STIM1

Summary

STIM1 (stromal interaction molecule 1, HGNC:11386) is a protein-coding gene on chromosome 11p15.4, encoding Stromal interaction molecule 1 (Q13586). Acts as a Ca(2+) sensor that gates 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.

This gene encodes a type 1 transmembrane protein that mediates Ca2+ influx after depletion of intracellular Ca2+ stores by gating of store-operated Ca2+ influx channels (SOCs). It is one of several genes located in the imprinted gene domain of 11p15.5, an important tumor-suppressor gene region. Alterations in this region have been associated with the Beckwith-Wiedemann syndrome, Wilms tumor, rhabdomyosarcoma, adrenocrotical carcinoma, and lung, ovarian, and breast cancer. This gene may play a role in malignancies and disease that involve this region, as well as early hematopoiesis, by mediating attachment to stromal cells. Mutations in this gene are associated with fatal classic Kaposi sarcoma, immunodeficiency due to defects in store-operated calcium entry (SOCE) in fibroblasts, ectodermal dysplasia and tubular aggregate myopathy. This gene is oriented in a head-to-tail configuration with the ribonucleotide reductase 1 gene (RRM1), with the 3’ end of this gene situated 1.6 kb from the 5’ end of the RRM1 gene. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 6786 — RefSeq curated summary.

At a glance

• Gene–disease (curated): tubular aggregate myopathy (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 19
• Clinical variants (ClinVar): 810 total — 22 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 91
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001382567

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11386
Approved symbol	STIM1
Name	stromal interaction molecule 1
Location	11p15.4
Locus type	gene with protein product
Status	Approved
Aliases	GOK, D11S4896E
Ensembl gene	ENSG00000167323
Ensembl biotype	protein_coding
OMIM	605921
Entrez	6786

Gene structure

Transcript identifiers

Ensembl transcripts: 35 — 23 protein_coding, 5 retained_intron, 5 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000300737, ENST00000524822, ENST00000525055, ENST00000525403, ENST00000526156, ENST00000526596, ENST00000526771, ENST00000527484, ENST00000527651, ENST00000528656, ENST00000530554, ENST00000531332, ENST00000532610, ENST00000532919, ENST00000532990, ENST00000533343, ENST00000533445, ENST00000533977, ENST00000534707, ENST00000616714, ENST00000698909, ENST00000698910, ENST00000698911, ENST00000698912, ENST00000698913, ENST00000698914, ENST00000698915, ENST00000698916, ENST00000698917, ENST00000698918, ENST00000698919, ENST00000698920, ENST00000862622, ENST00000862623, ENST00000952119

RefSeq mRNA: 19 — MANE Select: NM_001382567 NM_001277961, NM_001277962, NM_001382566, NM_001382567, NM_001382568, NM_001382569, NM_001382570, NM_001382571, NM_001382572, NM_001382573, NM_001382574, NM_001382575, NM_001382576, NM_001382577, NM_001382578, NM_001382579, NM_001382580, NM_001382581, NM_003156

CCDS: CCDS60706, CCDS73247, CCDS7749, CCDS91416, CCDS91417, CCDS91418, CCDS91419, CCDS91420, CCDS91421

Canonical transcript exons

ENST00000526596 — 13 exons

Exon	Start	End
ENSE00002161827	4084673	4084765
ENSE00002162132	4059281	4059396
ENSE00002198957	4091282	4093208
ENSE00003522616	3967552	3967682
ENSE00003552078	4055526	4055637
ENSE00003787177	4023873	4023987
ENSE00003914636	3855664	3856409
ENSE00003975155	4086477	4086543
ENSE00003975156	4074502	4074679
ENSE00003975157	4082184	4082351
ENSE00003975166	4082882	4082982
ENSE00003975176	4083263	4083498
ENSE00003975183	4070026	4070203

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 97.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.1073 / max 847.8642, expressed in 1812 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
112752	19.8994	1802
112751	4.5081	1596
112749	0.4559	179
112757	0.0965	48
112754	0.0545	19
112758	0.0357	17
112759	0.0306	20
112755	0.0265	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	97.10	gold quality
muscle of leg	UBERON:0001383	96.72	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.36	gold quality
minor salivary gland	UBERON:0001830	96.00	gold quality
stromal cell of endometrium	CL:0002255	95.96	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.96	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.95	gold quality
lower esophagus	UBERON:0013473	95.94	gold quality
right ovary	UBERON:0002118	95.92	gold quality
left ovary	UBERON:0002119	95.85	gold quality
popliteal artery	UBERON:0002250	95.66	gold quality
tibial artery	UBERON:0007610	95.65	gold quality
skin of leg	UBERON:0001511	95.62	gold quality
left uterine tube	UBERON:0001303	95.55	gold quality
mucosa of stomach	UBERON:0001199	95.42	gold quality
body of uterus	UBERON:0009853	95.39	gold quality
gall bladder	UBERON:0002110	95.37	gold quality
esophagus	UBERON:0001043	95.30	gold quality
aorta	UBERON:0000947	95.16	gold quality
skin of abdomen	UBERON:0001416	95.14	gold quality
ectocervix	UBERON:0012249	95.07	gold quality
endocervix	UBERON:0000458	95.01	gold quality
descending thoracic aorta	UBERON:0002345	94.95	gold quality
right coronary artery	UBERON:0001625	94.94	gold quality
right lobe of thyroid gland	UBERON:0001119	94.93	gold quality
esophagus mucosa	UBERON:0002469	94.81	gold quality
thoracic aorta	UBERON:0001515	94.76	gold quality
lower esophagus mucosa	UBERON:0035834	94.75	gold quality
ascending aorta	UBERON:0001496	94.71	gold quality
saliva-secreting gland	UBERON:0001044	94.53	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-75367	yes	307.18
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, AR, EGR1, ESR1, FOS, JUN, SNAI1, WT1

miRNA regulators (miRDB)

