ITPR2

Summary

ITPR2 (inositol 1,4,5-trisphosphate receptor type 2, HGNC:6181) is a protein-coding gene on chromosome 12p11.23, encoding Inositol 1,4,5-trisphosphate-gated calcium channel ITPR2 (Q14571). Inositol 1,4,5-trisphosphate-gated calcium channel that upon inositol 1,4,5-trisphosphate binding transports calcium from the endoplasmic reticulum lumen to cytoplasm.

The protein encoded by this gene belongs to the inositol 1,4,5-triphosphate receptor family, whose members are second messenger intracellular calcium release channels. These proteins mediate a rise in cytoplasmic calcium in response to receptor activated production of inositol triphosphate. Inositol triphosphate receptor-mediated signaling is involved in many processes including cell migration, cell division, smooth muscle contraction, and neuronal signaling. This protein is a type 2 receptor that consists of a cytoplasmic amino-terminus that binds inositol triphosphate, six membrane-spanning helices that contribute to the ion pore, and a short cytoplasmic carboxy-terminus. A mutation in this gene has been associated with anhidrosis, suggesting that intracellular calcium release mediated by this protein is required for eccrine sweat production.

Source: NCBI Gene 3709 — RefSeq curated summary.

At a glance

• Gene–disease (curated): isolated anhidrosis with normal sweat glands (Supportive, GenCC)
• GWAS associations: 84 (top 1% of genes corpus-wide)
• Clinical variants (ClinVar): 394 total — 2 pathogenic (top 8% of genes corpus-wide)
• Regional missense constraint (gnomAD): 2 of 9 regions constrained (≈2% of expected missense variation)
• GTEx eGene: eQTL in 28 tissues, sQTL in 4 (q < 0.05)
• Phenotypes (HPO): 5
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.72 (unconstrained)
• MANE Select transcript: NM_002223
• Notable: 394 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6181
Approved symbol	ITPR2
Name	inositol 1,4,5-trisphosphate receptor type 2
Location	12p11.23
Locus type	gene with protein product
Status	Approved
Aliases	IP3R2, CFAP48
Ensembl gene	ENSG00000123104
Ensembl biotype	protein_coding
OMIM	600144
Entrez	3709

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 5 protein_coding, 5 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined, 3 retained_intron

MANE Select: ENST00000381340

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 3: 5, TSL 4: 1

ENST00000381340, ENST00000242737, ENST00000451599, ENST00000536627, ENST00000538984, ENST00000540429, ENST00000540791, ENST00000543958, ENST00000545235, ENST00000545902, ENST00001002895, ENST00001108084, ENST00001108085, ENST00001120345, ENST00001120346, ENST00001141790

RefSeq mRNA: 3 — MANE Select: NM_002223 NM_001414174, NM_001414175, NM_002223

CCDS: CCDS41764

Canonical transcript exons

ENST00000381340 — 57 exons

Exon	Start	End
ENSE00001488260	26335352	26339483
ENSE00001488261	26340167	26340328
ENSE00001488263	26387434	26387594
ENSE00001488290	26487068	26487251
ENSE00001488291	26494153	26494340
ENSE00001488292	26495152	26495260
ENSE00001488294	26550247	26550355
ENSE00001488297	26556233	26556375
ENSE00001488298	26561762	26561952
ENSE00001488300	26578713	26578833
ENSE00001488302	26580027	26580155
ENSE00001488304	26595465	26595590
ENSE00001488306	26596883	26597134
ENSE00001488308	26599145	26599345
ENSE00001488309	26599987	26600109
ENSE00001488310	26602370	26602495
ENSE00001488312	26602617	26602706
ENSE00001488313	26621123	26621296
ENSE00001488319	26631866	26632059
ENSE00001488320	26653976	26654126
ENSE00001488321	26655708	26655852
ENSE00001488322	26656297	26656548
ENSE00001488324	26657707	26657892
ENSE00001488325	26658011	26658130
ENSE00001488326	26659113	26659285
ENSE00001488328	26663685	26663846
ENSE00001488329	26665910	26666051
ENSE00001488332	26681874	26682034
ENSE00001488333	26682574	26682673
ENSE00001488334	26686481	26686632
ENSE00001488335	26695606	26695650
ENSE00001488340	26715299	26715445
ENSE00001488341	26715752	26715835
ENSE00001488343	26716144	26716242
ENSE00001488348	26832690	26833194
ENSE00001602120	26790157	26790227
ENSE00003464550	26628033	26628162
ENSE00003467575	26427913	26428088
ENSE00003469369	26724656	26724742
ENSE00003479111	26486104	26486360
ENSE00003494789	26622240	26622405
ENSE00003496141	26443543	26443650
ENSE00003496421	26481131	26481241
ENSE00003515274	26400128	26400258
ENSE00003526274	26439127	26439319
ENSE00003540833	26483698	26483898
ENSE00003541635	26475296	26475418
ENSE00003562946	26624299	26624356
ENSE00003566948	26419049	26419213
ENSE00003572295	26722397	26722555
ENSE00003582056	26725650	26725765
ENSE00003582768	26415303	26415498
ENSE00003589588	26411320	26411412
ENSE00003621359	26476912	26477007
ENSE00003626369	26398876	26399041
ENSE00003652573	26711173	26711268
ENSE00003680829	26436221	26436346

Expression profiles

Bgee: expression breadth ubiquitous, 273 present calls, max score 94.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.5613 / max 343.7639, expressed in 1677 samples.

Highest expression (Bgee): calcaneal tendon, adrenal tissue, germinal epithelium of ovary, upper leg skin, colonic epithelium.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ITPR2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 28 tissues and its splicing (sQTL) in 4 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 32 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Brain Cerebellum	eqtl	1.4e-60	+1.27	12:26829972:C:T
Brain Cerebellar Hemisphere	eqtl	4.2e-53	+1.12	12:26848199:G:GT
Nerve Tibial	eqtl	2.1e-22	-0.30	12:26798318:C:T
Whole Blood	eqtl	3.2e-22	-0.33	12:26847472:A:G
Cells EBV-transformed lymphocytes	sqtl	2.6e-19	+0.98	12:26701191:C:A
Esophagus Mucosa	eqtl	2.1e-17	+0.26	12:26798318:C:T
Skin Sun Exposed Lower leg	sqtl	2.4e-17	+0.58	12:26701191:C:A
Thyroid	eqtl	3.2e-14	+0.34	12:26707681:C:T
Muscle Skeletal	eqtl	6.8e-09	+0.26	12:26833265:A:G
Cells Cultured fibroblasts	eqtl	4.2e-08	+0.29	12:26854435:TTA:T
Colon Transverse	eqtl	9.1e-07	+0.22	12:26828518:T:C
Heart Atrial Appendage	eqtl	8.0e-06	+1.04	12:26713750:A:C
Pancreas	eqtl	1.1e-05	-0.31	12:26815833:T:C
Brain Spinal cord cervical c-1	eqtl	2.8e-05	+0.39	12:26745821:G:C
Ovary	eqtl	3.0e-05	+0.52	12:26833265:A:G
Colon Sigmoid	eqtl	4.9e-05	-0.23	12:26804803:C:T
Esophagus Gastroesophageal Junction	eqtl	5.8e-04	+0.22	12:26828518:T:C
Testis	eqtl	2.2e-03	-0.21	12:26828518:T:C
Liver	eqtl	2.8e-03	-0.18	12:26718181:G:A
Skin Sun Exposed Lower leg	eqtl	4.9e-03	+0.14	12:26839768:A:G

