ORAI3

Summary

ORAI3 (ORAI calcium release-activated calcium modulator 3, HGNC:28185) is a protein-coding gene on chromosome 16p11.2, encoding Protein orai-3 (Q9BRQ5). Pore-forming subunit of two major inward rectifying Ca(2+) channels at the plasma membrane: Ca(2+) release-activated Ca(2+) (CRAC) channels and arachidonate-regulated Ca(2+)-selective (ARC) channels.

Enables store-operated calcium channel activity. Involved in store-operated calcium entry. Located in plasma membrane.

Source: NCBI Gene 93129 — automated summary from GO annotations (Alliance of Genome Resources).

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 48 total — 1 likely-pathogenic
• GTEx eGene: eQTL in 9 tissues, sQTL in 1 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.57 (unconstrained)
• MANE Select transcript: NM_152288

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28185
Approved symbol	ORAI3
Name	ORAI calcium release-activated calcium modulator 3
Location	16p11.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC13024
Ensembl gene	ENSG00000175938
Ensembl biotype	protein_coding
OMIM	610930
Entrez	93129

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 8 protein_coding, 1 nonsense_mediated_decay

MANE Select: ENST00000318663

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 1, TSL 3: 1, TSL 5: 1

ENST00000318663, ENST00000562699, ENST00000563161, ENST00000566237, ENST00001101371, ENST00001119724, ENST00001119725, ENST00001122034, ENST00001134313

RefSeq mRNA: 1 — MANE Select: NM_152288 NM_152288

CCDS: CCDS10697

Canonical transcript exons

ENST00000318663 — 2 exons

Exon	Start	End
ENSE00001239145	30953185	30954938
ENSE00001845367	30949068	30949517

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 92.80.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.0449 / max 178.4977, expressed in 1798 samples.

Highest expression (Bgee): lobe of liver, adrenal gland cortex, adrenal gland, liver, blood.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ORAI3 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 9 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

10 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Skin Sun Exposed Lower leg	eqtl	5.3e-04	-0.54	16:31344696:A:G
Artery Aorta	eqtl	4.8e-03	-0.48	16:30535243:C:T
Adipose Visceral Omentum	eqtl	7.5e-03	-0.10	16:31216587:C:T
Cells EBV-transformed lymphocytes	eqtl	1.3e-02	-0.31	16:31151103:T:G
Nerve Tibial	eqtl	1.4e-02	+0.27	16:31392266:G:T
Muscle Skeletal	eqtl	1.9e-02	+0.48	16:30663610:G:A
Brain Frontal Cortex BA9	eqtl	3.9e-02	-0.63	16:30184593:T:C
Cells Cultured fibroblasts	eqtl	4.1e-02	+0.07	16:30908486:C:T
Adrenal Gland	eqtl	4.4e-02	-0.36	16:30452070:AT:A
Muscle Skeletal	sqtl	4.6e-02	+1.07	16:31453922:A:G

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
153744	21.5691	1798
207840	0.4758	288

