ORAI2

Summary

ORAI2 (ORAI calcium release-activated calcium modulator 2, HGNC:21667) is a protein-coding gene on chromosome 7q22.1, encoding Protein orai-2 (Q96SN7). Pore-forming subunit of inward rectifying Ca(2+) release-activated Ca(2+) (CRAC) channels.

Enables store-operated calcium channel activity. Involved in store-operated calcium entry. Located in several cellular components, including cytosol; mitochondrion; and nucleoplasm.

Source: NCBI Gene 80228 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 57 total
• Regional missense constraint (gnomAD): 1 of 3 regions constrained (≈5% of expected missense variation)
• GTEx eGene: eQTL in 29 tissues, sQTL in 30 (q < 0.05)
• ChEMBL bioactivity: 1 clinical-phase molecule tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.01 (LoF-tolerant), LOEUF 1.03 (unconstrained)
• MANE Select transcript: NM_001126340
• Notable: 57 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21667
Approved symbol	ORAI2
Name	ORAI calcium release-activated calcium modulator 2
Location	7q22.1
Locus type	gene with protein product
Status	Approved
Aliases	CBCIP2, FLJ12474, FLJ14733, H_NH0514P08.8
Ensembl gene	ENSG00000160991
Ensembl biotype	protein_coding
OMIM	610929
Entrez	80228

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 9 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

MANE Select: ENST00000495936

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 4, TSL 4: 1, TSL 5: 1

ENST00000495936, ENST00000356387, ENST00000403646, ENST00000473939, ENST00000478730, ENST00000482237, ENST00000488996, ENST00000952428, ENST00001101425, ENST00001126927, ENST00001141509

RefSeq mRNA: 4 — MANE Select: NM_001126340 NM_001126340, NM_001271818, NM_001271819, NM_032831

CCDS: CCDS5722

Canonical transcript exons

ENST00000495936 — 4 exons

Exon	Start	End
ENSE00001408887	102438944	102439181
ENSE00001409383	102436225	102436333
ENSE00001902201	102446513	102456825
ENSE00001930645	102433575	102433661

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 97.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 10.1658 / max 252.8718, expressed in 1742 samples.

Highest expression (Bgee): renal medulla, ventral tegmental area, pylorus, superior vestibular nucleus, nipple.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ORAI2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 29 tissues and its splicing (sQTL) in 30 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 59 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	1.4e-90	+0.63	7:102424608:G:A
Whole Blood	sqtl	1.0e-64	+0.58	7:102436115:G:A
Cells Cultured fibroblasts	sqtl	2.4e-48	+0.80	7:102436115:G:A
Cells EBV-transformed lymphocytes	sqtl	7.9e-48	+1.21	7:102436115:G:A
Adipose Subcutaneous	sqtl	1.7e-37	+0.62	7:102436115:G:A
Pituitary	sqtl	3.9e-22	-0.88	7:102436115:G:A
Thyroid	sqtl	1.7e-20	-0.60	7:102438644:G:A
Breast Mammary Tissue	sqtl	2.6e-18	+0.54	7:102435529:C:T
Cells Cultured fibroblasts	eqtl	1.3e-17	+0.65	7:102433755:G:A
Thyroid	eqtl	5.4e-17	+0.17	7:102436115:G:A
Nerve Tibial	eqtl	4.6e-16	+0.21	7:102383801:T:A
Lung	sqtl	1.8e-15	-0.58	7:102367603:G:A
Brain Cerebellum	eqtl	1.1e-12	+0.52	7:102408944:CGAGTG:C
Adipose Subcutaneous	eqtl	1.7e-12	+0.19	7:102337534:T:C
Spleen	sqtl	2.3e-12	+0.71	7:102436115:G:A
Skin Sun Exposed Lower leg	eqtl	5.7e-12	+0.19	7:102344501:G:A
Adipose Visceral Omentum	sqtl	7.0e-12	+0.44	7:102436115:G:A
Brain Cerebellum	sqtl	2.7e-11	-0.71	7:102367603:G:A
Brain Cerebellar Hemisphere	eqtl	8.1e-11	+0.54	7:102408944:CGAGTG:C
Brain Cortex	sqtl	6.8e-10	-0.69	7:102436115:G:A

