ORAI1

Summary

ORAI1 (ORAI calcium release-activated calcium modulator 1, HGNC:25896) is a protein-coding gene on chromosome 12q24.31, encoding Calcium release-activated calcium channel protein 1 (Q96D31). 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.

The protein encoded by this gene is a membrane calcium channel subunit that is activated by the calcium sensor STIM1 when calcium stores are depleted. This type of channel is the primary way for calcium influx into T-cells. Defects in this gene are a cause of immune dysfunction with T-cell inactivation due to calcium entry defect type 1 (IDTICED1).

Source: NCBI Gene 84876 — RefSeq curated summary.

At a glance

• Gene–disease (curated): tubular aggregate myopathy (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 266 total — 6 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 62
• Druggable target: yes — 5 molecules with ChEMBL bioactivity

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25896
Approved symbol	ORAI1
Name	ORAI calcium release-activated calcium modulator 1
Location	12q24.31
Locus type	gene with protein product
Status	Approved
Aliases	FLJ14466, CRACM1
Ensembl gene	ENSG00000276045
Ensembl biotype	protein_coding
OMIM	610277
Entrez	84876

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding_CDS_not_defined, 1 protein_coding

ENST00000611718, ENST00000617316, ENST00000646827, ENST00000698901

RefSeq mRNA: 0 — MANE Select: None

Canonical transcript exons

ENST00000611718 — 2 exons

Exon	Start	End
ENSE00003743349	121641041	121641533
ENSE00003752823	121626816	121627174

Expression profiles

Bgee: expression breadth ubiquitous, 177 present calls, max score 94.63.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.7820 / max 214.2049, expressed in 1814 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
128436	16.0276	1795
128439	8.9590	1653
128437	2.7384	1247
128438	0.8280	413
128440	0.1758	59
128441	0.0532	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	94.63	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.23	gold quality
skin of leg	UBERON:0001511	93.33	gold quality
skin of abdomen	UBERON:0001416	93.02	gold quality
zone of skin	UBERON:0000014	91.04	gold quality
gastrocnemius	UBERON:0001388	90.13	gold quality
leukocyte	CL:0000738	90.01	gold quality
muscle of leg	UBERON:0001383	89.63	gold quality
monocyte	CL:0000576	89.60	gold quality
tibialis anterior	UBERON:0001385	88.83	silver quality
blood	UBERON:0000178	88.14	gold quality
spleen	UBERON:0002106	87.31	gold quality
ileal mucosa	UBERON:0000331	87.14	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	86.82	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.68	gold quality
mucosa of transverse colon	UBERON:0004991	86.58	gold quality
biceps brachii	UBERON:0001507	85.50	silver quality
upper lobe of left lung	UBERON:0008952	85.26	gold quality
vermiform appendix	UBERON:0001154	84.61	gold quality
minor salivary gland	UBERON:0001830	84.40	gold quality
right lung	UBERON:0002167	84.36	gold quality
upper lobe of lung	UBERON:0008948	84.20	gold quality
stromal cell of endometrium	CL:0002255	84.19	gold quality
body of stomach	UBERON:0001161	84.15	gold quality
apex of heart	UBERON:0002098	83.72	gold quality
lymph node	UBERON:0000029	83.23	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	83.10	silver quality
small intestine Peyer’s patch	UBERON:0003454	82.76	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.54	gold quality
mucosa of stomach	UBERON:0001199	82.43	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.57

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB

miRNA regulators (miRDB)

14 targeting ORAI1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-4753-5P	99.54	68.51	1356
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-5000-3P	98.79	65.63	1251
HSA-MIR-603	98.58	68.28	1603
HSA-MIR-4436A	98.05	64.83	1140
HSA-MIR-663B	97.40	62.91	664
HSA-MIR-874-5P	96.93	63.92	1014
HSA-MIR-597-5P	96.82	67.57	732

Literature-anchored findings (GeneRIF, showing 40)

