RYR3

Summary

RYR3 (ryanodine receptor 3, HGNC:10485) is a protein-coding gene on chromosome 15q13.3-q14, encoding Ryanodine receptor 3 (Q15413). Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytoplasm in muscle and thereby plays a role in triggering muscle contraction.

The protein encoded by this gene is a ryanodine receptor, which functions to release calcium from intracellular storage for use in many cellular processes. For example, the encoded protein is involved in skeletal muscle contraction by releasing calcium from the sarcoplasmic reticulum followed by depolarization of T-tubules. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 6263 — RefSeq curated summary.

At a glance

• Gene–disease (curated): genetic developmental and epileptic encephalopathy (Limited, ClinGen) — +1 more curated relationship
• GWAS associations: 13
• Clinical variants (ClinVar): 1,788 total — 1 pathogenic
• Phenotypes (HPO): 38
• Druggable target: yes
• MANE Select transcript: NM_001036

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10485
Approved symbol	RYR3
Name	ryanodine receptor 3
Location	15q13.3-q14
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000198838
Ensembl biotype	protein_coding
OMIM	180903
Entrez	6263

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 19 protein_coding_CDS_not_defined, 9 protein_coding, 3 retained_intron, 3 nonsense_mediated_decay

ENST00000389232, ENST00000415757, ENST00000557931, ENST00000558060, ENST00000559333, ENST00000559917, ENST00000560791, ENST00000634418, ENST00000634730, ENST00000634750, ENST00000634891, ENST00000635749, ENST00000635790, ENST00000635842, ENST00000635875, ENST00000636417, ENST00000636497, ENST00000636568, ENST00000636583, ENST00000636656, ENST00000636753, ENST00000636845, ENST00000636878, ENST00000637072, ENST00000637201, ENST00000637522, ENST00000637615, ENST00000637948, ENST00000637984, ENST00000638032, ENST00000638038, ENST00000638052, ENST00000638085, ENST00000638145

RefSeq mRNA: 2 — MANE Select: NM_001036 NM_001036, NM_001243996

CCDS: CCDS45210, CCDS58351

Canonical transcript exons

ENST00000634891 — 104 exons

Exon	Start	End
ENSE00000673516	33503631	33503738
ENSE00000673517	33530592	33530666
ENSE00000673518	33533311	33533389
ENSE00000673519	33539350	33539462
ENSE00000673520	33540791	33540890
ENSE00000673521	33543622	33543715
ENSE00000673522	33548130	33548204
ENSE00000673523	33550160	33550316
ENSE00000673524	33562837	33563010
ENSE00000673525	33566678	33566799
ENSE00000673581	33748114	33748260
ENSE00000673582	33748468	33748530
ENSE00000673583	33749979	33750054
ENSE00000673585	33750163	33750286
ENSE00000673596	33771920	33772158
ENSE00000673598	33773534	33773615
ENSE00000881088	33755065	33755180
ENSE00000881089	33757475	33757596
ENSE00000912834	33623807	33624023
ENSE00000912836	33628471	33628575
ENSE00000912838	33629940	33630043
ENSE00000912842	33632949	33633108
ENSE00000912844	33634586	33634733
ENSE00000912846	33635614	33635819
ENSE00000912848	33636376	33636550
ENSE00000912850	33644311	33644519
ENSE00000912852	33646351	33646526
ENSE00000912854	33647424	33647460
ENSE00000912856	33649072	33649235
ENSE00000912858	33652718	33652883
ENSE00000912859	33659720	33659806
ENSE00000912861	33660197	33660423
ENSE00000912863	33662153	33662948
ENSE00000912865	33663537	33663737
ENSE00000912867	33669354	33669456
ENSE00000912869	33670419	33670556
ENSE00000912871	33696218	33696491
ENSE00000912873	33697882	33697996
ENSE00000912874	33699704	33699833
ENSE00000912875	33700977	33701080
ENSE00000912877	33706919	33707054
ENSE00000912879	33722715	33722895
ENSE00000912898	33756306	33756373
ENSE00000912901	33780211	33780341
ENSE00000912903	33785662	33785982
ENSE00000912905	33788218	33788458
ENSE00000912907	33800770	33800857
ENSE00000912909	33801869	33801961
ENSE00000912911	33810479	33810649
ENSE00000912913	33810978	33811037
ENSE00000912915	33812863	33812994
ENSE00000912921	33818578	33818684
ENSE00000912923	33819756	33819807
ENSE00000912931	33825603	33825676
ENSE00000912935	33826672	33826752
ENSE00000912939	33830963	33831091
ENSE00001042867	33724065	33724176
ENSE00001042876	33728857	33729026
ENSE00001042922	33736235	33736325
ENSE00001042962	33820756	33820812
ENSE00001042979	33738450	33738590
ENSE00001043044	33726386	33726506
ENSE00001043120	33746068	33746157
ENSE00001043130	33739832	33739995
ENSE00001043152	33731474	33731694
ENSE00001043158	33821270	33821369
ENSE00001107909	33473419	33473538
ENSE00001107928	33581508	33581643
ENSE00001107931	33584395	33584490
ENSE00001107932	33601419	33601552
ENSE00001107934	33585998	33586116
ENSE00001107937	33603123	33603364
ENSE00001107942	33613183	33613375
ENSE00001143417	33631210	33631293
ENSE00001210555	33579976	33580144
ENSE00001540597	33816862	33816958
ENSE00001540603	33813467	33813579
ENSE00001540622	33769112	33769172
ENSE00001610752	33742366	33742444
ENSE00001612173	33859575	33859731
ENSE00001629349	33844862	33845062
ENSE00001633884	33827199	33827287
ENSE00001635754	33857780	33857914
ENSE00001668907	33864138	33864189
ENSE00001683941	33807555	33807569
ENSE00001693882	33843488	33843574
ENSE00001705476	33768658	33768707
ENSE00001713485	33836906	33836987
ENSE00001743057	33841864	33842035
ENSE00001751074	33837631	33838958
ENSE00001754292	33840825	33840883
ENSE00001754744	33861078	33861178
ENSE00001777651	33826252	33826269
ENSE00001787766	33860595	33860659
ENSE00002542180	33834968	33835072
ENSE00003505054	33854389	33854449
ENSE00003516160	33853045	33853087
ENSE00003593597	33854766	33854912
ENSE00003627444	33848291	33848421
ENSE00003646906	33822996	33823072
ENSE00003650388	33821523	33821602
ENSE00003677788	33853555	33853682
ENSE00003785090	33310967	33311096
ENSE00003788759	33865131	33866102

