RYR2

Summary

RYR2 (ryanodine receptor 2, HGNC:10484) is a protein-coding gene on chromosome 1q43, encoding Ryanodine receptor 2 (Q92736). 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.

This gene encodes a ryanodine receptor found in cardiac muscle sarcoplasmic reticulum. The encoded protein is one of the components of a calcium channel, composed of a tetramer of the ryanodine receptor proteins and a tetramer of FK506 binding protein 1B proteins, that supplies calcium to cardiac muscle. Mutations in this gene are associated with stress-induced polymorphic ventricular tachycardia and arrhythmogenic right ventricular dysplasia.

Source: NCBI Gene 6262 — RefSeq curated summary.

At a glance

• Gene–disease (curated): catecholaminergic polymorphic ventricular tachycardia (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 22
• Clinical variants (ClinVar): 9,309 total — 78 pathogenic, 133 likely-pathogenic
• Phenotypes (HPO): 28
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001035

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10484
Approved symbol	RYR2
Name	ryanodine receptor 2
Location	1q43
Locus type	gene with protein product
Status	Approved
Aliases	ARVC2, VTSIP
Ensembl gene	ENSG00000198626
Ensembl biotype	protein_coding
OMIM	180902
Entrez	6262

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000366574, ENST00000462585, ENST00000466626, ENST00000608590, ENST00000609119, ENST00000659194, ENST00000660292, ENST00000661330, ENST00000714018, ENST00000714019, ENST00000714021, ENST00000714022

RefSeq mRNA: 1 — MANE Select: NM_001035 NM_001035

CCDS: CCDS55691

Canonical transcript exons

ENST00000366574 — 105 exons

Exon	Start	End
ENSE00000908141	237550544	237550691
ENSE00000908143	237569145	237569319
ENSE00000908149	237602025	237602111
ENSE00000908150	237610762	237610988
ENSE00000908152	237617286	237617486
ENSE00000908157	237633578	237633710
ENSE00000908159	237638357	237638492
ENSE00000908162	237643327	237643447
ENSE00000908164	237649877	237650097
ENSE00000908166	237654274	237654414
ENSE00000908167	237655821	237655984
ENSE00000908169	237659985	237660074
ENSE00000908170	237660810	237660947
ENSE00000908171	237666512	237666589
ENSE00000908172	237667883	237667958
ENSE00000908206	237787988	237788135
ENSE00000908209	237793867	237793997
ENSE00000908211	237798037	237798170
ENSE00000908212	237801856	237801916
ENSE00000908214	237808901	237809035
ENSE00000908215	237819036	237819192
ENSE00000908216	237828381	237828445
ENSE00000908217	237830530	237830630
ENSE00001022769	237492954	237493087
ENSE00001022773	237387281	237387380
ENSE00001022774	237506710	237506814
ENSE00001022775	237441319	237441483
ENSE00001022777	237445401	237445522
ENSE00001022814	237511688	237511791
ENSE00001022824	237456600	237456735
ENSE00001022826	237374717	237374795
ENSE00001165465	237705213	237705343
ENSE00001165474	237701978	237702059
ENSE00001165512	237678048	237678112
ENSE00001165519	237674731	237674846
ENSE00001165528	237674096	237674219
ENSE00001165545	237651411	237651501
ENSE00001165554	237648444	237648613
ENSE00001165561	237640897	237641002
ENSE00001165569	237639015	237639201
ENSE00001165574	237634889	237634992
ENSE00001165593	237625661	237625804
ENSE00001165599	237614039	237614843
ENSE00001165606	237595498	237595657
ENSE00001165611	237593476	237593636
ENSE00001165618	237591739	237591853
ENSE00001165629	237589793	237590001
ENSE00001165645	237548431	237548590
ENSE00001165655	237530427	237530510
ENSE00001165664	237503289	237503505
ENSE00001165670	237500711	237500903
ENSE00001165676	237496511	237496752
ENSE00001165684	237491806	237491924
ENSE00001165690	237469092	237469187
ENSE00001165694	237454391	237454574
ENSE00001165701	237423092	237423248
ENSE00001165706	237417049	237417123
ENSE00001165710	237388087	237388183
ENSE00001165714	237377323	237377435
ENSE00001165752	237785969	237786036
ENSE00001165758	237566567	237566775
ENSE00001165779	237627807	237628080
ENSE00001165786	237623765	237623870
ENSE00001166352	237369534	237369608
ENSE00001303582	237590640	237590992
ENSE00001308608	237791429	237791515
ENSE00001329360	237783675	237784972
ENSE00001401585	237042184	237042569
ENSE00001422468	237832552	237833988
ENSE00001604858	237806137	237806283
ENSE00001611202	237657944	237658022
ENSE00001631808	237687455	237687504
ENSE00002211141	237330878	237330982
ENSE00002233717	237631427	237631541
ENSE00002242722	237795289	237795331
ENSE00003475557	237770807	237770887
ENSE00003485861	237730260	237730356
ENSE00003488686	237742296	237742349
ENSE00003507227	237759776	237759852
ENSE00003509423	237760955	237761028
ENSE00003517487	237732046	237732149
ENSE00003518284	237792105	237792323
ENSE00003524890	237727087	237727199
ENSE00003524981	237772012	237772100
ENSE00003531557	237700229	237700467
ENSE00003533550	237711745	237711837
ENSE00003533727	237708858	237709098
ENSE00003545364	237756288	237756387
ENSE00003557444	237831514	237831565
ENSE00003579451	237706949	237707269
ENSE00003582754	237778666	237778770
ENSE00003599358	237680456	237680577
ENSE00003604153	237723128	237723262
ENSE00003607820	237717198	237717368
ENSE00003612583	237773520	237773648
ENSE00003616334	237709480	237709567
ENSE00003620408	237757697	237757776
ENSE00003630461	237733705	237733756
ENSE00003645048	237698965	237699025
ENSE00003673763	237718462	237718521
ENSE00003674190	237781565	237781646
ENSE00003686434	237726273	237726308
ENSE00003728105	237270497	237270616
ENSE00004022506	237355965	237355985
ENSE00004022517	237364358	237364372

Expression profiles

Bgee: expression breadth ubiquitous, 210 present calls, max score 99.63.

FANTOM5 (CAGE): breadth broad, TPM avg 10.4210 / max 1158.8465, expressed in 330 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
9272	10.1640	327
9273	0.1653	72
9285	0.0627	8
9284	0.0290	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	99.63	gold quality
left ventricle myocardium	UBERON:0006566	99.37	gold quality
myocardium	UBERON:0002349	99.35	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.31	gold quality
apex of heart	UBERON:0002098	98.75	gold quality
cardiac atrium	UBERON:0002081	98.49	gold quality
right atrium auricular region	UBERON:0006631	98.42	gold quality
cardiac ventricle	UBERON:0002082	98.35	gold quality
heart left ventricle	UBERON:0002084	98.31	gold quality
endothelial cell	CL:0000115	97.64	gold quality
heart	UBERON:0000948	96.89	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.87	gold quality
vena cava	UBERON:0004087	94.74	gold quality
primary visual cortex	UBERON:0002436	93.05	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.91	gold quality
cerebellar hemisphere	UBERON:0002245	92.89	gold quality
cerebellar cortex	UBERON:0002129	92.88	gold quality
cerebellum	UBERON:0002037	92.06	gold quality
right coronary artery	UBERON:0001625	92.02	gold quality
orbitofrontal cortex	UBERON:0004167	90.65	gold quality
occipital lobe	UBERON:0002021	89.88	gold quality
postcentral gyrus	UBERON:0002581	89.83	gold quality
popliteal artery	UBERON:0002250	89.66	gold quality
tibial artery	UBERON:0007610	89.65	gold quality
superior frontal gyrus	UBERON:0002661	89.45	gold quality
parietal lobe	UBERON:0001872	88.94	gold quality
middle temporal gyrus	UBERON:0002771	88.77	gold quality
prefrontal cortex	UBERON:0000451	88.51	gold quality
Brodmann (1909) area 46	UBERON:0006483	88.39	gold quality
aorta	UBERON:0000947	88.27	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	26892.65
E-GEOD-180759	yes	2868.56
E-HCAD-35	yes	1943.69
E-HCAD-25	yes	1752.31
E-ANND-3	yes	9.67
E-MTAB-11268	no	24838.24

