ITPR1

Summary

ITPR1 (inositol 1,4,5-trisphosphate receptor type 1, HGNC:6180) is a protein-coding gene on chromosome 3p26.1, encoding Inositol 1,4,5-trisphosphate-gated calcium channel ITPR1 (Q14643). Inositol 1,4,5-trisphosphate-gated calcium channel that, upon inositol 1,4,5-trisphosphate binding, mediates calcium release from the endoplasmic reticulum (ER).

This gene encodes an intracellular receptor for inositol 1,4,5-trisphosphate. Upon stimulation by inositol 1,4,5-trisphosphate, this receptor mediates calcium release from the endoplasmic reticulum. Mutations in this gene cause spinocerebellar ataxia type 15, a disease associated with an heterogeneous group of cerebellar disorders. Multiple transcript variants have been identified for this gene.

Source: NCBI Gene 3708 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spinocerebellar ataxia type 29 (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 21
• Clinical variants (ClinVar): 2,246 total — 47 pathogenic, 34 likely-pathogenic
• Phenotypes (HPO): 187
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001378452

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6180
Approved symbol	ITPR1
Name	inositol 1,4,5-trisphosphate receptor type 1
Location	3p26.1
Locus type	gene with protein product
Status	Approved
Aliases	Insp3r1, IP3R1, ACV, PPP1R94
Ensembl gene	ENSG00000150995
Ensembl biotype	protein_coding
OMIM	147265
Entrez	3708

Gene structure

Transcript identifiers

Ensembl transcripts: 55 — 21 protein_coding, 20 retained_intron, 12 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 non_stop_decay

ENST00000302640, ENST00000354582, ENST00000357086, ENST00000443694, ENST00000456211, ENST00000463980, ENST00000467056, ENST00000467545, ENST00000472205, ENST00000477577, ENST00000478515, ENST00000479831, ENST00000481415, ENST00000487016, ENST00000490572, ENST00000491868, ENST00000493491, ENST00000494681, ENST00000544951, ENST00000647624, ENST00000647673, ENST00000647685, ENST00000647717, ENST00000647900, ENST00000647997, ENST00000648016, ENST00000648038, ENST00000648208, ENST00000648212, ENST00000648266, ENST00000648309, ENST00000648390, ENST00000648431, ENST00000648510, ENST00000648564, ENST00000648770, ENST00000649015, ENST00000649051, ENST00000649139, ENST00000649144, ENST00000649272, ENST00000649314, ENST00000649414, ENST00000649425, ENST00000649430, ENST00000649669, ENST00000649694, ENST00000649767, ENST00000649908, ENST00000650074, ENST00000650079, ENST00000650139, ENST00000650146, ENST00000650294, ENST00000650552

RefSeq mRNA: 4 — MANE Select: NM_001378452 NM_001099952, NM_001168272, NM_001378452, NM_002222

CCDS: CCDS46740, CCDS54550, CCDS54551, CCDS93191

Canonical transcript exons

ENST00000649015 — 62 exons

Exon	Start	End
ENSE00001121891	4795065	4795187
ENSE00001121897	4787947	4788139
ENSE00001121920	4782619	4782741
ENSE00001121929	4779550	4779645
ENSE00001121940	4775242	4775442
ENSE00001121949	4768511	4768764
ENSE00001121958	4766530	4766710
ENSE00001121982	4710325	4710473
ENSE00001121989	4706167	4706351
ENSE00001121993	4702830	4702950
ENSE00001121998	4699813	4699941
ENSE00001122003	4697147	4697272
ENSE00001122009	4693490	4693741
ENSE00001122015	4691144	4691344
ENSE00001122020	4688495	4688620
ENSE00001122027	4685069	4685206
ENSE00001122034	4684281	4684346
ENSE00001122044	4683386	4683551
ENSE00001122050	4681364	4681418
ENSE00001122057	4680553	4680691
ENSE00001122068	4676614	4676801
ENSE00001122088	4674202	4674343
ENSE00001122094	4673136	4673387
ENSE00001210818	4711757	4711868
ENSE00001210825	4683628	4683798
ENSE00001210837	4653842	4653886
ENSE00001210877	4777264	4777374
ENSE00001210890	4735164	4735354
ENSE00001258258	4675068	4675248
ENSE00001359824	4494431	4494506
ENSE00002264536	4493348	4493605
ENSE00003459644	4644136	4644234
ENSE00003462468	4669654	4669773
ENSE00003473040	4516476	4516583
ENSE00003473591	4521024	4521094
ENSE00003477552	4818082	4818242
ENSE00003486307	4642093	4642251
ENSE00003505787	4733088	4733220
ENSE00003513138	4670729	4670926
ENSE00003527234	4627763	4627878
ENSE00003533119	4815053	4815218
ENSE00003537321	4660988	4661087
ENSE00003538049	4663065	4663206
ENSE00003540372	4662082	4662242
ENSE00003543315	4727126	4727173
ENSE00003554383	4717367	4717399
ENSE00003556322	4652123	4652218
ENSE00003578784	4667377	4667549
ENSE00003579151	4645387	4645470
ENSE00003581689	4639384	4639470
ENSE00003609337	4813142	4813234
ENSE00003612123	4814423	4814562
ENSE00003614806	4645582	4645728
ENSE00003615304	4800425	4800600
ENSE00003618391	4658124	4658278
ENSE00003626946	4811265	4811460
ENSE00003633894	4783816	4783920
ENSE00003655134	4665138	4665296
ENSE00003659860	4836774	4836935
ENSE00003662513	4725546	4725581
ENSE00003667922	4806103	4806267
ENSE00003789875	4846139	4847506

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 98.27.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.2221 / max 425.9373, expressed in 1601 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
35034	14.6515	1529
35036	2.2139	617
35035	0.6089	254
35066	0.1622	73
202657	0.1410	68
35045	0.1227	9
35037	0.0783	34
35040	0.0608	18
35063	0.0469	12
35062	0.0463	24

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cauda epididymis	UBERON:0004360	98.27	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.19	gold quality
primary visual cortex	UBERON:0002436	98.09	gold quality
right coronary artery	UBERON:0001625	97.68	gold quality
adrenal tissue	UBERON:0018303	97.63	gold quality
popliteal artery	UBERON:0002250	97.62	gold quality
tibial artery	UBERON:0007610	97.61	gold quality
artery	UBERON:0001637	97.51	gold quality
seminal vesicle	UBERON:0000998	97.50	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.28	gold quality
occipital lobe	UBERON:0002021	97.24	gold quality
orbitofrontal cortex	UBERON:0004167	97.18	gold quality
aorta	UBERON:0000947	97.04	gold quality
left coronary artery	UBERON:0001626	97.04	gold quality
right frontal lobe	UBERON:0002810	97.01	gold quality
coronary artery	UBERON:0001621	96.86	gold quality
blood vessel layer	UBERON:0004797	96.84	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.81	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.77	gold quality
postcentral gyrus	UBERON:0002581	96.75	gold quality
parietal lobe	UBERON:0001872	96.71	gold quality
caput epididymis	UBERON:0004358	96.69	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.66	gold quality
superior frontal gyrus	UBERON:0002661	96.61	gold quality
descending thoracic aorta	UBERON:0002345	96.49	gold quality
frontal cortex	UBERON:0001870	96.47	gold quality
frontal lobe	UBERON:0016525	96.47	gold quality
prefrontal cortex	UBERON:0000451	96.36	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.35	gold quality
thoracic aorta	UBERON:0001515	96.34	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	91.78
E-CURD-119	yes	52.35
E-GEOD-81547	yes	19.93
E-GEOD-81608	yes	15.06
E-MTAB-6075	no	972.68
E-CURD-135	no	782.58
E-ENAD-27	no	7.88
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ESR1, KAT5, KAT7, MITF, MYB, MYC, NEUROD2, NFATC4, PLSCR1, RORA, TFAP2A, TP53

miRNA regulators (miRDB)