• Orai1 is an essential component or regulator of the CRAC channel complex (PMID:16582901)
• results demonstrate that the protein CRACM1 encoded by FLJ14466 is essential for store-operated Ca2+ influx via Ca2+ release-activated Ca2+ (CRAC) channels (PMID:16645049)
• STIM1 and CRACM1 interact functionally. Overexpression of both proteins greatly potentiates I(CRAC), suggesting that STIM1 and CRACM1 mutually limit store-operated currents and that CRACM1 may be the long-sought CRAC channel. (PMID:16733527)
• suppression of store-operated channels function by Orai1 overexpression likely reflects a required stoichiometry between STIM1 and Orai1 (PMID:16766533)
• strong evidence that Orai1 is a pore subunit of the CRAC channel. (PMID:16921383)
• CRACM1 multimers form the ion-selective pore of the CRAC channel. (PMID:16978865)
• Therefore, we propose that store depletion causes aggregation and translocation of STIM1 in close apposition to the plasma membrane. (PMID:17045966)
• Ca2+ entry supporting [Ca2+]i oscillations in HEK293 cells depends upon the Ca2+ sensor, Stim1, and calcium release-activated Ca2+ channel protein, Orai1 (PMID:17218358)
• dynamic assembly of TRPC1-STIM1-Orai1 ternary complex is involved in activation of SOC channel in response to internal Ca2+ store depletion (PMID:17224452)
• Orai1 physically interacts with the N and C termini of TRPC3 and TRPC6 (PMID:17360584)
• Results demonstrate biochemical and physiological relevance of Orai proteins in light of different evolutionary origins. (PMID:17400243)
• CRACM1, CRACM2, and CRACM3 are store-operated Ca2+ channels with distinct functional properties. (PMID:17442569)
• 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)
• analysis of the plasma membrane-endoplasmic reticulum contact sites reveals the presence of additional molecular components within the STIM1-Orai1 Complex (PMID:17684017)
• the interacting domains of STIM1 and Orai1 have roles in Ca2+ release-activated Ca2+ channel activation (PMID:17702753)
• analysis of how Orai1 mutations alter ion permeation and Ca2+-dependent fast inactivation of CRAC channels (PMID:17968026)
• 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 functional CRAC channel pore is formed by a tetrameric assembly of Orai1 subunits. (PMID:18006576)
• A mutation of Orai1 (V102I) close to the selectivity filter modified CRAC channel voltage sensitivity. (PMID:18096706)
• C-terminal coiled-coil motif of ORAI1 represents a key domain for dynamic coupling to STIM1. (PMID:18187424)
• Orai1-STIM1 protein complex is one of the molecular components involved in Pb2+ entry. (PMID:18190941)
• Results suggest that ORAI1 together with STIM1 are important contributors to store-operated calcium entry in airway smooth muscle cells. (PMID:18239188)
• results imply a positive feedback loop in which an initial TCR signal favors up-regulation of STIM1 and Orai proteins that would augment Ca2+ signaling during subsequent antigen encounter (PMID:18250319)
• demonstrate a functional requirement for Orai1 in TRPC1+STIM1-dependent SOCE (PMID:18326500)
• Intracellular Ca2+ store depletion enhances Orai1 plasma membrane expression in an exocytotic manner that involves SNAP-25, a process that contributes to store-dependent Ca2+ entry. (PMID:18400989)
• 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)
• data show that calcium influx in HL-60 cells relies on TRPC channels 1,3, and 6, and Orai1 for allowing NADPH oxidase activation (PMID:18436303)
• analysis of movement of the calcium sensor STIM1 and the calcium channel Orai1 in activated T-cells (PMID:18448669)
• Huh-7 and HepG2 cells (hepatoma cell lines) express transient receptor potential canonical 1 (TRPC1) and TRPC6, as well as STIM1 and Orai1, and these 4 channels are the most likely candidates to account for the Store-operated calcium entry in these cells. (PMID:18506892)
• ATP depletion induces translocation of STIM1 to puncta and formation of STIM1-ORAI1 clusters: translocation and re-translocation of STIM1 does not require ATP. (PMID:18542992)
• evidence for STIM1:Orai1 as a primary pathway for agonist-evoked Ca2+ influx in the platelet and megakaryocyte. (PMID:18569867)
• the STIM1-Orai1-hTRPC1 complex has a role in the activation of store-operated Ca(2+) entry (PMID:18644792)
• Data challenge the idea of direct conformational coupling between STIM1 and Orai1 as a viable mechanism of puncta formation and SOCE activation and uncover greater complexity in their relationship. (PMID:18768920)
• identify a STIM1-dependent conformational change in Orai1 during the activation of CRAC channels (PMID:18832420)
• TRPC1, Orai1 and STIM1 form a heteromultimer associated with lipid raft domains and regulated by the intracellular Ca2+ stores (PMID:18843204)
• Knockdown of Orai1 inhibits endothelial proliferation and causes cell cycle arrest at S and G2/M phase. (PMID:18845811)
• STIM1 gates TRPC1 by intermolecular electrostatic interaction, but is not required for Orai1 gating. (PMID:18995841)
• The Orai1 severe combined immune deficiency mutation and calcium release-activated Ca2+ channel function in the heterozygous condition. (PMID:19075015)
• STIM1 and Orai1 are key molecules for the induction of human myoblast differentiation (PMID:19088073)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	orai1b	ENSDARG00000004154
danio_rerio	orai1a	ENSDARG00000011515
mus_musculus	Orai1	ENSMUSG00000049686
rattus_norvegicus	Orai1	ENSRNOG00000001336
drosophila_melanogaster	Orai	FBGN0041585
caenorhabditis_elegans		WBGENE00015648

Paralogs (2): ORAI2 (ENSG00000160991), ORAI3 (ENSG00000175938)

Protein

Protein identifiers

Calcium release-activated calcium channel protein 1 — Q96D31 (reviewed: Q96D31)

Alternative names: Protein orai-1, Transmembrane protein 142A

All UniProt accessions (1): Q96D31

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 ORAI2 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. Activates NFATC2/NFAT1 and NFATC3/NFAT4-mediated transcriptional responses. 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 ORAI3 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. Plays a prominent role in Ca(2+) influx at the basolateral membrane of mammary epithelial cells independently of the Ca(2+) content of endoplasmic reticulum or Golgi stores. May mediate transepithelial transport of large quantities of Ca(2+) for milk secretion. Pore-forming subunit of both CRAC and ARC channels. Couples Ca(2+) influx to NFAT-mediated transcriptional responses. Pore-forming subunit of CRAC channels exclusively.

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 and STIM2; this regulates channel activity. Interacts with CALM; this may displace STIM1 and STIM2 and might thereby modulate channel activity. Interacts with CRACR2A/EFCAB4B; the interaction is direct and takes place in absence of Ca(2+). Forms a complex with CRACR2A/EFCAB4B and STIM1 at low concentration of Ca(2+), the complex dissociates at elevated Ca(2+) concentrations. Interacts with ASPH (isoform 8). Interacts with SLC35G1. Interacts with UBQLN1. Interacts with ADCY8; interaction is calcium store depletion independent; interaction occurs in membrane raft; interaction increases markedly after store depletion; positively regulates SOCE-induced adenylate cyclase activity; contributes to the targeting of ADCY8 to discrete regions of the plasma membrane that are shielded from other calcium events. Interacts with EFHB; the interaction takes place upon Ca(2+)-store depletion. Interacts (via N- and C-termini) with ATP2C2 (via N-terminus); this interaction regulates Ca(2+) influx at the plasma membrane. Interacts with TSPAN18; this interaction regulates ORAI1 exit from the endoplasmic (ER), and/or Golgi, and trafficking to the cell surface. Pore-forming subunit of both CRAC and ARC channels. Interacts (via N-terminus) with AKAP5 upon store depletion. Pore-forming subunit of CRAC channels exclusively.