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F6, NKX2-5, SP1

miRNA regulators (miRDB)

139 targeting RYR2, 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-1193	100.00	65.93	529
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-335-3P	99.93	73.36	4958

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Mutations in the gene coding for cardiac ryanodine receptor (hRYR2) may be a key step in molecular pathogenesis of ARVDs, and catecholaminergic ventricular arrhythmias or with familial ventricular tachyarrhythmia. (PMID:12015469)
• RyR2 mutations are associated with polymorphic ventricular arrhythmia, syncope and sudden death in response to physical or emotional stress. (PMID:12106942)
• identification of binding site for FKBP12.6 protein (PMID:12446682)
• Data show that VTSIP- and ARVD2-associated point mutations influence positively and negatively, respectively, the binding of RyR2 to its gating protein FKBP12.6. (PMID:12459180)
• the DR3 region of Ryanodine Receptor 2 has a role in excitation-contraction coupling and in channel regulation (PMID:12576471)
• data demonstrate that defective regulation of ryanodine receptor 2 causes altered cellular phenotype via profound perturbations in intracellular calcium signaling and highlight a key modulatory role of FK506 binding protein 12.6 (PMID:12754204)
• RYR2 mutations associated with ventricular tachycardia mediate increased calcium release in stimulated cardiomyocytes. (PMID:12919952)
• The RyR2 C-terminal tail may be important for the oligomeric assembly of the native channel. (PMID:12959641)
• the TM10 sequence constitutes an essential determinant for channel activation and gating; TM10 is an inner helix of RyR (PMID:14593104)
• there is a specific binding subdomain in RyR1 and RyR2 participating in RyR-RyR interaction (PMID:14722100)
• CaMKII-mediated phosphorylation of RyR2 at Ser-2815 may contribute to the enhanced contractility observed at higher heart rates. (PMID:15016728)
• This is the 1st evidence that RyRs directly control primary beta cell insulin secretion independently of glucose & by 2 mechanisms, including a novel cytosolic Ca2+-independent mechanism likely involving changes in Ca2+ in the lumens of non-ER organelles. (PMID:15033925)
• RyR2 activity seems to play an essential role in beta-cell survival in vitro by suppressing a death pathway mediated by calpain-10 (PMID:15044459)
• compelling evidence that specific interaction between cytoplasmic and transmembrane domains is an important mechanism in the intrinsic modulation of RyR Ca(2+) release channels (PMID:15047862)
• CLIC2 inhibited cardiac ryanodine receptor Ca2+ release channels in lipid bilayers when added to the cytoplasmic side of the channels and inhibited Ca2+ release from cardiac sarcoplasmic reticulum vesicles (PMID:15147738)
• 3 mutations (P2328S, Q4201R, & V4653F)had decreased FKBP12.6 binding, that stabilizes the channel’s closed state. After PKA phosphorylation, mutant channels had a gain-of-function defect (leaky Ca2+ release) & a rightward shift in the Mg2+ IC50. (PMID:15197150)
• five non-conserved amino acids in the C-terminal region flanking the CaM-binding domain have a key role in CaM inhibition of RyR2 (PMID:15215235)
• 9 new RYR2 mutations were found among people with long-QT syndrome revealed by swimming-triggered arrhythmias. (PMID:15466642)
• novel interaction site for FKBP12.6 may be present at the RyR2 C terminus, proximal to the channel pore, a sterically appropriate location that would enable this protein to play a central role in the modulation of this critical ion channel (PMID:15591045)
• The R2401H mutation can be expected to alter Ca-induced Ca release and E-C coupling resulting in CPVT. (PMID:15749201)
• Atrial tissue from both dogs and humans with chronic atrial fibrillation showed a significant increase in PKA phosphorylation of RyR2, with a corresponding decrease in calstabin2 binding to the channel (PMID:15851612)
• RyR2-encoded cardiac ryanodine receptor/calcium release channel mutations are responsible for catecholaminergic polymorphic ventricular tachycardia (CPVT)- a novel pathogenic basis for unexplained drownings. (PMID:15887426)
• Putative pathogenic type 1 catecholaminergic polymorphic ventricular tachycardia-causing mutations in RyR2 were detected in 6% of unrelated, genotype-negative long QT syndrome referrals. (PMID:16188589)
• RYR2 mutations may have a role in catecholaminergic polymorphic ventricular tachycardia (PMID:16272262)
• Ser-2030, but not Ser-2808, is the major PKA phosphorylation site in RyR2 responding to PKA activation upon beta-adrenergic stimulation in both normal and failing hearts, and that RyR2 is not hyperphosphorylated by PKA in heart failure. (PMID:16483256)
• Intracellular Ca2+ cycling in normal heart relies on intricate interplay of CASQ2 with proteins of RyR2 channel complex, and disruption of these interactions can lead to cardiac arrhythmia. (PMID:16601229)
• Putative CPVT1-causing mutations in RyR2 were seen in <40% of unrelated patients referred with a diagnosis of CPVT and preferentially in males. (PMID:16818210)
• The knock-in mouse harboring the RyR2 R4497C mutation(also found in patients with familial sudden death) cause cardiac arrhythmias through delayed afterdepolarization and triggered activity due to altered intracellular calcium handling. (PMID:16825580)
• Cardiac RyR2 plasmids with various CPVT mutations enable expression and analysis of Ca2+ release mediated by the wild-type and mutated RyR2. (PMID:17052226)
• Postmortem molecular screening of the RyR2 gene could be useful for investigation for cause of death in sudden unexplained death (SUD). The possible association of the RyR2 mutation with status thymico-lymphaticus is discussed. (PMID:17062961)
• the redox state of the RyR is intimately connected with FKBP binding affinity. (PMID:17200109)
• together, our results demonstrate that RyR1 differs markedly from RyR2 with respect to their responses to Ca(2+) overload and luminal Ca(2+). (PMID:17259277)
• Data show that K201 abolished spontaneous calcium release in cardiac myocytes, and that treating ventricular myocytes with FK506 to dissociate FKBP12.6 from ryanodine receptor RyR2 did not affect the suppression of spontaneous Ca2+ release by K201. (PMID:17313373)
• We provide the first evidence that RyR2 splice variants exquisitely modulate intracellular Ca(2+) signaling and are key determinants of cardiomyocyte apoptotic susceptibility. (PMID:17322175)
• P2X(7) receptor has an antiapoptotic function in melanoma cells (PMID:17330843)
• Finds a link between RyR2 mutations and the alterations of ion channels that may trigger cardiac arrhythmias associated with SIDS. (PMID:17556193)
• No disease-causing mutations in the RyR2 were found in Finish patients with sporadic arrhythmogenic right ventricular cardiomyopathy; an allelic variant A1136V was found in patients and health controls. (PMID:17558603)
• PKA-dependent phosphorylation enhances the response of RyR2 to luminal Ca(2+) and reduces the threshold for SOICR and this effect of PKA is largely mediated by phosphorylation at Ser-2,030 (PMID:17693412)
• large genomic deletion in RYR2 leads to extended clinical phenotypes eg, sinoatrial node and atrioventricular node dysfunction, atrial fibrillation, atrial standstill, and dilated cardiomyopathy (PMID:17875969)
• the loss of FKBP12.6 has no significant effect on the conduction and activation of RyR2 or the propensity for spontaneous Ca(2+) release and stress-induced ventricular arrhythmias (PMID:17921453)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ryr2b	ENSDARG00000003706
mus_musculus	Ryr2	ENSMUSG00000021313
rattus_norvegicus	Ryr2	ENSRNOG00000017060
drosophila_melanogaster	RyR	FBGN0011286
caenorhabditis_elegans		WBGENE00006801