FANTOM5 promoters

showing 10 of 13 alternative TSS:

Promoter ID	TPM avg	Samples expressed
130236	13.6125	1647
130238	0.3943	199
206653	0.3535	204
130235	0.2756	111
130239	0.2254	106
130237	0.2064	82
130234	0.1993	92
130229	0.0846	36
130228	0.0822	38
130231	0.0754	9

Top tissues by expression

showing 100 of 292 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	94.09	gold quality
adrenal tissue	UBERON:0018303	93.47	gold quality
germinal epithelium of ovary	UBERON:0001304	92.78	gold quality
upper leg skin	UBERON:0004262	90.58	gold quality
colonic epithelium	UBERON:0000397	90.46	gold quality
skin of hip	UBERON:0001554	90.41	gold quality
sural nerve	UBERON:0015488	90.36	gold quality
liver	UBERON:0002107	90.01	gold quality
oral cavity	UBERON:0000167	90.00	gold quality
tendon	UBERON:0000043	89.41	gold quality
bone marrow cell	CL:0002092	89.18	gold quality
mammary duct	UBERON:0001765	88.85	gold quality
epithelium of mammary gland	UBERON:0003244	88.58	gold quality
jejunal mucosa	UBERON:0000399	88.48	gold quality
tonsil	UBERON:0002372	87.10	gold quality
upper arm skin	UBERON:0004263	86.68	gold quality
caput epididymis	UBERON:0004358	86.61	gold quality
corpus epididymis	UBERON:0004359	86.58	gold quality
pigmented layer of retina	UBERON:0001782	86.24	gold quality
right lobe of liver	UBERON:0001114	85.78	gold quality
parotid gland	UBERON:0001831	85.71	gold quality
adrenal gland	UBERON:0002369	85.28	gold quality
corpus callosum	UBERON:0002336	85.25	gold quality
right adrenal gland	UBERON:0001233	84.88	gold quality
lower lobe of lung	UBERON:0008949	84.88	gold quality
left adrenal gland	UBERON:0001234	84.75	gold quality
right adrenal gland cortex	UBERON:0035827	84.64	gold quality
gingiva	UBERON:0001828	84.58	gold quality
mammary gland	UBERON:0001911	84.58	gold quality
left adrenal gland cortex	UBERON:0035825	84.53	gold quality
thoracic mammary gland	UBERON:0005200	84.48	gold quality
tendon of biceps brachii	UBERON:0008188	84.38	silver quality
endothelial cell	CL:0000115	84.31	gold quality
monocyte	CL:0000576	84.23	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.09	gold quality
adrenal cortex	UBERON:0001235	84.07	gold quality
mononuclear cell	CL:0000842	83.96	gold quality
medial globus pallidus	UBERON:0002477	83.96	gold quality
cartilage tissue	UBERON:0002418	83.87	gold quality
saliva-secreting gland	UBERON:0001044	83.85	gold quality
leukocyte	CL:0000738	83.77	gold quality
renal medulla	UBERON:0000362	83.62	gold quality
mouth mucosa	UBERON:0003729	83.61	gold quality
bone marrow	UBERON:0002371	83.26	gold quality
parietal pleura	UBERON:0002400	83.22	gold quality
minor salivary gland	UBERON:0001830	83.09	gold quality
gingival epithelium	UBERON:0001949	82.90	gold quality
thymus	UBERON:0002370	82.71	gold quality
cervix squamous epithelium	UBERON:0006922	82.59	silver quality
superficial temporal artery	UBERON:0001614	82.54	gold quality
zone of skin	UBERON:0000014	82.29	gold quality
pleura	UBERON:0000977	82.28	gold quality
skin of abdomen	UBERON:0001416	81.83	gold quality
squamous epithelium	UBERON:0006914	81.35	gold quality
visceral pleura	UBERON:0002401	81.13	gold quality
globus pallidus	UBERON:0001875	81.06	gold quality
skin of leg	UBERON:0001511	80.79	gold quality
penis	UBERON:0000989	80.73	gold quality
esophagus squamous epithelium	UBERON:0006920	80.71	gold quality
rectum	UBERON:0001052	80.59	gold quality
epithelial cell of pancreas	CL:0000083	80.47	silver quality
vermiform appendix	UBERON:0001154	80.37	gold quality
choroid plexus epithelium	UBERON:0003911	80.30	gold quality
kidney	UBERON:0002113	80.26	gold quality
stromal cell of endometrium	CL:0002255	80.06	gold quality
lymph node	UBERON:0000029	79.98	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.96	gold quality
epithelium of esophagus	UBERON:0001976	79.93	gold quality
mammalian vulva	UBERON:0000997	79.86	gold quality
esophagus mucosa	UBERON:0002469	79.66	gold quality
oviduct epithelium	UBERON:0004804	79.56	silver quality
adult mammalian kidney	UBERON:0000082	79.54	gold quality
jejunum	UBERON:0002115	79.53	gold quality
islet of Langerhans	UBERON:0000006	79.46	gold quality
mucosa of sigmoid colon	UBERON:0004993	79.27	gold quality
cranial nerve II	UBERON:0000941	79.26	gold quality
connective tissue	UBERON:0002384	79.25	gold quality
sigmoid colon	UBERON:0001159	79.21	gold quality
muscle layer of sigmoid colon	UBERON:0035805	79.19	gold quality
pancreas	UBERON:0001264	79.17	gold quality
blood	UBERON:0000178	79.15	gold quality
nephron tubule	UBERON:0001231	79.00	gold quality
adipose tissue	UBERON:0001013	78.99	gold quality
mucosa of paranasal sinus	UBERON:0005030	78.96	gold quality
uterine cervix	UBERON:0000002	78.86	gold quality
endometrium	UBERON:0001295	78.85	gold quality
placenta	UBERON:0001987	78.81	gold quality
cervix epithelium	UBERON:0004801	78.74	silver quality
caecum	UBERON:0001153	78.65	gold quality
trabecular bone tissue	UBERON:0002483	78.49	gold quality
tibia	UBERON:0000979	78.35	gold quality
esophagus	UBERON:0001043	78.20	gold quality
gall bladder	UBERON:0002110	78.20	gold quality
fallopian tube	UBERON:0003889	78.05	gold quality
smooth muscle tissue	UBERON:0001135	78.02	gold quality
body of pancreas	UBERON:0001150	77.88	gold quality
lung	UBERON:0002048	77.55	gold quality
spinal cord	UBERON:0002240	77.39	gold quality
large intestine	UBERON:0000059	77.12	gold quality
colon	UBERON:0001155	76.95	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	70.83
E-CURD-119	yes	38.79
E-HCAD-25	yes	23.93
E-CURD-114	yes	11.58
E-ANND-3	yes	9.09
E-CURD-53	no	133.31
E-MTAB-8410	no	3.24