Subcellular location. Cell membrane. Basolateral cell membrane Cell membrane Cell membrane.

Tissue specificity. Expressed in naive CD4 and CD8 T cells (at protein level). Expressed at similar levels in naive and effector T helper cells.

Post-translational modifications. N-glycosylated. N-glycosylation inhibits channel activity in T cells. Ubiquitinated. Cys-195 is oxidated, leading to inactivation of channel activity.

Disease relevance. Immunodeficiency 9 (IMD9) [MIM:612782] An immune disorder characterized by recurrent infections, impaired activation and proliferative response of T-cells, decreased T-cell production of cytokines, and normal lymphocytes counts and serum immunoglobulin levels. In surviving patients ectodermal dysplasia with anhidrosis and non-progressive myopathy may be observed. The disease is caused by variants affecting the gene represented in this entry. Myopathy, tubular aggregate, 2 (TAM2) [MIM:615883] A rare congenital myopathy characterized by regular arrays of membrane tubules on muscle biopsies without additional histopathological hallmarks. Tubular aggregates in muscle are structures of variable appearance consisting of an outer tubule containing either one or more microtubule-like structures or amorphous material. TAM2 patients have myopathy and pupillary abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Oxidation at Cys-195 leads to inactivation of channel activity. CRAC channels are regulated by fast Ca(2+)-dependent inactivation (FCDI), a mechanism that limits Ca(2+) influx and cell toxicity. Contrary to ORAI2 and ORAI3 subunits, ORAI1 displays small FCDI. Both CRAC and ARC channels are inhibited by lanthanides including La(3+) and Gd(3+) ions.

Domain organisation. The Pro-rich region of ORAI1 (residues 3-47) functionally interacts with the polybasic Lys-rich region of STIM1 (residues 672-685) and regulates CRAC channel gating at negative membrane potentials. AKAP5 association region (AKAR) mediates coupling of ORAI1 to AKAP5-dependent NFATC2/NFAT1 transcriptional responses.

Miscellaneous. In Greek mythology, the ‘Orai’ are the keepers of the gates of heaven: Eunomia (order or harmony), Dike (justice) and Eirene (peace).

Similarity. Belongs to the Orai family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96D31-1	alpha	yes
Q96D31-2	beta

RefSeq proteins (0): (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012446	CRAC_channel	Family
IPR038350	Orai_sf	Homologous_superfamily

Pfam: PF07856

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (51 total): mutagenesis site 19, region of interest 6, sequence variant 6, topological domain 5, transmembrane region 4, compositionally biased region 2, modified residue 2, helix 2, chain 1, site 1, glycosylation site 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4EHQ	X-RAY DIFFRACTION	1.9
2MAK	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96D31-F1	71.84	0.20

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): 106 (confers selective permeability to ca(2+) ions)

Post-translational modifications (2): 295, 298

Glycosylation sites (1): 223

Mutagenesis-validated functional residues (19):

Position	Phenotype
3	generates both inward and outward rectifying crac currents at negative membrane potentials; when associated with a-5. re
5	generates both inward and outward rectifying crac currents at negative membrane potentials; when associated with a-3. re
39	generates both inward and outward rectifying crac currents at negative membrane potentials; when associated with a-40. r
40	generates both inward and outward rectifying crac currents at negative membrane potentials; when associated with a-39. r
85–87	impairs interaction with cracr2a/efcab4b.
106	has dominant negative effect. abolishes store-operated ca(2+) influx. does not affect localization to the cell membrane.
106	markedly decreases store-operated ca(2+) influx. increases channel permeability to monovalent cations. does not affect l
106	dominant-negative. inhibits endogenous crac and arc channels. confers selective permeability to monovalent cations. does
190	does not affect store-operated ca(2+) influx or localization to the cell membrane.
190	impairs store-operated ca(2+) influx. increases channel permeability to monovalent cations. does not affect localization
195	abolishes oxidation and channel inhibition.
223	impairs n-glycosylation. increases channel activity in t cells but does not affect cell surface location.
273	strongly reduces the interaction with atp2c1. impairs crac channel gating by stim1. impairs orai1 and stim1 interaction
281	strongly reduces calcium current.
284	reduces the maximum current; when associated with a-287 and a-291.
286	strongly reduces calcium current.
287	reduces the maximum current; when associated with a-284 and a-291.
289	strongly reduces calcium current.
291	reduces the maximum current; when associated with a-284 and a-287.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-139853	Elevation of cytosolic Ca2+ levels
R-HSA-5578775	Ion homeostasis
R-HSA-983695	Antigen activates B Cell Receptor (BCR) leading to generation of second messengers

MSigDB gene sets: 313 (showing top): GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, CREL_01, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_MAMMARY_GLAND_EPITHELIUM_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_LYASE_ACTIVITY, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_EXOCYTOSIS, GOBP_REGULATION_OF_ADENYLATE_CYCLASE_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, GOBP_CALCIUM_ION_IMPORT, GOBP_POSITIVE_REGULATION_OF_MONOATOMIC_ION_TRANSPORT, GOBP_SECRETION

GO Biological Process (17): store-operated calcium entry (GO:0002115), adaptive immune response (GO:0002250), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), calcium-ion regulated exocytosis (GO:0017156), positive regulation of insulin secretion (GO:0032024), calcineurin-NFAT signaling cascade (GO:0033173), positive regulation of adenylate cyclase activity (GO:0045762), regulation of calcium ion transport (GO:0051924), positive regulation of calcium ion transport (GO:0051928), mammary gland epithelium development (GO:0061180), calcium ion import (GO:0070509), calcium ion transmembrane transport (GO:0070588), ligand-gated ion channel signaling pathway (GO:1990806), immune system process (GO:0002376), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), monoatomic ion transmembrane transport (GO:0034220)