Paralogs (5): ITPR3 (ENSG00000096433), ITPR2 (ENSG00000123104), ITPR1 (ENSG00000150995), RYR1 (ENSG00000196218), RYR3 (ENSG00000198838)

Protein

Protein identifiers

Ryanodine receptor 2 — Q92736 (reviewed: Q92736)

Alternative names: Cardiac muscle ryanodine receptor, Cardiac muscle ryanodine receptor-calcium release channel, Type 2 ryanodine receptor

All UniProt accessions (9): Q92736, A0A590UJF6, A0A590UJZ8, A0A590UK06, A0A590UKB7, A0AAQ5BHA4, A0AAQ5BHB1, A0AAQ5BHB3, A0AAQ5BHC6

UniProt curated annotations — full annotation on UniProt →

Function. 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. Aberrant channel activation can lead to cardiac arrhythmia. In cardiac myocytes, calcium release is triggered by increased Ca(2+) cytosolic levels due to activation of the L-type calcium channel CACNA1C. The calcium channel activity is modulated by formation of heterotetramers with RYR3. Required for cellular calcium ion homeostasis. Required for embryonic heart development.

Subunit / interactions. Homotetramer. Can also form heterotetramers with RYR1 and RYR3. Interacts with FKBP1A and FKBP1B; these interactions may stabilize the channel in its closed state and prevent Ca(2+) leaks. Interacts with CALM and S100A1; these interactions regulate channel activity. Identified in a complex composed of RYR2, FKBP1B, PKA catalytic subunit, PRKAR2A, AKAP6, and the protein phosphatases PP2A and PP1. Interacts directly with FKBP1B, PKA, PP1 and PP2A. Interacts with SELENON. In cardiac muscles, identified in a complex, composed of FSD2, CMYA5 and RYR2. Interacts with PKD2 (via N-terminus); regulates RYR2 channel activity.

Subcellular location. Sarcoplasmic reticulum membrane.

Tissue specificity. Detected in heart muscle (at protein level). Heart muscle, brain (cerebellum and hippocampus) and placenta.

Post-translational modifications. Channel activity is modulated by phosphorylation. Phosphorylation at Ser-2808 and Ser-2814 increases the open probability of the calcium channel. Phosphorylation is increased in failing heart, leading to calcium leaks and increased cytoplasmic Ca(2+) levels. Phosphorylation at Ser-2031 by PKA enhances the response to lumenal calcium.

Disease relevance. Ventricular tachycardia, catecholaminergic polymorphic, 1, with or without atrial dysfunction and/or dilated cardiomyopathy (CPVT1) [MIM:604772] An arrhythmogenic disorder characterized by stress-induced, bidirectional ventricular tachycardia that may degenerate into cardiac arrest and cause sudden death. Patients present with recurrent syncope, seizures, or sudden death after physical activity or emotional stress. CPVT1 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry. Ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (VACRDS) [MIM:115000] An autosomal dominant arrhythmogenic disorder characterized by syncope, cardiac arrest and/or sudden unexpected death, often in association with physical exertion or acute emotional stress. Patients who survive manifest polymorphic ventricular tachycardia and ventricular fibrillation. Unlike typical catecholaminergic ventricular tachycardia, arrhythmias are not reproducible on exercise stress testing or adrenaline challenge. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The calcium release is activated by increased cytosolic calcium levels, by nitric oxyde (NO), caffeine and ATP. Channel activity is modulated by the alkaloid ryanodine that binds to the open Ca-release channel with high affinity. At low concentrations, ryanodine maintains the channel in an open conformation. High ryanodine concentrations inhibit channel activity. Channel activity is regulated by calmodulin (CALM). Channel activity is inhibited by magnesium ions, possibly by competition for calcium binding sites.

Domain organisation. The calcium release channel activity resides in the C-terminal region while the remaining part of the protein resides in the cytoplasm.

Induction. By TGFB1.

Similarity. Belongs to the ryanodine receptor (TC 1.A.3.1) family. RYR2 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q92736-1	1	yes
Q92736-2	2

RefSeq proteins (1): NP_001026* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000699	RIH_dom	Domain
IPR001870	B30.2/SPRY	Domain
IPR002048	EF_hand_dom	Domain
IPR003032	Ryanodine_rcpt	Domain
IPR003877	SPRY_dom	Domain
IPR005821	Ion_trans_dom	Domain
IPR009460	Ryanrecept_TM4-6	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR013333	Ryan_recept	Family
IPR013662	RIH_assoc-dom	Domain
IPR014821	Ins145_P3_rcpt	Domain
IPR015925	Ryanodine_IP3_receptor	Family
IPR016093	MIR_motif	Domain
IPR035761	SPRY1_RyR	Domain
IPR035762	SPRY3_RyR	Domain
IPR035764	SPRY2_RyR	Domain
IPR035910	RyR/IP3R_RIH_dom_sf	Homologous_superfamily
IPR036300	MIR_dom_sf	Homologous_superfamily
IPR043136	B30.2/SPRY_sf	Homologous_superfamily
IPR048581	RYDR_Jsol	Domain

Pfam: PF00520, PF00622, PF01365, PF02026, PF02815, PF06459, PF08454, PF08709, PF13499, PF21119

Catalyzed reactions (Rhea), 1 shown:

• Ca(2+)(in) = Ca(2+)(out) (RHEA:29671)

UniProt features (160 total): sequence variant 53, strand 28, helix 15, modified residue 10, mutagenesis site 9, turn 9, domain 8, transmembrane region 6, region of interest 6, repeat 4, compositionally biased region 4, topological domain 2, sequence conflict 2, chain 1, coiled-coil region 1, splice variant 1, intramembrane region 1

Structure

Experimental structures (PDB)

26 structures.