Expression profiles

Bgee: expression breadth ubiquitous, 233 present calls, max score 97.96.

FANTOM5 (CAGE): breadth broad, TPM avg 2.5518 / max 186.5970, expressed in 259 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
145767	1.2127	193
145763	0.3478	116
145765	0.2646	98
145766	0.2577	97
145764	0.2483	101
145768	0.1735	88
207460	0.0472	25

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
diaphragm	UBERON:0001103	97.96	gold quality
sural nerve	UBERON:0015488	95.25	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.61	gold quality
caudate nucleus	UBERON:0001873	93.54	gold quality
putamen	UBERON:0001874	93.34	gold quality
right uterine tube	UBERON:0001302	92.91	gold quality
cerebellar hemisphere	UBERON:0002245	92.62	gold quality
cerebellar cortex	UBERON:0002129	92.06	gold quality
nucleus accumbens	UBERON:0001882	91.84	gold quality
right frontal lobe	UBERON:0002810	91.50	gold quality
body of uterus	UBERON:0009853	91.50	gold quality
gastrocnemius	UBERON:0001388	91.25	gold quality
amygdala	UBERON:0001876	91.09	gold quality
left uterine tube	UBERON:0001303	90.86	gold quality
muscle of leg	UBERON:0001383	90.75	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.00	gold quality
CA1 field of hippocampus	UBERON:0003881	89.86	gold quality
Brodmann (1909) area 9	UBERON:0013540	89.41	gold quality
hindlimb stylopod muscle	UBERON:0004252	89.14	gold quality
cingulate cortex	UBERON:0003027	88.90	gold quality
anterior cingulate cortex	UBERON:0009835	88.80	gold quality
Ammon’s horn	UBERON:0001954	88.64	gold quality
cerebellum	UBERON:0002037	88.46	gold quality
muscle organ	UBERON:0001630	88.36	gold quality
descending thoracic aorta	UBERON:0002345	87.31	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	87.30	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.18	gold quality
thoracic aorta	UBERON:0001515	87.05	gold quality
ascending aorta	UBERON:0001496	87.01	gold quality
lower esophagus muscularis layer	UBERON:0035833	86.90	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-CURD-6	yes	2448.77
E-GEOD-180759	yes	1675.85
E-HCAD-35	yes	103.72
E-CURD-119	yes	31.66
E-HCAD-25	yes	30.48
E-GEOD-84465	yes	12.48
E-ANND-3	yes	10.70
E-GEOD-70580	no	27.31