Top tissues by expression

showing 100 of 134 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	92.80	gold quality
right adrenal gland cortex	UBERON:0035827	91.80	gold quality
right adrenal gland	UBERON:0001233	91.40	gold quality
left adrenal gland	UBERON:0001234	90.04	gold quality
left adrenal gland cortex	UBERON:0035825	89.94	gold quality
liver	UBERON:0002107	89.84	gold quality
blood	UBERON:0000178	89.22	gold quality
mucosa of stomach	UBERON:0001199	88.83	gold quality
leukocyte	CL:0000738	88.71	gold quality
monocyte	CL:0000576	88.69	gold quality
granulocyte	CL:0000094	88.41	gold quality
adrenal gland	UBERON:0002369	88.38	gold quality
endocervix	UBERON:0000458	87.65	gold quality
lower esophagus muscularis layer	UBERON:0035833	87.23	gold quality
lower esophagus	UBERON:0013473	87.18	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	87.15	gold quality
prostate gland	UBERON:0002367	87.02	gold quality
urinary bladder	UBERON:0001255	86.94	gold quality
fundus of stomach	UBERON:0001160	86.93	gold quality
apex of heart	UBERON:0002098	86.77	gold quality
muscle layer of sigmoid colon	UBERON:0035805	86.46	gold quality
stromal cell of endometrium	CL:0002255	86.45	gold quality
ectocervix	UBERON:0012249	86.40	gold quality
right coronary artery	UBERON:0001625	85.86	gold quality
right ovary	UBERON:0002118	85.64	gold quality
spleen	UBERON:0002106	85.61	gold quality
uterine cervix	UBERON:0000002	85.14	gold quality
placenta	UBERON:0001987	85.08	gold quality
vagina	UBERON:0000996	85.05	gold quality
right uterine tube	UBERON:0001302	84.90	gold quality
adenohypophysis	UBERON:0002196	84.70	gold quality
body of uterus	UBERON:0009853	84.57	gold quality
myometrium	UBERON:0001296	84.49	gold quality
descending thoracic aorta	UBERON:0002345	84.49	gold quality
fallopian tube	UBERON:0003889	84.40	gold quality
adult mammalian kidney	UBERON:0000082	84.39	gold quality
esophagus	UBERON:0001043	84.34	gold quality
left uterine tube	UBERON:0001303	84.26	gold quality
pituitary gland	UBERON:0000007	84.24	gold quality
ovary	UBERON:0000992	84.09	gold quality
left ovary	UBERON:0002119	84.03	gold quality
cortex of kidney	UBERON:0001225	83.91	gold quality
body of pancreas	UBERON:0001150	83.68	gold quality
bone marrow cell	CL:0002092	83.64	gold quality
subcutaneous adipose tissue	UBERON:0002190	83.60	gold quality
omental fat pad	UBERON:0010414	83.60	gold quality
right lobe of thyroid gland	UBERON:0001119	83.59	gold quality
adipose tissue	UBERON:0001013	83.53	gold quality
body of stomach	UBERON:0001161	83.51	gold quality
left coronary artery	UBERON:0001626	83.48	gold quality
thoracic aorta	UBERON:0001515	83.33	gold quality
ascending aorta	UBERON:0001496	83.31	gold quality
metanephros cortex	UBERON:0010533	83.30	gold quality
right lung	UBERON:0002167	83.29	gold quality
colon	UBERON:0001155	83.21	gold quality
popliteal artery	UBERON:0002250	83.21	gold quality
tibial artery	UBERON:0007610	83.19	gold quality
left lobe of thyroid gland	UBERON:0001120	83.07	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.97	gold quality
heart left ventricle	UBERON:0002084	82.81	gold quality
thyroid gland	UBERON:0002046	82.68	gold quality
tibial nerve	UBERON:0001323	82.53	gold quality
adrenal tissue	UBERON:0018303	82.51	gold quality
intestine	UBERON:0000160	82.40	gold quality
small intestine Peyer’s patch	UBERON:0003454	82.38	gold quality
stomach	UBERON:0000945	82.22	gold quality
esophagus mucosa	UBERON:0002469	82.16	gold quality
right atrium auricular region	UBERON:0006631	82.15	gold quality
kidney	UBERON:0002113	82.11	gold quality
pancreas	UBERON:0001264	82.10	gold quality
heart	UBERON:0000948	82.03	gold quality
minor salivary gland	UBERON:0001830	82.01	gold quality
thoracic mammary gland	UBERON:0005200	82.01	gold quality
saliva-secreting gland	UBERON:0001044	81.99	gold quality
transverse colon	UBERON:0001157	81.91	gold quality
skin of leg	UBERON:0001511	81.85	gold quality
small intestine	UBERON:0002108	81.82	gold quality
multicellular organism	UBERON:0000468	81.75	gold quality
zone of skin	UBERON:0000014	81.69	gold quality
skin of abdomen	UBERON:0001416	81.67	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	81.52	gold quality
bone marrow	UBERON:0002371	81.38	gold quality
mucosa of transverse colon	UBERON:0004991	81.19	gold quality
lymph node	UBERON:0000029	80.76	gold quality
right testis	UBERON:0004534	80.51	gold quality
upper lobe of left lung	UBERON:0008952	80.50	gold quality
smooth muscle tissue	UBERON:0001135	80.24	gold quality
left testis	UBERON:0004533	80.02	gold quality
testis	UBERON:0000473	79.73	gold quality
lower esophagus mucosa	UBERON:0035834	79.70	gold quality
gall bladder	UBERON:0002110	79.30	gold quality
islet of Langerhans	UBERON:0000006	79.17	gold quality
lung	UBERON:0002048	79.13	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.91	gold quality
rectum	UBERON:0001052	77.74	gold quality
gastrocnemius	UBERON:0001388	77.65	gold quality
muscle of leg	UBERON:0001383	77.20	gold quality
duodenum	UBERON:0002114	76.99	gold quality
hindlimb stylopod muscle	UBERON:0004252	76.90	gold quality
amygdala	UBERON:0001876	76.78	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	7.10
E-CURD-112	yes	6.36
E-ANND-3	yes	5.81