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
80255	10.1658	1742

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
renal medulla	UBERON:0000362	97.91	gold quality
ventral tegmental area	UBERON:0002691	97.18	gold quality
pylorus	UBERON:0001166	96.92	gold quality
superior vestibular nucleus	UBERON:0007227	96.53	gold quality
nipple	UBERON:0002030	96.30	gold quality
inferior vagus X ganglion	UBERON:0005363	96.09	gold quality
superior surface of tongue	UBERON:0007371	95.88	gold quality
trigeminal ganglion	UBERON:0001675	95.55	gold quality
pericardium	UBERON:0002407	95.18	gold quality
subthalamic nucleus	UBERON:0001906	95.09	gold quality
cardia of stomach	UBERON:0001162	94.94	gold quality
buccal mucosa cell	CL:0002336	94.55	gold quality
endothelial cell	CL:0000115	93.91	gold quality
lateral globus pallidus	UBERON:0002476	93.28	gold quality
stromal cell of endometrium	CL:0002255	93.09	gold quality
dorsal root ganglion	UBERON:0000044	92.99	gold quality
blood	UBERON:0000178	92.91	gold quality
substantia nigra pars compacta	UBERON:0001965	92.79	gold quality
dorsal plus ventral thalamus	UBERON:0001897	92.63	gold quality
saphenous vein	UBERON:0007318	92.59	gold quality
pons	UBERON:0000988	92.50	gold quality
pharyngeal mucosa	UBERON:0000355	92.49	gold quality
substantia nigra pars reticulata	UBERON:0001966	92.31	gold quality
lateral nuclear group of thalamus	UBERON:0002736	92.19	gold quality
caecum	UBERON:0001153	90.91	gold quality
medulla oblongata	UBERON:0001896	90.83	gold quality
skin of hip	UBERON:0001554	90.69	gold quality
sperm	CL:0000019	89.98	gold quality
urethra	UBERON:0000057	89.74	gold quality
tongue	UBERON:0001723	89.57	gold quality
lymph node	UBERON:0000029	89.53	gold quality
pituitary gland	UBERON:0000007	89.51	gold quality
trachea	UBERON:0003126	89.46	gold quality
monocyte	CL:0000576	89.36	gold quality
bone marrow cell	CL:0002092	89.23	gold quality
mononuclear cell	CL:0000842	89.20	gold quality
leukocyte	CL:0000738	89.16	gold quality
vermiform appendix	UBERON:0001154	89.05	gold quality
adenohypophysis	UBERON:0002196	88.96	gold quality
body of tongue	UBERON:0011876	88.52	gold quality
vena cava	UBERON:0004087	88.42	gold quality
epithelium of nasopharynx	UBERON:0001951	88.22	gold quality
synovial joint	UBERON:0002217	87.79	gold quality
visceral pleura	UBERON:0002401	87.49	gold quality
bone marrow	UBERON:0002371	87.44	gold quality
granulocyte	CL:0000094	87.34	gold quality
cerebellar vermis	UBERON:0004720	86.85	gold quality
male germ cell	CL:0000015	86.56	gold quality
penis	UBERON:0000989	86.33	gold quality
bronchial epithelial cell	CL:0002328	85.94	gold quality
upper leg skin	UBERON:0004262	85.92	gold quality
nucleus accumbens	UBERON:0001882	85.85	gold quality
trabecular bone tissue	UBERON:0002483	85.79	gold quality
spleen	UBERON:0002106	85.68	gold quality
prefrontal cortex	UBERON:0000451	85.12	gold quality
hypothalamus	UBERON:0001898	84.85	gold quality
pleura	UBERON:0000977	84.47	gold quality
temporal lobe	UBERON:0001871	84.38	gold quality
mammalian vulva	UBERON:0000997	84.28	gold quality
amygdala	UBERON:0001876	84.25	gold quality
parietal pleura	UBERON:0002400	84.00	gold quality
parietal lobe	UBERON:0001872	83.98	gold quality
cerebellar cortex	UBERON:0002129	83.88	gold quality
entorhinal cortex	UBERON:0002728	83.80	gold quality
cerebellum	UBERON:0002037	83.78	gold quality
cerebellar hemisphere	UBERON:0002245	83.77	gold quality
right hemisphere of cerebellum	UBERON:0014890	83.58	gold quality
occipital lobe	UBERON:0002021	83.56	gold quality
Ammon’s horn	UBERON:0001954	83.51	gold quality
forebrain	UBERON:0001890	83.41	gold quality
brain	UBERON:0000955	83.19	gold quality
central nervous system	UBERON:0001017	82.98	gold quality
bronchus	UBERON:0002185	82.90	gold quality
frontal cortex	UBERON:0001870	82.84	gold quality
telencephalon	UBERON:0001893	82.66	gold quality
caudate nucleus	UBERON:0001873	82.49	gold quality
neocortex	UBERON:0001950	82.49	gold quality
epithelium of bronchus	UBERON:0002031	82.39	gold quality
cerebral cortex	UBERON:0000956	82.27	gold quality
tonsil	UBERON:0002372	82.24	gold quality
putamen	UBERON:0001874	82.22	gold quality
right frontal lobe	UBERON:0002810	81.94	gold quality
lower lobe of lung	UBERON:0008949	81.73	gold quality
superior frontal gyrus	UBERON:0002661	81.65	gold quality
cingulate cortex	UBERON:0003027	81.63	gold quality
postcentral gyrus	UBERON:0002581	81.43	gold quality
islet of Langerhans	UBERON:0000006	81.40	gold quality
anterior cingulate cortex	UBERON:0009835	81.39	gold quality
midbrain	UBERON:0001891	81.31	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	81.18	gold quality
gall bladder	UBERON:0002110	81.10	gold quality
cortical plate	UBERON:0005343	81.00	gold quality
adrenal cortex	UBERON:0001235	80.97	gold quality
tibia	UBERON:0000979	80.94	gold quality
primary visual cortex	UBERON:0002436	80.77	gold quality
ventricular zone	UBERON:0003053	80.66	gold quality
metanephros cortex	UBERON:0010533	80.41	gold quality
oral cavity	UBERON:0000167	80.38	gold quality
left adrenal gland cortex	UBERON:0035825	80.38	gold quality
right lobe of thyroid gland	UBERON:0001119	80.13	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.73
E-MTAB-7381	no	180.82