146 targeting ITPR1, 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-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-4778-3P	99.93	70.40	1818

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• results indicate the InsP3R channel does not significantly differ functionally in terms of Ca2+ release rates between isoforms (PMID:11587548)
• involved in the activation of store-mediated Ca(2+) entry by coupling to Trp1 in normal human platelets (PMID:12196544)
• study demonstrates the functional presence of type I InsP(3)R-operated Ca(2+) channels in human oocytes and further suggests an active role of InsP(3) in triggering the Ca(2+) rise and secondary activation phenomena at fertilization (PMID:12356940)
• IP3R interaction with TRPC1 is signaled by Rho activation at the plasma membrane of endothelial cells, and Ca2+ entry is triggered following store depletion (PMID:12766172)
• Mutation analysis from two representative affected family members excluded the coding region of the ITPR1 gene from being involved in the pathogenesis of spinocerebellar ataxia type 15. (PMID:12828938)
• These results indicate that inositol 1,4,5-trisphosphate receptors may be a specific target for cdc2/CyB during cell cycle progression. (PMID:14635192)
• differential expression of the IP(3)R subtype is critical for various forms of Ca(2+) signaling, and, particularly, IP(3)R1 and IP(3)R3 have opposite roles in generating Ca(2+) oscillations (PMID:14707143)
• one function of tyrosine phosphorylation of IP3R1-Y353 is to enhance Ca2+ signaling in lymphocytes (PMID:14761954)
• The causative gene for some Japanese spinocerebellar ataxia is allelic to SCA15. (PMID:14981189)
• Altered mRNA expression is associated with prostate cancer recurrence. (PMID:15067324)
• PLSCR1 binds to the promoter region of the IP3R1 gene to enhance its expression (PMID:16091359)
• PC2 and IP3R functionally interact and modulate intracellular Ca2+ signaling (PMID:16223735)
• Cdc2/cyclin B1 interacts with and modulates inositol 1,4,5-trisphosphate receptor (type 1) functions. (PMID:16237118)
• ATP binding specifically to the ATPC site in S2- InsP3R-1 controls the susceptibility of the receptor to protein kinase A-mediated phosphorylation (PMID:16621795)
• CIB1 is a ubiquitously expressed activating and inhibiting protein ligand of the InsP(3)R (PMID:16723353)
• Signaling via IP(3)R may therefore be sufficient to drive essential DC Ca(2+) signaling processes in the absence of RyR expression or function. (PMID:16844763)
• We show that Fas-mediated apoptosis requires endoplasmic reticulum-mediated calcium release in a mechanism dependent on phospholipase C-gamma1 (PLC-gamma1) activation and Ca2+ release from inositol 1,4,5-trisphosphate receptor (IP3R) channels. (PMID:17130290)
• These results strongly suggest that IP(3)R exerts a major role in the physiological control of autophagy. (PMID:17256008)
• Antibodies in Sjogren’s syndrome recognized residues 224-604 of the core protein IP(3)R1. (PMID:17437169)
• Heterozygous deletion of the 5’ part of the ITPR1 gene, encompassing exons 1-10, 1-40, and 1-44 in three studied families, underlies spinocerebellar ataxia 15 in humans. (PMID:17590087)
• Nitric oxide-induced motility in osteoclasts requires regulated Ca(2+) release, which activates mu-calpain. This occurs via the Ins(1,4,5)P(3)R1. (PMID:17690304)
• Our data provide evidence that haploinsufficiency of ITPR1 alone causes SCA16 and SCA15. (PMID:17932120)
• IP(3)R1 binds to the scaffolding protein linker of activated T cells and colocalizes with the T cell receptor during activation, resulting in persistent phosphorylation of IP(3)R1 at Tyr353. (PMID:18056410)
• Ankyrin B modulates the function of Na,K-ATPase/inositol 1,4,5-trisphosphate receptor signaling microdomain (PMID:18303017)
• inositol 1,4,5-trisphosphate receptors are required for tumor-mediated lymphocyte apoptosis (PMID:18364356)
• Our results strongly confirm that ITPR1 is the causative gene for SCA15 and suggest that we need to investigate the point mutation in ITPR1 in the patients with autosomal dominant cerebellar ataxia and tremor. (PMID:18579805)
• The interaction of Bcl-2 with IP3Rs contributes to the regulation of proapoptotic Ca2+ signals by Bcl-2. (PMID:18657507)
• these results indicate the involvement of the InsP3R-mediated pathway in the modulation of depressive conditions and may be useful for the development of new therapeutical strategies for the treatment of mood disorders (PMID:18708078)
• 80K-H is a novel regulator of IP3R1 activity, and it may contribute to neuronal functions. (PMID:18990696)
• Insulin promotes the interaction of Hsp90 with the IP(3)R to dampen its Ca(2+) release activity by a complex mechanism involving mammalian target of rapamycin and the Src kinase. (PMID:19147678)
• These results identify IP(3)R as a new regulator of the Beclin 1 complex that may bridge signals converging on the ER and initial phagophore formation. (PMID:19325567)
• a key pathway by which TNF-alpha in a neuronal environment modulates IP(3)R expression and intracellular Ca(2+) homeostasis (PMID:19666470)
• PC1 inhibits Ca(2+) release, perhaps opposing the effect of PC2, which facilitates Ca(2+) release through the IP(3)R. (PMID:19854836)
• Increased InsP(3)R expression may be a general phenomenon that underlies Ca(2+) changes during hypertrophy. (PMID:19934645)
• ITPR1-reduced expression in blood may be a useful marker to identify SCA15 patients harboring genomic deletions and possibly point mutations causing reduction of mRNA level. (PMID:20082166)
• In Duchenne muscular dystrophy biopsies, all fibers display a homogeneous IP(3)R2 label, whereas 24 +/- 7% of type II fibers have lost the IP(3)R1 label. (PMID:20395455)
• These findings identify inositol (1,4,5)-triphosphate receptor as a new determinant in HIV-1 trafficking during Gag assembly and introduce IP3R-regulated Ca(2+) signaling as a potential novel cofactor in viral particle release. (PMID:20427533)
• results indicate that point mutations in ITPR1 are at best a rare cause of ADCA III. (PMID:20437544)
• the heterogeneous expression of the IP3R1-nls-lacZ transgene in Purkinje cell subsets may be useful as a molecular indicator of functional units, such as microcomplexes, of the cerebellar circuitry. (PMID:20632399)
• SCA15 is a slowly or nonprogressive pure cerebellar ataxia, which appears to be caused by a loss of ITPR1 function and a reduction in the translated protein (PMID:20669319)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	itpr1a	ENSDARG00000014655
danio_rerio	itpr1b	ENSDARG00000074149
mus_musculus	Itpr1	ENSMUSG00000030102
rattus_norvegicus	Itpr1	ENSRNOG00000007104
drosophila_melanogaster	RyR	FBGN0011286
caenorhabditis_elegans		WBGENE00006801

Paralogs (5): ITPR3 (ENSG00000096433), ITPR2 (ENSG00000123104), RYR1 (ENSG00000196218), RYR2 (ENSG00000198626), RYR3 (ENSG00000198838)

Protein

Protein identifiers

Inositol 1,4,5-trisphosphate-gated calcium channel ITPR1 — Q14643 (reviewed: Q14643)