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Liver	tissue	41.5	medium
Spinal cord	tissue	40.7
Superior colliculi	tissue	37.6
Postcentral gyrus	tissue	37.0
Hippocampus	tissue	36.7	not detected
Locus coeruleus	tissue	33.0
Medulla oblongata	tissue	31.0
Substantia nigra	tissue	30.6
Midbrain	tissue	29.5
Periaqueductal gray	tissue	28.5
Choroid plexus	tissue	27.9
Nucleus accumbens	tissue	27.8
Hypothalamus	tissue	27.0
Thalamus	tissue	26.5
Corpus callosum	tissue	26.2
Hippocampal formation	tissue	24.9
Pons	tissue	24.7
Septum	tissue	23.7
Entorhinal cortex	tissue	23.5
Cerebral cortex	tissue	23.3	medium
Amygdala	tissue	23.3
Temporal cortex	tissue	23.3
Ventral forebrain	tissue	22.8
Insular cortex	tissue	22.7
Basal ganglia	tissue	22.4	low
Putamen	tissue	22.1
Prefrontal cortex	tissue	22.0
Motor cortex	tissue	21.8
Retrosplenial and cingulate cortex	tissue	21.3
Somatosensory cortex	tissue	20.3
Retrosplenial cortex	tissue	20.1
Thymus	tissue	18.7
Occipital cortex	tissue	18.1
Breast	tissue	16.2	high
Salivary gland	tissue	15.9	medium
Olfactory bulb	tissue	14.1
Kidney	tissue	11.8	high
Cerebellum	tissue	10.8	low
Parathyroid gland	tissue	10.7	high
Placenta	tissue	10.3	low
Skin 1	tissue	9.7	medium
Adrenal gland	tissue	8.6	medium
Retina	tissue	8.1
Adipose tissue	tissue	7.8	medium
Appendix	tissue	7.7	medium
Lymph node	tissue	7.4	not detected
Caudate putamen	tissue	7.4
Pancreas	tissue	7.2	medium
Esophagus	tissue	6.9	low
Tonsil	tissue	6.4	low
Spleen	tissue	6.3	not detected
Rectum	tissue	6.2	medium
Frontal cortex	tissue	5.7
Bone marrow	tissue	5.7	low
Epididymis	tissue	5.4	medium
Colon	tissue	5.3	medium
Lung	tissue	5.3	low
Gallbladder	tissue	5.2	medium
Prostate	tissue	5.2	not detected
Fallopian tube	tissue	5.2	medium

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Area postrema (61.8), Nucleus raphe pallidus (55.2), Habenula (54.8), Lateral funiculus (white matter) (53.8), Medial olivary nucleus (51.8).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYCN, NFATC1

miRNA regulators (miRDB)

Targeting ITPR2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 194 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-3119	99.92	71.34	2390

Functional genomics

gnomAD constraint: pLI 9.36e-27, LOEUF 0.724, missense Z 4.49 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000381340 splits into 9 regions with different missense tolerance; 2 are missense-constrained (≈2% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
12:26,339,400–26,387,532	119 / 144.3	0.82	no
12:26,387,533–26,399,011	28 / 76.0	0.37	no
12:26,399,012–26,415,358	113 / 129.2	0.87	no
12:26,415,359–26,415,479	14 / 48.2	0.29	yes (p 8.4e-07)
12:26,415,480–26,427,990	78 / 110.3	0.71	no
12:26,427,991–26,596,941	926 / 1072.8	0.86	no
12:26,596,942–26,596,984	3 / 16.3	0.18	yes (p 9.8e-04)
12:26,596,985–26,658,060	817 / 897.6	0.91	no
12:26,658,061–26,832,781	515 / 789.4	0.65	no

Literature-anchored findings (GeneRIF, showing 31)