GO Molecular Function (5): calcium channel activity (GO:0005262), calmodulin binding (GO:0005516), store-operated calcium channel activity (GO:0015279), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (7): plasma membrane (GO:0005886), membrane (GO:0016020), basolateral plasma membrane (GO:0016323), calcium channel complex (GO:0034704), plasma membrane raft (GO:0044853), membrane raft (GO:0045121), cell periphery (GO:0071944)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Platelet calcium homeostasis	1
Cardiac conduction	1
Signaling by the B Cell Receptor (BCR)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
calcium ion transport	5
protein binding	2
cellular anatomical structure	2
plasma membrane region	2
immune response	1
G protein-coupled receptor signaling pathway	1
phospholipase C activator activity	1
regulated exocytosis	1
insulin secretion	1
positive regulation of protein secretion	1
regulation of insulin secretion	1
positive regulation of peptide hormone secretion	1
calcineurin-mediated signaling	1
adenylate cyclase activity	1
positive regulation of cyclase activity	1
regulation of adenylate cyclase activity	1
positive regulation of lyase activity	1
regulation of metal ion transport	1
positive regulation of monoatomic ion transport	1
regulation of calcium ion transport	1
mammary gland development	1
epithelium development	1
monoatomic cation transmembrane transport	1
signal transduction	1
ligand-gated monoatomic ion channel activity	1
biological_process	1
transport	1
metal ion transport	1
monoatomic ion transport	1
transmembrane transport	1
monoatomic cation channel activity	1
calcium ion transmembrane transporter activity	1
calcium channel activity	1
binding	1
membrane	1
cell periphery	1
basal plasma membrane	1
cation channel complex	1
plasma membrane	1
membrane raft	1

Protein interactions and networks

STRING

1086 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ORAI1	STIM2	Q9P246	999
ORAI1	STIM1	Q13586	999
ORAI1	TRPC1	P48995	995
ORAI1	ORAI3	Q9BRQ5	972
ORAI1	ORAI2	Q96SN7	947
ORAI1	TRPC3	Q13507	921
ORAI1	KCNN3	Q9UGI6	918
ORAI1	TRPC4	Q9UBN4	883
ORAI1	CALML3	P27482	882
ORAI1	CALML5	Q9NZT1	882
ORAI1	CALML6	Q8TD86	876
ORAI1	CALML4	Q96GE6	876
ORAI1	ATP2C2	O75185	850
ORAI1	CACNA1C	Q13936	844
ORAI1	CALM1	P02593	808

IntAct

98 interactions, top by confidence:

A	B	Type	Score
ORAI1	STIM1	psi-mi:“MI:0915”(physical association)	0.960
STIM1	ORAI1	psi-mi:“MI:0915”(physical association)	0.960
STIM1	ORAI1	psi-mi:“MI:0403”(colocalization)	0.960
ORAI1	STIM1	psi-mi:“MI:0914”(association)	0.960
ORAI1	STIM1	psi-mi:“MI:2364”(proximity)	0.960
ORAI1	STIM1	psi-mi:“MI:0403”(colocalization)	0.960
ORAI1	STIM1	psi-mi:“MI:0407”(direct interaction)	0.960
STIM1	STIM1	psi-mi:“MI:0407”(direct interaction)	0.910
ORAI1	ORAI1	psi-mi:“MI:0407”(direct interaction)	0.890

BioGRID (55): ORAI1 (Affinity Capture-MS), ORAI1 (Affinity Capture-MS), ORAI1 (Affinity Capture-MS), ORAI1 (Affinity Capture-MS), ORAI1 (Synthetic Lethality), ORAI1 (Affinity Capture-MS), ORAI1 (Affinity Capture-MS), GHITM (Affinity Capture-MS), ACSL4 (Affinity Capture-MS), TTC28 (Affinity Capture-MS), CYP2S1 (Affinity Capture-MS), ORAI1 (Affinity Capture-MS), POTEF (Affinity Capture-MS), ORAI1 (Affinity Capture-MS), ORAI1 (Affinity Capture-MS)

ESM2 similar proteins: A0A291SJC7, A0PM48, A0R109, A3KI17, A4FG19, B5GW45, B5H7H3, D3KYU2, F8JK18, G2P5T1, O33011, O69833, O86810, O88039, P0DPK6, P23159, P54977, P63750, P64714, P95038, P9WIX6, P9WIX7, P9WIX8, P9WIX9, P9WJC4, P9WJC5, P9WKU4, P9WKU5, P9WL20, P9WL21, P9WPH4, P9WPH5, Q04943, Q0RJF1, Q5E9N5, Q5M848, Q60649, Q825U9, Q82KZ4, Q8BLI4

Diamond homologs: Q09232, Q5EAU0, Q5M848, Q5ZL05, Q5ZLW2, Q616J1, Q6AXR8, Q6NZI6, Q6P8G8, Q6TLE6, Q8BH10, Q8BWG9, Q96D31, Q96SN7, Q9BRQ5, Q9U6B8

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PRKCB	down-regulates	ORAI1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	9
Uncertain significance	142
Likely benign	86
Benign	14