Alternative names: IP3 receptor isoform 1, Inositol 1,4,5 trisphosphate receptor, Inositol 1,4,5-trisphosphate receptor type 1, Type 1 inositol 1,4,5-trisphosphate receptor

All UniProt accessions (17): Q14643, A0A3B3IRP0, A0A3B3IRT5, A0A3B3IS59, A0A3B3ISE3, A0A3B3ISR4, A0A3B3ITM1, A0A3B3ITM6, A0A3B3ITQ1, A0A3B3ITQ4, A0A3B3ITU8, A0A3B3IU04, A0A3B3IU05, A0A3B3IU13, A0A3F2YNW8, A0A8C8KBY2, B7ZMI3

UniProt curated annotations — full annotation on UniProt →

Function. Inositol 1,4,5-trisphosphate-gated calcium channel that, upon inositol 1,4,5-trisphosphate binding, mediates calcium release from the endoplasmic reticulum (ER). Undergoes conformational changes upon ligand binding, suggesting structural flexibility that allows the channel to switch from a closed state, capable of interacting with its ligands such as 1,4,5-trisphosphate and calcium, to an open state, capable of transferring calcium ions across the ER membrane. Cytoplasmic calcium released from the ER triggers apoptosis by the activation of CAMK2 complex. Involved in the regulation of epithelial secretion of electrolytes and fluid through the interaction with AHCYL1. Part of a complex composed of HSPA9, ITPR1 and VDAC1 that regulates mitochondrial calcium-dependent apoptosis by facilitating calcium transport from the ER lumen to the mitochondria intermembrane space thus providing calcium for the downstream calcium channel MCU that directly releases it into mitochondria matrix. Regulates fertilization and egg activation by tuning the frequency and amplitude of calcium oscillations.

Subunit / interactions. Homotetramer. Homodimer. Interacts with ERP44 in a pH-, redox state- and calcium-dependent manner which results in the inhibition the calcium channel activity. The strength of this interaction inversely correlates with calcium concentration. Part of cGMP kinase signaling complex at least composed of ACTA2/alpha-actin, CNN1/calponin H1, PLN/phospholamban, PRKG1 and ITPR1. Interacts with IRAG1. Interacts with CABP1 (via N-terminus). Interacts with TESPA1. Interacts (when not phosphorylated) with AHCYL1 (when phosphorylated); the interaction suppresses inositol 1,4,5-trisphosphate binding to ITPR1 and is increased in the presence of BCL2L10. Interacts with AHCYL2 (with lower affinity than with AHCYL1). Interacts with BCL2L10; the interaction is increased in the presence of AHCLY1. Interacts with BOK (via BH4 domain); protects ITPR1 from proteolysis by CASP3 during apoptosis. Interacts with TRPC4. Interacts with CHGA and CHGB. Interacts with CALM1; this interaction inhibits inositol 1,4,5 trisphosphate binding in both the presence and absence of calcium and 1,4,5 trisphosphate-induced calcium release in the presence of calcium. Interacts with the complex composed by ERLIN1, ERLIN2 and RNF170 through ERLIN2; this interaction triggers its ubiquitin-proteasomal degradation. Interacts with HSPA9; this interaction couples ITPR1 to VDAC1.

Subcellular location. Endoplasmic reticulum membrane. Cytoplasmic vesicle. Secretory vesicle membrane. Cytoplasm. Perinuclear region.

Tissue specificity. Widely expressed.

Post-translational modifications. Polyubiquitinated. Polyubiquitination targets ITPR1 for proteasomal degradation. Approximately 40% of the ITPR1-associated ubiquitin is monoubiquitin, and polyubiquitins are both ‘Lys-48’- and ‘Lys-63’-linked. Phosphorylated by cAMP kinase (PKA) enhances calcium release. Phosphorylation by PKA increases the interaction with inositol 1,4,5-trisphosphate and decreases the interaction with AHCYL1. Phosphorylated on tyrosine residues. Palmitoylated by ZDHHC6 in immune cells, leading to regulation of ITPR1 stability and function.

Disease relevance. Spinocerebellar ataxia 15 (SCA15) [MIM:606658] Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA15 is an autosomal dominant cerebellar ataxia (ADCA). It is very slow progressing form with a wide range of onset, ranging from childhood to adult. Most patients remain ambulatory. The disease is caused by variants affecting the gene represented in this entry. Spinocerebellar ataxia 29 (SCA29) [MIM:117360] An autosomal dominant, congenital spinocerebellar ataxia characterized by early motor delay, hypotonia and mild cognitive delay. Affected individuals develop a very slowly progressive or non-progressive gait and limb ataxia associated with cerebellar atrophy on brain imaging. Additional variable features include nystagmus, dysarthria, and tremor. The disease is caused by variants affecting the gene represented in this entry. Gillespie syndrome (GLSP) [MIM:206700] A rare disease characterized by bilateral iris hypoplasia, congenital hypotonia, non-progressive ataxia, progressive cerebellar atrophy, and intellectual disability. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inositol 1,4,5-trisphosphate-gated calcium channel activity is regulated by cytosolic calcium in a biphasic manner, with low concentrations causing activation and higher concentrations inhibiting channel opening, giving rise to calcium oscillations. ATP increases the open probability of ITPR1 by synergizing with the activating effect of these two primarily ligands, inositol 1,4,5-trisphosphate and calcium. Inositol 1,4,5-trisphosphate-gated calcium channel activity is activated by zinc ions. Inositol 1,4,5-trisphosphate-gated calcium channel activity is inhibited by CALM1 in a calcium-dependent manner.

Domain organisation. The ITPR1 structure has a large solenoid CY assembly built around the central helical bundle made of the C-terminal domains from four ITPR1 subunits. The solenoid scaffold includes domains responsible for binding of ligands and regulatory proteins and is connected via an allosteric nexus at the cytosolic-membrane interface to the transmembrane channel assembly. Six transmembrane helices from each subunit form the central ion-conduction pore.

Similarity. Belongs to the InsP3 receptor family.

Isoforms (8)

UniProt ID	Names	Canonical?
Q14643-1	1, SISIIISIIAC	yes
Q14643-2	2, SI-SIIISIIAC
Q14643-3	3, SISIII-SII
Q14643-4	4, SI-SIII-SII
Q14643-5	5, SI-SIII-SIIAC
Q14643-6	6, SISIIISIIA
Q14643-7	7, SI-SIII-SIIA
Q14643-8	8, SI-SIII-SIIA

RefSeq proteins (4): NP_001093422, NP_001161744, NP_001365381, NP_002213 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000493	InsP3_rcpt	Family
IPR000699	RIH_dom	Domain
IPR005821	Ion_trans_dom	Domain
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
IPR035910	RyR/IP3R_RIH_dom_sf	Homologous_superfamily
IPR036300	MIR_dom_sf	Homologous_superfamily

Pfam: PF00520, PF01365, PF02815, PF08454, PF08709

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (103 total): binding site 24, mutagenesis site 13, cross-link 11, sequence variant 9, region of interest 8, topological domain 7, transmembrane region 6, domain 5, compositionally biased region 5, sequence conflict 4, splice variant 4, modified residue 2, lipid moiety-binding region 2, chain 1, glycosylation site 1, disulfide bond 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for Q14643 — 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.

