:CACC:C	donor_loss	0.9900

AlphaMissense

4453 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:44118546:C:G	R416P	1.000
20:44118549:G:T	A415D	1.000
20:44118559:A:G	S412P	1.000
20:44118612:G:T	A394D	1.000
20:44118613:C:G	A394P	1.000
20:44118623:C:A	R390S	1.000
20:44118623:C:G	R390S	1.000
20:44159618:C:A	R390M	1.000
20:44159618:C:G	R390T	1.000
20:44159627:G:T	A387D	1.000
20:44159833:C:A	W318C	1.000
20:44159833:C:G	W318C	1.000
20:44159835:A:G	W318R	1.000
20:44159835:A:T	W318R	1.000
20:44159889:G:T	R300S	1.000
20:44159894:T:A	D298V	1.000
20:44159895:C:G	D298H	1.000
20:44159902:C:A	W295C	1.000
20:44159902:C:G	W295C	1.000
20:44159903:C:G	W295S	1.000
20:44159904:A:G	W295R	1.000
20:44159904:A:T	W295R	1.000
20:44159910:C:G	G293R	1.000
20:44160187:G:C	F200L	1.000
20:44160187:G:T	F200L	1.000
20:44160189:A:G	F200L	1.000
20:44160349:G:C	S146R	1.000
20:44160349:G:T	S146R	1.000
20:44160351:T:G	S146R	1.000
20:44160356:C:G	R144P	1.000

dbSNP variants (sampled 300 via entrez): RS1000040263 (20:44181659 G>A), RS1000048351 (20:44140254 A>G), RS1000122465 (20:44139039 G>A), RS1000124880 (20:44110779 T>C), RS1000141853 (20:44151737 C>G), RS1000183783 (20:44168816 T>G), RS1000185940 (20:44175474 C>T), RS1000203850 (20:44133805 G>A), RS1000212334 (20:44149989 G>A,T), RS1000236058 (20:44168658 G>A), RS1000246287 (20:44126979 C>T), RS1000317475 (20:44169216 G>T), RS1000415145 (20:44181412 T>C), RS1000437553 (20:44133355 C>T), RS1000469245 (20:44176771 G>T)

Disease associations

OMIM: gene MIM:605267 | disease phenotypes: MIM:613873, MIM:619492, MIM:192600, MIM:603829, MIM:115195

GenCC curated gene-disease

Disease	Classification	Inheritance
cardiomyopathy, dilated, 2E	Strong	Autosomal recessive
hypertrophic cardiomyopathy 17	Strong	Autosomal dominant
hypertrophic cardiomyopathy	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (3)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hypertrophic cardiomyopathy	Moderate	AD
cardiomyopathy, dilated, 2E	Strong	AR
dilated cardiomyopathy	Limited	AD

Mondo (10): hypertrophic cardiomyopathy (MONDO:0005045), hypertrophic cardiomyopathy 17 (MONDO:0013474), cardiomyopathy, dilated, 2E (MONDO:0030366), long QT syndrome (MONDO:0002442), familial hypertrophic cardiomyopathy (MONDO:0024573), dilated cardiomyopathy (MONDO:0005021), ventricular fibrillation, paroxysmal familial, type 1 (MONDO:0011376), cardiomyopathy (MONDO:0004994), hypertrophic cardiomyopathy 1 (MONDO:0008647), hypertrophic cardiomyopathy 2 (MONDO:0007266)

Orphanet (6): Rare hypertrophic cardiomyopathy (Orphanet:217569), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), Dilated cardiomyopathy (Orphanet:217604), Idiopathic ventricular fibrillation (Orphanet:228140), Rare cardiomyopathy (Orphanet:167848), NON RARE IN EUROPE: Familial isolated hypertrophic cardiomyopathy (Orphanet:155)

HPO phenotypes

28 total (28 of 28 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000969	Edema
HP:0001522	Death in infancy
HP:0001635	Congestive heart failure
HP:0001639	Hypertrophic cardiomyopathy
HP:0001644	Dilated cardiomyopathy
HP:0001681	Angina pectoris
HP:0001685	Myocardial fibrosis
HP:0001712	Left ventricular hypertrophy
HP:0001727	Thromboembolic stroke
HP:0001962	Palpitations
HP:0002094	Dyspnea
HP:0002875	Exertional dyspnea
HP:0003198	Myopathy
HP:0003457	EMG abnormality
HP:0003819	Death in childhood
HP:0004756	Ventricular tachycardia
HP:0005110	Atrial fibrillation
HP:0006673	Reduced systolic function
HP:0010316	Ebstein anomaly of the tricuspid valve
HP:0011462	Young adult onset
HP:0011675	Arrhythmia
HP:0012378	Fatigue
HP:0012764	Orthopnea
HP:0025169	Left ventricular systolic dysfunction
HP:0100578	Lipoatrophy