PDB	Method	Resolution (Å)
7KL5	X-RAY DIFFRACTION	1.65
6Y4O	X-RAY DIFFRACTION	1.84
6Y4P	X-RAY DIFFRACTION	2.13
4JKQ	X-RAY DIFFRACTION	2.39
7U9X	ELECTRON MICROSCOPY	2.58
7U9T	ELECTRON MICROSCOPY	2.68
7UA5	ELECTRON MICROSCOPY	2.83
8UXC	ELECTRON MICROSCOPY	2.86
7UA4	ELECTRON MICROSCOPY	2.93
7UA3	ELECTRON MICROSCOPY	2.97
8UQ2	ELECTRON MICROSCOPY	2.98
7UA1	ELECTRON MICROSCOPY	2.99
8UXG	ELECTRON MICROSCOPY	3.08
7U9Q	ELECTRON MICROSCOPY	3.11
8UXL	ELECTRON MICROSCOPY	3.12
8UXF	ELECTRON MICROSCOPY	3.13
8UQ3	ELECTRON MICROSCOPY	3.18
7U9Z	ELECTRON MICROSCOPY	3.29
8UXI	ELECTRON MICROSCOPY	3.29
8UXH	ELECTRON MICROSCOPY	3.52
8UXE	ELECTRON MICROSCOPY	3.53
8UXM	ELECTRON MICROSCOPY	3.56
7UA9	ELECTRON MICROSCOPY	3.59
8UQ4	ELECTRON MICROSCOPY	3.64
7U9R	ELECTRON MICROSCOPY	3.69
8UQ5	ELECTRON MICROSCOPY	3.96

Predicted structure (AlphaFold)

No AlphaFold model available for Q92736 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

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

Post-translational modifications (10): 1341, 1869, 2031, 2369, 2697, 2797, 2808, 2811, 2814, 2947

Mutagenesis-validated functional residues (9):

Position	Phenotype
3995	decreased function in release of sequestered calcium ion into cytosol by sarcoplasmic reticulum. changed ryanodine-sensi
4108	changed ryanodine-sensitive calcium-release channel activity characterized by increased sensitivity to cytosolic calcium
4112	decreased function in release of sequestered calcium ion into cytosol by sarcoplasmic reticulum. changed ryanodine-sensi
4855	decreased function in release of sequestered calcium ion into cytosol by sarcoplasmic reticulum. changed ryanodine-sensi
4879	decreased function in release of sequestered calcium ion into cytosol by sarcoplasmic reticulum. changed ryanodine-sensi
2808	abolishes phosphorylation by pka.
3946	changed ryanodine-sensitive calcium-release channel activity characterized by increased sensitivity to cytosolic calcium
3978	changed ryanodine-sensitive calcium-release channel activity characterized by increased sensitivity to cytosolic calcium

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels
R-HSA-5578775	Ion homeostasis
R-HSA-382551	Transport of small molecules
R-HSA-397014	Muscle contraction
R-HSA-5576891	Cardiac conduction
R-HSA-983712	Ion channel transport

MSigDB gene sets: 377 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_SEQUESTERING_OF_CALCIUM_ION, MODY_HIPPOCAMPUS_POSTNATAL, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_RESPONSE_TO_MUSCLE_STRETCH, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_CARDIAC_LEFT_VENTRICLE_MORPHOGENESIS, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ENDOPLASMIC_RETICULUM, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, CTATGCA_MIR153, GOBP_REGULATION_OF_CARDIAC_MUSCLE_CONTRACTION_BY_REGULATION_OF_THE_RELEASE_OF_SEQUESTERED_CALCIUM_ION

GO Biological Process (43): response to hypoxia (GO:0001666), regulation of heart rate (GO:0002027), embryonic heart tube morphogenesis (GO:0003143), left ventricular cardiac muscle tissue morphogenesis (GO:0003220), cardiac muscle hypertrophy (GO:0003300), detection of calcium ion (GO:0005513), calcium ion transport (GO:0006816), intracellular calcium ion homeostasis (GO:0006874), striated muscle contraction (GO:0006941), positive regulation of heart rate (GO:0010460), regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion (GO:0010881), regulation of cardiac muscle contraction by calcium ion signaling (GO:0010882), release of sequestered calcium ion into cytosol by sarcoplasmic reticulum (GO:0014808), response to muscle activity (GO:0014850), calcium-mediated signaling (GO:0019722), response to caffeine (GO:0031000), response to muscle stretch (GO:0035994), release of sequestered calcium ion into cytosol (GO:0051209), obsolete positive regulation of sequestering of calcium ion (GO:0051284), regulation of cytosolic calcium ion concentration (GO:0051480), establishment of localization in cell (GO:0051649), response to redox state (GO:0051775), regulation of cardiac muscle contraction (GO:0055117), cardiac muscle contraction (GO:0060048), calcium ion transport into cytosol (GO:0060402), sarcoplasmic reticulum calcium ion transport (GO:0070296), cellular response to caffeine (GO:0071313), cellular response to epinephrine stimulus (GO:0071872), establishment of protein localization to endoplasmic reticulum (GO:0072599), ventricular cardiac muscle cell action potential (GO:0086005), Purkinje myocyte to ventricular cardiac muscle cell signaling (GO:0086029), cell communication by electrical coupling involved in cardiac conduction (GO:0086064), type B pancreatic cell apoptotic process (GO:0097050), positive regulation of the force of heart contraction (GO:0098735), regulation of AV node cell action potential (GO:0098904), regulation of SA node cell action potential (GO:0098907), regulation of atrial cardiac muscle cell action potential (GO:0098910), regulation of ventricular cardiac muscle cell action potential (GO:0098911), monoatomic ion transport (GO:0006811), monoatomic ion transmembrane transport (GO:0034220)

GO Molecular Function (15): ryanodine-sensitive calcium-release channel activity (GO:0005219), calcium channel activity (GO:0005262), calcium ion binding (GO:0005509), calmodulin binding (GO:0005516), intracellularly gated calcium channel activity (GO:0015278), enzyme binding (GO:0019899), protein kinase A catalytic subunit binding (GO:0034236), protein kinase A regulatory subunit binding (GO:0034237), identical protein binding (GO:0042802), suramin binding (GO:0043924), transmembrane transporter binding (GO:0044325), calcium-induced calcium release activity (GO:0048763), monoatomic ion channel activity (GO:0005216), protein binding (GO:0005515), protein kinase binding (GO:0019901)

GO Cellular Component (11): smooth endoplasmic reticulum (GO:0005790), plasma membrane (GO:0005886), junctional sarcoplasmic reticulum membrane (GO:0014701), membrane (GO:0016020), sarcoplasmic reticulum (GO:0016529), Z disc (GO:0030018), protein-containing complex (GO:0032991), sarcoplasmic reticulum membrane (GO:0033017), calcium channel complex (GO:0034704), sarcolemma (GO:0042383), sarcomere (GO:0030017)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Ion channel transport	1
Cardiac conduction	1
Muscle contraction	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	4
cellular anatomical structure	3
protein kinase A binding	2
endoplasmic reticulum	2
response to stress	1
response to decreased oxygen levels	1
regulation of heart contraction	1
regulation of biological quality	1
heart morphogenesis	1
embryonic heart tube development	1
embryonic organ morphogenesis	1
embryonic morphogenesis	1
epithelial tube morphogenesis	1
cardiac left ventricle morphogenesis	1
ventricular cardiac muscle tissue morphogenesis	1
striated muscle hypertrophy	1
detection of chemical stimulus	1
response to calcium ion	1
metal ion transport	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
muscle contraction	1
regulation of heart rate	1
positive regulation of heart contraction	1
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1
regulation of cardiac muscle contraction by calcium ion signaling	1
calcium-mediated signaling	1
regulation of cardiac muscle contraction	1
cardiac muscle contraction	1
sarcoplasmic reticulum calcium ion transport	1
release of sequestered calcium ion into cytosol by endoplasmic reticulum	1
response to activity	1
intracellular signaling cassette	1
response to purine-containing compound	1
response to alkaloid	1
response to mechanical stimulus	1
intercellular transport	1
calcium ion transmembrane import into cytosol	1
intracellular calcium ion homeostasis	1
calcium-induced calcium release activity	1

