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): 268 total — 6 pathogenic, 8 likely-pathogenic
• GTEx eGene: eQTL in 23 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 62
• ChEMBL bioactivity: 5 clinical-phase molecules tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.24 (unconstrained)

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

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

ENST00000611718, ENST00000617316, ENST00000646827, ENST00000698901

RefSeq mRNA: 0

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.

Highest expression (Bgee): granulocyte, hindlimb stylopod muscle, skin of leg, skin of abdomen, zone of skin.

Genetic regulation across tissues (GTEx eQTL / sQTL)

ORAI1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 23 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 24 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	2.1e-19	+0.24	12:121646075:C:T
Esophagus Mucosa	eqtl	8.2e-15	+0.33	12:121634923:C:A
Thyroid	eqtl	8.7e-13	+0.26	12:121623129:T:C
Nerve Tibial	eqtl	1.1e-08	-0.18	12:121660261:T:TCAAA
Pancreas	eqtl	1.1e-07	+0.29	12:121642853:G:A
Colon Transverse	eqtl	5.7e-07	+0.27	12:121641283:C:T
Muscle Skeletal	eqtl	1.2e-05	+0.16	12:121694606:C:T
Skin Sun Exposed Lower leg	eqtl	2.1e-05	-0.08	12:121576687:C:G
Artery Aorta	eqtl	3.5e-05	+0.51	12:121681507:T:TC
Cells Cultured fibroblasts	eqtl	4.3e-05	+0.08	12:121667544:T:C
Esophagus Muscularis	eqtl	1.9e-04	+0.41	12:121615312:T:C
Heart Atrial Appendage	eqtl	2.6e-04	+0.23	12:121634923:C:A
Stomach	eqtl	2.6e-04	+0.24	12:121642853:G:A
Esophagus Gastroesophageal Junction	eqtl	5.1e-04	+0.24	12:121634923:C:A
Lung	eqtl	1.7e-03	+0.16	12:121674310:C:T
Adipose Visceral Omentum	eqtl	2.1e-03	+0.16	12:121641283:C:T
Cells EBV-transformed lymphocytes	eqtl	2.8e-03	+0.21	12:121629033:T:C
Spleen	eqtl	4.7e-03	-0.48	12:121643514:C:T
Artery Coronary	sqtl	3.0e-02	-3.05	12:122110544:C:T
Adipose Subcutaneous	eqtl	3.1e-02	-0.19	12:121640189:G:A