Ligand- & substrate-binding residues (24): 265; 267; 268; 269; 508; 511; 567; 568; 748; 1137; 1140; 1986 …

Post-translational modifications (15): 1598, 1764, 56, 850, 917, 972, 1581, 1780, 1893, 1894, 1895, 1910, 1933, 2127, 2266

Disulfide bonds (1): 2536–2542

Glycosylation sites (1): 2512

Mutagenesis-validated functional residues (13):

Position	Phenotype
241	abolishes interaction with ahcyl1.
249	abolishes interaction with ahcyl1.
265	no effect on interaction with ahcyl1.
267	no effect on interaction with ahcyl1.
269	abolishes interaction with ahcyl1.
504	abolishes interaction with ahcyl1.
506	abolishes interaction with ahcyl1.
508	abolishes interaction with ahcyl1.
511	abolishes interaction with ahcyl1.
567	abolishes interaction with ahcyl1.
568	abolishes interaction with ahcyl1.
569	abolishes interaction with ahcyl1.
1059	creates a dileucine motif and recruits clathrin.

Function

Pathways and Gene Ontology

Reactome pathways

51 pathways

ID	Pathway
R-HSA-112043	PLC beta mediated events
R-HSA-114508	Effects of PIP2 hydrolysis
R-HSA-139853	Elevation of cytosolic Ca2+ levels
R-HSA-1489509	DAG and IP3 signaling
R-HSA-2029485	Role of phospholipids in phagocytosis
R-HSA-2871809	FCERI mediated Ca+2 mobilization
R-HSA-381676	Glucagon-like Peptide-1 (GLP1) regulates insulin secretion
R-HSA-4086398	Ca2+ pathway
R-HSA-418457	cGMP effects
R-HSA-422356	Regulation of insulin secretion
R-HSA-5218921	VEGFR2 mediated cell proliferation
R-HSA-5578775	Ion homeostasis
R-HSA-5607763	CLEC7A (Dectin-1) induces NFAT activation
R-HSA-9664323	FCGR3A-mediated IL10 synthesis
R-HSA-983695	Antigen activates B Cell Receptor (BCR) leading to generation of second messengers
R-HSA-109582	Hemostasis
R-HSA-111885	Opioid Signalling
R-HSA-112040	G-protein mediated events
R-HSA-1280218	Adaptive Immune System
R-HSA-1430728	Metabolism
R-HSA-162582	Signal Transduction
R-HSA-163685	Integration of energy metabolism
R-HSA-1643685	Disease
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-194138	Signaling by VEGF
R-HSA-195721	Signaling by WNT
R-HSA-2029480	Fcgamma receptor (FCGR) dependent phagocytosis
R-HSA-2454202	Fc epsilon receptor (FCERI) signaling
R-HSA-372790	Signaling by GPCR

MSigDB gene sets: 925 (showing top): GOBP_SINGLE_FERTILIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GOBP_PROTEIN_HOMOTETRAMERIZATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, BASSO_B_LYMPHOCYTE_NETWORK, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GGGNRMNNYCAT_UNKNOWN, TGCACTT_MIR519C_MIR519B_MIR519A, GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS

GO Biological Process (30): cell morphogenesis (GO:0000902), response to hypoxia (GO:0001666), calcium ion transport (GO:0006816), signal transduction (GO:0007165), phospholipase C-activating G protein-coupled acetylcholine receptor signaling pathway (GO:0007207), single fertilization (GO:0007338), post-embryonic development (GO:0009791), regulation of autophagy (GO:0010506), positive regulation of insulin secretion (GO:0032024), endoplasmic reticulum calcium ion homeostasis (GO:0032469), calcium import into the mitochondrion (GO:0036444), epithelial fluid transport (GO:0042045), positive regulation of apoptotic process (GO:0043065), regulation of calcium-mediated signaling (GO:0050848), negative regulation of calcium-mediated signaling (GO:0050849), voluntary musculoskeletal movement (GO:0050882), release of sequestered calcium ion into cytosol (GO:0051209), protein homotetramerization (GO:0051289), regulation of cytosolic calcium ion concentration (GO:0051480), intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress (GO:0070059), release of sequestered calcium ion into cytosol by endoplasmic reticulum (GO:1903514), ligand-gated ion channel signaling pathway (GO:1990806), monoatomic ion transport (GO:0006811), apoptotic process (GO:0006915), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), calcium-mediated signaling (GO:0019722), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085), calcium ion transmembrane transport (GO:0070588), regulation of postsynaptic cytosolic calcium ion concentration (GO:0099566)

GO Molecular Function (16): inositol 1,4,5-trisphosphate-gated calcium channel activity (GO:0005220), calcium ion binding (GO:0005509), ATP binding (GO:0005524), calcium ion transmembrane transporter activity (GO:0015085), intracellularly gated calcium channel activity (GO:0015278), calcium channel inhibitor activity (GO:0019855), protein domain specific binding (GO:0019904), phosphatidylinositol binding (GO:0035091), protein homodimerization activity (GO:0042803), inositol 1,4,5 trisphosphate binding (GO:0070679), inositol 1,4,5-trisphosphate receptor activity involved in regulation of postsynaptic cytosolic calcium levels (GO:0098695), nucleotide binding (GO:0000166), monoatomic ion channel activity (GO:0005216), calcium channel activity (GO:0005262), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (23): nuclear inner membrane (GO:0005637), nucleolus (GO:0005730), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), calcineurin complex (GO:0005955), postsynaptic density (GO:0014069), membrane (GO:0016020), sarcoplasmic reticulum (GO:0016529), transport vesicle membrane (GO:0030658), secretory granule membrane (GO:0030667), platelet dense granule membrane (GO:0031088), platelet dense tubular network (GO:0031094), platelet dense tubular network membrane (GO:0031095), TCR signalosome (GO:0036398), perinuclear region of cytoplasm (GO:0048471), Schaffer collateral - CA1 synapse (GO:0098685), nuclear envelope (GO:0005635), cytoplasm (GO:0005737), endomembrane system (GO:0012505), cytoplasmic vesicle (GO:0031410), protein-containing complex (GO:0032991), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-19 pathways:

Category	Pathways
G-protein mediated events	1
G alpha (q) signalling events	1
Platelet activation, signaling and aggregation	1
Platelet calcium homeostasis	1
Intracellular signaling by second messengers	1
Fcgamma receptor (FCGR) dependent phagocytosis	1
Fc epsilon receptor (FCERI) signaling	1
Regulation of insulin secretion	1
Beta-catenin independent WNT signaling	1
Nitric oxide stimulates guanylate cyclase	1
Integration of energy metabolism	1
VEGFA-VEGFR2 Pathway	1
Cardiac conduction	1
CLEC7A (Dectin-1) signaling	1
Anti-inflammatory response favouring Leishmania parasite infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
bounding membrane of organelle	3
endoplasmic reticulum	2
intracellular calcium ion homeostasis	2
intercellular transport	2
calcium-mediated signaling	2
anion binding	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
cytoplasmic vesicle membrane	2
anatomical structure morphogenesis	1
response to stress	1
response to decreased oxygen levels	1
metal ion transport	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
phospholipase C-activating G protein-coupled receptor signaling pathway	1
G protein-coupled acetylcholine receptor signaling pathway	1
fertilization	1
multicellular organism development	1
multicellular organismal process	1
autophagy	1
regulation of catabolic process	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
mitochondrial calcium ion transmembrane transport	1
fluid transport	1
transepithelial transport	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
regulation of intracellular signal transduction	1
regulation of calcium-mediated signaling	1
negative regulation of intracellular signal transduction	1