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Choroid plexus	tissue	35.9
Liver	tissue	35.8	low
Frontal cortex	tissue	21.2
Vagina	tissue	19.4	medium
Parathyroid gland	tissue	17.7	medium
Pituitary gland	tissue	17.4
Bone marrow	tissue	16.6	high
Adrenal gland	tissue	16.2	high
Ovary	tissue	16.1	medium
Seminal vesicle	tissue	16.1	high
Prostate	tissue	15.8	medium
Epididymis	tissue	15.3	medium
Cervix	tissue	14.7	high
Fallopian tube	tissue	14.7	medium
Placenta	tissue	14.0	high
Locus coeruleus	tissue	13.7
Kidney	tissue	13.6	high
Spleen	tissue	12.7	medium
Hippocampus	tissue	12.7	high
Salivary gland	tissue	11.9	high
Skin 1	tissue	11.8	medium
Pancreas	tissue	11.8	high
Testis	tissue	11.6	high
Nucleus accumbens	tissue	11.5
Thyroid gland	tissue	11.5	high
Caudate putamen	tissue	11.3
Lymph node	tissue	11.1	medium
Heart muscle	tissue	10.9	medium
Urinary bladder	tissue	10.5	high
Spinal cord	tissue	10.5
Thymus	tissue	10.4
Lung	tissue	9.9	high
Tonsil	tissue	9.9	high
Hypothalamus	tissue	9.7
Endometrium 1	tissue	9.6	medium
Superior colliculi	tissue	9.5
Gallbladder	tissue	9.3	high
Substantia nigra	tissue	9.2
Periaqueductal gray	tissue	9.2
Smooth muscle	tissue	9.1	medium
Medulla oblongata	tissue	9.1
Postcentral gyrus	tissue	9.1
Adipose tissue	tissue	8.8	medium
Stomach 1	tissue	8.7	medium
Midbrain	tissue	8.6
Duodenum	tissue	8.6	low
Colon	tissue	8.4	medium
Thalamus	tissue	8.4
Pons	tissue	8.3
Hippocampal formation	tissue	8.2
Rectum	tissue	8.1	medium
Septum	tissue	8.1
Appendix	tissue	7.7	medium
Breast	tissue	7.5	medium
Tongue	tissue	7.5
Amygdala	tissue	7.5
Basal ganglia	tissue	7.4	high
Cerebral cortex	tissue	7.2	high
Small intestine	tissue	7.2	medium
Temporal cortex	tissue	7.2