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

showing 100 of 245 tissues 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
skeletal muscle tissue	UBERON:0001134	82.19	gold quality
small intestine	UBERON:0002108	81.89	gold quality
right lobe of thyroid gland	UBERON:0001119	81.88	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	81.88	gold quality
upper leg skin	UBERON:0004262	81.86	gold quality
right lobe of liver	UBERON:0001114	81.84	gold quality
mouth mucosa	UBERON:0003729	81.69	gold quality
muscle layer of sigmoid colon	UBERON:0035805	81.52	gold quality
lower esophagus muscularis layer	UBERON:0035833	81.28	gold quality
lower esophagus	UBERON:0013473	81.26	gold quality
transverse colon	UBERON:0001157	81.25	gold quality
duodenum	UBERON:0002114	81.19	gold quality
saliva-secreting gland	UBERON:0001044	81.16	gold quality
left lobe of thyroid gland	UBERON:0001120	81.10	gold quality
omental fat pad	UBERON:0010414	80.97	gold quality
muscle tissue	UBERON:0002385	80.89	gold quality
peritoneum	UBERON:0002358	80.87	gold quality
tibial nerve	UBERON:0001323	80.65	gold quality
stomach	UBERON:0000945	80.64	gold quality
pancreatic ductal cell	CL:0002079	80.47	silver quality
quadriceps femoris	UBERON:0001377	80.39	silver quality
left uterine tube	UBERON:0001303	80.24	gold quality
adipose tissue of abdominal region	UBERON:0007808	80.16	gold quality
metanephros cortex	UBERON:0010533	80.03	gold quality
esophagus	UBERON:0001043	79.75	gold quality
left testis	UBERON:0004533	79.52	gold quality
right ovary	UBERON:0002118	79.32	gold quality
thyroid gland	UBERON:0002046	79.05	gold quality
esophagus mucosa	UBERON:0002469	78.97	gold quality
subcutaneous adipose tissue	UBERON:0002190	78.94	gold quality
gall bladder	UBERON:0002110	78.89	gold quality
bone marrow cell	CL:0002092	78.88	gold quality
heart left ventricle	UBERON:0002084	78.83	gold quality
endocervix	UBERON:0000458	78.58	gold quality
left coronary artery	UBERON:0001626	78.56	gold quality
right testis	UBERON:0004534	78.40	gold quality
right atrium auricular region	UBERON:0006631	78.32	gold quality
ectocervix	UBERON:0012249	78.28	gold quality
intestine	UBERON:0000160	78.10	gold quality
cardiac ventricle	UBERON:0002082	77.96	gold quality
testis	UBERON:0000473	77.89	gold quality
body of uterus	UBERON:0009853	77.86	gold quality
colon	UBERON:0001155	77.80	gold quality
jejunal mucosa	UBERON:0000399	77.38	gold quality
large intestine	UBERON:0000059	77.30	gold quality
right coronary artery	UBERON:0001625	77.20	gold quality
ventricular zone	UBERON:0003053	77.17	gold quality
left adrenal gland	UBERON:0001234	77.16	gold quality
right adrenal gland	UBERON:0001233	77.13	gold quality
cardiac atrium	UBERON:0002081	77.10	gold quality
body of pancreas	UBERON:0001150	76.97	gold quality
lower esophagus mucosa	UBERON:0035834	76.76	gold quality
left adrenal gland cortex	UBERON:0035825	76.56	gold quality
right adrenal gland cortex	UBERON:0035827	76.46	gold quality
thoracic aorta	UBERON:0001515	76.40	gold quality
coronary artery	UBERON:0001621	76.39	gold quality
ascending aorta	UBERON:0001496	76.38	gold quality
secondary oocyte	CL:0000655	76.36	silver quality
left ovary	UBERON:0002119	76.33	gold quality
heart	UBERON:0000948	76.27	gold quality
anatomical system	UBERON:0000467	76.04	gold quality
lung	UBERON:0002048	76.01	gold quality
bone marrow	UBERON:0002371	75.82	gold quality
multicellular organism	UBERON:0000468	75.70	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	75.69	gold quality
material anatomical entity	UBERON:0000465	75.67	gold quality
descending thoracic aorta	UBERON:0002345	75.46	gold quality
adult mammalian kidney	UBERON:0000082	75.43	gold quality
smooth muscle tissue	UBERON:0001135	75.33	gold quality
aorta	UBERON:0000947	75.23	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