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Cerebral cortex	tissue	56.7	low
Somatosensory cortex	tissue	56.7
Occipital cortex	tissue	47.8
Caudate putamen	tissue	45.9
Motor cortex	tissue	41.7
Temporal cortex	tissue	41.0
Hippocampal formation	tissue	40.8
Entorhinal cortex	tissue	40.8
Frontal cortex	tissue	39.8
Prefrontal cortex	tissue	39.6
Thalamus	tissue	39.0
Retrosplenial and cingulate cortex	tissue	35.3
Superior colliculi	tissue	34.9
Insular cortex	tissue	34.7
Putamen	tissue	34.0
Basal ganglia	tissue	31.5	low
Midbrain	tissue	30.6
Retrosplenial cortex	tissue	30.3
Cerebellum	tissue	29.6	medium
Pons	tissue	29.1
Locus coeruleus	tissue	28.9
Choroid plexus	tissue	28.2
Hippocampus	tissue	27.0	not detected
Ventral forebrain	tissue	27.0
Septum	tissue	26.4
Amygdala	tissue	23.8
Hypothalamus	tissue	22.6
Medulla oblongata	tissue	22.4
Periaqueductal gray	tissue	22.4
Postcentral gyrus	tissue	21.1
Nucleus accumbens	tissue	20.8
Substantia nigra	tissue	17.8
Spinal cord	tissue	17.2
Olfactory bulb	tissue	16.1
Bone marrow	tissue	15.0	not detected
Pituitary gland	tissue	14.4
Parathyroid gland	tissue	11.9	medium
Corpus callosum	tissue	11.1
Appendix	tissue	11.0	medium
Lymph node	tissue	10.2	low
Spleen	tissue	9.1	low
Tonsil	tissue	8.6	low
Thyroid gland	tissue	4.3	medium
Stomach 1	tissue	3.9	medium
Thymus	tissue	3.9
Epididymis	tissue	3.6	low
Seminal vesicle	tissue	3.4	low
Adrenal gland	tissue	3.2	high
Fallopian tube	tissue	3.1	medium
Adipose tissue	tissue	2.8	not detected
Urinary bladder	tissue	2.8	medium
Small intestine	tissue	2.8	medium
Gallbladder	tissue	2.8	medium
Lung	tissue	2.7	high
Salivary gland	tissue	2.6	medium
Colon	tissue	2.5	medium
Pancreas	tissue	2.4	medium
Endometrium 1	tissue	2.4	medium
Duodenum	tissue	2.4	medium
Kidney	tissue	2.3	medium

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Dorsal hippocampus (40.1), Ventral hippocampus (32.7), Hippocampus, CA1 (31.3), Flocculonodular lobe (30.8), Habenula (30.3).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting ORAI2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 326 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-7162-3P	99.89	68.16	1682