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Posterior thalamic nucleus (24.6), Pulvinar (23.6), Anterior thalamic nucleus, ventral (23.5), Centromedial thalamic nucleus (23.2), Ventral posterolateral thalamic nucleus (22.9).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting ORAI3 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 47 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-139-5P	99.80	69.50	1399
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-451B	99.55	68.28	1380
HSA-MIR-6733-3P	99.54	67.80	1281
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-8065	99.19	70.38	1289
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-519A-2-5P	98.78	71.74	1401
HSA-MIR-520B-5P	98.78	71.74	1401
HSA-MIR-7851-3P	98.72	64.88	980
HSA-MIR-6887-5P	98.56	68.49	1295
HSA-MIR-6795-5P	98.52	68.51	1277

Functional genomics

gnomAD constraint: pLI 4.48e-06, LOEUF 1.57, missense Z -0.237 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000318663 — one region, missense o/e 1.02.

Literature-anchored findings (GeneRIF, showing 38)

• 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)
• Expression of a dominant-negative mutant Orai3, either alone or in cells expressing wild-type Orai1, profoundly and specifically reduces currents through the ARC channels without affecting those through the CRAC channels. (PMID:17991693)
• The effects of 2-aminoethoxydiphenyl borate on orai1, orai2, orai3 metabolism in HEK293 cells with and without STIM1 are reported. (PMID:18403424)
• analysis of store-dependent and -independent modes regulating Ca2+ release-activated Ca2+ channel activity of human Orai1 and Orai3 (PMID:18420579)
• stimulation of Orai3 currents by 2-aminoethoxydiphenyl borate occurred along with an alteration of the permeation pathway that represents a unique mechanism for regulating ion channel selectivity by chemical compounds (PMID:18499656)
• 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)
• Heteromeric Orai1/3 protein assembly provides a concept for less Ca(2+)-selective store-operated channels. (PMID:19887627)
• differential redox sensitivity of ORAI1 and ORAI3 channels depends mainly on an extracellularly located reactive cysteine, which is absent in ORAI3 (PMID:20354224)
• there is a selective requirement for Orai3 versus Orai1 in estrogen receptor-positive versus estrogen receptor-negative breast cancer cells (PMID:20395295)
• 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)
• Results provide strong evidence for a significant effect of Orai3 on breast cancer cell growth in vitro and show that this effect is associated with the induction of cell cycle and apoptosis resistance. (PMID:20683915)
• the N-terminal conserved region plays a multifaceted role in Orai3 current gating with distinct structural requirements for STIM1- and 2-APB-stimulated activation. (PMID:21724845)
• data establish Orai3 as an ERalpha-regulated channel and a potential selective therapeutic target for ERalpha(+) breast cancers (PMID:22993197)
• High ORAI3 expression is associated with breast cancer. (PMID:23266555)
• Orai3 constitutes a native store-operated calcium entry pathway in non small cell lung adenocarcinoma that controls cell proliferation and cell cycle progression, likely via Akt pathway. (PMID:24058448)
• Orai1 and Orai3 proteins are more important than calcium influx to control cell proliferation. (PMID:24321771)
• 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)
• A channel chimera of Orai3 with the N terminus of Orai1 was able to couple local Ca(2+) entry to NFAT activation, identifying the N-terminal domain of Orai1 as central to Ca(2+) nanodomain-transcription coupling. (PMID:24909327)
• Suggest disrupted dynamic equilibrium of channel-forming ORAI proteins as an oncogenic mechanism in prostate cancer. (PMID:24954132)
• Orai3 down-tunes efficient STIM1 gating when in a heteromeric complex with Orai1. (PMID:25791427)
• Overall high Orai3/Orai1 ratios in human prostate epithelial cells and androgen-insensitive cancer cells contribute to their ROS resistance and thereby may have a share in making the prostate one of the most prominent cancer susceptible organs (PMID:26445441)
• results identified the ORAI-NOX2 feedback loop as a determinant of monocyte immune responses. (PMID:26956485)