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Skeletal muscle	tissue	57.2	low
Choroid plexus	tissue	41.9
Skin 1	tissue	26.3	high
Duodenum	tissue	20.4	medium
Substantia nigra	tissue	13.5
Spleen	tissue	13.5	low
Tongue	tissue	13.3
Spinal cord	tissue	12.8
Lymph node	tissue	12.5	not detected
Periaqueductal gray	tissue	11.8
Medulla oblongata	tissue	11.7
Hypothalamus	tissue	11.7
Superior colliculi	tissue	11.6
Pons	tissue	11.4
Salivary gland	tissue	11.4	not detected
Small intestine	tissue	11.1	low
Thalamus	tissue	10.1
Midbrain	tissue	9.9
Septum	tissue	9.7
Appendix	tissue	9.7	low
Parathyroid gland	tissue	9.5	medium
Bone marrow	tissue	9.4	not detected
Corpus callosum	tissue	7.9
Hippocampal formation	tissue	7.9
Stomach 1	tissue	7.8	not detected
Basal ganglia	tissue	7.8	not detected
Putamen	tissue	7.7
Ventral forebrain	tissue	7.7
Lung	tissue	7.4	low
Vagina	tissue	7.1	not detected
Amygdala	tissue	7.1
Cerebral cortex	tissue	7.0	low
Motor cortex	tissue	7.0
Olfactory bulb	tissue	6.8
Prefrontal cortex	tissue	6.7
Caudate putamen	tissue	6.7
Entorhinal cortex	tissue	6.6
Retrosplenial and cingulate cortex	tissue	6.6
Temporal cortex	tissue	6.6
Insular cortex	tissue	6.6
Frontal cortex	tissue	6.3
Retrosplenial cortex	tissue	6.3
Occipital cortex	tissue	6.3
Somatosensory cortex	tissue	6.2
Thymus	tissue	6.0
Cerebellum	tissue	5.9	not detected
Pancreas	tissue	5.5	not detected
Esophagus	tissue	5.2	medium
Testis	tissue	4.7	high
Placenta	tissue	4.6	not detected
Urinary bladder	tissue	4.4	low
Ovary	tissue	4.3	not detected
Adipose tissue	tissue	4.2	not detected
Colon	tissue	3.9	low
Locus coeruleus	tissue	3.8
Liver	tissue	3.6	not detected
Gallbladder	tissue	3.4	medium
Heart muscle	tissue	3.1	medium
Tonsil	tissue	3.1	low
Cervix	tissue	2.9	medium

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Dorsal spinal cord (12.8), Ventral spinal cord (11.3), Dorsal hippocampus (7.9), White matter (7.9), Ventral hippocampus (7.6).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB

miRNA regulators (miRDB)

Targeting ORAI1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

14 miRNAs:

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

Functional genomics

gnomAD constraint: pLI 0.000206, LOEUF 1.24, missense Z 1.01 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000617316 splits into 2 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
12:121,626,743–121,627,013	183 / 138.3	1.32	no
12:121,627,014–121,641,640	235 / 297.3	0.79	no

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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1925542) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 81 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased circulating calcium level	2
impaired muscle contractility	2
decreased body weight	2
abnormal mast cell physiology	2
increased muscle fatigability	2
abnormal calcium ion homeostasis	2
abnormal B cell activation	2
decreased interferon-gamma secretion	2
decreased interleukin-2 secretion	2
kyphosis	1
extramedullary hematopoiesis	1
alopecia	1
muscle weakness	1
seminiferous tubule degeneration	1
abnormal spermatogenesis	1
thin skin	1
decreased body length	1
decreased body size	1
short vibrissae	1
pup cannibalization	1
abnormal embryo size	1
abnormal T cell activation	1
male infertility	1
abnormal spermiogenesis	1
abnormal muscle physiology	1

+56 more (showing top 25).

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
MIR7107	ncRNA	102465665
RNF34	protein-coding	80196
KDM2B	protein-coding	84678
TMEM120B	protein-coding	144404
SETD1B	protein-coding	23067
MORN3	protein-coding	283385
LINC01089	ncRNA	338799
RHOF	protein-coding	54509
KDM2B-DT	ncRNA	101928346
TIALD	ncRNA	105370035
HPD	protein-coding	3242
ANAPC5	protein-coding	51433

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)

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

UniProt features (52 total): mutagenesis site 19, region of interest 6, sequence variant 6, topological domain 5, transmembrane region 4, helix 3, compositionally biased region 2, modified residue 2, chain 1, site 1, glycosylation site 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures by resolution:

PDB	Title	Method	Resolution (Å)
4EHQ	Crystal Structure of Calmodulin Binding Domain of Orai1 in Complex with Ca2+/Calmodulin …	X-RAY DIFFRACTION	1.9
2MAK	Solution structure of the STIM1 CC1-CC2 homodimer in complex with two Orai1 C-terminal …	SOLUTION NMR