Functional genomics

gnomAD constraint: pLI 0.00825, LOEUF 1.03, missense Z 2.37 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000495936 splits into 3 regions with different missense tolerance; 1 is missense-constrained (≈5% 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
7:102,438,957–102,439,111	61 / 72.7	0.84	no
7:102,439,112–102,439,156	1 / 16.9	0.06	yes (p 1.1e-04)
7:102,439,157–102,447,049	176 / 265.9	0.66	no

Literature-anchored findings (GeneRIF, showing 18)

• Results suggest that Orai1, -2, and -3 channels are similarly inhibited by extracellular calcium, indicating similar affinities for Ca(2+) within the selectivity filter. (PMID:17452328)
• The effects of 2-aminoethoxydiphenyl borate on orai1, orai2, orai3 metabolism in HEK293 cells with and without STIM1 are reported. (PMID:18403424)
• analysis of activation of Orai1-3 channels by a STIM1 coiled-coil mutant (PMID:19506081)
• Data show that the fast Ca(2+)-dependent inactivation is mediated by three conserved glutamates in the C termini (CT) of Orai2 and Orai3, which show prominent fast Ca(2+)-dependent inactivation compared with Orai1. (PMID:19706554)
• With these data we show a new Ca(2)(+) entry pathway linked to the Ca(2)(+)/inositolphosphate second-messenger system in RPE cells which help to further understand regulatory pathways of agonists. (PMID:20607548)
• Orai1 and Orai2 operate in a STIM-dependent manner, Orai3 does not interact with STIM isoforms upon calcium store depletion in platelets. (PMID:22640869)
• Orai1 but not Orai2 plays a major role in the influx of extracellular Ca2+ into and mediator release from HLMCs following their activation (PMID:24040356)
• The higher amplitude of store-operated Ca2+ entry was associated to the over-expression for Stim2, Orai2-3, and TRPC1 while Stim2 levels remained constant and Stim1, Orai1, Orai3, TRPC1 and TRPC4 proteins were over-expressed in primary myelofibrosis. (PMID:24603752)
• Orai1, Orai2 and STIM1 form functional Ca(2+) release-activated Ca(2+) channels in OUMS-27 cells (chondrocytes) and that these complexes are responsible for sustained Ca(2+) entry in response to agonist stimulation. (PMID:25769459)
• results identified the ORAI-NOX2 feedback loop as a determinant of monocyte immune responses. (PMID:26956485)
• findings provide evidence for a role for Orai1 and Orai2, in SOCE and migration in the human HL60 promyeloblastic cell line (PMID:27865925)
• ORAI1-3, are preferentially expressed in proximal tubular epithelial cells and downregulated in patients with diabetic nephropathy. (PMID:29203863)
• Higher expression of Orai2 was independently associated with a worse prognosis of patients with the classical and mesenchymal subtypes of glioblastoma.A strong association between Orai2 expression and apoptosis, stemness, and an epithelial-mesenchymal transition in the glioblastoma. (PMID:31772693)
• ORAI2 Down-Regulation Potentiates SOCE and Decreases Abeta42 Accumulation in Human Neuroglioma Cells. (PMID:32722509)
• Orai-1 and Orai-2 regulate oral cancer cell migration and colonisation by suppressing Akt/mTOR/NF-kappaB signalling. (PMID:32882268)
• Distinct pharmacological profiles of ORAI1, ORAI2, and ORAI3 channels. (PMID:32896813)
• ORAI2 Promotes Gastric Cancer Tumorigenicity and Metastasis through PI3K/Akt Signaling and MAPK-Dependent Focal Adhesion Disassembly. (PMID:33310726)
• Atlas of RNA editing events affecting protein expression in aged and Alzheimer’s disease human brain tissue. (PMID:34857756)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	orai2	ENSDARG00000035148
mus_musculus	Orai2	ENSMUSG00000039747
rattus_norvegicus	Orai2	ENSRNOG00000001427
drosophila_melanogaster	Orai	FBGN0041585
caenorhabditis_elegans		WBGENE00015648