• Antibodies are detected most frequently in rheumatoid arthritis. (PMID:17437169)
• Genetic variation is susceptibility factor for amyotrophic lateral sclerosis(ALS). Involved in glutamate-mediated neurotransmission, is one of main regulators of intracellular calcium concentrations, and has important role in apoptosis. (PMID:17827064)
• Provide evidence for a functional role of the de novo coupling between hTRPC1 and IP3RII in the activation of store operated calcium entry in platelets. (PMID:18249094)
• Parathyroid hormone communicates with IP(3)R via “cAMP junctions” that allow local delivery of a supramaximal concentration of cAMP to IP(3)R, directly increasing their sensitivity to IP(3). (PMID:18936250)
• The result of this study suggested that ITPR2 that do not modulate the risk for SALS in the German population. (PMID:19464757)
• Elevated InsP(3)R2 expression was also detected in hearts from human patients with heart failure after ischemic dilated cardiomyopathy, as well as in aortic-banded hypertrophic mouse hearts. (PMID:19549843)
• Dystrophic (RCDMD) human muscle cells show 5-fold overexpression of IP(3)R2 and down-regulation of IP(3)R3 compared with normal human muscle cells. (PMID:20395455)
• The knock down of IP3R-2 significantly reduced the intracellular Ca2+ response and this reduced Ca2+ response did not affect the activation of CREB but significantly decreased the activation of NFAT. (PMID:21063100)
• ITPR2 is a functional target gene of the BACH1 transcription factor according to ChIP-seq and knockdown analysis in HEK 293 cells. (PMID:21555518)
• Functional IP3R2s are expressed in the mouse sinoatrial node and could serve as an additional divalent calcium ion-dependent mechanism in modulating cardiac pacemaker. (PMID:21852551)
• These data suggest that ER Ca(2+) released by IP(3) receptors may be detrimental in amyotrophic lateral sclerosis and that motor neurons are vulnerable to impaired Ca(2+) metabolism. (PMID:23131553)
• These results suggest an involvement of hydrogen sulfide in both IP3-induced calcium signalling and induction of apoptosis, possibly through the activation of endoplasmic reticulum stress. (PMID:23582047)
• Studies indicate that three subtypes of inositol 1,4,5-trisphosphate (IP3) receptors (IP3R1, -2, and -3) are assembled to form homo- and heterotetrameric channels that mediate Ca(2+) release from intracellular stores. (PMID:23955339)
• The Galphaq-protein/coupled receptor/IP3R axis modulates the electromechanical properties of the human myocardium and its propensity to develop arrhythmias. (PMID:23983250)
• ITPR2 and hypertrophy specific gene expression is regulated, in part, by a positive feedback regulation between InsP3R2 and calcineurin-NFATc signaling pathways. (PMID:24415751)
• results show a functional role of calcium release by the ITPR2 channel and its subsequent accumulation in the mitochondria (PMID:24797322)
• A genome-wide association study identifies ITPR2 as a susceptibility gene for Kashin-Beck disease in Han Chinese. (PMID:25303641)
• Loss of InsP3R2-mediated calcium release causes isolated anhidrosis in humans. (PMID:25329695)
• Disrupting IP3R/Bcl-2 interaction therefore leads in those cells to increased Ca(2) release and apoptosis. Intriguingly, IP3R2 is not only implicated in apoptosis but also in the induction of senescence, another tumour-suppressive mechanism. (PMID:25499268)
• High expression of inositol 1,4,5-trisphosphate receptor, type 2 is associated with acute myeloid leukemia. (PMID:25779662)
• 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)
• the ability to generate tetramers with defined wild type and mutant subunits will be useful in probing fundamental questions relating to IP3Rs (R1, R2, R3) structure and function. (PMID:26009177)
• Data suggest miR-1290 as the new oncomiR involved in laryngeal squamous cell carcinoma pathogenesis probably through downregulation of its target genes MAF and ITPR2. (PMID:26694163)
• we systematically evaluating RCC risk-associated SNPs indentified from previous GWAS in a Chinese population, finding that one SNP located in PDZD2 and two SNPs located in ITPR2 were ccRCC-risk associated in Chinese population. (PMID:26918600)
• Fatty liver induces a c-Jun-mediated decrease in ITPR2 in hepatocytes. (PMID:29023819)
• Molecular cloning, bacterial expression and protein purification of the IBC domain from human IP3R2 have been described. (PMID:30244130)
• The SNP rs11048526 were significantly association with Kashin-Beck Disease which increased the Kashin-Beck Disease risk. (PMID:31066235)
• Type 3 Inositol 1,4,5-Trisphosphate Receptor is a Crucial Regulator of Calcium Dynamics Mediated by Endoplasmic Reticulum in HEK Cells. (PMID:31979185)
• Calcium channel ITPR2 and mitochondria-ER contacts promote cellular senescence and aging. (PMID:33526781)
• Candidate Gene of NOS3, MMP3, AGT, and AGT1R and Pathway Analyses for Platelet Reactivity and Clinical Outcomes of Repeat Revascularization After First PCI in Chinese Patients. (PMID:34860335)
• Inositol 1,4,5-trisphosphate receptor gene variants are related to the risk of breast cancer in a Chinese population. (PMID:36350267)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	itpr2	ENSDARG00000011909
mus_musculus	Itpr2	ENSMUSG00000030287
rattus_norvegicus	Itpr2	ENSRNOG00000001804
drosophila_melanogaster	RyR	FBGN0011286
caenorhabditis_elegans		WBGENE00006801

Paralogs (5): ITPR3 (ENSG00000096433), ITPR1 (ENSG00000150995), RYR1 (ENSG00000196218), RYR2 (ENSG00000198626), RYR3 (ENSG00000198838)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:99418) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 2 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal sweat gland physiology	1
hypohidrosis	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Oryctolagus cuniculus	P30957	98.4%	Diamond
Bos taurus	Q8WN96	97.3%	Diamond
Sus scrofa	P16960	95.8%	Diamond
Patiria pectinifera	Q8WSR4	67.4%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
ITPR2-AS2	ncRNA	139355255
FGFR1OP2	protein-coding	26127
INTS13	protein-coding	55726
SSPN-AS1	ncRNA	101928554
BHLHE41	protein-coding	79365
SSPN	protein-coding	8082
RASSF8	protein-coding	11228
TM7SF3	protein-coding	51768
MED21	protein-coding	9412

Protein

Protein identifiers

Inositol 1,4,5-trisphosphate-gated calcium channel ITPR2 — Q14571 (reviewed: Q14571)

Alternative names: IP3 receptor isoform 2, Inositol 1,4,5-trisphosphate receptor type 2, Type 2 inositol 1,4,5-trisphosphate receptor

All UniProt accessions (3): F5GYT5, H7C2X9, Q14571

UniProt curated annotations — full annotation on UniProt →

Function. Inositol 1,4,5-trisphosphate-gated calcium channel that upon inositol 1,4,5-trisphosphate binding transports calcium from the endoplasmic reticulum lumen to cytoplasm. Exists in two states; a long-lived closed state where the channel is essentially ‘parked’ with only very rare visits to an open state and that ligands facilitate the transition from the ‘parked’ state into a ‘drive’ mode represented by periods of bursting activity.

Subunit / interactions. Homotetramer. Interacts with CABP1. Interacts with BOK; regulates ITPR2 expression. Interacts with BCL2L10. Interacts with TRPC4. Interacts with CHGA and CHGB.

Subcellular location. Endoplasmic reticulum membrane. Cytoplasmic vesicle. Secretory vesicle membrane.

Tissue specificity. Found in skeletal muscle and heart.

Post-translational modifications. Phosphorylation by cAMP-dependent PKA on Ser-937 increases calcium release. Phosphorylation by CaMK2 on Ser-150 significantly decreases the channel open probability.

Disease relevance. Anhidrosis, isolated, with normal sweat glands (ANHD) [MIM:106190] An autosomal recessive disorder characterized by generalized, isolated anhidrosis, severe heat intolerance, and morphologically normal eccrine sweat glands. Body growth, teeth, hair, nails, and skin are normal. 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 increased by cAMP that occurs independently of PKA activation. ATP and cytosolic calcium modulate the open probability (Po) predominantly by facilitating extended ‘bursting’ activity of the channel. Inositol 1,4,5-trisphosphate-gated calcium channel activity is inhibited by CALM1 in a calcium-dependent manner.

Similarity. Belongs to the InsP3 receptor family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14571-1	Long	yes
Q14571-2	Short, TIPR

RefSeq proteins (3): NP_001401103, NP_001401104, NP_002214* (*=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)

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

UniProt features (63 total): binding site 28, topological domain 7, transmembrane region 6, modified residue 6, domain 5, sequence variant 4, sequence conflict 3, splice variant 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

6 structures by resolution:

PDB	Title	Method	Resolution (Å)
9YKK	Human type 2 IP3 receptor in apo state	ELECTRON MICROSCOPY	2.95
9YMZ	Human type 2 IP3 receptor in the inactive-like state (IP3/ATP)	ELECTRON MICROSCOPY	3.14
9YKY	IP3/ATP-bound human type 2 IP3 receptor in the resting state	ELECTRON MICROSCOPY	3.31
9YLI	IP3/ATP-bound human type 2 IP3 receptor in the preactivated state	ELECTRON MICROSCOPY	3.33
9YNK	Human type 2 IP3 receptor in the inactive-like state (IP3/ATP/Ca2+)	ELECTRON MICROSCOPY	3.42
9YNO	Human type 2 IP3 receptor dimer (IP3/ATP/Ca2+)	ELECTRON MICROSCOPY	4.06