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Transporters, Transporter channels and pores, Predicted membrane proteins, Disease related genes, Potential drug targets, Human disease related genes, Primary immunodeficiency

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH 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
106	confers selective permeability to ca(2+) ions

Post-translational modifications (2)

Type	Positions
Phosphothreonine	295
Phosphoserine	298

Glycosylation sites (1)

Type	Positions
N-linked (glcnac…) asparagine	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. reduces the …
5	generates both inward and outward rectifying crac currents at negative membrane potentials; when associated with a-3. reduces the …
39	generates both inward and outward rectifying crac currents at negative membrane potentials; when associated with a-40. reduces the …
40	generates both inward and outward rectifying crac currents at negative membrane potentials; when associated with a-39. reduces the …
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 localization to the …
106	dominant-negative. inhibits endogenous crac and arc channels. confers selective permeability to monovalent cations. does not affect …
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 to the cell …
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 and clustering in …
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

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: 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 (14): 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), 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), calcium ion transmembrane transport (GO:0070588), immune system process (GO:0002376), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), calcium-mediated signaling (GO:0019722), 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

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

34 GO namespaces:

Category	Terms
calcium ion transport	4
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
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
monoatomic cation transmembrane transport	1
biological_process	1
transport	1
metal ion transport	1
intracellular signaling cassette	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
membrane microdomain	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 15 of 26 annotations. The rest are phylogenetic / computational / electronic (IEA).

15 experimentally-supported GO terms:

GO term	NS	Evidence
calcineurin-NFAT signaling cascade	BP	mutant phenotype
calcium ion transmembrane transport	BP	direct assay
calcium-ion regulated exocytosis	BP	mutant phenotype
positive regulation of adenylate cyclase activity	BP	direct assay
positive regulation of calcium ion transport	BP	direct assay
regulation of calcium ion transport	BP	mutant phenotype
store-operated calcium entry	BP	direct assay
cell periphery	CC	direct assay
membrane	CC	high-throughput assay
membrane raft	CC	direct assay
plasma membrane	CC	direct assay
plasma membrane raft	CC	direct assay
calcium channel activity	MF	direct assay
identical protein binding	MF	physical interaction
store-operated calcium channel activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,092 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ORAI1	STIM1	Q13586	993
ORAI1	STIM2	Q9P246	974
ORAI1	TRPC1	P48995	910
ORAI1	TRPC3	Q13507	864
ORAI1	TRPC6	Q9Y210	793
ORAI1	TRPC4	Q9UBN4	791
ORAI1	SARAF	Q96BY9	770
ORAI1	ITPR1	Q14643	763
ORAI1	ITPR3	Q14573	763
ORAI1	TRPC5	Q9UL62	758
ORAI1	CACNA1C	Q13936	733
ORAI1	TRPM2	O94759	677
ORAI1	RYR1	P21817	616
ORAI1	ATP2C2	O75185	612
ORAI1	TRPM7	Q96QT4	589

IntAct

Human interaction partners of ORAI1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

14 partners by confidence:

Partner	Interaction type	MIscore	Records
STIM1	physical association	0.960	21
USP11	physical association	0.650	4
ORAI3	direct interaction	0.640	4
ATP2C2	physical association	0.610	10
CRACR2A	direct interaction	0.590	3
SLC35G1	physical association	0.560	5
TRPC3	direct interaction	0.540	2
EFHB	physical association	0.400	2
TRPC1	physical association	0.400	2
UBE3B	physical association	0.400	1
SARAF	colocalization	0.380	1
WLS	physical association	0.370	3
IPO5	association	0.350	1
POTEF	association	0.350	1