Paralogs (2): ORAI3 (ENSG00000175938), ORAI1 (ENSG00000276045)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2443195) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 5 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal mast cell physiology	1
abnormal T cell physiology	1
abnormal macrophage physiology	1
increased susceptibility to type I hypersensitivity reaction	1
increased mast cell degranulation	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
Gallus gallus	Q5ZLW2	89.1%	Diamond
Xenopus laevis	Q6NZI6	88.4%	Diamond
Caenorhabditis briggsae	Q616J1	86.8%	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
MIR548O	ncRNA	100313829
ALKBH4	protein-coding	54784
SPDYE6	protein-coding	729597
PRKRIP1	protein-coding	79706
MIR5090	ncRNA	100847073
LRWD1	protein-coding	222229
RASA4B	protein-coding	100271927
POLR2J	protein-coding	5439
MIR4467	ncRNA	100616367
UPK3BL2	protein-coding	107983993
POLR2J3-UPK3BL2	ncRNA	123258399

Protein

Protein identifiers

Protein orai-2 — Q96SN7 (reviewed: Q96SN7)

Alternative names: CAP-binding protein complex-interacting protein 2, Transmembrane protein 142B

All UniProt accessions (3): C9JQR7, C9JUY6, Q96SN7

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming subunit of inward rectifying Ca(2+) release-activated Ca(2+) (CRAC) channels. Assembles with ORAI1 and ORAI3 to form hexameric CRAC channels that mediate Ca(2+) influx upon depletion of endoplasmic reticulum Ca(2+) store and channel activation by Ca(2+) sensor STIM1, a process known as store-operated Ca(2+) entry (SOCE). Various pore subunit combinations may account for distinct CRAC channel spatiotemporal and cell-type specific dynamics. ORAI1 mainly contributes to the generation of Ca(2+) plateaus involved in sustained Ca(2+) entry and is dispensable for cytosolic Ca(2+) oscillations, whereas ORAI2 and ORAI3 generate oscillatory patterns. CRAC channels assemble in Ca(2+) signaling microdomains where Ca(2+) influx is coupled to calmodulin and calcineurin signaling and activation of NFAT transcription factors recruited to ORAI1 via AKAP5. CRAC channels are the main pathway for Ca(2+) influx in T cells and promote the immune response to pathogens by activating NFAT-dependent cytokine and chemokine transcription.

Subunit / interactions. Oligomerizes in homomeric and heteromeric ORAI complexes. Native CRAC channels most likely consist of hexameric ORAI heteromers, implying that diverse ORAI1, ORAI2 and ORAI3 subunit combinations with distinct biophysical properties can operate in a cell-type specific way. Interacts with STIM1; this regulates channel activity. Interacts with CRACR2A/EFCAB4B.

Subcellular location. Cell membrane.

Activity regulation. CRAC channels are regulated by fast Ca(2+)-dependent inactivation (FCDI), a mechanism that limits Ca(2+) influx and cell toxicity. ORAI2 channels display prominent FCDI. Inhibited by lanthanides such as Gd(3+) ions.

Similarity. Belongs to the Orai family.

RefSeq proteins (4): NP_001119812, NP_001258747, NP_001258748, NP_116220 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012446	CRAC_channel	Family
IPR038350	Orai_sf	Homologous_superfamily

Pfam: PF07856

Catalyzed reactions (Rhea)

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

UniProt features (11 total): transmembrane region 4, mutagenesis site 4, chain 1, site 1, sequence variant 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96SN7-F1	80.59	0.33

Human Protein Atlas

Protein class: Predicted membrane proteins, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): mitochondria; nucleoplasm; cytosol

Antibody reliability (HPA): IH uncertain · IF supported

Functional residue map

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

Catalytic / active sites (1)

Position	Role
80	confers selective permeability to ca(2+) ions

Mutagenesis-validated functional residues (4)

Position	Phenotype
236	reduces fast ca(2+)-dependent inactivation; when associated with a-233 and a-235.
80	has dominant negative effect. impairs store-operated ca(2+) influx. decreases regenerative ca(2+) oscillations.
233	reduces fast ca(2+)-dependent inactivation; when associated with a-235 and a-236.
235	reduces fast ca(2+)-dependent inactivation; when associated with a-233 and a-236.