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
1069742	NC_000012.12:g.121641056G>A	Pathogenic
139640	NM_032790.4(ORAI1):c.734C>T (p.Pro245Leu)	Pathogenic
1428101	NC_000012.11:g.(?122064648)(122064976_?)del	Pathogenic
192287	NM_032790.4(ORAI1):c.308C>A (p.Ala103Glu)	Pathogenic
3383981	NM_032790.1(ORAI1):c.493dup	Pathogenic
3754970	NC_000012.12:g.121641254G>T	Pathogenic
1464680	NM_032790.4(ORAI1):c.750dup (p.Ile251Tyrfs)	Likely pathogenic
1505011	NC_000012.12:g.121641350C>T	Likely pathogenic
192288	NM_032790.4(ORAI1):c.581T>C (p.Leu194Pro)	Likely pathogenic
2171110	NM_032790.4(ORAI1):c.802C>T (p.Arg268Ter)	Likely pathogenic
2432388	NM_032790.4(ORAI1):c.777dup (p.Ser260Leufs)	Likely pathogenic
2944495	NM_032790.4(ORAI1):c.505dup (p.His169fs)	Likely pathogenic
3780063	NM_032790.3(ORAI1):c.131_132insGCCGC	Likely pathogenic
4791642	NR_186857.1(ORAI1):n.906_909dup	Likely pathogenic
639606	NC_000012.12:g.121641283del	Likely pathogenic

SpliceAI

213 predictions. Top by Δscore:

Variant	Effect	Δscore
12:121641039:AGG:A	acceptor_loss	1.0000
12:121627047:CATGG:C	donor_loss	0.9900
12:121627051:G:GA	donor_loss	0.9900
12:121627051:G:GG	donor_gain	0.9900
12:121627052:T:G	donor_loss	0.9900
12:121641036:C:CA	acceptor_gain	0.9900
12:121641039:A:AG	acceptor_gain	0.9900
12:121641039:AG:A	acceptor_gain	0.9900
12:121641039:AGGT:A	acceptor_gain	0.9900
12:121641039:AGGTG:A	acceptor_gain	0.9900
12:121641040:G:GG	acceptor_gain	0.9900
12:121641040:GG:G	acceptor_gain	0.9900
12:121641040:GGT:G	acceptor_gain	0.9900
12:121641040:GGTG:G	acceptor_gain	0.9900
12:121641040:GGTGG:G	acceptor_gain	0.9900
12:121627053:GA:G	donor_loss	0.9800
12:121628260:C:G	donor_gain	0.9700
12:121627049:TG:T	donor_gain	0.9600
12:121627050:GG:G	donor_gain	0.9600
12:121627048:ATG:A	donor_gain	0.9100
12:121626937:A:AG	donor_gain	0.8900
12:121629642:G:A	acceptor_gain	0.8500
12:121627046:CCATG:C	donor_gain	0.8300
12:121628255:G:GG	donor_gain	0.8100
12:121639959:GGC:G	donor_gain	0.8100
12:121639960:GCG:G	donor_gain	0.8100
12:121628254:A:AG	donor_gain	0.8000
12:121640011:G:GA	donor_gain	0.7900
12:121629641:T:A	acceptor_gain	0.7800
12:121629638:ACCTG:A	acceptor_gain	0.7400

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000278371 (12:121629129 C>T), RS1000318586 (12:121640495 C>T), RS1000647924 (12:121630097 A>G,T), RS1000715971 (12:121628830 C>A,T), RS1000787497 (12:121635002 C>A,T), RS1000823434 (12:121635664 G>A), RS1001341260 (12:121627479 G>A), RS1001380275 (12:121633365 G>A,C), RS1002177716 (12:121639365 A>G,T), RS1002210225 (12:121639110 C>T), RS1003182097 (12:121638073 G>A), RS1003214718 (12:121637819 T>C), RS1003609035 (12:121626291 G>A), RS1003682864 (12:121625994 C>G), RS1003791013 (12:121632026 C>G,T)

Disease associations

OMIM: gene MIM:610277 | disease phenotypes: MIM:612782, MIM:615883, MIM:160565

GenCC curated gene-disease

Disease	Classification	Inheritance
combined immunodeficiency due to ORAI1 deficiency	Strong	Autosomal recessive
myopathy, tubular aggregate, 2	Strong	Autosomal dominant
tubular aggregate myopathy	Strong	Autosomal dominant
Stormorken syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
tubular aggregate myopathy	Definitive	AD

Mondo (5): combined immunodeficiency due to ORAI1 deficiency (MONDO:0013007), myopathy, tubular aggregate, 2 (MONDO:0014383), myopathy, tubular aggregate, 1 (MONDO:0024531), tubular aggregate myopathy (MONDO:0008051), Stormorken syndrome (MONDO:0008497)

Orphanet (2): Combined immunodeficiency due to CRAC channel dysfunction (Orphanet:169090), Combined immunodeficiency due to ORAI1 deficiency (Orphanet:317428)

HPO phenotypes

62 total (30 of 62 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000348	High forehead
HP:0000467	Neck muscle weakness
HP:0000490	Deeply set eye
HP:0000616	Miosis
HP:0000705	Amelogenesis imperfecta
HP:0000778	Hypoplasia of the thymus
HP:0000968	Ectodermal dysplasia
HP:0000979	Purpura
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001288	Gait disturbance
HP:0001324	Muscle weakness
HP:0001508	Failure to thrive
HP:0001522	Death in infancy
HP:0001746	Asplenia
HP:0001872	Abnormality of thrombocytes
HP:0001888	Decreased total lymphocyte count
HP:0001903	Anemia
HP:0001928	Abnormality of coagulation
HP:0001954	Recurrent fever
HP:0002028	Chronic diarrhea
HP:0002046	Heat intolerance
HP:0002167	Abnormal speech pattern
HP:0002522	Areflexia of lower limbs
HP:0002527	Falls
HP:0002719	Recurrent infections
HP:0002720	Decreased circulating IgA concentration
HP:0002721	Immunodeficiency