Predicted structure (AlphaFold)

No AlphaFold model available for Q14571 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Human Protein Atlas

Protein class: Predicted membrane proteins, Predicted intracellular proteins, Plasma proteins, Disease related genes, Human disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): endoplasmic reticulum; mid piece; end piece; nucleoplasm; principal piece

Antibody reliability (HPA): IH uncertain · IF approved

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 (28)

Position	Role
265	1D-myo-inositol 1,4,5-trisphosphate
267	1D-myo-inositol 1,4,5-trisphosphate
268	1D-myo-inositol 1,4,5-trisphosphate
269	1D-myo-inositol 1,4,5-trisphosphate
503	1D-myo-inositol 1,4,5-trisphosphate
507	1D-myo-inositol 1,4,5-trisphosphate
510	1D-myo-inositol 1,4,5-trisphosphate
567	1D-myo-inositol 1,4,5-trisphosphate
568	1D-myo-inositol 1,4,5-trisphosphate
569	1D-myo-inositol 1,4,5-trisphosphate
744	Ca(2+)
1124	Ca(2+)
1127	Ca(2+)
1930	Ca(2+)
1994	Ca(2+)
2044	ATP
2177	ATP
2562	ATP
2562	Zn(2+)
2563	ATP
2565	Zn(2+)
2582	Zn(2+)
2584	ATP
2587	ATP
2587	Zn(2+)
2588	ATP
2589	ATP
2605	Ca(2+)

Post-translational modifications (6)

Type	Positions
Phosphoserine	937, 1160, 1709, 2633, 2636
Phosphotyrosine	2607

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 49; 7 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

49 pathways:

ID	Pathway	Evidence
R-HSA-114508	Effects of PIP2 hydrolysis	curated
R-HSA-139853	Elevation of cytosolic Ca2+ levels	curated
R-HSA-381676	Glucagon-like Peptide-1 (GLP1) regulates insulin secretion	curated
R-HSA-9662851	Anti-inflammatory response favouring Leishmania parasite infection ⚕	—
R-HSA-1643685	Disease ⚕	—
R-HSA-9664323	FCGR3A-mediated IL10 synthesis ⚕	electronic
R-HSA-5663205	Infectious disease ⚕	—
R-HSA-9658195	Leishmania infection ⚕	—
R-HSA-9664433	Leishmania parasite growth and survival ⚕	—
R-HSA-9824443	Parasitic Infection Pathways ⚕	—
R-HSA-1280218	Adaptive Immune System	—
R-HSA-983695	Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	electronic
R-HSA-3858494	Beta-catenin independent WNT signaling	—
R-HSA-5621481	C-type lectin receptors (CLRs)	—
R-HSA-5607763	CLEC7A (Dectin-1) induces NFAT activation	electronic
R-HSA-5607764	CLEC7A (Dectin-1) signaling	—
R-HSA-4086398	Ca2+ pathway	electronic
R-HSA-5576891	Cardiac conduction	—
R-HSA-1489509	DAG and IP3 signaling	electronic
R-HSA-2871809	FCERI mediated Ca+2 mobilization	electronic
R-HSA-2454202	Fc epsilon receptor (FCERI) signaling	—
R-HSA-2029480	Fcgamma receptor (FCGR) dependent phagocytosis	—
R-HSA-418594	G alpha (i) signalling events	—
R-HSA-416476	G alpha (q) signalling events	—
R-HSA-112040	G-protein mediated events	—
R-HSA-388396	GPCR downstream signalling	—
R-HSA-109582	Hemostasis	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-163685	Integration of energy metabolism	—
R-HSA-9006925	Intracellular signaling by second messengers	—
R-HSA-5578775	Ion homeostasis	electronic
R-HSA-1430728	Metabolism	—
R-HSA-397014	Muscle contraction	—
R-HSA-111885	Opioid Signalling	—
R-HSA-112043	PLC beta mediated events	electronic
R-HSA-76002	Platelet activation, signaling and aggregation	—
R-HSA-418360	Platelet calcium homeostasis	—
R-HSA-418346	Platelet homeostasis	—
R-HSA-422356	Regulation of insulin secretion	electronic
R-HSA-2029485	Role of phospholipids in phagocytosis	electronic
R-HSA-162582	Signal Transduction	—
R-HSA-372790	Signaling by GPCR	—
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases	—
R-HSA-194138	Signaling by VEGF	—
R-HSA-195721	Signaling by WNT	—
R-HSA-983705	Signaling by the B Cell Receptor (BCR)	—
R-HSA-4420097	VEGFA-VEGFR2 Pathway	—
R-HSA-5218921	VEGFR2 mediated cell proliferation	electronic

MSigDB gene sets: 416 (showing top): MORF_RAGE, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ETHANOL, MORF_FLT1, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, BASSO_B_LYMPHOCYTE_NETWORK, GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, CERVERA_SDHB_TARGETS_1_DN, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_1, RIZKI_TUMOR_INVASIVENESS_3D_DN, MORF_ESR1, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_MONOATOMIC_CATION_TRANSPORT

GO Biological Process (10): response to hypoxia (GO:0001666), signal transduction (GO:0007165), release of sequestered calcium ion into cytosol (GO:0051209), cellular response to cAMP (GO:0071320), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), calcium-mediated signaling (GO:0019722), monoatomic ion transmembrane transport (GO:0034220), transmembrane transport (GO:0055085), calcium ion transmembrane transport (GO:0070588)

GO Molecular Function (14): 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), phosphatidylinositol binding (GO:0035091), transmembrane transporter binding (GO:0044325), inositol 1,4,5 trisphosphate binding (GO:0070679), scaffold protein binding (GO:0097110), nucleotide binding (GO:0000166), monoatomic ion channel activity (GO:0005216), calcium channel activity (GO:0005262), protein binding (GO:0005515), intracellularly gated calcium channel activity (GO:0015278), metal ion binding (GO:0046872)

GO Cellular Component (13): endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), cell cortex (GO:0005938), membrane (GO:0016020), sarcoplasmic reticulum (GO:0016529), transport vesicle membrane (GO:0030658), secretory granule membrane (GO:0030667), platelet dense tubular network membrane (GO:0031095), sarcoplasmic reticulum membrane (GO:0033017), signaling receptor complex (GO:0043235), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

18 top-level categories:

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
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
Signaling by the B Cell Receptor (BCR)	1
G alpha (i) signalling events	1
Opioid Signalling	1
Immune System	1