Protein interactions and networks

STRING

2556 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RYR2	FKBP1B	P68106	999
RYR2	TRDN	Q13061	998
RYR2	CALM1	P02593	994
RYR2	CALML6	Q8TD86	993
RYR2	CALML3	P27482	993
RYR2	ASPH	Q12797	993
RYR2	CALML4	Q96GE6	993
RYR2	CALML5	Q9NZT1	993
RYR2	CASQ2	O14958	987
RYR2	AKAP6	Q13023	984
RYR2	CACNA1C	Q13936	970
RYR2	FKBP1A	P20071	951
RYR2	SRI	P30626	946
RYR2	CACNA1D	Q01668	911
RYR2	S100A1	P23297	895

IntAct

23 interactions, top by confidence:

A	B	Type	Score
FKBP1B	RYR2	psi-mi:“MI:2364”(proximity)	0.720
RYR2	FKBP1B	psi-mi:“MI:0915”(physical association)	0.720
FKBP1B	RYR2	psi-mi:“MI:0915”(physical association)	0.720
MDM2	RYR2	psi-mi:“MI:0915”(physical association)	0.520
MAP1LC3B	RYR2	psi-mi:“MI:0407”(direct interaction)	0.440
CAMK2D	RYR2	psi-mi:“MI:0915”(physical association)	0.400
RYR2	GOLGA2	psi-mi:“MI:0915”(physical association)	0.400
FKBP1A	RYR2	psi-mi:“MI:0915”(physical association)	0.400
RYR2	PRKACA	psi-mi:“MI:0915”(physical association)	0.400
HSPB2	RYR2	psi-mi:“MI:0915”(physical association)	0.370
SMAD5	RYR2	psi-mi:“MI:0915”(physical association)	0.370
CFTR	SNHG32	psi-mi:“MI:0914”(association)	0.350
ALB	SH3BP5	psi-mi:“MI:0914”(association)	0.350
SNTA1	GNAT3	psi-mi:“MI:0914”(association)	0.350
AKAP6	RYR2	psi-mi:“MI:0403”(colocalization)	0.270
BIN1	RYR2	psi-mi:“MI:0915”(physical association)	0.000
MDM2	RYR2	psi-mi:“MI:0915”(physical association)	0.000
RYR2		psi-mi:“MI:0915”(physical association)	0.000
	RYR2	psi-mi:“MI:0915”(physical association)	0.000
FKBP1A	FKBP1B	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (74): RYR2 (Two-hybrid), PSEN1 (Reconstituted Complex), RYR2 (Affinity Capture-Western), RYR2 (FRET), RYR2 (FRET), RYR2 (Affinity Capture-RNA), RYR2 (Two-hybrid), RYR2 (Affinity Capture-Western), RYR2 (Co-fractionation), CALM1 (Affinity Capture-Western), RYR2 (Reconstituted Complex), RYR2 (Reconstituted Complex), RYR2 (Co-purification), RYR2 (Reconstituted Complex), RYR1 (Reconstituted Complex)

ESM2 similar proteins: A0A0R4IES7, A0JN62, A0JNW5, A2AAE1, A2AGL3, A2RSJ4, A2RT67, A2RUS2, A2RV80, B0LPN4, B1H2P5, E7F240, E9Q401, O00507, O94967, P30957, P48553, P51593, Q14161, Q2LD37, Q3TLI0, Q3UHE1, Q3UVG3, Q3UX43, Q5F361, Q5M7Q1, Q5RAQ5, Q5ZJK1, Q658Y4, Q68CL5, Q6BDS2, Q6P6Y1, Q6TEP1, Q6VNB8, Q7TMY8, Q7TSG1, Q7Z6Z7, Q8BHY8, Q8CB44, Q8CGF6

Diamond homologs: A0A5F9C6I2, A1L252, A2VD92, B0LPN4, D3ZXK7, E9PZQ0, E9Q401, F1LMY4, O94712, P11716, P16960, P21817, P30957, P69566, Q15413, Q19614, Q1LUS8, Q28FM1, Q5R881, Q5XH91, Q5XPI3, Q5XPI4, Q6VN19, Q8BVR6, Q90WU3, Q92736, Q95LP3, Q96DX4, Q96S59, Q9PTY5, Q9VNV3, A2AGL3, P11881, P29993, P29994, P29995, P70227, Q14571, Q14573, Q14643

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SPEG	“down-regulates activity”	RYR2	phosphorylation
PRKACA	“up-regulates activity”	RYR2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 17 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
Cellular responses to stimuli	5	11.2×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

9309 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	78
Likely pathogenic	133
Uncertain significance	4618
Likely benign	3238
Benign	388

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1051501	NM_001035.3(RYR2):c.6504C>A (p.His2168Gln)	Pathogenic
1066599	NM_001035.3(RYR2):c.14234A>G (p.Asp4745Gly)	Pathogenic
1069130	NM_001035.3(RYR2):c.6933G>C (p.Glu2311Asp)	Pathogenic
1070571	NM_001035.3(RYR2):c.12269C>T (p.Pro4090Leu)	Pathogenic
1072597	NM_001035.3(RYR2):c.7421G>A (p.Arg2474Lys)	Pathogenic
1072928	NM_001035.3(RYR2):c.514G>A (p.Gly172Arg)	Pathogenic
1119950	NM_001035.3(RYR2):c.11983A>C (p.Ile3995Leu)	Pathogenic
12954	NM_001035.3(RYR2):c.6737C>T (p.Ser2246Leu)	Pathogenic
12955	NM_001035.3(RYR2):c.7422G>C (p.Arg2474Ser)	Pathogenic
12956	NM_001035.3(RYR2):c.12312C>G (p.Asn4104Lys)	Pathogenic
12957	NM_001035.3(RYR2):c.13489C>T (p.Arg4497Cys)	Pathogenic
12958	NM_001035.3(RYR2):c.7157A>T (p.Asn2386Ile)	Pathogenic
12959	NM_001035.3(RYR2):c.1298T>C (p.Leu433Pro)	Pathogenic
12960	NM_001035.3(RYR2):c.6982C>T (p.Pro2328Ser)	Pathogenic
12961	NM_001035.3(RYR2):c.13957G>T (p.Val4653Phe)	Pathogenic
1363823	NM_001035.3(RYR2):c.13836T>G (p.Phe4612Leu)	Pathogenic
1383749	NM_001035.3(RYR2):c.7580T>G (p.Leu2527Trp)	Pathogenic
1384586	NM_001035.3(RYR2):c.6900C>G (p.Asp2300Glu)	Pathogenic
1439521	NM_001035.3(RYR2):c.14638G>A (p.Val4880Ile)	Pathogenic
1441921	NM_001035.3(RYR2):c.13798T>C (p.Phe4600Leu)	Pathogenic
1451617	NM_001035.3(RYR2):c.7213G>A (p.Glu2405Lys)	Pathogenic
1474443	NM_001035.3(RYR2):c.11959G>C (p.Glu3987Gln)	Pathogenic
1479669	NM_001035.3(RYR2):c.14710G>A (p.Gly4904Ser)	Pathogenic
1693182	NM_001035.3(RYR2):c.14020A>G (p.Lys4674Glu)	Pathogenic
1710227	NM_001035.3(RYR2):c.10630_10652dup (p.Val3551_Leu3552insGlnArgArgArgTer)	Pathogenic
1805845	NM_001035.3(RYR2):c.7175A>G (p.Tyr2392Cys)	Pathogenic
1932217	NM_001035.3(RYR2):c.12322C>T (p.His4108Tyr)	Pathogenic
201188	NM_001035.3(RYR2):c.11814C>A (p.Ser3938Arg)	Pathogenic
201190	NM_001035.3(RYR2):c.239A>G (p.Glu80Gly)	Pathogenic
201194	NM_001035.3(RYR2):c.527G>A (p.Arg176Gln)	Pathogenic