• mRNA expression in differentiated keratinocytes increased with increasing age of donors, and the increase corresponded well to slower recovery of [Ca2+]i from hydraulic stress-induced elevation in keratinocytes of older donors (PMID:27571764)
• These data suggest that Orai3 channel does not participate in the thapsigargin-revealed ER Ca(2+) leak but forms an ER Ca(2+) leak channel that is limiting the overloading with Ca(2+) of the ER store. (PMID:28179072)
• ORAI1-3, are preferentially expressed in proximal tubular epithelial cells and downregulated in patients with diabetic nephropathy. (PMID:29203863)
• discovered that it was not the N termini, but the loop2 regions connecting TM2 and TM3 of Orai1 and Orai3 that featured distinct properties, which explained the different, isoform-specific behavior of Orai N-truncation mutants. (PMID:29237733)
• the conserved portion of the Orai N terminus is essential for STIM1, as it fine-tunes the open Orai channel gating, thereby establishing authentic CRAC channel activity. (PMID:29237734)
• Resistance was dependent on external calcium presence and thus Orai3 functionality. This effect allowed a downregulation of the p53 tumor suppressor protein expression via the pro-survival PI3K/Sgk-1/Sek-1 pathway. We demonstrated that p53 degradation occurred not only via Mdm2, but also via another unexpected E3 ubiquitin ligase, Nedd4-2. (PMID:29323264)
• miR18a and miR18b positively regulate Orai3 whereas miR34a represses Orai3 expression and function. (PMID:30216788)
• The differential expression of 55 genes involved in Ca(2+) signaling highlighted that only ORAI3 expression was significantly altered in smokers (regardless of COPD status). ORAI3 is involved in epithelial cell calcium signaling. ORAI3 is additionally involved in ciliary beating. (PMID:30943377)
• Distinct pharmacological profiles of ORAI1, ORAI2, and ORAI3 channels. (PMID:32896813)
• ORAI3 silencing alters cell proliferation and promotes mitotic catastrophe and apoptosis in pancreatic adenocarcinoma. (PMID:33798603)
• High ORAI3 expression correlates with good prognosis in human muscle-invasive bladder cancer. (PMID:34626722)
• Role of Orai3 in the Pathophysiology of Cancer. (PMID:34768857)
• Orai3 Calcium Channel Regulates Breast Cancer Cell Migration through Calcium-Dependent and -Independent Mechanisms. (PMID:34943998)
• Orai3 Calcium Channel Contributes to Oral/Oropharyngeal Cancer Stemness through the Elevation of ID1 Expression. (PMID:37759448)
• Orai1 and Orai3 act through distinct signalling axes to promote stemness and tumorigenicity of breast cancer stem cells. (PMID:39135143)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Orai3	ENSMUSG00000043964
rattus_norvegicus	Orai3	ENSRNOG00000039730
drosophila_melanogaster	Orai	FBGN0041585
caenorhabditis_elegans		WBGENE00015648

Paralogs (2): ORAI2 (ENSG00000160991), ORAI1 (ENSG00000276045)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:3039586) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 2 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal retina outer nuclear layer morphology	1
abnormal B cell activation	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
Danio rerio	Q6TLE6	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
MIR762	ncRNA	100313837
MIR762HG	ncRNA	101928736
CTF1	protein-coding	1489
FBXL19-AS1	ncRNA	283932
FBXL19	protein-coding	54620
BCL7C	protein-coding	9274
SETD1A	protein-coding	9739
HSD3B7	protein-coding	80270
STX1B	protein-coding	112755
STX4	protein-coding	6810

Protein

Protein identifiers

Protein orai-3 — Q9BRQ5 (reviewed: Q9BRQ5)

Alternative names: Transmembrane protein 142C

All UniProt accessions (4): H3BT51, H3BTK7, H3BTY7, Q9BRQ5

UniProt curated annotations — full annotation on UniProt →

Function. Pore-forming subunit of two major inward rectifying Ca(2+) channels at the plasma membrane: Ca(2+) release-activated Ca(2+) (CRAC) channels and arachidonate-regulated Ca(2+)-selective (ARC) channels. Assembles with ORAI1 and ORAI2 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. Assembles with ORAI1 to form channels that mediate store-independent Ca(2+) influx in response to inflammatory metabolites arachidonate or its derivative leukotriene C4, termed ARC and LRC channels respectively.