GO top-level categories

59 GO namespaces:

Category	Terms
bounding membrane of organelle	4
anion binding	3
cytoplasm	3
cellular process	2
transport	2
protein binding	2
cell periphery	2
cellular anatomical structure	2
cytoplasmic vesicle membrane	2
response to stress	1
response to decreased oxygen levels	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
calcium ion transmembrane import into cytosol	1
response to cAMP	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
metal ion transport	1
intracellular signaling cassette	1
monoatomic ion transport	1
transmembrane transport	1
calcium ion transport	1
monoatomic cation transmembrane transport	1
intracellularly gated calcium channel activity	1
inositol 1,4,5 trisphosphate binding	1
metal ion binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
metal ion transmembrane transporter activity	1
calcium ion transmembrane transport	1
alcohol binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
monoatomic ion transmembrane transporter activity	1
channel activity	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
binding	1
intracellularly ligand-gated monoatomic ion channel activity	1
ligand-gated calcium channel activity	1
cation binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
endoplasmic reticulum	1
sarcoplasm	1
transport vesicle	1
secretory granule	1
platelet dense tubular network	1
endoplasmic reticulum membrane	1
sarcoplasmic reticulum	1
protein-containing complex	1
intracellular anatomical structure	1
endomembrane system	1
intracellular membrane-bounded organelle	1
intracellular vesicle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 7 of 37 annotations. The rest are phylogenetic / computational / electronic (IEA).

7 experimentally-supported GO terms:

GO term	NS	Evidence
response to hypoxia	BP	direct assay
membrane	CC	high-throughput assay
plasma membrane	CC	direct assay
sarcoplasmic reticulum membrane	CC	mutant phenotype
signaling receptor complex	CC	direct assay
scaffold protein binding	MF	physical interaction
transmembrane transporter binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,235 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ITPR2	SSPN	Q14714	749
ITPR2	MPP4	Q96JB8	730
ITPR2	ATP2A2	P16614	713
ITPR2	GRK7	Q8WTQ7	668
ITPR2	GRK1	Q15835	661
ITPR2	STIM1	Q13586	656
ITPR2	MCU	Q8NE86	626
ITPR2	BANK1	Q8NDB2	595
ITPR2	DPP6	P42658	595
ITPR2	TRPM7	Q96QT4	573
ITPR2	STIM2	Q9P246	561
ITPR2	LIN7C	Q9NUP9	550
ITPR2	RCVRN	P35243	547
ITPR2	ORAI1	Q96D31	536
ITPR2	ORAI3	Q9BRQ5	532

IntAct

Human interaction partners of ITPR2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

5 partners by confidence:

Partner	Interaction type	MIscore	Records
TRPC4	physical association	0.530	2
BCL2L10	physical association	0.400	1
EIF4G1	physical association	0.400	1
IRAG1	association	0.350	1
EXOC1	physical association	0.000	1

BioGRID (196 interactions; top human partners by supporting records): BBOX1 (Affinity Capture-MS; 3 records), CA8 (Affinity Capture-MS; 3 records), CACNG2 (Affinity Capture-MS; 3 records), EIF4G1 (Cross-Linking-MS (XL-MS); 3 records), P2RY12 (Affinity Capture-MS; 3 records), TESPA1 (Affinity Capture-MS; 3 records), ANLN (Affinity Capture-MS; 2 records), CHRNA3 (Affinity Capture-MS; 2 records), FAM19A4 (Affinity Capture-MS; 2 records), IPPK (Affinity Capture-MS; 2 records), L3MBTL2 (Affinity Capture-MS; 2 records), LPAR1 (Affinity Capture-MS; 2 records), MAD2L2 (Proximity Label-MS; 2 records), RAB29 (Affinity Capture-MS; 2 records), RPL35 (Cross-Linking-MS (XL-MS); 2 records)

SIGNOR signaling

3 signaling interactions:

A	Effect	B	Mechanism
RNF170	“down-regulates activity”	ITPR2	polyubiquitination
CAMK2D	“down-regulates activity”	ITPR2	phosphorylation
Erlin	“down-regulates quantity by destabilization”	ITPR2	binding

Disease & clinical

Genetic variants

Variant evidence for ITPR2: 394 ClinVar records (2 pathogenic / likely pathogenic); 84 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	264
Likely benign	54
Benign	19

Top pathogenic / likely-pathogenic (2)

Showing all 2 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
189316	NM_002223.4(ITPR2):c.7492G>A (p.Gly2498Ser)	Pathogenic	no assertion criteria provided	1
4082119	NM_002223.4(ITPR2):c.7391del (p.Ala2463_Ser2464insTer)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore ITPR2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 33 predictions of 6,604):

Position(s)	Effect	Δscore	Sites
12:26340165–26340166	donor_loss	1.0000	4
12:26387595–26387596	acceptor_loss	1.0000	6
12:26400126	donor_loss	1.0000	2
12:26400172	donor_gain	1.0000
12:26400259–26400260	acceptor_loss	1.0000	3
12:26400261	acceptor_gain	1.0000
12:26400271	acceptor_gain	1.0000
12:26415301–26415302	donor_loss	1.0000	5
12:26415499–26415500	acceptor_loss	1.0000	5
12:26439125–26439126	donor_loss	1.0000	5

AlphaMissense

6,100 missense substitutions predicted likely pathogenic (of 17,997 scored), across 1,357 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M2207	9	0.961	0.995
M1438	9	0.929	0.992
M1231	9	0.922	0.985
M1210	9	0.917	0.989
M1332	9	0.891	0.993
M2674	9	0.883	0.989
M2052	9	0.877	0.983
M2484	9	0.877	0.993
M1359	9	0.841	0.968
D2542	8	0.998	0.999
F2544	8	0.997	1.000
D2521	8	0.996	0.999
F2537	8	0.996	1.000
D2373	8	0.993	0.998
F2524	8	0.991	0.999
H2582	8	0.991	0.998
D986	8	0.987	0.997
D1105	8	0.987	0.996
F2409	8	0.987	0.999
N2534	8	0.987	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000477

Disease associations

OMIM: gene MIM:600144 | disease phenotypes: MIM:106190, MIM:143890

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
isolated anhidrosis with normal sweat glands	Supportive	Autosomal recessive	2

Mondo (2): isolated anhidrosis with normal sweat glands (MONDO:0007118), familial hypercholesterolemia (MONDO:0005439)

Orphanet (1): Isolated generalized anhidrosis with normal sweat glands (Orphanet:468666)

HPO phenotypes

5 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001507	Growth abnormality
HP:0001595	Abnormal hair morphology
HP:0002046	Heat intolerance
HP:0007459	Generalized anhidrosis

GWAS associations

showing 30 of 84 associations:

Study	Trait	p-value
GCST006979_994	Heel bone mineral density	1e-28
GCST90020025_1413	Waist-to-hip ratio adjusted for BMI	2e-26
GCST90020027_358	Waist-hip index	3e-26
GCST004576_30	Waist-to-hip ratio adjusted for body mass index	4e-19
GCST004576_50	Waist-to-hip ratio adjusted for body mass index	3e-18
GCST004567_91	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	4e-18
GCST004576_137	Waist-to-hip ratio adjusted for body mass index	6e-18
GCST000829_5	Waist-hip ratio	1e-17
GCST004576_64	Waist-to-hip ratio adjusted for body mass index	3e-17
GCST004567_104	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	6e-17
GCST004567_11	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	2e-16
GCST002782_98	Waist-to-hip ratio adjusted for body mass index	4e-16
GCST004567_60	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	4e-16
GCST004505_46	Waist-to-hip ratio adjusted for BMI (adjusted for smoking behaviour)	9e-16
GCST002782_100	Waist-to-hip ratio adjusted for body mass index	2e-15
GCST90020024_637	A body shape index	2e-15
GCST90020025_1411	Waist-to-hip ratio adjusted for BMI	2e-15
GCST004578_45	Waist-to-hip ratio adjusted for BMI in active individuals	3e-15
GCST90020027_356	Waist-hip index	3e-15
GCST002782_99	Waist-to-hip ratio adjusted for body mass index	5e-15
GCST002782_97	Waist-to-hip ratio adjusted for body mass index	6e-15
GCST004578_57	Waist-to-hip ratio adjusted for BMI in active individuals	7e-15
GCST004578_130	Waist-to-hip ratio adjusted for BMI in active individuals	1e-14
GCST004578_83	Waist-to-hip ratio adjusted for BMI in active individuals	2e-14
GCST005956_19	Waist-to-hip ratio adjusted for BMI	4e-14
GCST004505_45	Waist-to-hip ratio adjusted for BMI (adjusted for smoking behaviour)	1e-13
GCST010002_64	Refractive error	2e-13
GCST005962_43	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	3e-13
GCST008362_217	Birth weight	4e-13
GCST90020029_1262	Waist circumference adjusted for body mass index	1e-12

EFO canonical traits (from GWAS)

21 canonical traits:

EFO ID	Trait name
EFO:0004343	waist-hip ratio
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004318	smoking behavior
EFO:0007789	BMI-adjusted waist circumference
EFO:0008002	physical activity measurement
EFO:0004344	birth weight
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0004530	triglyceride measurement
EFO:0004574	total cholesterol measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0009443	BRCAX breast cancer
EFO:0009270	heel bone mineral density
EFO:0005939	parental genotype effect measurement
EFO:0006939	cup-to-disc ratio measurement
EFO:0004531	urate measurement
EFO:0004587	lymphocyte count
EFO:0007985	platelet crit
EFO:0004533	alkaline phosphatase measurement
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2111451 (PROTEIN FAMILY)

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: lgic — IP₃ receptors

Binding affinities (BindingDB)

4 measured of 4 human assays (5 total across all organisms); most potent 4 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL3349691	IC50	26.5 nM
CHEMBL1161456	EC50	130 nM
CHEMBL1160286	IC50	172 nM
(L)-2,2-difluoro-2-deoxy-myo-inositol 1,4,5-triphosphate	EC50	410 nM

ChEMBL bioactivities

9 potent at pChembl≥5 of 12 total, top 9 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
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
6.76	IC50	172	nM	CHEMBL1160286
6.70	IC50	200	nM	INS(1,4,5)P3
6.39	EC50	410	nM	CHEMBL1161466

PubChem BioAssay actives

6 with measured affinity, of 6 total; 3 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
[(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
(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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases methylation, affects methylation, decreases expression	8
Valproic Acid	affects cotreatment, increases expression, decreases expression, decreases methylation	7
Tretinoin	affects expression, increases expression	4
trichostatin A	affects cotreatment, increases expression	3
potassium chromate(VI)	affects cotreatment, decreases expression	2
mercuric bromide	increases expression, affects cotreatment	2
perfluorooctane sulfonic acid	affects cotreatment, increases expression, affects expression	2
Panobinostat	affects cotreatment, increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Cisplatin	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	decreases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
Particulate Matter	affects response to substance, decreases expression	2
aristolochic acid I	decreases expression	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	affects cotreatment, affects expression	1
triphenyl phosphate	affects expression	1
uranyl acetate	increases expression	1
bisphenol A	decreases methylation, affects cotreatment	1
beta-lapachone	decreases expression	1
sodium bichromate	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases methylation, increases abundance	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	affects cotreatment, affects expression	1
benzo(e)pyrene	decreases methylation	1
periodate-oxidized adenosine	affects expression	1

ChEMBL screening assays

8 unique, capped per target: 7 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

13 cell lines: 7 cancer cell line, 6 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7SV	Ubigene A-549 ITPR2 KO	Cancer cell line	Male
CVCL_D8NM	Ubigene HCT 116 ITPR2 KO	Cancer cell line	Male
CVCL_D9HM	Ubigene HEK293 ITPR2 KO	Transformed cell line	Female
CVCL_E0FR	Ubigene HeLa ITPR2 KO	Cancer cell line	Female
CVCL_F6EX	EDITGENE ITPR1 and ITPR2 and ITPR3 Knockout HEK293 Cell Line	Transformed cell line	Female
CVCL_HB82	HEK-3KO	Transformed cell line	Female
CVCL_HB83	HEKR1	Transformed cell line	Female
CVCL_HB85	HEKR2R1	Transformed cell line	Female
CVCL_HB86	HEKR2R3	Transformed cell line	Female
CVCL_ST60	HAP1 ITPR2 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 300 trials:

NCT	Phase	Status	Title
NCT00655265	Phase 4	COMPLETED	A Study of the Safety and Efficacy of Patients With Familial Hypercholesterolaemia Taking Colesevelam as add-on Therapy to Their Existing Medication
NCT00916643	Phase 4	COMPLETED	Low-Density Lipoprotein (LDL) Apheresis Using H.E.L.P. Therapy
NCT03331666	Phase 4	TERMINATED	Impact of LDL-cholesterol Lowering on Platelet Activation
NCT05465278	Phase 4	COMPLETED	Alirocumab and Plaque Burden In Familial Hypercholesterolaemia
NCT05657860	Phase 4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	Phase 4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	Phase 4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	Phase 4	RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00355615	Phase 3	COMPLETED	PLUTO: Pediatric Lipid-redUction Trial of rOsuvastatin
NCT00552097	Phase 3	COMPLETED	Effect of Ezetimibe Plus Simvastatin Versus Simvastatin Alone on Atherosclerosis in the Carotid Artery (ENHANCE)(P02578)
NCT00607373	Phase 3	COMPLETED	Study to Assess the Safety and Efficacy of ISIS 301012 (Mipomersen) in Homozygous Familial Hypercholesterolemia
NCT00694109	Phase 3	COMPLETED	An Open-label Extension Study to Assess the Long-term Safety and Efficacy of ISIS 301012 (Mipomersen) in Patients With Familial Hypercholesterolemia or Severe-Hypercholesterolemia
NCT00827606	Phase 3	COMPLETED	Atorvastatin Three Year Pediatric Study
NCT00943306	Phase 3	COMPLETED	Long Term, Follow-on Study of Lomitapide in Patients With Homozygous Familial Hypercholesterolemia
NCT01524289	Phase 3	COMPLETED	Study to Assess the Tolerability and Efficacy of Anacetrapib (MK-0859) Co-Administered With Statin in Participants With Heterozygous Familial Hypercholesterolemia (MK-0859-020)
NCT01813006	Phase 3	COMPLETED	Effect of Omega-3 Fatty Acid on Endothelial Function
NCT01841684	Phase 3	TERMINATED	Efficacy and Tolerability of Anacetrapib Added to Ongoing Lipid-Lowering Therapy in Adult Participants With Homozygous Familial Hypercholesterolemia (HoFH) (MK-0859-042)
NCT02624869	Phase 3	COMPLETED	Safety, Tolerability and Efficacy of Evolocumab (AMG 145) in Children With Inherited Elevated Low-density Lipoprotein Cholesterol (Familial Hypercholesterolemia)
NCT02748057	Phase 3	COMPLETED	A Clinical Trial to Assess the Long Term Safety and Tolerability of MK-0653H in Japanese Participants With Hypercholesterolemia (MK-0653H-833)
NCT03884452	Phase 3	COMPLETED	Ezetimibe (SCH 58235) Taken With Either Atorvastatin or Simvastatin in Participants With Familial Hypercholesterolemia (MK-0653-018)
NCT04798430	Phase 3	ENROLLING_BY_INVITATION	Long-term Efficacy and Safety of OLE LIB003 in HoFH, HeFH, and High-risk CVD Patients Requiring Further LDL-C Reduction
NCT05142722	Phase 3	COMPLETED	Randomized Study to Evaluate the Effect of Obicetrapib on Top of Maximum Tolerated Lipid-Modifying Therapies
NCT05238519	Phase 3	COMPLETED	Improved Diagnosis of Familial Hypercholesterolemia Across the Northland (ID-FH)
NCT05425745	Phase 3	COMPLETED	Evaluate the Effect of Obicetrapib in Patients With HeFH on Top of Maximum Tolerated Lipid-Modifying Therapies.
NCT05952856	Phase 3	COMPLETED	A Study of Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) in Adults With Hypercholesterolemia (MK-0616-013) CORALreef Lipids
NCT05952869	Phase 3	COMPLETED	A Study of Enlicitide Decanoate (MK-0616 Oral PCSK9 Inhibitor) in Adults With Heterozygous Familial Hypercholesterolemia (MK-0616-017/CORALreef HeFH)
NCT06005597	Phase 3	COMPLETED	Study of Obicetrapib & Ezetimibe Fixed Dose Combination on Top of Maximum Tolerated Lipid-Modifying Therapies
NCT02270736	Phase 3	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
NCT00079846	Phase 2	TERMINATED	Implitapide in Patients With Homozygous Familial Hypercholesterolemia (HoFH) on Maximal Concurrent Lipid-Lowering Therapy
NCT00079859	Phase 2	TERMINATED	Implitapide in Patients With Heterozygous Familial Hypercholesterolemia (HeFH) on Maximal Concurrent Lipid-Lowering Therapy
NCT00477594	Phase 2	COMPLETED	Open Label Extension of ISIS 301012 (Mipomersen) to Treat Familial Hypercholesterolemia
NCT00751608	Phase 2	WITHDRAWN	Effect of APL180 on Endothelial Function in Familial Hypercholesterolemia Patients
NCT02597127	Phase 2	COMPLETED	Trial to Evaluate the Effect of ALN-PCSSC Treatment on Low Density Lipoprotein Cholesterol (LDL-C)
NCT03060577	Phase 2	COMPLETED	An Extension Trial of Inclisiran in Participants With Cardiovascular Disease and High Cholesterol
NCT04455581	Phase 2	UNKNOWN	A Study to Determine the Safety, Tolerability, and Efficacy of SHR-1209 in Patients With Familial Hypercholesterolemia
NCT04941599	Phase 2	RECRUITING	2-Hydroxybenzylamine (2-HOBA) to Reduce HDL Modification and Improve HDL Function in Familial Hypercholesterolemia (FH)
NCT05261126	Phase 2	COMPLETED	A Study of the Efficacy and Safety of Enclitide Chloride (MK-0616 Oral PCSK9 Inhibitor) in Adults With Hypercholesterolemia (MK-0616-008)
NCT02304302	Phase 2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	Phase 2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	Phase 2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	Phase 2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00004809	Phase 1	COMPLETED	Phase I Study of Ex Vivo Liver-Directed Gene Therapy for Familial Hypercholesterolemia
NCT02709850	Phase 1	COMPLETED	Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of IONIS ANGPTL3-LRx in Healthy Volunteers With Elevated Triglycerides and Participants With Familial Hypercholesterolemia
NCT03747224	Phase 1	COMPLETED	Study of ARO-ANG3 in Healthy Volunteers and in Dyslipidemic Patients
NCT05043181	Phase 1	NOT_YET_RECRUITING	Exosome-based Nanoplatform for Ldlr mRNA Delivery in FH
NCT05851066	Phase 1	COMPLETED	A VSA003 Phase 1 Study in Chinese Adult Healthy Volunteers
NCT05273320	Phase 1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	Phase 1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	Phase 1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	Phase 1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	Phase 1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT02048410	Phase 1/2	COMPLETED	Efficacy of a New Symbiotic Formulation in Children With Familial Hypercholesterolemia
NCT02100839	Phase 1/2	COMPLETED	Safety Study of AEM-28 to Treat Refractory Hypercholesterolemia
NCT03832985	Early Phase 1	COMPLETED	Pediatric Reporting of Adult-Onset Genomic Results
NCT06293729	Early Phase 1	NOT_YET_RECRUITING	Safety and Efficacy Study of NGGT006 in Refractory Hypercholesterolemia Patients
NCT06458010	Early Phase 1	RECRUITING	Clinical Exploration Trial of YOLT-101 in the Treatment of Familial Hypercholesterolemia (FH)
NCT06461702	Early Phase 1	UNKNOWN	Clinical Exploration Trial of YOLT-101 in the Treatment of Familial Hypercholesterolemia (FH)
NCT00704444	Not specified	COMPLETED	A 12-week Post-marketing, Observational Study to Confirm the Safety and Efficacy of Zetia Alone or in Combination With Other Lipid-lowering Drugs in Japanese Subjects With Hypercholesterolemia (Study P05244)
NCT00705211	Not specified	COMPLETED	A 52-week Post-marketing, Observational Study to Confirm the Safety and Efficacy of Zetia Alone or in Combination With Other Lipid-lowering Drugs in Japanese Subjects With Hypercholesterolemia (Study P05245)
NCT00924274	Not specified	UNKNOWN	Effect of Rapeseed Oil and Sunflower Oil

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for ITPR2 across ~30M SureChEMBL compounds — explore on Sugi Predict.