BioGRID (56 interactions; top human partners by supporting records): ATP2C2 (Affinity Capture-Western; 3 records), LPAR6 (Affinity Capture-MS; 3 records), STIM1 (Affinity Capture-Western; 3 records), CCDC47 (Affinity Capture-Western; 2 records), FAF2 (Affinity Capture-MS; 2 records), TSPAN18 (Affinity Capture-Western; 2 records), ACE2 (Affinity Capture-Western), ACSL4 (Affinity Capture-MS), ARFGEF1 (Affinity Capture-MS), ARFGEF2 (Affinity Capture-MS), ATP7A (Affinity Capture-MS), BPIFA1 (Affinity Capture-Western), CDC123 (Affinity Capture-MS), CHPT1 (Affinity Capture-MS), CPA5 (Affinity Capture-MS)

SIGNOR signaling

showing 1 of 2 signaling interactions:

A	Effect	B	Mechanism
PRKCB	down-regulates	ORAI1	phosphorylation

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
TRPC1-STIM1-ORAI1 complex	3	ORAI1, STIM1, TRPC1

Disease & clinical

Genetic variants

Variant evidence for ORAI1: 268 ClinVar records (14 pathogenic / likely pathogenic); 2 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	8
Uncertain significance	143
Likely benign	87
Benign	12

Top pathogenic / likely-pathogenic (14)

Showing all 14 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
192288	NM_032790.4(ORAI1):c.581T>C (p.Leu194Pro)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
2171110	NM_032790.4(ORAI1):c.802C>T (p.Arg268Ter)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
3383981	NM_032790.1(ORAI1):c.493dup	Pathogenic	criteria provided, single submitter	1
1464680	NM_032790.4(ORAI1):c.750dup (p.Ile251Tyrfs)	Likely pathogenic	criteria provided, single submitter	1
2432388	NM_032790.4(ORAI1):c.777dup (p.Ser260Leufs)	Likely pathogenic	criteria provided, single submitter	1
2944495	NM_032790.4(ORAI1):c.505dup (p.His169fs)	Likely pathogenic	criteria provided, single submitter	1
4791642	NR_186857.1(ORAI1):n.906_909dup	Likely pathogenic	criteria provided, single submitter	1
1069742	NC_000012.12:g.121641056G>A	Pathogenic	criteria provided, single submitter	1
1428101	NC_000012.11:g.(?122064648)(122064976_?)del	Pathogenic	criteria provided, single submitter	1
3754970	NC_000012.12:g.121641254G>T	Pathogenic	criteria provided, single submitter	1
639606	NC_000012.12:g.121641283del	Likely pathogenic	criteria provided, single submitter	1
1505011	NC_000012.12:g.121641350C>T	Likely pathogenic	criteria provided, single submitter	1
139640	NM_032790.4(ORAI1):c.734C>T (p.Pro245Leu)	Pathogenic	no assertion criteria provided	1
192287	NM_032790.4(ORAI1):c.308C>A (p.Ala103Glu)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore ORAI1’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.

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Disease associations

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

GenCC curated gene-disease

4 curated gene-disease records:

Disease	Classification	Inheritance	Records
combined immunodeficiency due to ORAI1 deficiency	Strong	Autosomal recessive	3
myopathy, tubular aggregate, 2	Strong	Autosomal dominant
tubular aggregate myopathy	Strong	Autosomal dominant	2
Stormorken syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
tubular aggregate myopathy	Definitive	AD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (10 panels, 8 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

10 panels:

Panel	Rating
Amelogenesis imperfecta	green
Arthrogryposis	green
COVID-19 research	green
Congenital myopathy	green
Hypotonic infant	green
Limb girdle muscular dystrophies, myofibrillar myopathies and distal myopathies	green
Other rare neuromuscular disorders	green
Primary immunodeficiency or monogenic inflammatory bowel disease	green
Fetal anomalies	amber
Inherited bleeding disorders	amber