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

86 targeting RYR3, 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-4262	100.00	73.26	3931
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4803	99.98	71.99	3117
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-9-3P	99.96	70.88	2068
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917

Literature-anchored findings (GeneRIF, showing 29)

• RyR3 KO mice show changes in hippocampal synaptic plasticity and a reduced flexibility in re-learning a new target in the water-maze. In the open-field, KO mice displayed a normal exploration and habituation, but had an increased speed of locomotion. (PMID:10508160)
• smooth muscle RYR3 may function as a suppressor of RyR2-mediated Ca2+ release by forming heteromeric channels with a decreased sensitivity to activation by luminal Ca2+ (PMID:12213830)
• essential in the sustained Ca(2+) response in T cells (PMID:12354756)
• smooth muscle tissues express a major dominant negative splice variant of the type 3 Ca2+ release channel (ryanodine receptor) (PMID:12471029)
• This is the first published report on RyR3 and also establishes the first evidence of wide expression of the RyR3 gene. (PMID:1320290)
• RNase protection assay and in situ hybridization revealed that RYR2 mRNA expresses widely in the heart including the SA-node, while RYR3 mRNA expression is limited to the SA-node and to the right atrium. (PMID:14550562)
• the central binding site for the 12 kDa FK506-binding protein of type-3 ryanodine receptor, encompassing the critical valine proline motif, plays a crucial role in the modulation of the Ca2+ release properties (PMID:14970260)
• We genotyped 14 tag SNPs in 166 Japanese patients with autism and 375 controls. (PMID:18588595)
• Upregulation of the expression of ryanodine receptor 3 is suggestive of an intracellular calcium leak. (PMID:19581603)
• Alterations in RyR3 expression at early disease stages may reflect the onset of pathologic mechanisms leading to later neurodegeneration. (PMID:21531043)
• A putative binding site for microRNA-367 exists in the 3’UTR of RYR3, and a genetic variant, rs1044129 A–>G, is present in this binding region. (PMID:21810988)
• RyR expressed in epidermal keratinocytes is associated with both differentiation of keratinocytes and epidermal barrier homeostasis. (PMID:21881589)
• The study provides biochemical evidence of the interaction between FKBP12 and RYR1, RYR3 and IP3R. (PMID:22100703)
• RYR3 gene polymorphisms are associated with common carotid intima-media thickness in HIV-infected white males. (PMID:22627881)
• The findings reported here for the case-only analysis of the antihypertensive pharmacogenetic effect of RYR3 among 3058 CHD cases . (PMID:22664477)
• RyR1, RyR2, and RyR3 transcripts were detected in human T cells, RyR1/2 transcript levels increased, whereas those of RyR3 decreased after T cell activation. (PMID:22948152)
• The current study suggests that the functional variant (rs1044129) in the miR-367 binding site of RYR3 may be a potential marker for prognosis in patients following curative surgery for colorectal cancer (PMID:23393343)
• a genetic interaction between the RYR3 and CACNA1C genes explained variance in amyloid deposition above and beyond other major known risk factors for late-onset Alzheimer’s disease (PMID:24026422)
• the rectified RyR3 channel in open conformation may be regulated in situ by two cytosolic activating Ca(2+) sites (PMID:24211435)
• rs877087 and rs2229116 of RYR3 gene are associated with atherosclerosis severity in Japanese. (PMID:24423397)
• SNPs within the RYR3 region were associated with subclinical atherosclerosis among HIV-infected women. Allelic heterogeneity observed across the three races suggests that the contribution of the RYR3 gene to CCA cIMT is complex. (PMID:24561552)
• Data show that the common variant single-nucleotide polymorphism rs2229116 of the ryanodine receptor 3 gene (RYR3) was significantly associated with carotid intima-media thickness (cIMT). (PMID:25500725)
• Studies indicate that the ryanodine receptors (RyRs: RyR1, RyR2, RyR3) and inositol 1,4,5-trisphosphate receptors (IP3Rs: IP3R1, IP3R2, IP3R3) are the major Ca(2+) release channels (CRCs) on the endo/sarcoplasmic reticulum (ER/SR). (PMID:25966694)
• a genome-wide linkage scan and regional association fine-mapping identified variants in the RYR3 gene as a quantitative trail locus for plasma adiponectin levels in Chinese population (PMID:27858853)
• Mutations in RYR3 Gene is associated with Gender Dysphoria. (PMID:28827537)
• RYR3 variants are associated with risk of and age of onset for hypertension, diabetes, and Alzheimer disease. (PMID:29590321)
• The Ryr Ca2+ release channel is central to cytoplasmic Ca2+ signalling in skeletal muscle, the heart, and many other tissues, playing a vital role in muscular contraction. (PMID:31263958)
• The genomic and clinical landscape of fetal akinesia. (PMID:31680123)
• RyR3 is expressed in all murine skeletal muscles during the post-natal phase of muscle development and in fewer muscles in adult mice. In agreement, RyR3 KO mice present impaired contractility during the first weeks after birth but not in adult life. (PMID:9384575)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	ryr3	ENSDARG00000071331
danio_rerio		ENSDARG00000112343
danio_rerio		ENSDARG00000115424
mus_musculus	Ryr3	ENSMUSG00000057378
rattus_norvegicus	Ryr3	ENSRNOG00000006645
drosophila_melanogaster	RyR	FBGN0011286
caenorhabditis_elegans		WBGENE00006801