Protein interactions and networks

STRING

3210 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ITPR1	VDAC1	P21796	996
ITPR1	HSPA9	P30036	995
ITPR1	CYCS	P00001	993
ITPR1	BCL2	P10415	993
ITPR1	ERP44	Q9BS26	983
ITPR1	BECN1	Q14457	978
ITPR1	ATXN3	P54252	969
ITPR1	ATXN2	Q99700	969
ITPR1	AKT1	P31749	968
ITPR1	ATXN3L	Q9H3M9	965
ITPR1	PPIF	P30405	960
ITPR1	TRPC1	P48995	959
ITPR1	HTT	P42858	944
ITPR1	HOMER1	Q86YM7	941
ITPR1	SIGMAR1	Q99720	937

IntAct

73 interactions, top by confidence:

A	B	Type	Score
SGF29	NDC80	psi-mi:“MI:0914”(association)	0.840
ITPR1	BCL2L10	psi-mi:“MI:0915”(physical association)	0.660
ITPR1	BCL2L10	psi-mi:“MI:0407”(direct interaction)	0.660
BCL2L10	AHCYL1	psi-mi:“MI:0915”(physical association)	0.590
ITPR1	AKT1	psi-mi:“MI:2364”(proximity)	0.540
ITPR1	AKT1	psi-mi:“MI:0915”(physical association)	0.540
CA8	IGLL5	psi-mi:“MI:0914”(association)	0.530
TAFA4	NRP1	psi-mi:“MI:0914”(association)	0.530
FBXL14	CRYZL1	psi-mi:“MI:0914”(association)	0.530
RAB29	CHM	psi-mi:“MI:0914”(association)	0.530
FGL2	ITPR3	psi-mi:“MI:0914”(association)	0.530
PRKG1	PDE5A	psi-mi:“MI:0914”(association)	0.500
PDE5A	PRKG1	psi-mi:“MI:0914”(association)	0.500
ITPR1	AHCYL1	psi-mi:“MI:0914”(association)	0.500
ITPR1	AHCYL1	psi-mi:“MI:0915”(physical association)	0.500
BCL2	ITPR1	psi-mi:“MI:0915”(physical association)	0.400
CRTC2	ITPR1	psi-mi:“MI:0915”(physical association)	0.400
ITPR1	PLEC	psi-mi:“MI:0915”(physical association)	0.400
ITPR1	LAT	psi-mi:“MI:0915”(physical association)	0.400
ERP44	ITPR1	psi-mi:“MI:0915”(physical association)	0.400
ITPR1	HSPA9	psi-mi:“MI:2364”(proximity)	0.380
VDAC1	ITPR1	psi-mi:“MI:2364”(proximity)	0.380
ITPR1	VDAC1	psi-mi:“MI:2364”(proximity)	0.380
ITPR1	VDAC1	psi-mi:“MI:0403”(colocalization)	0.380
ITPR1	HSPA9	psi-mi:“MI:0403”(colocalization)	0.380
ERBB2	ITPR1	psi-mi:“MI:0915”(physical association)	0.370
STARD13	ITPR1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (200): AKT1 (Affinity Capture-Western), ITPR1 (Affinity Capture-Western), AKT1 (PCA), ITPR1 (Biochemical Activity), ITPR1 (Affinity Capture-Western), BCL2 (Reconstituted Complex), ITPR1 (Affinity Capture-MS), ITPR1 (Affinity Capture-MS), BRCA1 (Reconstituted Complex), BRCA1 (Affinity Capture-Western), BRCA1 (Co-fractionation), BRCA1 (FRET), ITPR1 (Affinity Capture-MS), ITPR1 (Affinity Capture-MS), ITPR1 (Affinity Capture-MS)

ESM2 similar proteins: A2AGL3, B0LPN4, E9PZQ0, E9Q401, F1LMY4, F1Q8X5, P0C7A6, P11716, P11881, P16960, P21817, P29994, P29995, P30957, P42694, P48553, Q0VEJ0, Q14571, Q14643, Q15413, Q1LVW0, Q24498, Q28C34, Q3TLI0, Q5F361, Q5RCP7, Q6NRC7, Q6NRD0, Q6NYU2, Q6QI06, Q6R327, Q7SXV1, Q7Z3V4, Q7ZUV0, Q7ZYD9, Q80UK0, Q86VW0, Q8BHL5, Q8BIK4, Q8BWW9

Diamond homologs: A2AGL3, B0LPN4, E9PZQ0, E9Q401, F1LMY4, P11716, P11881, P16960, P21817, P29993, P29994, P29995, P30957, P70227, Q14571, Q14573, Q14643, Q15413, Q24498, Q5R881, Q63269, Q8BVR6, Q8WN95, Q8WN96, Q8WSR4, Q92736, Q95LP3, Q96DX4, Q9TS33, Q9TU34, Q9Y0A1, Q9Z329, A0A5F9C6I2, D3ZXK7, Q5XPI3, Q5XPI4, Q9SIZ8, Q9VNV3, Q19614, Q91X20

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
FYN	up-regulates	ITPR1	phosphorylation
ITPRIPL1	up-regulates	ITPR1	binding
ITPR1	“up-regulates quantity”	calcium(2+)	“chemical modification”
“1D-myo-inositol 1,4,5-trisphosphate”	“up-regulates activity”	ITPR1	“chemical activation”
ERP44	“down-regulates activity”	ITPR1	binding
RNF170	“down-regulates activity”	ITPR1	polyubiquitination
RORA	“up-regulates quantity by expression”	ITPR1	“transcriptional regulation”
PRKG1	unknown	ITPR1	phosphorylation
PRKACA	“down-regulates activity”	ITPR1	phosphorylation
Erlin	“down-regulates quantity by destabilization”	ITPR1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 90 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
G-protein mediated events	5	25.1×	5e-04
DAG and IP3 signaling	5	24.4×	5e-04
Opioid Signalling	5	20.4×	6e-04
PLC beta mediated events	5	20.4×	6e-04
Ion homeostasis	5	15.7×	2e-03
Intracellular signaling by second messengers	6	8.4×	5e-03
Muscle contraction	6	7.1×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

2246 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	47
Likely pathogenic	34
Uncertain significance	978
Likely benign	736
Benign	225

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1204039	NM_001378452.1(ITPR1):c.5063T>C (p.Leu1688Pro)	Pathogenic
1386082	NM_001378452.1(ITPR1):c.1781C>T (p.Thr594Ile)	Pathogenic
1456420	NM_001378452.1(ITPR1):c.2377C>T (p.Arg793Ter)	Pathogenic
14801	NM_001378452.1(ITPR1):c.3248C>T (p.Pro1083Leu)	Pathogenic
155690	GRCh38/hg38 3p26.1(chr3:4471708-4531661)x1	Pathogenic
1691646	NM_001378452.1(ITPR1):c.1705A>G (p.Lys569Glu)	Pathogenic
1695412	NM_001378452.1(ITPR1):c.7073T>G (p.Leu2358Ter)	Pathogenic
1808049	GRCh37/hg19 3p26.1(chr3:4416176-4609952)x1	Pathogenic
1809202	GRCh37/hg19 3p26.1(chr3:4333903-4652945)x1	Pathogenic
1935236	NM_001378452.1(ITPR1):c.1867C>T (p.Arg623Ter)	Pathogenic
208786	NM_001378452.1(ITPR1):c.800C>T (p.Thr267Met)	Pathogenic
2110209	NM_001378452.1(ITPR1):c.5056C>T (p.Gln1686Ter)	Pathogenic
224119	NM_001378452.1(ITPR1):c.7784G>A (p.Gly2595Glu)	Pathogenic
235915	NM_001378452.1(ITPR1):c.4699C>T (p.Gln1567Ter)	Pathogenic
235916	NM_001378452.1(ITPR1):c.2182C>T (p.Arg728Ter)	Pathogenic
235917	NM_001378452.1(ITPR1):c.6510+3A>T	Pathogenic
235918	NM_001378452.1(ITPR1):c.6808+5G>T	Pathogenic
235920	NM_001378452.1(ITPR1):c.7803T>G (p.Phe2601Leu)	Pathogenic
235921	NM_001378452.1(ITPR1):c.6326A>G (p.Glu2109Gly)	Pathogenic
235923	NM_001378452.1(ITPR1):c.7660G>C (p.Gly2554Arg)	Pathogenic
2424371	NC_000003.11:g.(?4558176)(4562798_?)del	Pathogenic
2424372	NC_000003.11:g.(?4669427)(4715091_?)del	Pathogenic
2436832	NM_001378452.1(ITPR1):c.1252-1G>A	Pathogenic
253023	NM_001378452.1(ITPR1):c.5504T>C (p.Leu1835Pro)	Pathogenic
253517	GRCh37/hg19 3p26.1(chr3:4134224-4665869)x1	Pathogenic
2579948	NM_001378452.1(ITPR1):c.1700A>G (p.Tyr567Cys)	Pathogenic
2854043	NM_001378452.1(ITPR1):c.7899del (p.Val2634fs)	Pathogenic
3062741	GRCh37/hg19 3p26.1(chr3:4495034-4543463)x1	Pathogenic
3246983	NC_000003.11:g.(?4558176)(4558287_?)del	Pathogenic
3257467	NM_001378452.1(ITPR1):c.3025C>T (p.Arg1009Ter)	Pathogenic