Mondo (4): combined immunodeficiency due to ORAI1 deficiency (MONDO:0013007), myopathy, tubular aggregate, 2 (MONDO:0014383), 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

showing 60 of 62 phenotypes (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
HP:0002747	Respiratory insufficiency due to muscle weakness
HP:0002850	Decreased circulating IgM concentration
HP:0002901	Hypocalcemia
HP:0003011	Abnormality of the musculature
HP:0003198	Myopathy
HP:0003236	Elevated circulating creatine kinase activity
HP:0003306	Spinal rigidity
HP:0003324	Generalized muscle weakness
HP:0003326	Myalgia
HP:0003391	Gowers sign
HP:0003394	Muscle spasm
HP:0003458	EMG: myopathic abnormalities
HP:0003473	Fatigable weakness
HP:0003554	Type 2 muscle fiber atrophy
HP:0003557	Increased variability in muscle fiber diameter
HP:0003577	Congenital onset
HP:0003621	Juvenile onset
HP:0003677	Slowly progressive
HP:0003687	Centrally nucleated skeletal muscle fibers
HP:0003701	Proximal muscle weakness
HP:0004315	Decreased circulating IgG concentration
HP:0004322	Short stature
HP:0006466	Ankle flexion contracture
HP:0008064	Ichthyosis
HP:0009027	Foot dorsiflexor weakness
HP:0010280	Stomatitis
HP:0011107	Recurrent aphthous stomatitis
HP:0011463	Childhood onset
HP:0020086	BCGitis
HP:0030200	Fatiguable weakness of proximal limb muscles

GWAS associations

2 associations:

Study	Trait	p-value
GCST006944_52	Experiencing mood swings	6e-10
GCST005547_11	Major depressive disorder	9e-7

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0008475	mood instability measurement

MeSH disease descriptors

2 disease descriptors:

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

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 87,147 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

5 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL808	ECONAZOLE	4	25,002
CHEMBL45816	MIBEFRADIL	4	7,926
CHEMBL91	MICONAZOLE	4	46,246
CHEMBL973	TERIFLUNOMIDE	4	7,705
CHEMBL4753998	ZEGOCRACTIN	2	268

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
rs12320939	erythropoietin	Efficacy	Genotypes GG + GT is associated with increased resistance to erythropoietin in people with Kidney Diseases and Anemia as compared to genotype TT.	PMID:39214396

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)