Paralogs (5): ITPR3 (ENSG00000096433), ITPR2 (ENSG00000123104), ITPR1 (ENSG00000150995), RYR1 (ENSG00000196218), RYR2 (ENSG00000198626)

Protein

Protein identifiers

Ryanodine receptor 3 — Q15413 (reviewed: Q15413)

Alternative names: Brain ryanodine receptor-calcium release channel, Brain-type ryanodine receptor, Type 3 ryanodine receptor

All UniProt accessions (11): Q15413, A0A0U1RR21, A0A0U1RR54, A0A0U1RRH1, A0A0X1KG73, A0A1B0GTF2, A0A1B0GTT7, A0A1B0GU27, A0A1B0GUB0, A0A1B0GVA9, A0A1B0GVS2

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 cytoplasm in muscle and thereby plays a role in triggering muscle contraction. May regulate Ca(2+) release by other calcium channels. Calcium channel that mediates Ca(2+)-induced Ca(2+) release from the endoplasmic reticulum in non-muscle cells. Contributes to cellular calcium ion homeostasis. Plays a role in cellular calcium signaling.

Subunit / interactions. Homotetramer. Heterotetramer with RYR2. Interacts with CALM. Interacts with FKBP1A. Interacts with SELENON.

Subcellular location. Sarcoplasmic reticulum membrane.

Tissue specificity. Brain, skeletal muscle, placenta and possibly liver and kidney. In brain, highest levels are found in the cerebellum, hippocampus, caudate nucleus and amygdala, with lower levels in the corpus callosum, substantia nigra and thalamus.

Disease relevance. Congenital myopathy 20 (CMYO20) [MIM:620310] An autosomal recessive neuromuscular disorder characterized by variable manifestations. Some patients have congenital limb or distal contractures manifesting soon after birth, while others develop muscle weakness with difficulty running and climbing stairs in early childhood. Additional features may include facial dysmorphism, and delayed development with intellectual disability. Skeletal muscle biopsy may show variation in fiber size with type 1 fiber predominance and atrophy, hypertrophic type 2 fibers, and abundant nemaline bodies. The disease may be caused by variants affecting the gene represented in this entry.

Activity regulation. Channel activity is modulated by the alkaloid ryanodine that binds to the open calcium-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). The calcium release is activated by elevated cytoplasmic calcium levels in the micromolar range, by caffeine and adenine nucleotides, such as AMP and ATP. Inhibited by Mg(2+) and ruthenium red.

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

Similarity. Belongs to the ryanodine receptor (TC 1.A.3.1) family. RYR3 subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q15413-1	1	yes
Q15413-2	2
Q15413-3	3

RefSeq proteins (2): NP_001027, NP_001230925 (=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
IPR016024	ARM-type_fold	Homologous_superfamily
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, PF21119

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (88 total): sequence conflict 18, helix 17, sequence variant 11, domain 8, transmembrane region 7, region of interest 5, repeat 4, turn 4, strand 4, splice variant 3, topological domain 2, compositionally biased region 2, chain 1, site 1, intramembrane region 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
4ERV	X-RAY DIFFRACTION	1.75
9L92	X-RAY DIFFRACTION	1.97
9LS7	X-RAY DIFFRACTION	2.49
6UHB	X-RAY DIFFRACTION	2.5
9L90	X-RAY DIFFRACTION	2.79
9L9B	X-RAY DIFFRACTION	2.84
6UHA	X-RAY DIFFRACTION	2.85
6UHE	X-RAY DIFFRACTION	2.89
9L91	X-RAY DIFFRACTION	3
6UHH	X-RAY DIFFRACTION	3.14

Predicted structure (AlphaFold)

No AlphaFold model available for Q15413 — 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.