SpliceAI

10488 predictions. Top by Δscore:

Variant	Effect	Δscore
1:237042565:GAACT:G	donor_gain	1.0000
1:237042570:G:GG	donor_gain	1.0000
1:237042574:GCGCC:G	donor_gain	1.0000
1:237270492:T:TA	acceptor_gain	1.0000
1:237270495:A:AG	acceptor_gain	1.0000
1:237270495:A:T	acceptor_loss	1.0000
1:237270495:AG:A	acceptor_gain	1.0000
1:237270495:AGGAT:A	acceptor_gain	1.0000
1:237270496:G:A	acceptor_gain	1.0000
1:237270496:G:GT	acceptor_gain	1.0000
1:237270496:GGA:G	acceptor_gain	1.0000
1:237270496:GGAT:G	acceptor_gain	1.0000
1:237270496:GGATG:G	acceptor_gain	1.0000
1:237330877:GA:G	acceptor_gain	1.0000
1:237330877:GAAT:G	acceptor_gain	1.0000
1:237369530:A:AG	acceptor_gain	1.0000
1:237369531:A:G	acceptor_gain	1.0000
1:237369604:GCATG:G	donor_gain	1.0000
1:237369607:TGGTG:T	donor_loss	1.0000
1:237369608:GGT:G	donor_loss	1.0000
1:237369609:GTG:G	donor_loss	1.0000
1:237369610:T:G	donor_loss	1.0000
1:237369611:G:GG	donor_loss	1.0000
1:237369612:A:AC	donor_loss	1.0000
1:237374715:A:AG	acceptor_gain	1.0000
1:237374716:G:GG	acceptor_gain	1.0000
1:237374716:GT:G	acceptor_gain	1.0000
1:237377304:C:G	acceptor_gain	1.0000
1:237377306:T:G	acceptor_gain	1.0000
1:237386932:A:AG	donor_gain	1.0000

AlphaMissense

32953 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:237377337:T:A	W160R	1.000
1:237377337:T:C	W160R	1.000
1:237387323:T:C	F207L	1.000
1:237387325:C:A	F207L	1.000
1:237387325:C:G	F207L	1.000
1:237417098:T:A	W275R	1.000
1:237417098:T:C	W275R	1.000
1:237496566:T:A	W673R	1.000
1:237496566:T:C	W673R	1.000
1:237496638:T:A	W697R	1.000
1:237496638:T:C	W697R	1.000
1:237500773:A:C	S756R	1.000
1:237500775:T:A	S756R	1.000
1:237500775:T:G	S756R	1.000
1:237500813:G:C	R769P	1.000
1:237500831:T:A	V775D	1.000
1:237500836:G:A	G777R	1.000
1:237500836:G:C	G777R	1.000
1:237503483:C:A	P864H	1.000
1:237506750:T:C	L885P	1.000
1:237506753:C:A	A886E	1.000
1:237506760:T:A	N888K	1.000
1:237506760:T:G	N888K	1.000
1:237506764:C:G	H890D	1.000
1:237506765:A:C	H890P	1.000
1:237506771:T:C	L892P	1.000
1:237506773:T:A	W893R	1.000
1:237506773:T:C	W893R	1.000
1:237506774:G:C	W893S	1.000
1:237506775:G:C	W893C	1.000

dbSNP variants (sampled 300 via entrez): RS1000000301 (1:237133287 A>G), RS1000001634 (1:237262373 A>C), RS1000008762 (1:237174013 T>C), RS1000008896 (1:237580720 A>C), RS1000010878 (1:237805293 A>C,G), RS1000022284 (1:237408262 T>C), RS1000023508 (1:237532527 C>T), RS1000030613 (1:237232346 T>A,C), RS1000039048 (1:237434213 G>A), RS1000041735 (1:237166782 G>A,C), RS1000043466 (1:237726287 G>A), RS1000048138 (1:237088710 T>C,G), RS1000049322 (1:237540379 A>C), RS1000051982 (1:237635634 C>T), RS1000059891 (1:237453590 T>C)

Disease associations

OMIM: gene MIM:180902 | disease phenotypes: MIM:600996, MIM:604772, MIM:115000, MIM:192600, MIM:604169, MIM:603829, MIM:115080, MIM:107970, MIM:194200, MIM:115200, MIM:115197, MIM:611938, MIM:601144, MIM:601493, MIM:192500

GenCC curated gene-disease

Disease	Classification	Inheritance
arrhythmogenic right ventricular dysplasia 2	Definitive	Autosomal dominant
catecholaminergic polymorphic ventricular tachycardia	Definitive	Autosomal dominant
catecholaminergic polymorphic ventricular tachycardia 1	Strong	Autosomal dominant
hypertrophic cardiomyopathy	Limited	Autosomal dominant
arrhythmogenic right ventricular cardiomyopathy	Refuted Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (4)

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

Disease	Classification	Inheritance
catecholaminergic polymorphic ventricular tachycardia	Definitive	AD
hypertrophic cardiomyopathy	Limited	AD
arrhythmogenic right ventricular cardiomyopathy	Refuted	AD
dilated cardiomyopathy	Limited	AD

Mondo (30): catecholaminergic polymorphic ventricular tachycardia 1 (MONDO:0011484), ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome (MONDO:0020745), cardiomyopathy (MONDO:0004994), catecholaminergic polymorphic ventricular tachycardia (MONDO:0017990), long QT syndrome (MONDO:0002442), dilated cardiomyopathy (MONDO:0005021), familial hypertrophic cardiomyopathy (MONDO:0024573), polymorphic ventricular tachycardia (MONDO:0020575), hypertrophic cardiomyopathy (MONDO:0005045), left ventricular noncompaction (MONDO:0018901), arrhythmogenic right ventricular cardiomyopathy (MONDO:0016587), cardiac arrest (MONDO:0000745), ventricular fibrillation, paroxysmal familial, type 1 (MONDO:0011376), cardiac conduction defect (MONDO:0100042), cardiac rhythm disease (MONDO:0007263)

Orphanet (18): Catecholaminergic polymorphic ventricular tachycardia (Orphanet:3286), Rare cardiomyopathy (Orphanet:167848), Dilated cardiomyopathy (Orphanet:217604), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), Rare hypertrophic cardiomyopathy (Orphanet:217569), Left ventricular noncompaction (Orphanet:54260), Inherited arrhythmogenic cardiomyopathy (Orphanet:247), Idiopathic ventricular fibrillation (Orphanet:228140), Hereditary progressive cardiac conduction defect (Orphanet:871), Uhl anomaly (Orphanet:3403), Familial dilated cardiomyopathy (Orphanet:217607), Childhood-onset schizophrenia (Orphanet:641496), Brugada syndrome (Orphanet:130), Familial isolated dilated cardiomyopathy (Orphanet:154), Romano-Ward syndrome (Orphanet:101016)