147 measured of 242 human assays (249 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(2,5-dioxo-1-phenylpyrrolidin-3-yl) N-[5-(hydroxymethyl)-2-methoxyphenyl]-N’-[2-(4-sulfamoylphenyl)ethyl]carbamimidothioate	IC50	0.2 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
ethyl 4-[3-(N’-cyclopropyl-N-phenylcarbamimidoyl)sulfanyl-2,5-dioxopyrrolidin-1-yl]benzoate	IC50	0.95 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
(2,5-dioxo-1-phenylpyrrolidin-3-yl) N-[4-(hydroxymethyl)phenyl]-N’-[2-(4-sulfamoylphenyl)ethyl]carbamimidothioate	IC50	1.6 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
[1-(4-methoxyphenyl)-2,5-dioxopyrrolidin-3-yl] N-phenyl-N’-[2-(4-sulfamoylphenyl)ethyl]carbamimidothioate	IC50	5.01 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
(2,5-dioxo-1-phenylpyrrolidin-3-yl) N-(4-methylphenyl)-N’-[2-(4-sulfamoylphenyl)ethyl]carbamimidothioate	IC50	5.83 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
[1-(4-methylphenyl)-2,5-dioxopyrrolidin-3-yl] N-(4-methylphenyl)-N’-[2-(4-sulfamoylphenyl)ethyl]carbamimidothioate	IC50	5.84 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
ethyl 4-[2,5-dioxo-3-(N-phenyl-N’-propan-2-ylcarbamimidoyl)sulfanylpyrrolidin-1-yl]benzoate	IC50	6.34 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
methyl 4-[3-[N-(4-methylphenyl)-N’-[2-(4-sulfamoylphenyl)ethyl]carbamimidoyl]sulfanyl-2,5-dioxopyrrolidin-1-yl]benzoate	IC50	9.2 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
methyl 4-[3-[N-(1,3-benzodioxol-5-yl)-N’-ethylcarbamimidoyl]sulfanyl-2,5-dioxopyrrolidin-1-yl]benzoate	IC50	10.5 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
(2,5-dioxo-1-phenylpyrrolidin-3-yl) N-phenyl-N’-[2-(4-sulfamoylphenyl)ethyl]carbamimidothioate	IC50	10.9 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
methyl 4-[3-[N-(3-methoxyphenyl)-N’-[2-(4-sulfamoylphenyl)ethyl]carbamimidoyl]sulfanyl-2,5-dioxopyrrolidin-1-yl]benzoate	IC50	11.2 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
methyl 4-[3-[N-(3-chloro-4-methylphenyl)-N’-ethylcarbamimidoyl]sulfanyl-2,5-dioxopyrrolidin-1-yl]benzoate	IC50	11.3 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
methyl 4-[2,5-dioxo-3-(N-phenyl-N’-propan-2-ylcarbamimidoyl)sulfanylpyrrolidin-1-yl]benzoate	IC50	11.7 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
methyl 4-[2,5-dioxo-3-[N-phenyl-N’-[2-(4-sulfamoylphenyl)ethyl]carbamimidoyl]sulfanylpyrrolidin-1-yl]benzoate	IC50	13 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
methyl 4-[3-[N-[4-(hydroxymethyl)phenyl]-N’-[2-(4-sulfamoylphenyl)ethyl]carbamimidoyl]sulfanyl-2,5-dioxopyrrolidin-1-yl]benzoate	IC50	14.8 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
ethyl 4-[2,5-dioxo-3-[N-phenyl-N’-[2-(4-sulfamoylphenyl)ethyl]carbamimidoyl]sulfanylpyrrolidin-1-yl]benzoate	IC50	15.8 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
[1-[4-(methylcarbamoyl)phenyl]-2,5-dioxopyrrolidin-3-yl] N-phenyl-N’-[2-(4-sulfamoylphenyl)ethyl]carbamimidothioate	IC50	18.2 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
N-[4-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]-3-fluoropyridine-4-carboxamide	IC50	20.4 nM	US-10668051: Modulators of calcium release-activated calcium channel
N-[4-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]-3-fluorophenyl]-5-methyl-1,2-oxazole-4-carboxamide	IC50	20.8 nM	US-10668051: Modulators of calcium release-activated calcium channel
methyl 4-[3-[N-(2,5-dimethoxyphenyl)-N’-[2-(4-sulfamoylphenyl)ethyl]carbamimidoyl]sulfanyl-2,5-dioxopyrrolidin-1-yl]benzoate	IC50	21.2 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
ethyl 4-[3-(N’-methyl-N-phenylcarbamimidoyl)sulfanyl-2,5-dioxopyrrolidin-1-yl]benzoate	IC50	22.4 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
N-[6-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]-2-methylbenzamide	IC50	23 nM	US-10668051: Modulators of calcium release-activated calcium channel
methyl 4-[3-(N’-methyl-N-phenylcarbamimidoyl)sulfanyl-2,5-dioxopyrrolidin-1-yl]benzoate	IC50	24.9 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
methyl 4-[3-[N-(2,5-dichlorophenyl)-N’-methylcarbamimidoyl]sulfanyl-2,5-dioxopyrrolidin-1-yl]benzoate	IC50	30.6 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
N-[4-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]-3-fluorophenyl]-2,3-difluorobenzamide	IC50	32.6 nM	US-10668051: Modulators of calcium release-activated calcium channel
4-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]-N-(4-methyl-1,3-thiazol-5-yl)benzamide	IC50	34.1 nM	US-10668051: Modulators of calcium release-activated calcium channel