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST005547_11	Major depressive disorder	9.000000e-07
GCST006944_52	Experiencing mood swings	6.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008475	mood instability measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C557826	Immune dysfunction with T-cell inactivation due to calcium entry defect 1 (supp.)
C566108	Stormorken Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (5): CHEMBL2384891 (SINGLE PROTEIN), CHEMBL3038476 (PROTEIN FAMILY), CHEMBL3832644 (PROTEIN COMPLEX), CHEMBL4296083 (PROTEIN COMPLEX), CHEMBL4296084 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

5 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 86,397 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL45816	MIBEFRADIL	4	7,838
CHEMBL808	ECONAZOLE	4	24,813
CHEMBL91	MICONAZOLE	4	45,914
CHEMBL973	TERIFLUNOMIDE	4	7,575
CHEMBL4753998	ZEGOCRACTIN	2	257

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs12320939	ORAI1		0.00	0

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	Channel blocker	6.92	pIC50
GSK-7975A	Channel blocker	6.4	pIC50

Binding affinities (BindingDB)

11 measured of 12 human assays (18 total across all organisms); most potent 11 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-(benzotriazol-1-yl)-N-[4-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]acetamide	IC50	39.2 nM	US-8993612: Modulators of calcium release-activated calcium channel and methods for treatment of non-small cell lung cancer
2-(benzotriazol-1-yl)-N-[4-(3,5-dicyclopropylpyrazol-1-yl)phenyl]acetamide	IC50	51.3 nM	US-8993612: Modulators of calcium release-activated calcium channel and methods for treatment of non-small cell lung cancer
N-[4-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]quinoxaline-6-carboxamide	IC50	53.4 nM	US-8993612: Modulators of calcium release-activated calcium channel and methods for treatment of non-small cell lung cancer
N-[4-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]quinoline-6-carboxamide;hydrochloride	IC50	86.1 nM	US-8993612: Modulators of calcium release-activated calcium channel and methods for treatment of non-small cell lung cancer
2-(benzotriazol-2-yl)-N-[4-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]acetamide	IC50	139 nM	US-8993612: Modulators of calcium release-activated calcium channel and methods for treatment of non-small cell lung cancer
N-[4-(3,5-dicyclopropylpyrazol-1-yl)phenyl]-2-quinolin-6-ylacetamide	IC50	147 nM	US-8993612: Modulators of calcium release-activated calcium channel and methods for treatment of non-small cell lung cancer
2-(benzotriazol-1-yl)-N-[4-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]-3-fluorophenyl]acetamide	IC50	160 nM	US-8993612: Modulators of calcium release-activated calcium channel and methods for treatment of non-small cell lung cancer
N-[4-(3,5-dicyclopropylpyrazol-1-yl)phenyl]-2H-benzotriazole-5-carboxamide	IC50	182 nM	US-8993612: Modulators of calcium release-activated calcium channel and methods for treatment of non-small cell lung cancer
N-[4-(3,5-dicyclopropylpyrazol-1-yl)-3-fluorophenyl]-2-quinolin-6-ylacetamide	IC50	263 nM	US-8993612: Modulators of calcium release-activated calcium channel and methods for treatment of non-small cell lung cancer
2-(benzimidazol-1-yl)-N-[4-(3,5-dicyclopropylpyrazol-1-yl)phenyl]acetamide	IC50	383 nM	US-8993612: Modulators of calcium release-activated calcium channel and methods for treatment of non-small cell lung cancer
3,5-diamino-6-chloro-N-(diaminomethylene)pyrazinamide;hydrochloride	IC50	6630 nM

ChEMBL bioactivities

100 potent at pChembl≥5 of 166 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.58	IC50	26	nM	CHEMBL3984105
7.41	IC50	39.17	nM	CHEMBL3699940
7.29	IC50	51.31	nM	CHEMBL3699935
7.27	IC50	53.36	nM	CHEMBL3699939
7.12	IC50	76	nM	CHEMBL4868242
7.07	IC50	86.12	nM	CHEMBL3699938
6.98	IC50	104	nM	CHEMBL3403751
6.92	IC50	119	nM	ZEGOCRACTIN
6.86	IC50	139	nM	CHEMBL3699941
6.83	IC50	146.7	nM	CHEMBL3699936
6.79	IC50	160.5	nM	CHEMBL3699942
6.74	IC50	182.5	nM	CHEMBL3699933
6.64	IC50	228	nM	CHEMBL3403742
6.58	IC50	263.2	nM	CHEMBL3699937
6.52	IC50	300	nM	CHEMBL101896
6.44	IC50	361	nM	CHEMBL4753023
6.42	IC50	383.1	nM	CHEMBL3699934
6.36	IC50	440	nM	CHEMBL3403753
6.30	IC50	500	nM	CHEMBL4177187
6.22	IC50	600	nM	CHEMBL3727719
6.22	IC50	600	nM	CHEMBL3729028
6.22	IC50	600	nM	CHEMBL3732851
6.22	IC50	600	nM	CHEMBL3729649
6.22	IC50	600	nM	CHEMBL3727896
6.22	IC50	600	nM	CHEMBL3733110
6.22	IC50	600	nM	CHEMBL3728586
6.22	IC50	600	nM	CHEMBL3731683
6.22	IC50	600	nM	CHEMBL3727419
6.22	IC50	600	nM	CHEMBL3731241
6.22	IC50	600	nM	CHEMBL3732488
6.22	IC50	600	nM	CHEMBL3732982
6.22	IC50	600	nM	CHEMBL3731485
6.22	IC50	600	nM	CHEMBL3731250
6.22	IC50	600	nM	CHEMBL3728232
6.22	IC50	600	nM	CHEMBL3732761
6.22	IC50	600	nM	CHEMBL3730656
6.22	IC50	600	nM	CHEMBL3727447
6.22	IC50	600	nM	CHEMBL3728969
6.22	IC50	600	nM	CHEMBL3731765
6.22	IC50	600	nM	CHEMBL3728323
6.22	IC50	600	nM	CHEMBL3731488
6.22	IC50	600	nM	CHEMBL3727611
6.22	IC50	600	nM	CHEMBL3728468
6.22	IC50	600	nM	CHEMBL3727989
6.22	IC50	600	nM	CHEMBL3729551
6.22	IC50	600	nM	CHEMBL3732114
6.22	IC50	600	nM	CHEMBL4162723
6.11	IC50	781	nM	CHEMBL4794288
6.10	IC50	802	nM	CHEMBL4780000
6.09	IC50	807	nM	CHEMBL4751678