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 11; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

11 pathways:

ID	Pathway	Evidence
R-HSA-1280218	Adaptive Immune System	—
R-HSA-983695	Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	electronic
R-HSA-5576891	Cardiac conduction	—
R-HSA-139853	Elevation of cytosolic Ca2+ levels	electronic
R-HSA-109582	Hemostasis	—
R-HSA-168256	Immune System	—
R-HSA-5578775	Ion homeostasis	electronic
R-HSA-397014	Muscle contraction	—
R-HSA-418360	Platelet calcium homeostasis	—
R-HSA-418346	Platelet homeostasis	—
R-HSA-983705	Signaling by the B Cell Receptor (BCR)	—

MSigDB gene sets: 229 (showing top): REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_MONOATOMIC_CATION_TRANSPORT, FOSTER_TOLERANT_MACROPHAGE_DN, USF_01, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, LIAO_METASTASIS, RYTTCCTG_ETS2_B, GOBP_CALCIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_TRANSMEMBRANE_TRANSPORT, SCHLOSSER_SERUM_RESPONSE_UP, SENESE_HDAC3_TARGETS_DN, TGGAAA_NFAT_Q4_01, MARSON_BOUND_BY_FOXP3_STIMULATED, MARSON_BOUND_BY_FOXP3_UNSTIMULATED, GOMF_METAL_ION_TRANSMEMBRANE_TRANSPORTER_ACTIVITY

GO Biological Process (5): store-operated calcium entry (GO:0002115), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), monoatomic ion transmembrane transport (GO:0034220), calcium ion transmembrane transport (GO:0070588)

GO Molecular Function (3): store-operated calcium channel activity (GO:0015279), calcium channel activity (GO:0005262), protein binding (GO:0005515)

GO Cellular Component (5): nucleoplasm (GO:0005654), mitochondrion (GO:0005739), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

8 top-level categories:

Category	Pathways
Platelet calcium homeostasis	1
Cardiac conduction	1
Signaling by the B Cell Receptor (BCR)	1
Immune System	1
Hemostasis	1
Platelet homeostasis	1
Muscle contraction	1
Adaptive Immune System	1

GO top-level categories

16 GO namespaces:

Category	Terms
cellular anatomical structure	3
calcium ion transport	2
cytoplasm	2
transport	1
metal ion transport	1
monoatomic ion transport	1
transmembrane transport	1
monoatomic cation transmembrane transport	1
calcium channel activity	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
binding	1
nuclear lumen	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 6 of 13 annotations. The rest are phylogenetic / computational / electronic (IEA).

6 experimentally-supported GO terms:

GO term	NS	Evidence
store-operated calcium entry	BP	direct assay
cytosol	CC	direct assay
mitochondrion	CC	direct assay
nucleoplasm	CC	direct assay
plasma membrane	CC	direct assay
store-operated calcium channel activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 436 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ORAI2	STIM1	Q13586	982
ORAI2	STIM2	Q9P246	975
ORAI2	TRPC1	P48995	892
ORAI2	TRPC3	Q13507	847
ORAI2	TRPC6	Q9Y210	811
ORAI2	TRPC4	Q9UBN4	811
ORAI2	TRPC5	Q9UL62	753
ORAI2	TRPM2	O94759	637
ORAI2	CACNA1C	Q13936	635
ORAI2	ITPR1	Q14643	622
ORAI2	ITPR3	Q14573	622
ORAI2	ORAI3	Q9BRQ5	607
ORAI2	SARAF	Q96BY9	606
ORAI2	FKBP1A	P20071	563
ORAI2	FKBP2	P26885	549

IntAct

Human interaction partners of ORAI2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

8 partners by confidence:

Partner	Interaction type	MIscore	Records
CRACR2A	physical association	0.400	1
STIM1	physical association	0.400	1
TRPC3	physical association	0.400	1
COPS6	physical association	0.000	1
GDF9	physical association	0.000	1
MED31	physical association	0.000	1
SETDB1	physical association	0.000	1
UNC119	physical association	0.000	1

BioGRID (8 interactions; top human partners by supporting records): COPS6 (Two-hybrid), GDF9 (Two-hybrid), KIAA1429 (Affinity Capture-RNA), MED31 (Two-hybrid), SETDB1 (Two-hybrid), SLC19A2 (Affinity Capture-MS), TRIM71 (Affinity Capture-RNA), UNC119 (Two-hybrid)

Disease & clinical

Genetic variants

Variant evidence for ORAI2: 57 ClinVar records (0 pathogenic / likely pathogenic); 3 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	36
Likely benign	1
Benign	1

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 28 predictions of 565):