N-[4-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]-3-fluorophenyl]-4-methylthiadiazole-5-carboxamide	IC50	35.7 nM	US-10668051: Modulators of calcium release-activated calcium channel
N-[4-(3,5-dicyclopropylpyrazol-1-yl)phenyl]-2-methylbenzamide	IC50	36.4 nM	US-10668051: Modulators of calcium release-activated calcium channel
N-[6-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]-3-fluoropyridine-4-carboxamide	IC50	37.6 nM	US-10668051: Modulators of calcium release-activated calcium channel
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
N-[6-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]pyridine-3-carboxamide	IC50	47.2 nM	US-10668051: Modulators of calcium release-activated calcium channel
4-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]-N-[(4-methyl-1,3-thiazol-5-yl)methyl]aniline	IC50	48 nM	US-10668051: Modulators of calcium release-activated calcium channel
N-[4-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]-2-pyridin-3-ylacetamide	IC50	48.2 nM	US-10668051: Modulators of calcium release-activated calcium channel
N-[4-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]-3-fluorophenyl]-4-methyl-1,3-thiazole-5-carboxamide	IC50	48.2 nM	US-10668051: Modulators of calcium release-activated calcium channel
N-[6-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]-2,6-difluorobenzamide	IC50	50.6 nM	US-10668051: Modulators of calcium release-activated calcium channel
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-(difluoromethyl)-3-(trifluoromethyl)pyrazol-1-yl]phenyl]-4-methyl-1,3-thiazole-5-carboxamide	IC50	52.6 nM	US-10668051: Modulators of calcium release-activated calcium channel
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-[6-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]-2-fluorobenzamide	IC50	60 nM	US-10668051: Modulators of calcium release-activated calcium channel
N-[4-(3,5-dicyclopropylpyrazol-1-yl)-3-fluorophenyl]-4-methylthiadiazole-5-carboxamide	IC50	60.3 nM	US-10668051: Modulators of calcium release-activated calcium channel
3-[[5-[(3-chloro-4-hydroxyphenyl)methyl]-3-methyl-4-oxo-1,3-thiazolidin-2-ylidene]amino]benzoate	IC50	60.3 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
N-[4-(3,5-dicyclopropylpyrazol-1-yl)phenyl]-4-methylthiadiazole-5-carboxamide	IC50	62.4 nM	US-10668051: Modulators of calcium release-activated calcium channel
N-[6-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]pyridine-4-carboxamide	IC50	62.6 nM	US-10668051: Modulators of calcium release-activated calcium channel
N-[4-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]-5-methyl-1,2-oxazole-4-carboxamide	IC50	63.2 nM	US-10668051: Modulators of calcium release-activated calcium channel
3,5-dichloro-N-[4-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]pyridine-4-carboxamide	IC50	65.5 nM	US-10668051: Modulators of calcium release-activated calcium channel
N-[6-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]-3-pyridinyl]-2,3-difluorobenzamide	IC50	70.3 nM	US-10668051: Modulators of calcium release-activated calcium channel
N-[4-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]-4-methyl-1,3-thiazole-5-carboxamide	IC50	72 nM	US-10668051: Modulators of calcium release-activated calcium channel
6-[5-cyclopropyl-3-(trifluoromethyl)pyrazol-1-yl]-N-(2,6-difluorophenyl)pyridine-3-carboxamide	IC50	72.1 nM	US-10668051: Modulators of calcium release-activated calcium channel
methyl 4-[3-[N-(2-methoxyphenyl)-N’-methylcarbamimidoyl]sulfanyl-2,5-dioxopyrrolidin-1-yl]benzoate	IC50	74.4 nM	US-11905244: Chemical modulators of store-operated calcium channels and their therapeutic applications
CHEMBL4868242	IC50	76 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

63 with measured affinity, of 401 total; 46 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
1-(cyclopropylmethyl)-N-(3-fluoro-4-pyridinyl)indazole-3-carboxamide	2204101: Inhibition of myc-tagged human orai-1 G98S mutant expressed in HEK293 cells assessed as decrease in inward current by patch clamp electrophysiology technique	ic50	4.9000	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

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
Estradiol	decreases expression, increases reaction, affects expression, increases 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)

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

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for ORAI1 across ~30M SureChEMBL compounds — explore on Sugi Predict.