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST002595_20	Clozapine-induced agranulocytosis	6.000000e-06
GCST003372_6	Glomerular filtration rate (creatinine)	3.000000e-07
GCST004632_83	Lymphocyte percentage of white cells	9.000000e-11
GCST004633_15	Neutrophil percentage of white cells	9.000000e-14
GCST005979_23	Systolic blood pressure	3.000000e-09
GCST006010_19	Mean arterial pressure	3.000000e-09
GCST007096_231	Pulse pressure	3.000000e-11
GCST007097_50	Pulse pressure	5.000000e-06
GCST007099_190	Systolic blood pressure	2.000000e-08
GCST007267_158	Systolic blood pressure	6.000000e-17
GCST007269_142	Pulse pressure	1.000000e-09
GCST007703_78	Systolic blood pressure	2.000000e-06
GCST007706_126	Mean arterial pressure	2.000000e-06
GCST007706_94	Mean arterial pressure	2.000000e-11
GCST007928_23	Medication use (diuretics)	4.000000e-09
GCST007929_47	Medication use (calcium channel blockers)	8.000000e-10
GCST007930_149	Medication use (agents acting on the renin-angiotensin system)	5.000000e-10
GCST010219_20	Attention deficit hyperactivity disorder (inattention symptoms)	3.000000e-07
GCST011836_5	Cervical high-risk human papilloma virus infection (persistent)	3.000000e-07
GCST90000025_687	Appendicular lean mass	1.000000e-09
GCST90002388_580	Lymphocyte count	5.000000e-12
GCST90002389_422	Lymphocyte percentage of white cells	6.000000e-14
GCST90002399_453	Neutrophil percentage of white cells	1.000000e-19
GCST90002400_300	Plateletcrit	5.000000e-12

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes
EFO:0006335	systolic blood pressure
EFO:0006340	mean arterial pressure
EFO:0005763	pulse pressure measurement
EFO:0009928	Diuretic use measurement
EFO:0009930	Calcium channel blocker use measurement
EFO:0009931	Agents acting on the renin-angiotensin system use measurement
EFO:0004980	appendicular lean mass
EFO:0004587	lymphocyte count
EFO:0007985	platelet crit

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D009202	Cardiomyopathies	C14.280.238
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
C566171	Cardiomyopathy, Familial Hypertrophic, 2 (supp.)
C567851	Ventricular Fibrillation, Paroxysmal Familial, 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

40 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, increases methylation	3
Cadmium Chloride	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
fluorene-9-bisphenol	increases expression	1
methyleugenol	decreases expression	1
trimellitic anhydride	decreases expression	1
sulforaphane	decreases expression	1
sodium arsenite	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
benzo(e)pyrene	increases methylation	1
chromium hexavalent ion	increases abundance, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases response to substance, decreases expression	1
jinfukang	affects cotreatment, decreases expression	1
prothioconazole	increases expression	1
(+)-JQ1 compound	increases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Bleomycin	decreases expression	1
Cannabidiol	decreases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Methapyrilene	increases methylation	1
Nickel	decreases expression	1

Cellosaurus cell lines

3 cell lines: 2 induced pluripotent stem cell, 1 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_ZA77	TAUi001-A	Induced pluripotent stem cell	Male
CVCL_ZA78	TAUi001-A-1	Induced pluripotent stem cell	Male
CVCL_ZX63	WAe009-A-36	Embryonic stem cell	Female

Clinical trials (associated diseases)