Catalytic / active sites (1): 3883 (important for activation by ca(2+))

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: 344 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BENPORATH_ES_WITH_H3K27ME3, GOBP_PROTEIN_HOMOTETRAMERIZATION, TGCACTT_MIR519C_MIR519B_MIR519A, chr15q13, CTATGCA_MIR153, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, MORF_RAD51L3, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_RESPONSE_TO_METAL_ION, MODULE_66, GOBP_RESPONSE_TO_MAGNESIUM_ION, GTGCCTT_MIR506, GOBP_CELLULAR_RESPONSE_TO_ATP, GOBP_RESPONSE_TO_ALKALOID

GO Biological Process (15): calcium ion transport (GO:0006816), intracellular calcium ion homeostasis (GO:0006874), striated muscle contraction (GO:0006941), release of sequestered calcium ion into cytosol by sarcoplasmic reticulum (GO:0014808), release of sequestered calcium ion into cytosol (GO:0051209), protein homotetramerization (GO:0051289), calcium ion transmembrane transport (GO:0070588), cellular response to calcium ion (GO:0071277), cellular response to magnesium ion (GO:0071286), cellular response to caffeine (GO:0071313), cellular response to ATP (GO:0071318), monoatomic ion transport (GO:0006811), calcium-mediated signaling (GO:0019722), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085)

GO Molecular Function (8): ryanodine-sensitive calcium-release channel activity (GO:0005219), calcium ion binding (GO:0005509), calmodulin binding (GO:0005516), intracellularly gated calcium channel activity (GO:0015278), calcium-induced calcium release activity (GO:0048763), monoatomic ion channel activity (GO:0005216), calcium channel activity (GO:0005262), protein binding (GO:0005515)

GO Cellular Component (7): smooth endoplasmic reticulum (GO:0005790), membrane (GO:0016020), Z disc (GO:0030018), sarcoplasmic reticulum membrane (GO:0033017), calcium channel complex (GO:0034704), sarcolemma (GO:0042383), sarcoplasmic reticulum (GO:0016529)

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
cellular response to metal ion	2
transport	2
endoplasmic reticulum	2
cellular anatomical structure	2
metal ion transport	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
muscle contraction	1
sarcoplasmic reticulum calcium ion transport	1
release of sequestered calcium ion into cytosol by endoplasmic reticulum	1
intercellular transport	1
calcium ion transmembrane import into cytosol	1
protein homooligomerization	1
protein tetramerization	1
calcium ion transport	1
monoatomic cation transmembrane transport	1
response to calcium ion	1
response to magnesium ion	1
response to caffeine	1
cellular response to alkaloid	1
cellular response to purine-containing compound	1
response to ATP	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
intracellular signaling cassette	1
monoatomic ion transport	1
transmembrane transport	1
cellular process	1
calcium-induced calcium release activity	1
metal ion binding	1
protein binding	1
intracellularly ligand-gated monoatomic ion channel activity	1
ligand-gated calcium channel activity	1
intracellularly gated calcium channel activity	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
binding	1
I band	1

Protein interactions and networks

STRING

1664 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RYR3	FKBP1B	P68106	818
RYR3	OPCML	Q14982	723
RYR3	CACNA1C	Q13936	705
RYR3	RYR2	Q92736	697
RYR3	FKBP1A	P20071	686
RYR3	SELENON	Q9NZV5	620
RYR3	ITPR1	Q14643	613
RYR3	ITPR3	Q14573	607
RYR3	PSEN2	P49810	592
RYR3	TRDN	Q13061	590
RYR3	AKAP6	Q13023	580
RYR3	CACNA1S	Q13698	565
RYR3	ITPR2	Q14571	555
RYR3	ATP2A1	O14983	552
RYR3	APH1B	Q8WW43	549

IntAct

10 interactions, top by confidence:

A	B	Type	Score
RYR3	RTN4	psi-mi:“MI:0915”(physical association)	0.400
RYR3	UGGT1	psi-mi:“MI:0915”(physical association)	0.400
APBB1	SSPOP	psi-mi:“MI:0914”(association)	0.350
APBB1	ATP2A2	psi-mi:“MI:0914”(association)	0.350
CUL1	LGALS8	psi-mi:“MI:0914”(association)	0.350
HCN1	POTEF	psi-mi:“MI:0914”(association)	0.350
HNF1A	RYR3	psi-mi:“MI:0915”(physical association)	0.000
	RYR3	psi-mi:“MI:0915”(physical association)	0.000
TIAM1	RYR3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (31): RYR3 (Affinity Capture-MS), RYR3 (Reconstituted Complex), RYR3 (Reconstituted Complex), RYR3 (Affinity Capture-MS), BCL2L1 (Affinity Capture-Western), BCL2L1 (Reconstituted Complex), BCL2L1 (Two-hybrid), RYR3 (Affinity Capture-MS), RYR3 (Affinity Capture-Western), RYR2 (Affinity Capture-Western), RYR3 (Reconstituted Complex), RTN4 (Proximity Label-MS), UGGT1 (Proximity Label-MS), FKBP1A (Reconstituted Complex), RYR3 (Affinity Capture-RNA)

ESM2 similar proteins: A0A3L7I2I8, A0FKG7, A2AGL3, A7MB89, B0LPN4, E9Q401, O60733, P30957, P42694, P49754, P97570, P97819, Q15413, Q29RM5, Q2KIX2, Q2T9K6, Q32PW3, Q3SX45, Q4V890, Q59H18, Q5F361, Q5GIG6, Q5KU39, Q5RF15, Q5U2S6, Q5ZKK2, Q66H07, Q66H63, Q6B858, Q6DFV5, Q6NYU2, Q7T3P8, Q7TQP6, Q8C0T1, Q8CEF1, Q8K0L0, Q8K114, Q8TC84, Q91W86, Q92736

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

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1788 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	1112
Likely benign	466
Benign	106

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1342869	NM_001036.6(RYR3):c.6248A>C (p.Gln2083Pro)	Pathogenic

SpliceAI

19217 predictions. Top by Δscore:

Variant	Effect	Δscore
15:33311092:GGACT:G	donor_gain	1.0000
15:33311093:GACT:G	donor_gain	1.0000
15:33311093:GACTG:G	donor_gain	1.0000
15:33311094:ACT:A	donor_gain	1.0000
15:33311095:CT:C	donor_gain	1.0000
15:33311096:TGT:T	donor_loss	1.0000
15:33311097:G:GG	donor_gain	1.0000
15:33446300:G:GT	donor_gain	1.0000
15:33473413:T:TA	acceptor_gain	1.0000
15:33473414:G:A	acceptor_gain	1.0000
15:33473414:GGCA:G	acceptor_loss	1.0000
15:33473417:A:AG	acceptor_gain	1.0000
15:33473417:A:C	acceptor_loss	1.0000
15:33473417:AG:A	acceptor_gain	1.0000
15:33473417:AGGAG:A	acceptor_gain	1.0000
15:33473418:G:GA	acceptor_loss	1.0000
15:33473418:G:GC	acceptor_gain	1.0000
15:33473418:GG:G	acceptor_gain	1.0000
15:33473418:GGA:G	acceptor_gain	1.0000
15:33473418:GGAGG:G	acceptor_gain	1.0000
15:33473535:CAAGG:C	donor_loss	1.0000
15:33473538:GGT:G	donor_loss	1.0000
15:33473539:G:A	donor_loss	1.0000
15:33473540:T:A	donor_loss	1.0000
15:33503630:GTAC:G	acceptor_gain	1.0000
15:33503736:GGG:G	donor_gain	1.0000
15:33503737:GGG:G	donor_gain	1.0000
15:33533309:A:AG	acceptor_gain	1.0000
15:33533310:G:GG	acceptor_gain	1.0000
15:33533310:GT:G	acceptor_gain	1.0000

AlphaMissense

32297 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:33539364:T:A	W150R	1.000
15:33539364:T:C	W150R	1.000
15:33540848:T:A	W202R	1.000
15:33540848:T:C	W202R	1.000
15:33628534:T:A	W880R	1.000
15:33628534:T:C	W880R	1.000
15:33628536:G:C	W880C	1.000
15:33628536:G:T	W880C	1.000
15:33628561:T:A	W889R	1.000
15:33628561:T:C	W889R	1.000
15:33629992:T:C	L911P	1.000
15:33633038:T:C	L986P	1.000
15:33633052:C:G	H991D	1.000
15:33633061:T:A	W994R	1.000
15:33633061:T:C	W994R	1.000
15:33633063:G:C	W994C	1.000
15:33633063:G:T	W994C	1.000
15:33633075:A:C	R998S	1.000
15:33633075:A:T	R998S	1.000
15:33633088:T:A	W1003R	1.000
15:33633088:T:C	W1003R	1.000
15:33634614:T:C	L1019P	1.000
15:33635745:T:A	W1103R	1.000
15:33635745:T:C	W1103R	1.000
15:33649132:T:A	W1347R	1.000
15:33649132:T:C	W1347R	1.000
15:33311085:T:C	F14L	0.999
15:33311087:T:A	F14L	0.999
15:33311087:T:G	F14L	0.999
15:33539428:T:C	L171P	0.999