SpliceAI

9561 predictions. Top by Δscore:

Variant	Effect	Δscore
3:4516470:GTCTA:G	acceptor_loss	1.0000
3:4516472:CTA:C	acceptor_loss	1.0000
3:4516473:TAG:T	acceptor_loss	1.0000
3:4516474:A:AG	acceptor_gain	1.0000
3:4516474:A:G	acceptor_loss	1.0000
3:4516475:G:GG	acceptor_gain	1.0000
3:4516580:TGGGG:T	donor_loss	1.0000
3:4516581:GGG:G	donor_gain	1.0000
3:4516582:GG:G	donor_gain	1.0000
3:4516582:GGG:G	donor_gain	1.0000
3:4516583:GG:G	donor_gain	1.0000
3:4516584:G:GG	donor_gain	1.0000
3:4516584:GTA:G	donor_loss	1.0000
3:4516585:T:TC	donor_loss	1.0000
3:4521018:TTACA:T	acceptor_loss	1.0000
3:4521019:TACA:T	acceptor_loss	1.0000
3:4521020:ACAG:A	acceptor_loss	1.0000
3:4521021:CAGCC:C	acceptor_loss	1.0000
3:4521022:A:AG	acceptor_gain	1.0000
3:4521022:AGCC:A	acceptor_loss	1.0000
3:4521022:AGCCT:A	acceptor_gain	1.0000
3:4521023:G:GG	acceptor_gain	1.0000
3:4521023:GC:G	acceptor_gain	1.0000
3:4521023:GCC:G	acceptor_gain	1.0000
3:4521023:GCCT:G	acceptor_gain	1.0000
3:4521023:GCCTG:G	acceptor_gain	1.0000
3:4627875:GCAC:G	donor_gain	1.0000
3:4627879:G:GG	donor_gain	1.0000
3:4639381:C:G	acceptor_gain	1.0000
3:4642091:A:AG	acceptor_gain	1.0000

AlphaMissense

18395 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:4521038:G:C	R36P	1.000
3:4627802:C:A	A68D	1.000
3:4627874:T:A	L92Q	1.000
3:4627874:T:C	L92P	1.000
3:4639388:C:A	A95D	1.000
3:4639390:G:C	A96P	1.000
3:4639399:G:A	E99K	1.000
3:4639401:A:C	E99D	1.000
3:4639401:A:T	E99D	1.000
3:4642121:T:C	L132P	1.000
3:4642136:G:T	R137M	1.000
3:4642137:G:C	R137S	1.000
3:4642137:G:T	R137S	1.000
3:4642145:C:A	A140D	1.000
3:4642163:C:A	A146D	1.000
3:4642172:T:A	V149D	1.000
3:4642198:G:A	G158R	1.000
3:4642198:G:C	G158R	1.000
3:4642198:G:T	G158W	1.000
3:4642204:T:A	W160R	1.000
3:4642204:T:C	W160R	1.000
3:4644148:G:C	D180H	1.000
3:4644149:A:T	D180V	1.000
3:4644161:T:C	L184P	1.000
3:4645414:T:A	W218R	1.000
3:4645414:T:C	W218R	1.000
3:4645463:T:C	L234S	1.000
3:4645595:G:C	R241T	1.000
3:4645595:G:T	R241M	1.000
3:4645596:G:C	R241S	1.000

dbSNP variants (sampled 300 via entrez): RS1000006622 (3:4823052 G>A), RS1000012368 (3:4585741 A>G,T), RS1000015475 (3:4748962 T>C), RS1000016884 (3:4655644 C>T), RS1000040620 (3:4826167 G>A), RS1000047862 (3:4639747 A>T), RS1000053562 (3:4749942 C>T), RS1000055266 (3:4491844 T>C), RS1000065859 (3:4615986 T>C,G), RS1000071944 (3:4509804 C>G), RS1000077126 (3:4498471 A>T), RS1000081029 (3:4785220 G>A), RS1000090745 (3:4674783 C>T), RS1000093715 (3:4709660 T>C), RS1000096472 (3:4616204 C>T)

Disease associations

OMIM: gene MIM:147265 | disease phenotypes: MIM:117360, MIM:206700, MIM:606658, MIM:164400, MIM:107250, MIM:272200, MIM:108600

GenCC curated gene-disease

Disease	Classification	Inheritance
aniridia-cerebellar ataxia-intellectual disability syndrome	Definitive	Autosomal dominant
spinocerebellar ataxia type 29	Strong	Autosomal dominant
spinocerebellar ataxia type 15/16	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (3)

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

Disease	Classification	Inheritance
spinocerebellar ataxia type 29	Definitive	AD
aniridia-cerebellar ataxia-intellectual disability syndrome	Definitive	AD
aniridia-cerebellar ataxia-intellectual disability syndrome	Definitive	AR

Mondo (12): spinocerebellar ataxia type 29 (MONDO:0007298), aniridia-cerebellar ataxia-intellectual disability syndrome (MONDO:0008795), spinocerebellar ataxia type 15/16 (MONDO:0011694), autosomal dominant cerebellar ataxia (MONDO:0020380), intellectual disability (MONDO:0001071), anterior segment dysgenesis (MONDO:0019503), mucosulfatidosis (MONDO:0010088), neurodevelopmental disorder (MONDO:0700092), multiple sclerosis (MONDO:0005301), movement disorder (MONDO:0005395), spastic ataxia (MONDO:0017845), cerebellar ataxia (MONDO:0000437)

Orphanet (11): Spinocerebellar ataxia type 29 (Orphanet:208513), Aniridia-cerebellar ataxia-intellectual disability syndrome (Orphanet:1065), Spinocerebellar ataxia type 15/16 (Orphanet:98769), Autosomal dominant cerebellar ataxia (Orphanet:99), Anterior segment developmental anomaly (Orphanet:88632), Multiple sulfatase deficiency (Orphanet:585), Spastic ataxia (Orphanet:316226), Rare ataxia (Orphanet:102002), Spinocerebellar ataxia type 16 (Orphanet:98770), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Multiple sclerosis (Orphanet:802)