HPO phenotypes

28 total (30 of 28 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001250	Seizure
HP:0001279	Syncope
HP:0001644	Dilated cardiomyopathy
HP:0001645	Sudden cardiac death
HP:0001663	Ventricular fibrillation
HP:0001664	Torsade de pointes
HP:0001678	Atrioventricular block
HP:0001695	Cardiac arrest
HP:0001962	Palpitations
HP:0002321	Vertigo
HP:0003621	Juvenile onset
HP:0004755	Supraventricular tachycardia
HP:0004756	Ventricular tachycardia
HP:0004757	Paroxysmal atrial fibrillation
HP:0004758	Effort-induced polymorphic ventricular tachycardia
HP:0005110	Atrial fibrillation
HP:0006673	Reduced systolic function
HP:0006696	Polymorphic and polytopic ventricular extrasystoles
HP:0011462	Young adult onset
HP:0011463	Childhood onset
HP:0011664	Left ventricular noncompaction cardiomyopathy
HP:0011704	Sick sinus syndrome
HP:0025478	Atrial standstill
HP:0031628	Aborted sudden cardiac death
HP:0031677	Polymorphic ventricular tachycardia
HP:0034039	Ventricular couplet
HP:0034040	Bidirectional ventricular tachycardia
HP:0001639	Hypertrophic cardiomyopathy
HP:0001635	Congestive heart failure

GWAS associations

22 associations (top):

Study	Trait	p-value
GCST000041_1	Hypertension	8.000000e-07
GCST000089_2	Exercise treadmill test traits	4.000000e-06
GCST000464_2	Acute lymphoblastic leukemia (childhood)	2.000000e-06
GCST001002_1	Cerivastatin-induced rhabdomyolysis	2.000000e-07
GCST001692_15	Response to taxane treatment (docetaxel)	6.000000e-06
GCST001762_185	Obesity-related traits	8.000000e-06
GCST001762_815	Obesity-related traits	2.000000e-06
GCST002321_6	Lipid traits	3.000000e-07
GCST003135_2	Bipolar disorder and eating disorder	7.000000e-06
GCST006481_11	Lung function (FEV1)	4.000000e-08
GCST006483_3	Lung function (FVC)	4.000000e-08
GCST006483_4	Lung function (FVC)	3.000000e-07
GCST007325_262	General risk tolerance (MTAG)	3.000000e-09
GCST007325_30	General risk tolerance (MTAG)	4.000000e-08
GCST007977_4	Postoperative stroke after cardiac surgery	6.000000e-07
GCST008810_84	Smoking initiation (ever regular vs never regular)	8.000000e-07
GCST008959_6	Lipid traits	5.000000e-09
GCST009260_3	Hippocampal volume	4.000000e-06
GCST009391_1276	Metabolite levels	2.000000e-06
GCST010320_95	PR interval	7.000000e-09
GCST010321_184	PR interval	7.000000e-09
GCST012162_1	cognitive impairment (MMSE score) in Parkinson’s disease	3.000000e-06

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0004328	exercise test
EFO:0003867	rhabdomyolysis
EFO:0004730	hormone measurement
EFO:0005134	amino acid measurement
EFO:0004530	triglyceride measurement
EFO:0004314	forced expiratory volume
EFO:0004312	vital capacity
EFO:0008579	risk-taking behaviour
EFO:0009951	response to surgery
EFO:0009956	post-operative stroke
EFO:0005670	smoking initiation
EFO:0005035	hippocampal volume
EFO:0010546	uridine measurement
EFO:0004462	PR interval

MeSH disease descriptors (17)

Descriptor	Name	Tree numbers
D019571	Arrhythmogenic Right Ventricular Dysplasia	C14.240.400.145; C14.280.238.028; C14.280.400.145; C16.131.240.400.145
D053840	Brugada Syndrome	C14.280.067.322; C14.280.123.250; C16.320.100
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
D006323	Heart Arrest	C14.280.383
D006331	Heart Diseases	C14.280
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D017180	Tachycardia, Ventricular	C14.280.067.845.940; C14.280.123.875.940; C23.550.073.845.940
D014693	Ventricular Fibrillation	C14.280.067.922; C23.550.073.922
D014927	Wolff-Parkinson-White Syndrome	C14.280.067.780.977; C14.280.123.750.977; C16.131.240.400.980
C563409	Arrhythmogenic Right Ventricular Dysplasia, Familial, 2 (supp.)
C563307	Cardiomyopathy, Dilated, 1C (supp.)
C566169	Cardiomyopathy, Familial Hypertrophic, 4 (supp.)
C567851	Ventricular Fibrillation, Paroxysmal Familial, 1 (supp.)
C536231	familial dilated cardiomyopathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4403 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 63 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL2104951	ALADORIAN	2	63

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2819742	Toxicity	3	cerivastatin	Rhabdomyolysis
rs2819742	Toxicity	3	atorvastatin;simvastatin	Cardiovascular Disease

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2819742	RYR2	3	0.50	2	atorvastatin;simvastatin;cerivastatin

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: vgic — Ryanodine receptors (RyR)

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
carvedilol	Inhibition	4.8	pIC50
VK-II-86	Inhibition	4.77	pIC50

ChEMBL bioactivities

57 potent at pChembl≥5 of 57 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.99	EC50	10.2	nM	CHEMBL5413930
7.82	EC50	15	nM	ALADORIAN
7.73	EC50	18.6	nM	CHEMBL5409619
7.70	EC50	20	nM	CHEMBL3958409
7.60	EC50	25	nM	CHEMBL3958287
7.40	EC50	40	nM	CHEMBL3982028
7.40	EC50	40	nM	CHEMBL3933375
7.40	EC50	40	nM	CHEMBL3965149
7.36	EC50	44	nM	CHEMBL3984280
7.36	EC50	44	nM	CHEMBL3980215
7.35	EC50	45	nM	CHEMBL3894901
7.30	EC50	50	nM	CHEMBL3928727
7.28	EC50	52	nM	CHEMBL3892168
7.26	EC50	55	nM	CHEMBL3952083
7.26	EC50	55	nM	CHEMBL3962505
7.22	EC50	60	nM	CHEMBL3955655
7.17	EC50	68	nM	CHEMBL3954061
7.14	EC50	73	nM	CHEMBL3943880
7.11	EC50	77	nM	CHEMBL3970844
7.10	EC50	80	nM	CHEMBL3957737
7.10	EC50	80	nM	CHEMBL3893618
7.09	EC50	81	nM	CHEMBL3953088
7.09	EC50	81.5	nM	CHEMBL5398491
7.05	EC50	89	nM	CHEMBL3978868
7.02	EC50	95	nM	CHEMBL3925875
7.02	EC50	95	nM	CHEMBL3951388
7.00	EC50	100	nM	CHEMBL3932540
7.00	EC50	100	nM	CHEMBL333343
7.00	EC50	100	nM	CHEMBL3904927
6.99	EC50	102	nM	CHEMBL3902651
6.99	EC50	102	nM	CHEMBL3971511
6.98	EC50	105	nM	CHEMBL3909873
6.96	EC50	111	nM	CHEMBL3916053
6.96	EC50	110	nM	CHEMBL3930185
6.96	EC50	111	nM	CHEMBL3892659
6.92	EC50	121	nM	CHEMBL3984065
6.87	EC50	135	nM	CHEMBL3963470
6.84	EC50	143	nM	CHEMBL3925184
6.82	EC50	150	nM	CHEMBL3941132
6.82	EC50	150	nM	CHEMBL3918890
6.82	EC50	150	nM	CHEMBL3915771
6.76	EC50	174	nM	CHEMBL3936508
6.76	EC50	175	nM	CHEMBL3961914
6.74	EC50	181	nM	CHEMBL3906571
6.74	EC50	182	nM	CHEMBL3895741
6.72	EC50	190	nM	CHEMBL2440854
6.71	EC50	197	nM	CHEMBL3933756
6.69	EC50	205	nM	CHEMBL3909362
6.68	EC50	211	nM	CHEMBL3932239
6.68	EC50	208	nM	CHEMBL3899882