PubChem BioAssay actives

62 with measured affinity, of 395 total; 45 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-[4-(2,5-dimethoxyphenyl)phenyl]-3-fluoro-N-methylpyridine-4-carboxamide	1330318: Inhibition of Orai1 (unknown origin) by patch clamp assay	ic50	0.0260	uM
2,6-difluoro-N-[4-[2-methyl-3-(4-methyl-5-oxo-1,3,4-oxadiazol-2-yl)phenyl]phenyl]benzamide	1774779: Inhibition of Orai1/STIM1 (unknown origin) expressed in HEK293 cells assessed as reduction in Ca2+-release activated Ca2+ entry current by manual patch clamp based electrophysiological method	ic50	0.0760	uM
2-(2-chloro-6-fluorophenyl)-5-[1-methyl-3-(trifluoromethyl)pyrazol-5-yl]-1H-pyrrolo[2,3-b]pyridine	1192973: Inhibition of human Orai1/STIM1 expressed in HEK293 cells assessed as inhibition of channel-mediated calcium current by electrophysiology assay in presence of 10 mM EGTA	ic50	0.1000	uM
2-(2-chloro-6-fluorophenyl)-5-(6-methoxy-4-methyl-3-pyridinyl)-1H-pyrrolo[2,3-b]pyridine	1192973: Inhibition of human Orai1/STIM1 expressed in HEK293 cells assessed as inhibition of channel-mediated calcium current by electrophysiology assay in presence of 10 mM EGTA	ic50	0.1040	uM
N-[5-(6-chloro-2,2-difluoro-1,3-benzodioxol-5-yl)pyrazin-2-yl]-2-fluoro-6-methylbenzamide	1774820: Inhibition of Orai1/STIM1 (unknown origin)	ic50	0.1190	uM
N-[4-(2,5-dimethoxyphenyl)phenyl]-3-fluoropyridine-4-carboxamide	1683722: Inhibition of STIM1/Orai1 (unknown origin) expressed in HEK293 cells assessed as reduction in tBHQ-induced calcium response	ic50	0.2280	uM
N-[4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl]-3-fluoropyridine-4-carboxamide	1363555: Modulation of TRPC1/TRPC3/STIM1/Orai1 in HEK cells assessed as induction of store-operated calcium entry by measuring residual activity preincubated for 30 mins followed by tBhQ-mediated Ca2+ depletion and Ca2+ re-addition to extracellular solution measured for 600 secs by Fluo-4 AM-based fluorometric assay relative to control	ic50	0.3000	uM
3-[1-[4-(2-fluoro-5-methoxyphenyl)phenyl]triazol-4-yl]benzoic acid	1683722: Inhibition of STIM1/Orai1 (unknown origin) expressed in HEK293 cells assessed as reduction in tBHQ-induced calcium response	ic50	0.3610	uM
2-(2-chloro-6-fluorophenyl)-5-(4,6-dimethoxy-3-pyridinyl)-1H-pyrrolo[2,3-b]pyridine	1192973: Inhibition of human Orai1/STIM1 expressed in HEK293 cells assessed as inhibition of channel-mediated calcium current by electrophysiology assay in presence of 10 mM EGTA	ic50	0.4400	uM
ethyl 1-[4-(2,3,3-trichloroprop-2-enoylamino)phenyl]-5-(trifluoromethyl)pyrazole-4-carboxylate	1363555: Modulation of TRPC1/TRPC3/STIM1/Orai1 in HEK cells assessed as induction of store-operated calcium entry by measuring residual activity preincubated for 30 mins followed by tBhQ-mediated Ca2+ depletion and Ca2+ re-addition to extracellular solution measured for 600 secs by Fluo-4 AM-based fluorometric assay relative to control	ic50	0.5000	uM
3-[1-[4-[4-ethoxycarbonyl-5-(trifluoromethyl)pyrazol-1-yl]phenyl]triazol-4-yl]benzoic acid	1363555: Modulation of TRPC1/TRPC3/STIM1/Orai1 in HEK cells assessed as induction of store-operated calcium entry by measuring residual activity preincubated for 30 mins followed by tBhQ-mediated Ca2+ depletion and Ca2+ re-addition to extracellular solution measured for 600 secs by Fluo-4 AM-based fluorometric assay relative to control	ic50	0.6000	uM
3-[4-[4-(2,3-dimethoxyphenyl)phenyl]triazol-1-yl]benzoic acid	1683722: Inhibition of STIM1/Orai1 (unknown origin) expressed in HEK293 cells assessed as reduction in tBHQ-induced calcium response	ic50	0.7810	uM
3-[1-[4-(3,5-dimethoxyphenyl)phenyl]triazol-4-yl]benzoic acid	1683722: Inhibition of STIM1/Orai1 (unknown origin) expressed in HEK293 cells assessed as reduction in tBHQ-induced calcium response	ic50	0.8020	uM
3-[1-[4-(3-methoxyphenyl)phenyl]triazol-4-yl]benzoic acid	1683722: Inhibition of STIM1/Orai1 (unknown origin) expressed in HEK293 cells assessed as reduction in tBHQ-induced calcium response	ic50	0.8070	uM
3-[1-[4-(2,3-dimethoxyphenyl)phenyl]triazol-4-yl]benzoic acid	1683722: Inhibition of STIM1/Orai1 (unknown origin) expressed in HEK293 cells assessed as reduction in tBHQ-induced calcium response	ic50	0.8510	uM
3-[4-[4-(2-fluoro-5-methoxyphenyl)phenyl]triazol-1-yl]benzoic acid	1683722: Inhibition of STIM1/Orai1 (unknown origin) expressed in HEK293 cells assessed as reduction in tBHQ-induced calcium response	ic50	0.8660	uM
2,6-difluoro-N-[1-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]pyrazol-3-yl]benzamide	1774779: Inhibition of Orai1/STIM1 (unknown origin) expressed in HEK293 cells assessed as reduction in Ca2+-release activated Ca2+ entry current by manual patch clamp based electrophysiological method	ic50	1.0000	uM
3-[1-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]triazol-4-yl]benzoic acid	1683722: Inhibition of STIM1/Orai1 (unknown origin) expressed in HEK293 cells assessed as reduction in tBHQ-induced calcium response	ic50	1.1980	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
3-[1-[4-(2,3-dihydro-1,4-benzodioxin-5-yl)phenyl]triazol-4-yl]benzoic acid	1683722: Inhibition of STIM1/Orai1 (unknown origin) expressed in HEK293 cells assessed as reduction in tBHQ-induced calcium response	ic50	1.6210	uM
3-[4-[4-(2,5-dimethoxyphenyl)phenyl]triazol-1-yl]benzoic acid	1683722: Inhibition of STIM1/Orai1 (unknown origin) expressed in HEK293 cells assessed as reduction in tBHQ-induced calcium response	ic50	1.7900	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
N-[4-[3,5-bis(trifluoromethyl)pyrazol-1-yl]phenyl]-4-methylthiadiazole-5-carboxamide	1330311: Inhibition of Orai1-mediated store operated Ca2+ entry in human MDA-MB-231 cells assessed as reduction in BAPTA-induced Ca2+ depletion-stimulated SOCE activity preincubated for 15 mins followed by BAPTA addition in presence of extracellular Ca2+ by PBX-based FLIPR assay	ic50	2.8000	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
3-[1-[4-[4-propan-2-yloxycarbonyl-5-(trifluoromethyl)pyrazol-1-yl]phenyl]triazol-4-yl]benzoic acid	1363555: Modulation of TRPC1/TRPC3/STIM1/Orai1 in HEK cells assessed as induction of store-operated calcium entry by measuring residual activity preincubated for 30 mins followed by tBhQ-mediated Ca2+ depletion and Ca2+ re-addition to extracellular solution measured for 600 secs by Fluo-4 AM-based fluorometric assay relative to control	ic50	3.1000	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	1774818: Inhibition of human STIM1/Orai1 expressed in HEK293 cells assessed as reduction in Orai1 current by electrophysiological method	ic50	4.0000	uM
Teriflunomide	1683722: Inhibition of STIM1/Orai1 (unknown origin) expressed in HEK293 cells assessed as reduction in tBHQ-induced calcium response	ic50	4.3000	uM
3-[1-[4-[4-pentan-2-yloxycarbonyl-5-(trifluoromethyl)pyrazol-1-yl]phenyl]triazol-4-yl]benzoic acid	1363555: Modulation of TRPC1/TRPC3/STIM1/Orai1 in HEK cells assessed as induction of store-operated calcium entry by measuring residual activity preincubated for 30 mins followed by tBhQ-mediated Ca2+ depletion and Ca2+ re-addition to extracellular solution measured for 600 secs by Fluo-4 AM-based fluorometric assay relative to control	ic50	4.4000	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