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. ARC channels are heteropentamers consisting of three ORAI1 and two ORAI3 subunits. Interacts with STIM1; this regulates channel activity. Interacts with CRACR2A/EFCAB4B.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in both naive and effector T helper cells with higher levels in effector cells.

Activity regulation. CRAC channels are regulated by fast Ca(2+)-dependent inactivation (FCDI), a mechanism that limits Ca(2+) influx and cell toxicity. ORAI3 subunit displays prominent FCDI. Inhibited by lanthanides such as Gd(3+) ions.

Similarity. Belongs to the Orai family.

RefSeq proteins (1): NP_689501* (*=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 (16 total): mutagenesis site 5, transmembrane region 4, modified residue 2, region of interest 2, chain 1, compositionally biased region 1, site 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BRQ5-F1	71.98	0.17

Human Protein Atlas

Protein class: Transporters, Transporter channels and pores, Predicted membrane proteins, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; nucleoplasm

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.

Catalytic / active sites (1)

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

Post-translational modifications (2)

Type	Positions
Phosphoserine	45, 42

Mutagenesis-validated functional residues (5)

Position	Phenotype
81	dominant-negative. inhibits endogenous arc and crac channel currents. decreases regenerative calcium oscillations.
170	causes redox sensitivity with channel activity inhibited by hydrogen peroxide.
281	impairs fast ca(2+)-dependent inactivation; when associated with a-283 and a-284.
283	impairs fast ca(2+)-dependent inactivation; when associated with a-281 and a-284.
284	impairs fast ca(2+)-dependent inactivation; when associated with a-281 and a-283.

Function

Pathways and Gene Ontology

Reactome pathways

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

MSigDB gene sets: 154 (showing top): AP4_Q6, GGGTGGRR_PAX4_03, EFC_Q6, GOBP_MONOATOMIC_CATION_TRANSPORT, chr16p11, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, ZHOU_INFLAMMATORY_RESPONSE_LIVE_DN, TATA_C, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_DN, MYB_Q3, TGGNNNNNNKCCAR_UNKNOWN, CREB_Q3, P300_01, RFX1_02

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 (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

13 GO namespaces:

Category	Terms
calcium ion transport	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
membrane	1
cell periphery	1
cellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 3 of 10 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

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

Protein interactions and networks

STRING

showing 15 of 446 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ORAI3	STIM1	Q13586	981
ORAI3	STIM2	Q9P246	975
ORAI3	TRPC1	P48995	893
ORAI3	TRPC3	Q13507	863
ORAI3	TRPC4	Q9UBN4	816
ORAI3	TRPC6	Q9Y210	813
ORAI3	TRPC5	Q9UL62	781
ORAI3	SARAF	Q96BY9	675
ORAI3	TRPM2	O94759	642
ORAI3	ITPR3	Q14573	641
ORAI3	CACNA1C	Q13936	633
ORAI3	ITPR1	Q14643	623
ORAI3	ORAI2	Q96SN7	607
ORAI3	ATP2C2	O75185	595
ORAI3	FKBP1A	P20071	561

IntAct

Human interaction partners of ORAI3 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

4 partners by confidence:

Partner	Interaction type	MIscore	Records
ORAI1	direct interaction	0.640	4
CRACR2A	physical association	0.400	1
STIM1	physical association	0.400	1
TRPC3	physical association	0.400	1