PubChem BioAssay actives

5 with measured affinity, of 25 total; 5 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
1-[4-[3-(4-methoxyphenyl)sulfanylpropylamino]butyl]cyclopropan-1-ol	2023093: Modulator activity at wild type RyR2 (unknown origin) expressed in HEK293T co-expressed with R-CEPIA1er assessed as decrease in RyR2-mediated calcium leak in presence of calcium chloride by time-lapse fluorescence analysis	ec50	0.0102	uM
1-[4-[4-(1-hydroxycyclopropyl)butyl-[3-(4-methoxyphenyl)sulfanylpropyl]amino]butyl]cyclopropan-1-ol	2023093: Modulator activity at wild type RyR2 (unknown origin) expressed in HEK293T co-expressed with R-CEPIA1er assessed as decrease in RyR2-mediated calcium leak in presence of calcium chloride by time-lapse fluorescence analysis	ec50	0.0186	uM
1-[4-[3-(4-methoxyphenoxy)propylamino]butyl]cyclopropan-1-ol	2023093: Modulator activity at wild type RyR2 (unknown origin) expressed in HEK293T co-expressed with R-CEPIA1er assessed as decrease in RyR2-mediated calcium leak in presence of calcium chloride by time-lapse fluorescence analysis	ec50	0.0815	uM
1-[4-[4-(1-hydroxycyclopropyl)butyl-[4-(7-methoxy-3,5-dihydro-2H-1,4-benzothiazepin-4-yl)butyl]amino]butyl]cyclopropan-1-ol	2023093: Modulator activity at wild type RyR2 (unknown origin) expressed in HEK293T co-expressed with R-CEPIA1er assessed as decrease in RyR2-mediated calcium leak in presence of calcium chloride by time-lapse fluorescence analysis	ec50	2.7000	uM
1-[4-[4-(7-methoxy-3,5-dihydro-2H-1,4-benzothiazepin-4-yl)butylamino]butyl]cyclopropan-1-ol	2023093: Modulator activity at wild type RyR2 (unknown origin) expressed in HEK293T co-expressed with R-CEPIA1er assessed as decrease in RyR2-mediated calcium leak in presence of calcium chloride by time-lapse fluorescence analysis	ec50	8.1700	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, decreases expression, affects splicing, increases expression	4
Benzo(a)pyrene	decreases expression, increases mutagenesis, affects methylation	4
Doxorubicin	decreases expression	3
Carvedilol	decreases reaction, increases phosphorylation, affects binding, increases reaction, increases activity (+1 more)	2
Daunorubicin	decreases expression	2
Mitoxantrone	decreases expression	2
Rotenone	decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
MYK-461	decreases expression, decreases reaction	1
methylmercuric chloride	increases expression	1
methyleugenol	decreases expression	1
bisphenol A	affects cotreatment, increases methylation, decreases methylation	1
terbufos	increases methylation	1
sulforaphane	decreases expression	1
perfluorooctanoic acid	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
CGP 52608	affects binding, increases reaction	1
(+)-JQ1 compound	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Vorinostat	decreases expression	1
Arsenic	affects methylation	1
Atenolol	affects binding, increases reaction, increases activity	1
Calcium	decreases reaction, increases activity	1
Diethylhexyl Phthalate	increases expression	1
Fonofos	increases methylation	1
Etoposide	decreases expression	1
Isoproterenol	decreases reaction, increases phosphorylation	1
Methapyrilene	increases methylation	1
Metoprolol	increases activity, affects binding, increases reaction	1

ChEMBL screening assays

15 unique, capped per target: 15 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1028512	Binding	Activation of ryanodine receptor in human IMR32 cells assessed as induction of calcium mobilization	New and selective ryanodine receptor activators for insect control. — Bioorg Med Chem

Cellosaurus cell lines

26 cell lines: 22 induced pluripotent stem cell, 2 cancer cell line, 1 transformed cell line, 1 hybrid cell line

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

Cellosaurus	Name	Category	Sex
CVCL_2Z94	UKKi007-A	Induced pluripotent stem cell	Female
CVCL_9S36	UKKi007-B	Induced pluripotent stem cell	Female
CVCL_A4KY	UMGi041-A	Induced pluripotent stem cell	Male
CVCL_A4KZ	UMGi041-B.2	Induced pluripotent stem cell	Male
CVCL_A5QG	UMGi041-B.3	Induced pluripotent stem cell	Male
CVCL_A8LS	INSRMi011-A	Induced pluripotent stem cell	Male
CVCL_B5QA	ITXi009-A	Induced pluripotent stem cell	Female
CVCL_B5QB	ITXi010-A	Induced pluripotent stem cell	Female
CVCL_B5QC	ITXi011-A	Induced pluripotent stem cell	Female
CVCL_C7YF	SCVIi077-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

551 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
NCT00348530	PHASE4	UNKNOWN	Carvedilol Versus Verapamil in Chronic Heart Failure Secondary to Non-Ischemic Cardiomyopathy
NCT00371891	PHASE4	COMPLETED	Ontario Multidetector Computed Tomographic (MDCT) Coronary Angiography Study (OMCAS)
NCT00401856	PHASE4	COMPLETED	CMR to Assess Fibrosis in Cardiomyopathy Using Eplerenone
NCT00559338	PHASE4	COMPLETED	Impact of Nesiritide Infusion for Decompensated Heart Failure in the Emergency Department
NCT00606775	PHASE4	UNKNOWN	The Preventive Efficacy of Carvedilol on Cardiac Dysfunction in Duchenne Muscular Dystrophy
NCT00658203	PHASE4	COMPLETED	Clinical Evaluation on Advanced Resynchronization
NCT00701220	PHASE4	COMPLETED	Statin Therapy for Ischemic and Nonischemic Cardiomyopathy
NCT00800761	PHASE4	COMPLETED	Intensive Combined Chelation Therapy for Iron-Induced Cardiac Disease in Patients With Thalassemia Major
NCT00806390	PHASE4	TERMINATED	Prevention of Anthracycline or Trastuzumab Induced Cardiomyopathy by Metoprolol
NCT01006473	PHASE4	COMPLETED	Exercise Training in Chagas Cardiomyopathy
NCT01261065	PHASE4	COMPLETED	Mechanisms of Improvement With Beta-Blocker Treatment in Heart Failure
NCT01345188	PHASE4	COMPLETED	Ranolazine in Ischemic Cardiomyopathy
NCT01868841	PHASE4	COMPLETED	123-I mIBG (AdreView) Heart-to-Mediastinal (H/M) Ratio and SPECT Imaging on a Small Field of View-High Efficiency Cardiac SPECT System
NCT02640846	PHASE4	UNKNOWN	Effects of Levosimendan, Milrinone and Norepinephrine on Left and Right Ventricular Function in Septic Shock
NCT03228823	PHASE4	UNKNOWN	Prospective Assessment of Premature Ventricular Contractions Suppression in Cardiomyopathy(PAPS)
NCT04323852	PHASE4	COMPLETED	Can Vitamin D Reduce Heart Muscle Damage After Bypass Surgery?
NCT05034432	PHASE4	RECRUITING	The PIVATAL Study -Study of Ventricular Arrhythmia (VTA) Ablation in Left Ventricular Assist Device (LVAD) Patients
NCT05718128	PHASE4	RECRUITING	Clinical Study of Endocardial Myocardial Biopsy
NCT06964464	PHASE4	RECRUITING	Comparative Effectiveness of Carvedilol Versus Metoprolol Succinate in Heart Failure Patients With an Implantable Cardioverter Defibrillator
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