Position(s)	Effect	Δscore	Sites
7:102433662–102433663	donor_loss	0.9900	5
7:102438942–102438943	acceptor_loss	0.9900	6
7:102439182–102439183	donor_loss	0.9900	5
7:102441786	donor_gain	0.9900
7:102446511–102446512	acceptor_loss	0.9900	6
7:102441883	donor_gain	0.9800
7:102434956	donor_gain	0.9700
7:102441687	acceptor_gain	0.9600
7:102447026	donor_gain	0.9600
7:102438937	acceptor_loss	0.9500

AlphaMissense

950 missense substitutions predicted likely pathogenic (of 1,476 scored), across 183 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
M75	9	0.971	1.000
M78	9	0.916	0.999
M204	9	0.855	0.998
F73	8	0.998	1.000
H108	8	0.997	0.999
F161	8	0.997	1.000
F214	8	0.991	0.999
S115	8	0.988	1.000
F218	8	0.987	0.999
F97	8	0.986	0.999
H139	8	0.986	0.996
F173	8	0.982	0.999
F211	8	0.981	0.995
F110	8	0.957	0.977
S64	8	0.955	0.999
H225	8	0.952	0.993
S56	8	0.951	0.996
H129	8	0.950	0.987
F152	8	0.942	0.994
S126	8	0.924	0.999

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
Bladder Urothelial Carcinoma (TCGA)	favorable	0.000725

Disease associations

OMIM: gene MIM:610929 | disease phenotypes:

GWAS associations

3 associations:

Study	Trait	p-value
GCST003837_4	Chronotype	8e-15
GCST007576_384	Chronotype	1e-12
GCST003838_11	Morning vs. evening chronotype	7e-7

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0008328	chronotype measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3038476 (PROTEIN FAMILY), CHEMBL4888450 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 268 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

1 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL4753998	ZEGOCRACTIN	2	268

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: other ic — Orai channels

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

Ligand	Action	Affinity	Parameter
zegocractin	Inhibition	6.05	pIC50
GSK-7975A	Inhibition	5.84	pIC50

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL4753998	IC50	119 nM

ChEMBL bioactivities

36 potent at pChembl≥5 of 65 total, top 36 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.05	IC50	895	nM	ZEGOCRACTIN
5.80	IC50	1600	nM	CHEMBL2386009
5.68	IC50	2100	nM	CHEMBL2386172
5.66	IC50	2200	nM	CHEMBL2386000
5.62	IC50	2400	nM	CHEMBL2386180
5.57	IC50	2700	nM	CHEMBL2386179
5.55	IC50	2800	nM	CHEMBL2386186
5.50	IC50	3200	nM	CHEMBL2386172
5.47	IC50	3400	nM	CHEMBL2386185
5.46	IC50	3500	nM	CHEMBL2386180
5.31	IC50	4900	nM	CHEMBL2386185
5.29	IC50	5100	nM	CHEMBL2385996
5.23	IC50	5900	nM	CHEMBL2386174
5.22	IC50	6000	nM	CHEMBL2386000
5.19	IC50	6400	nM	CHEMBL2386184
5.16	IC50	6900	nM	CHEMBL2386005
5.14	IC50	7200	nM	CHEMBL2386186
5.13	IC50	7400	nM	CHEMBL2386009
5.12	IC50	7600	nM	CHEMBL2386171
5.11	IC50	7700	nM	CHEMBL2386181
5.10	IC50	7900	nM	CHEMBL2385999
5.10	IC50	8000	nM	CHEMBL2385998
5.09	IC50	8200	nM	CHEMBL2385999
5.07	IC50	8600	nM	CHEMBL2386179
5.06	IC50	8700	nM	DIPHENYL BORINIC ACID
5.05	IC50	9000	nM	CHEMBL2386174
5.05	IC50	8900	nM	CHEMBL2385997
5.05	IC50	8900	nM	CHEMBL2385996
5.03	IC50	9300	nM	CHEMBL2386177
5.02	IC50	9500	nM	CHEMBL2386171
5.01	IC50	9800	nM	CHEMBL2386177
5.01	IC50	9800	nM	CHEMBL2386004
5.01	IC50	9800	nM	DIPHENYL BORINIC ACID
5.00	IC50	9900	nM	CHEMBL2386178
5.00	IC50	1.01e+04	nM	CHEMBL2385998
5.00	IC50	1e+04	nM	CHEMBL2386178