BioGRID (3 interactions; top human partners by supporting records): MARCH8 (Affinity Capture-Western; 2 records)

Disease & clinical

Genetic variants

Variant evidence for ORAI3: 48 ClinVar records (1 pathogenic / likely pathogenic); 2 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	38
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (1)

Showing all 1 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
443135	GRCh37/hg19 16p11.2(chr16:30952806-31177641)x1	Likely pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore ORAI3’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; 18 predictions of 67):

Position(s)	Effect	Δscore	Sites
16:30953183–30953184	acceptor_loss	1.0000	5
16:30949518–30949519	donor_loss	0.9900	5
16:30953184	acceptor_loss	0.9900
16:30949519	donor_loss	0.9700
16:30949489	donor_gain	0.9600
16:30953174	acceptor_gain	0.9400
16:30949487	donor_gain	0.9300
16:30949492	donor_gain	0.9100
16:30953180	acceptor_gain	0.8900
16:30951202	acceptor_gain	0.8100

AlphaMissense

894 missense substitutions predicted likely pathogenic (of 1,887 scored), across 185 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
M76	9	0.943	0.999
M79	9	0.881	0.997
F74	8	0.997	1.000
F162	8	0.995	0.999
H109	8	0.992	0.999
F98	8	0.983	0.999
H140	8	0.980	0.993
F174	8	0.976	0.998
F262	8	0.972	0.996
F259	8	0.970	0.993
F153	8	0.957	0.992
F266	8	0.954	0.996
S57	8	0.946	0.997
F111	8	0.943	0.973
S65	8	0.932	0.998
H130	8	0.932	0.974
S127	8	0.901	0.998
H44	8	0.789	0.900
W51	7	0.995	0.999
W151	7	0.993	0.999

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Disease associations

OMIM: gene MIM:610930 | disease phenotypes:

GWAS associations

2 associations:

Study	Trait	p-value
GCST90002383_214	Hematocrit	1e-10
GCST90002380_162	Basophil percentage of white cells	6e-9

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0007992	basophil percentage of leukocytes
EFO:0004348	hematocrit

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3038476 (PROTEIN FAMILY), CHEMBL4888461 (PROTEIN COMPLEX)

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

1 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs754623108	caffeine	Toxicity	Genotype CT is associated with increased sensitivity to caffeine as compared to genotype CC.	PMID:42650172

GtoPdb / IUPHAR curated pharmacology

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

Target class: other ic — Orai channels

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
CHEMBL4570175	IC50	4000 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
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
5.40	IC50	4000	nM	CHEMBL4570175
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
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
2,6-difluoro-N-[1-[[4-hydroxy-2-(trifluoromethyl)phenyl]methyl]pyrazol-3-yl]benzamide	1774819: Inhibition of human STIM1/Orai3 expressed in HEK293 cells assessed as reduction in Orai3 current by electrophysiological method	ic50	4.0000	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

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, decreases expression	5
Cyclosporine	affects expression, decreases expression	3
Aflatoxin B1	decreases expression, increases expression	3
sodium arsenite	decreases expression	2
(+)-JQ1 compound	increases expression	2
Cisplatin	decreases expression, affects cotreatment, increases expression	2
Estradiol	affects cotreatment, increases expression, decreases expression	2
Ethyl Methanesulfonate	decreases expression, increases expression	2
Cadmium Chloride	decreases expression	2
chloroacetaldehyde	increases expression	1
trichostatin A	decreases expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
cupric chloride	decreases expression	1
polyhexamethyleneguanidine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
perfluoro-n-nonanoic acid	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
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	increases expression, affects cotreatment	1
Rosiglitazone	decreases expression	1
Sunitinib	increases expression	1
Norethindrone Acetate	affects cotreatment, increases expression	1
Adenine	decreases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases 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 ORAI3 across ~30M SureChEMBL compounds — explore on Sugi Predict.