dbSNP variants (sampled 300 via entrez): RS1000004277 (15:33425695 G>A), RS1000009435 (15:33438308 C>T), RS1000011520 (15:33493550 T>G), RS1000011713 (15:33385258 G>A,C,T), RS1000018750 (15:33816622 A>C), RS1000024782 (15:33567817 C>T), RS1000029606 (15:33313055 T>C), RS1000029844 (15:33341681 C>A), RS1000040927 (15:33540484 A>G), RS1000041738 (15:33454748 T>C), RS1000042350 (15:33384268 C>T), RS1000044208 (15:33584073 A>G), RS1000045346 (15:33704799 C>T), RS1000052906 (15:33547038 G>A,T), RS1000058988 (15:33775977 G>A,T)

Disease associations

OMIM: gene MIM:180903 | disease phenotypes: MIM:620310, MIM:602440

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital myopathy	Limited	Autosomal recessive
genetic developmental and epileptic encephalopathy	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
genetic developmental and epileptic encephalopathy	Limited	AD
congenital myopathy	Disputed	AR

Mondo (8): congenital myopathy 20 (MONDO:0957215), hydrops fetalis (MONDO:0015193), familial colorectal cancer (MONDO:0023113), primary ovarian failure (MONDO:0005387), monomelic amyotrophy (MONDO:0011224), congenital portosystemic shunt (MONDO:0018811), congenital myopathy (MONDO:0019952), genetic developmental and epileptic encephalopathy (MONDO:0100062)

Orphanet (4): Hydrops fetalis (Orphanet:1041), Monomelic amyotrophy (Orphanet:65684), Congenital portosystemic shunt (Orphanet:480531), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

38 total (30 of 38 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000275	Narrow face
HP:0000286	Epicanthus
HP:0000337	Broad forehead
HP:0000347	Micrognathia
HP:0000592	Blue sclerae
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001508	Failure to thrive
HP:0001762	Talipes equinovarus
HP:0002028	Chronic diarrhea
HP:0002359	Frequent falls
HP:0002650	Scoliosis
HP:0002803	Congenital contracture
HP:0002827	Hip dislocation
HP:0003202	Skeletal muscle atrophy
HP:0003391	Gowers sign
HP:0003551	Difficulty climbing stairs
HP:0003557	Increased variability in muscle fiber diameter
HP:0003621	Juvenile onset
HP:0003687	Centrally nucleated skeletal muscle fibers
HP:0003691	Scapular winging
HP:0003701	Proximal muscle weakness
HP:0003798	Nemaline bodies
HP:0003803	Type 1 muscle fiber predominance
HP:0005280	Depressed nasal bridge
HP:0009046	Difficulty running
HP:0009381	Short finger