HPO phenotypes

187 total (30 of 187 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000089	Renal hypoplasia
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000298	Mask-like facies
HP:0000364	Hearing abnormality
HP:0000448	Prominent nose
HP:0000474	Thickened nuchal skin fold
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000514	Slow saccadic eye movements
HP:0000526	Aniridia
HP:0000540	Hypermetropia
HP:0000555	Leukocoria
HP:0000563	Keratoconus
HP:0000565	Esotropia
HP:0000570	Abnormal saccadic eye movements
HP:0000571	Hypometric saccades
HP:0000582	Upslanted palpebral fissure
HP:0000616	Miosis
HP:0000617	Abnormality of ocular smooth pursuit
HP:0000639	Nystagmus
HP:0000640	Gaze-evoked nystagmus
HP:0000641	Dysmetric saccades
HP:0000657	Oculomotor apraxia
HP:0000666	Horizontal nystagmus
HP:0000716	Depression

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST001621_7	Airflow obstruction	8.000000e-06
GCST001762_144	Obesity-related traits	7.000000e-07
GCST001937_51	Breast cancer	2.000000e-12
GCST002935_21	Lead levels	7.000000e-06
GCST003098_9	Diabetic kidney disease	1.000000e-06
GCST003670_8	Systolic blood pressure	6.000000e-06
GCST004640_14	Western dietary pattern	5.000000e-06
GCST005411_3	Thrombin-activatable fibrinolysis inhibitor activation peptide	4.000000e-07
GCST005830_36	Hand grip strength	3.000000e-08
GCST005982_1	Calcium levels	3.000000e-10
GCST006019_25	Gamma glutamyl transferase levels	3.000000e-15
GCST006462_6	Uterine fibroids	3.000000e-08
GCST008152_91	Weight	3.000000e-06
GCST009391_208	Metabolite levels	1.000000e-06
GCST009597_317	Multiple sclerosis	6.000000e-08
GCST010173_180	Triglyceride levels	2.000000e-08
GCST010244_397	Triglyceride levels	2.000000e-10
GCST011349_44	Gamma glutamyl transferase levels	1.000000e-14
GCST011743_13	HDL cholesterol levels in HIV infection	6.000000e-06
GCST012490_31	Femur bone mineral density x serum urate levels interaction	2.000000e-12
GCST90002383_354	Hematocrit	1.000000e-09

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0004810	interleukin-6 measurement
EFO:0006335	systolic blood pressure
EFO:0008111	diet measurement
EFO:0006941	grip strength measurement
EFO:0004838	calcium measurement
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0004338	body weight
EFO:0004530	triglyceride measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004531	urate measurement
EFO:0004348	hematocrit

MeSH disease descriptors (10)

Descriptor	Name	Tree numbers
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009069	Movement Disorders	C10.228.662
D009103	Multiple Sclerosis	C10.114.375.500; C10.314.350.500; C20.111.258.250.500
D052517	Multiple Sulfatase Deficiency Disease	C10.228.140.163.100.435.825.850.750; C16.320.565.189.435.825.850.750; C16.320.565.398.641.803.925.750; C16.320.565.595.554.825.850.750; C18.452.132.100.435.825.850.750; C18.452.584.563.641.803.925.750; C18.452.648.189.435.825.850.750; C18.452.648.398.641.803.925.750; C18.452.648.595.554.825.850.750
D065886	Neurodevelopmental Disorders	F03.625
C536370	Aniridia cerebellar ataxia mental deficiency (supp.)
C564815	Spastic Ataxia (supp.)
C564685	Spinocerebellar Ataxia 15 (supp.)
C537206	Spinocerebellar Ataxia 29 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2111451 (PROTEIN FAMILY), CHEMBL4046 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: lgic — IP₃ receptors

ChEMBL bioactivities

22 potent at pChembl≥5 of 25 total, top 22 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.93	Kd	1.17	nM	CHEMBL172534
8.35	IC50	4.43	nM	INS(1,4,5)P3
7.85	IC50	14	nM	CHEMBL3349691
7.58	IC50	26.5	nM	CHEMBL3349691
7.47	IC50	33.5	nM	INS(1,4,5)P3
7.28	IC50	52	nM	INS(1,4,5)P3
6.89	EC50	130	nM	CHEMBL1161456
6.85	Kd	140	nM	CHEMBL434103
6.80	Kd	160	nM	CHEMBL169923
6.77	Kd	170	nM	CHEMBL352326
6.76	IC50	172	nM	CHEMBL1160286
6.70	IC50	200	nM	INS(1,4,5)P3
6.58	Kd	260	nM	INS(1,4,5)P3
6.52	IC50	300	nM	INS(1,4,5)P3
6.39	EC50	410	nM	CHEMBL1161466
6.21	Kd	620	nM	CHEMBL369479
5.82	Kd	1500	nM	CHEMBL297235
5.58	Kd	2600	nM	CHEMBL434103
5.50	Kd	3200	nM	CHEMBL352326
5.48	Kd	3280	nM	CHEMBL3752910
5.46	ED50	3435	nM	CHEMBL3752910
5.08	Kd	8400	nM	CHEMBL169923

PubChem BioAssay actives

17 with measured affinity, of 28 total; 10 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
[4-[[4-(dimethylamino)phenyl]-[4-[3-[hydroxy-[(1R,2R,3S,4R,5R,6S)-2,3,6-trihydroxy-4,5-diphosphonooxycyclohexyl]oxyphosphoryl]oxypropylcarbamoyl]phenyl]methylidene]cyclohexa-2,5-dien-1-ylidene]-dimethylazanium	215783: Dissociation constant using IP3-binding domain (IBD) of human Type 1 inositol 1,4,5-trisphosphate receptor	kd	0.0012	uM
[(1R,2S,3R,4R,5S,6R)-2,3,5-trihydroxy-4,6-diphosphonooxycyclohexyl] dihydrogen phosphate	92895: The compound was tested for inhibitory activity against IInositol 1,4,5-trisphosphate receptor in SH-SY5Y cell line	ic50	0.0044	uM
[(1S,2R,4R,5R)-2,4-dihydroxy-3,5,6-triphosphonooxycyclohexyl] dihydrogen phosphate	92896: The compound was tested for inhibitory activity against Inositol 1,4,5-trisphosphate receptor in SH-SY5Y cell line	ic50	0.0140	uM
3-(4-pyren-1-ylbutanoylamino)propyl [(1R,2R,3S,4R,5R,6S)-2,3,6-trihydroxy-4,5-diphosphonooxycyclohexyl] hydrogen phosphate	215783: Dissociation constant using IP3-binding domain (IBD) of human Type 1 inositol 1,4,5-trisphosphate receptor	kd	0.1400	uM
3-(naphthalene-1-carbonylamino)propyl [(1R,2R,3S,4R,5R,6S)-2,3,6-trihydroxy-4,5-diphosphonooxycyclohexyl] hydrogen phosphate	215783: Dissociation constant using IP3-binding domain (IBD) of human Type 1 inositol 1,4,5-trisphosphate receptor	kd	0.1600	uM
3-[[4-[bis[4-(dimethylamino)phenyl]methyl]benzoyl]amino]propyl [(1R,2R,3S,4R,5R,6S)-2,3,6-trihydroxy-4,5-diphosphonooxycyclohexyl] hydrogen phosphate	215783: Dissociation constant using IP3-binding domain (IBD) of human Type 1 inositol 1,4,5-trisphosphate receptor	kd	0.1700	uM
(2,5-dihydroxy-3,4,6-triphosphonooxycyclohexyl)oxy-trihydroxyphosphanium	92898: The compound was tested for inhibitory activity against Inositol 1,4,5-trisphosphate receptor in L15 cell line	ic50	0.1720	uM
2-[3-(dimethylamino)-6-dimethylazaniumylidenexanthen-9-yl]-5-[3-[hydroxy-[(1R,2R,3S,4R,5R,6S)-2,3,6-trihydroxy-4,5-diphosphonooxycyclohexyl]oxyphosphoryl]oxypropylcarbamoyl]benzoate	215783: Dissociation constant using IP3-binding domain (IBD) of human Type 1 inositol 1,4,5-trisphosphate receptor	kd	0.6200	uM
3-aminopropyl [(1R,2R,3S,4R,5R,6S)-2,3,6-trihydroxy-4,5-diphosphonooxycyclohexyl] hydrogen phosphate	215783: Dissociation constant using IP3-binding domain (IBD) of human Type 1 inositol 1,4,5-trisphosphate receptor	kd	1.5000	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149873: Binding affinity to human ITPR1 incubated for 45 mins by Kinobead based pull down assay	kd	3.2797	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	8
Benzo(a)pyrene	increases expression, affects expression, affects methylation, decreases expression	7
Estradiol	decreases expression, decreases reaction, increases reaction, affects expression, affects cotreatment (+1 more)	6
Tetrachlorodibenzodioxin	affects binding, increases reaction, decreases reaction, increases expression, affects cotreatment (+1 more)	6
Aflatoxin B1	decreases methylation, affects expression, decreases expression	5
trichostatin A	affects cotreatment, increases expression, affects expression	4
(+)-JQ1 compound	decreases expression, increases expression	4
bisphenol A	decreases methylation, increases expression, decreases reaction, affects binding	3
Resveratrol	affects cotreatment, decreases expression, increases expression	3
arsenite	increases methylation, affects binding, decreases reaction	2
sodium arsenite	decreases expression, increases expression, affects splicing	2
perfluorooctanoic acid	affects expression, increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
Acetaminophen	increases expression	2
Glyphosate	decreases expression, increases expression	2
Calcitriol	increases expression, affects cotreatment, increases reaction	2
Cycloheximide	decreases reaction, increases expression	2
Methotrexate	affects response to substance, increases expression	2
Quercetin	affects cotreatment, decreases phosphorylation, decreases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Tretinoin	decreases expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Genistein	increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	affects cotreatment, affects expression	1
anemoside B4	decreases phosphorylation	1
TAK-243	affects sumoylation	1
dicrotophos	increases expression	1
linsidomine	increases expression, decreases reaction	1