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Estradiol	increases reaction, affects expression, increases expression, decreases expression	2
FR900359	decreases phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
methylmercuric chloride	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
di-n-butylphosphoric acid	affects expression	1
usnic acid	increases expression, decreases reaction	1
perfluorooctane sulfonic acid	increases expression	1
2-aminoethoxydiphenyl borate	decreases reaction, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	increases expression	1
Ethanol	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Carbamazepine	affects expression	1
Demecolcine	decreases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Lead	affects binding, affects response to substance, increases transport	1
Methamphetamine	increases expression, affects reaction	1
Plant Extracts	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Testosterone	decreases expression	1
Thiram	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	increases methylation	1
Vincristine	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Okadaic Acid	increases expression	1

ChEMBL screening assays

59 unique, capped per target: 57 binding, 1 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3405048	Binding	Inhibition of human Orai1/STIM1 expressed in HEK293 cells assessed as inhibition of channel-mediated calcium current by electrophysiology assay in presence of 10 mM EGTA	Discovery of 7-azaindole derivatives as potent Orai inhibitors showing efficacy in a preclinical model of asthma. — Bioorg Med Chem Lett
CHEMBL3734079	Functional	Inhibition of human Orai1/STIM1 expressed in HEK293 cells assessed as intracellular calcium level after 30 mins by FLIPR assay	Compounds that modulate intracellular calcium
CHEMBL4714763	ADMET	Inhibition of STIM/Orai1 (unknown origin) expressed in HEK293 cells assessed as reduction in thapsigargin-induced Ca2+ influx at 10 uM in presence of Ca2+ by whole cell patch clamp method	Discovery of a Highly Selective and Potent TRPC3 Inhibitor with High Metabolic Stability and Low Toxicity. — ACS Med Chem Lett

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1XZ	Abcam A-549 ORAI1 KO	Cancer cell line	Male
CVCL_D2C8	Abcam HCT 116 ORAI1 KO	Cancer cell line	Male
CVCL_D9LW	Ubigene HEK293 ORAI1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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