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST000555_3	Carotid atherosclerosis in HIV infection	3.000000e-08
GCST002127_2	Periodontitis (Mean PAL)	7.000000e-06
GCST002337_156	Amyotrophic lateral sclerosis (sporadic)	5.000000e-06
GCST003944_19	Hepcidin/ferritin ratio	2.000000e-06
GCST003944_20	Hepcidin/ferritin ratio	7.000000e-06
GCST007201_43	Schizophrenia	9.000000e-06
GCST009260_10	Hippocampal volume	1.000000e-06
GCST010307_13	Urinary albumin excretion	1.000000e-08
GCST010397_53	Gut microbiota (bacterial taxa, rank normal transformation method)	3.000000e-06
GCST010725_22	Malaria	3.000000e-06
GCST010725_37	Malaria	3.000000e-06
GCST010725_54	Malaria	5.000000e-06
GCST011823_7	Parkinson’s disease progression (cognitive)	1.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007901	hepcidin:ferritin ratio
EFO:0005035	hippocampal volume
EFO:0004285	albuminuria
EFO:0007874	gut microbiome measurement
EFO:0008336	disease progression measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D015160	Hydrops Fetalis	C12.050.703.277.060.480; C15.378.295.480; C15.378.420.826.100.350; C16.300.060.480; C16.320.365.826.100.350; C20.306.480; C23.888.277.395
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
C538253	Amyotrophy, monomelic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2062 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs877087	RYR3		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: vgic — Ryanodine receptors (RyR)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	6
trichostatin A	affects cotreatment, decreases expression	3
entinostat	decreases expression, affects cotreatment	2
Vorinostat	affects cotreatment, decreases expression	2
Panobinostat	decreases expression, affects cotreatment	2
Benzo(a)pyrene	decreases methylation, increases mutagenesis	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
methylmercuric chloride	decreases expression	1
sodium arsenite	affects methylation	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
quinocetone	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression, affects cotreatment	1
Arsenic	affects methylation	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Methapyrilene	increases methylation	1
Methylcholanthrene	affects binding, increases reaction	1
Potassium Dichromate	increases expression	1
Progesterone	increases expression, affects cotreatment	1
Dronabinol	increases expression	1
Thimerosal	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4354689	Binding	Inhibition of wild type RyR3 (unknown origin) stably expressed in HEK293 cells coexpressing R-CEPIA1er assessed as suppression in caffeine-activated Ca2+ leakage from ER at 10 uM compound addition at 100 secs and measured every 10 secs for	Structural development of a type-1 ryanodine receptor (RyR1) Ca2+-release channel inhibitor guided by endoplasmic reticulum Ca2+ assay. — Eur J Med Chem

Cellosaurus cell lines

3 cell lines: 1 finite cell line, 1 cancer cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A2VE	GM26113	Finite cell line	Male
CVCL_E0N4	Ubigene HeLa RYR3 KO	Cancer cell line	Female
CVCL_F0ZK	GM29523	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT02986698	PHASE1	TERMINATED	In Utero Hematopoietic Stem Cell Transplantation for Alpha-thalassemia Major (ATM)
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT02020187	Not specified	COMPLETED	Aerobic Training in Patients With Congenital Myopathies
NCT03018184	Not specified	COMPLETED	Contractile Cross Sectional Areas and Muscle Strength in Patients With Congenital Myopathies
NCT04733976	Not specified	COMPLETED	Bullying in Youth With Muscular Dystrophy and Congenital Myopathies
NCT05099107	Not specified	COMPLETED	Changes of Motor Function Tests in Congenital Myopathy Subjects Treated With Oral Salbutamol as Compared to no Treatment
NCT05199246	Not specified	COMPLETED	Assessment of Safety and Acute Effects of a Lower-limb Powered Dermoskeleton in Patients With Neuromuscular Disorders
NCT05200702	Not specified	COMPLETED	Assessment of Safety and Acute Effects of a Knee-hip Powered Soft Exoskeleton in Patients With Neuromuscular Disorders
NCT05692349	Not specified	UNKNOWN	Magnetic Resonance Imaging and Ultrasonography in Evaluation of Muscle Diseases
NCT06791369	Not specified	NOT_YET_RECRUITING	The Prevalence of RYR1-related Disease
NCT06833489	Not specified	RECRUITING	Transcriptomic Analysis to Put an End to Misdiagnosis in Patients With Rare Muscle Diseases
NCT07138963	Not specified	RECRUITING	Phenotype - Genotype Correlation in a Sample of Egyptian Patients With Congenital Myopathies and Congenital Muscular Dystrophies
NCT07415837	Not specified	RECRUITING	Evaluation of the Role of miR-1 in the Pathogenesis and as a Biomarker in Muscular Dystrophies and Congenital Myopathies
NCT07502989	Not specified	RECRUITING	Muscle Health Measurements Using Electrical Impedance Myography
NCT07580365	Not specified	NOT_YET_RECRUITING	VirtualPark_Pediatric
NCT05364021	PHASE1/PHASE2	COMPLETED	Study to Investigate LP352 in Subjects With Developmental and Epileptic Encephalopathies
NCT06983158	PHASE1/PHASE2	SUSPENDED	A Clinical Trial of CAP-002 Gene Therapy in Pediatric Patients With Syntaxin-Binding Protein 1 (STXBP1) Encephalopathy
NCT04937062	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Phenylbutyrate for Monogenetic Developmental and Epileptic Encephalopathy
NCT06149663	Not specified	AVAILABLE	Intermediate-Size Expanded Access Protocol (EAP) for LP352