227 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00879060	PHASE4	COMPLETED	Clinical and Therapeutic Implications of Fibrosis in Hypertrophic Cardiomyopathy
NCT01721967	PHASE4	COMPLETED	Ranolazine for the Treatment of Chest Pain in HCM Patients
NCT02948998	PHASE4	UNKNOWN	Evaluating the Effect of Spironolactone on Hypertrophic Cardiomyopathy
NCT03249272	PHASE4	TERMINATED	Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve
NCT04133532	PHASE4	COMPLETED	Effect of Metoprolol in Post Alcohol Septal Ablation Patients With Hypertrophic Cardiomyopathy
NCT06401343	PHASE4	RECRUITING	Use of SGLT2i in noHCM With HFpEF
NCT07103655	PHASE4	NOT_YET_RECRUITING	The Therapeutic Value of Mavacamten in Hypertrophic Cardiomyopathy With Mid-to-Apical Left Ventricular Obstruction
NCT07600177	PHASE4	RECRUITING	Mavacamten to Aficamten Transition in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT00317967	PHASE3	COMPLETED	Study to Determine if Atorvastatin Reduces Size and Stiffness of Muscle in the Left Ventricle of the Heart
NCT00698074	PHASE3	UNKNOWN	Diastolic Ventricular Interaction and the Effects of Biventricular Pacing in Hypertrophic Cardiomyopathy
NCT00821353	PHASE3	COMPLETED	Antiarrhythmic Therapy Versus Catheter Ablation for Atrial Fibrillation in Hypertrophic Cardiomyopathy
NCT02431221	PHASE3	WITHDRAWN	Efficacy, Safety, and Tolerability of Perhexiline in Subjects With Hypertrophic Cardiomyopathy and Heart Failure
NCT03470545	PHASE3	COMPLETED	Clinical Study to Evaluate Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT05174416	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mavacamten in Chinese Adults With Symptomatic Obstructive HCM
NCT05182658	PHASE3	ACTIVE_NOT_RECRUITING	Empagliflozin in Hypertrophic Cardiomyopathy
NCT05186818	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Placebo in Adults With Symptomatic oHCM
NCT05767346	PHASE3	COMPLETED	Phase 3 Trial to Evaluate the Efficacy and Safety of Aficamten Compared to Metoprolol Succinate in Adults With Symptomatic oHCM
NCT06116968	PHASE3	COMPLETED	An Open-Label Study of Aficamten for Chinese Patients With Symptomatic oHCM
NCT06873828	PHASE3	NOT_YET_RECRUITING	Evaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter MonitoringEvaluation of the Efficacy and Safety of Wearable ECG (AT-Patch) in Patients With Hypertrophic Cardiomyopathy Requiring 48-Hour Holter Monitoring
NCT07021976	PHASE3	RECRUITING	A Phase III Trial of HRS-1893 in Patients With Obstructive Hypertrophic Cardiomyopathy
NCT07023341	PHASE3	ACTIVE_NOT_RECRUITING	A Study to Learn More About How Well Aficamten Works in Japanese Participants With Symptomatic Obstructive Hypertrophic Cardiomyopathy
NCT07202897	PHASE3	NOT_YET_RECRUITING	LA-HCM Study : Rivaroxaban for Antithrombotic Prevention in Hypertrophic Cardiomyopathy Patients With Abnormal Left Atrial Strain.
NCT00001631	PHASE2	COMPLETED	Study of Blood Flow in Heart Muscle
NCT00001894	PHASE2	COMPLETED	A Comparison of Two Treatments: Pacemaker and Percutaneous Transluminal Septal Ablation for Hypertrophic Cardiomyopathy
NCT00001960	PHASE2	COMPLETED	Studying the Effectiveness of Pacemaker Therapy in Children Who Have Thickened Heart Muscle
NCT00011076	PHASE2	COMPLETED	Pirfenidone to Treat Hypertrophic Cardiomyopathy
NCT00035386	PHASE2	COMPLETED	Alcohol Septal Ablation in Obstructive Hypertrophic Cardiomyopathy: A Pilot Study
NCT00430833	PHASE2	UNKNOWN	CHANCE - Candesartan in Hypertrophic Cardiomyopathy
NCT00500552	PHASE2	COMPLETED	Perhexiline Therapy in Patients With Hypertrophic Cardiomyopathy
NCT01150461	PHASE2	COMPLETED	Effect of Losartan in Patients With Nonobstructive Hypertrophic Cardiomyopathy
NCT01230918	PHASE2	TERMINATED	Study to Develop a Non-invasive Marker for Monitoring Myocardial Fibrosis
NCT01447654	PHASE2	COMPLETED	Inhibition of the Renin Angiotensin System With Losartan in Patients With Hypertrophic Cardiomyopathy
NCT01696370	PHASE2	UNKNOWN	Trimetazidine Therapy in Hypertrophic Cardiomyopathy
NCT01912534	PHASE2	COMPLETED	Valsartan for Attenuating Disease Evolution In Early Sarcomeric HCM
NCT02590809	PHASE2	COMPLETED	Hypertrophic Cardiomyopathy Symptom Release by BX1514M
NCT03496168	PHASE2	COMPLETED	Extension Study of Mavacamten (MYK-461) in Adults With Symptomatic Obstructive Hypertrophic Cardiomyopathy Previously Enrolled in PIONEER
NCT03532802	PHASE2	COMPLETED	The Effect of Metoprolol in Patients With Hypertrophic Obstructive Cardiomyopathy.
NCT03832660	PHASE2	COMPLETED	Sacubitril/Valsartan vs Lifestyle in Hypertrophic Cardiomyopathy
NCT04219826	PHASE2	COMPLETED	Dose-finding Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of CK-3773274 in Adults With Hypertrophic Cardiomyopathy
NCT04426578	PHASE2	UNKNOWN	Role of Perhexiline in Hypertrophic Cardiomyopathy