ChEMBL screening assays

13 unique, capped per target: 12 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL697190	Binding	Compound was evaluated for its ability to inhibit Inositol phosphorylation	Total synthesis of L-2,2-difluoro-2-deoxy-MYO-inositol 1,4,5-trisphosphate, a potent inhibitor of the enzymes of d-MYO-inositol 1,4,5-trisphosphate metabolism — Bioorg Med Chem Lett
CHEMBL699700	Functional	Compound was evaluated for its effective dose to inhibit the calcium release as a measure of affinity for Inositol 1,4,5-trisphosphate receptor	Total synthesis of L-2,2-difluoro-2-deoxy-MYO-inositol 1,4,5-trisphosphate, a potent inhibitor of the enzymes of d-MYO-inositol 1,4,5-trisphosphate metabolism — Bioorg Med Chem Lett

Cellosaurus cell lines

20 cell lines: 13 cancer cell line, 5 transformed cell line, 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B8IX	Abcam HCT 116 ITPR1 KO	Cancer cell line	Male
CVCL_B8XT	Abcam MCF-7 ITPR1 KO	Cancer cell line	Female
CVCL_B9L8	Abcam A-549 ITPR1 KO	Cancer cell line	Male
CVCL_D1T9	Abcam U-87MG ITPR1 KO	Cancer cell line	Male
CVCL_D7SU	Ubigene A-549 ITPR1 KO	Cancer cell line	Male
CVCL_D8NL	Ubigene HCT 116 ITPR1 KO	Cancer cell line	Male
CVCL_D9HL	Ubigene HEK293 ITPR1 KO	Transformed cell line	Female
CVCL_E0FQ	Ubigene HeLa ITPR1 KO	Cancer cell line	Female
CVCL_E7L4	KOLF2.1J ITPR1 N602D SNV/SNV	Induced pluripotent stem cell	Male
CVCL_E7L5	KOLF2.1J ITPR1 N602D SNV/WT	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT03408080	PHASE3	ACTIVE_NOT_RECRUITING	Open Pilot Trial of BHV-4157
NCT03701399	PHASE3	ACTIVE_NOT_RECRUITING	Troriluzole in Adult Participants With Spinocerebellar Ataxia
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT01350440	PHASE2	COMPLETED	Safety and Efficacy of Intravenous Immune Globulin in Treating Spinocerebellar Ataxia
NCT04301284	PHASE2	WITHDRAWN	Study of CAD-1883 for Spinocerebellar Ataxia
NCT06397274	PHASE2	NOT_YET_RECRUITING	Stemchymal® for Polyglutamine Spinocerebellar Ataxia
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00683943	PHASE1	COMPLETED	Lithium Treatment for Patients With Spinocerebellar Ataxia Type I
NCT02287064	PHASE1	UNKNOWN	An Open-label Trial of Intravenous Immune Globulin (IVIG)in Treating Spinocerebellar Ataxias
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT06840366	Not specified	COMPLETED	Motor Rehabilitation and Physical, Mental and Cognitive Health in Patients With Stroke
NCT02960893	PHASE2/PHASE3	COMPLETED	Trial in Adult Participants With Spinocerebellar Ataxia (SCA)
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00654251	Not specified	COMPLETED	Measuring Neurological Impairment and Functional Visual Assessment In Spinocerebellar Ataxias
NCT01037777	Not specified	COMPLETED	RISCA : Prospective Study of Individuals at Risk for SCA1, SCA2, SCA3, SCA6, SCA7
NCT01975909	Not specified	COMPLETED	Transcranial Magnetic Stimulation in Spino-Cerebellar Ataxia
NCT01983631	Not specified	COMPLETED	The Effect of Whole Body Vibration Training on Neuromuscular Property in Individuals With Ataxia
NCT02103075	Not specified	COMPLETED	Neuromuscular Electrical Stimulation on Median Nerve Facilitates Low Motor Cortex Excitability in Human With Spinocerebellar Ataxia
NCT02440763	Not specified	RECRUITING	The EUROSCA Natural History Study
NCT02488031	Not specified	COMPLETED	Functional and Structural Imaging and Motor Control in Spinocerebellar Ataxia
NCT02741440	Not specified	RECRUITING	Natural History of Spinocerebellar Ataxia Type 7 (SCA7)
NCT02867969	Not specified	UNKNOWN	Slowing Down Disease Progression in Premanifest SCA: a Piloting Interventional Exergame Trial
NCT02874911	Not specified	COMPLETED	Coordination Training With Complete Body Video Games in Children and Adults With Degenerative Ataxias
NCT03120013	Not specified	COMPLETED	Rehabilitative Trial With Cerebello-Spinal tDCS in Neurodegenerative Ataxia
NCT03336008	Not specified	RECRUITING	Hong Kong Spinocerebellar Ataxias Registry
NCT03687190	Not specified	COMPLETED	Could Tai-chi Help Maintain Balance of Spinocerebellar Ataxia Patients
NCT03701776	Not specified	COMPLETED	Ataxia and Exercise Disease Using MRI and Gait Analysis
NCT03745248	Not specified	COMPLETED	Aerobic Exercise, Balance Training, and Ataxia