PubChem BioAssay actives

35 with measured affinity, of 83 total; 21 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
N-[5-(6-chloro-2,2-difluoro-1,3-benzodioxol-5-yl)pyrazin-2-yl]-2-fluoro-6-methylbenzamide	1774821: Inhibition of Orai2/STIM1 (unknown origin)	ic50	0.8950	uM
2,2-bis(4-methylphenyl)-1-oxa-3-azonia-2-boranuidacyclopentane	749403: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Ca2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	1.6000	uM
2,2-bis[4-(trifluoromethyl)phenyl]-1-oxa-3-azonia-2-boranuidacyclopentane	749403: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Ca2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	2.1000	uM
1,1-diphenyl-2-oxa-8-aza-5-azonia-1-boranuidaspiro[4.5]decane	749402: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Cd2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	2.2000	uM
2-(4-butylphenyl)-2-phenyl-1-oxa-3-azonia-2-boranuidacyclopentane	749402: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Cd2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	2.4000	uM
2-(4-methylphenyl)-2-phenyl-1-oxa-3-azonia-2-boranuidacyclopentane	749402: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Cd2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	2.7000	uM
2-(4-iodophenyl)-2-phenyl-1-oxa-3-azonia-2-boranuidacyclopentane	749403: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Ca2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	2.8000	uM
2-(4-bromophenyl)-2-phenyl-1-oxa-3-azonia-2-boranuidacyclopentane	749403: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Ca2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	3.4000	uM
3,3-dimethyl-2,2-diphenyl-1-oxa-3-azonia-2-boranuidacyclopentane	749402: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Cd2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	5.1000	uM
2,2-bis(4-fluorophenyl)-1-oxa-3-azonia-2-boranuidacyclopentane	749402: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Cd2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	5.9000	uM
(4-chlorophenyl)-phenylborinic acid	749402: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Cd2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	6.4000	uM
(4S)-4-(1H-indol-3-ylmethyl)-2,2-diphenyl-1-oxa-3-azonia-2-boranuidacyclopentan-5-one	749403: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Ca2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	6.9000	uM
bis[4-(trifluoromethyl)phenyl]borinic acid	749403: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Ca2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	7.6000	uM
2-phenyl-2-(4-phenylphenyl)-1-oxa-3-azonia-2-boranuidacyclopentane	749402: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Cd2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	7.7000	uM
2,2-diphenyl-1-oxa-3-azonia-2-boranuidacyclohexane	749403: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Ca2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	7.9000	uM
(5R)-2,2-diphenyl-3-oxa-1-azonia-2-boranuidabicyclo[3.3.0]octane	749403: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Ca2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	8.0000	uM
diphenylborinic acid	749402: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Cd2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	8.7000	uM
(5S)-2,2-diphenyl-3-oxa-1-azonia-2-boranuidabicyclo[3.3.0]octane	749403: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Ca2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	8.9000	uM
2-(4-fluorophenyl)-2-phenyl-1-oxa-3-azonia-2-boranuidacyclopentane	749403: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Ca2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	9.3000	uM
(4S)-4-(hydroxymethyl)-2,2-diphenyl-1-oxa-3-azonia-2-boranuidacyclopentan-5-one	749402: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Cd2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	9.8000	uM
2-(2-methylphenyl)-2-phenyl-1-oxa-3-azonia-2-boranuidacyclopentane	749402: Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Cd2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	ic50	9.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	increases expression, affects cotreatment, decreases expression	3
Air Pollutants	affects expression, increases abundance, increases expression	2
Arsenic	increases abundance, affects methylation, affects cotreatment, decreases expression	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Estradiol	affects cotreatment, increases expression	2
Nickel	increases expression	2
Smoke	increases expression, decreases expression, increases abundance	2
Valproic Acid	increases expression, increases methylation	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
sodium arsenite	increases abundance, affects cotreatment, decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Bortezomib	decreases expression	1
Sunitinib	decreases expression	1
Benzene	increases expression	1
Doxorubicin	decreases expression	1
Lead	decreases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Methyl Methanesulfonate	decreases expression	1
Ozone	affects expression, increases abundance	1
Plant Oils	decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2388390	Binding	Inhibition of ORAl1/2/3 in HEK293 cells assessed as inhibition of Ca2+ influx after 10 mins by FLIPR assay in presence of thapsigargin	Design, synthesis and pharmacological characterization of analogs of 2-aminoethyl diphenylborinate (2-APB), a known store-operated calcium channel blocker, for inhibition of TRPV6-mediated calcium transport. — *Bioorg Med Chem*

Clinical trials (associated diseases)

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

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for ORAI2 across ~30M SureChEMBL compounds — explore on Sugi Predict.