119 targeting STIM1, 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-5692A	100.00	74.40	6850
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-6756-5P	99.82	67.97	2466

Literature-anchored findings (GeneRIF, showing 40)

• STIM proteins function as Ca(2+) store sensors in the signaling pathway connecting Ca(2+) store depletion to Ca(2+) influx. (PMID:16005298)
• Increased expression levels of STIM1 correlate with a gain in function of Ca(2+) release-activated Ca(2+) (CRAC) channel activity. (PMID:16537481)
• 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)
• STIM1 is a required mediator of store-operated channel (SOC) activation and plays a coordinated role with STIM2 in controlling SOC-mediated Ca(2+) entry signals. (PMID:16860747)
• Interaction of STIM1 with endogenously expressed human canonical TRP1 upon depletion of intracellular Ca2+ stores. (PMID:16870612)
• STIM1 is a key regulator of activity rather than a channel component, and reveal similar regulation of SOC, I(crac) and TRPC channel activation by STIM1. (PMID:16906149)
• These studies identify an ER structure underlying store-operated Ca(2+) entry, whose extreme proximity to the PM may enable STIM1 to interact with CRAC channels or associated proteins. (PMID:16966422)
• STIM1 acts as a key signal for store operated calcium channel activation in human airway myocytes. (PMID:16987424)
• STIM1 has a role as an Endoplasmic Reticulum Ca2+ sensor (PMID:17020874)
• Therefore, we propose that store depletion causes aggregation and translocation of STIM1 in close apposition to the plasma membrane. (PMID:17045966)
• in contrast to store-operated channels, regulation of ARC channels by STIM1 depends exclusively on the pool of STIM1 constitutively residing in the plasma membrane (PMID:17158173)
• 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)
• endoplasmic reticulum refilling is largely preserved at reduced STIM1 levels (PMID:17283081)
• peripheral STIM1 relocalization that is causal in regulation of SOCE is determined by the status of [Ca(2+)] in the ER in close proximity to the plasma membrane (PMID:17298947)
• LPA and UTP may exert distinct effects on the duration of STIM1 localization at the plasma membrane, and thus, on the magnitude and duration of agonist-induced calcium entry (PMID:17299780)
• analysis of STIM1 surface exposure by fluorescent imaging with a hexahistidine-Zn2+-dye (PMID:17360414)
• We propose a new definition of SOCs, as channels that are regulated by STIM1 and require the store depletion-mediated clustering of STIM1. By this definition, all TRPC channels, except TRPC7, function as SOCs. (PMID:17486119)
• STIM1 oligomers translocate on average only 2 mum to reach endoplasmic reticulum-plasma membrane junctions (PMID:17517596)
• 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)
• Data suggest that microtubules play a facilitative role in the store-operated Ca(2+) entry signaling pathway by optimizing the localization of STIM1. (PMID:17925382)
• Our biophysical studies reveal a structural stability difference in the EF-SAM region between STIM1 and STIM2, which may account for their different biological functions. (PMID:18166150)
• 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)
• STIM1 directly binds to the microtubule-plus-end-tracking protein EB1 and forms EB1-dependent comet-like accumulations at the sites where polymerizing microtubule ends come in contact with the ER network. (PMID:18249114)
• 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)
• Soft substrate up-regulates the interaction of STIM1 with store-operated Ca(2+) channels, which results in the activation of mu-calpain and subsequently induces normal epithelial cell apoptosis. (PMID:18337467)
• The effects of 2-aminoethoxydiphenyl borate on orai1, orai2, orai3 metabolism in HEK293 cells with and without STIM1 are reported. (PMID:18403424)
• Data show that STIM1 and TRPC1 interact and insert TRPC1 into lipid rafts, where TRPC1 functions as a store-operated channel; in the absence of STIM1, TRPC1 associates with other members from the TRPC family of channels to form receptor-operated channels. (PMID:18420269)
• intact lipid raft domains determine targeting of STIM1 clusters to ER-plasma membrane junctions following store depletion which facilitates the functional interaction of STIM1 with TRPC1 and activation of store-operated Ca(2+) entry (PMID:18430726)
• 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)
• plasma membrane STIM1 may play a regulatory role in store-operated channel activation (PMID:18635545)
• 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)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	stim1a	ENSDARG00000060723
danio_rerio	stim1b	ENSDARG00000061560
mus_musculus	Stim1	ENSMUSG00000030987
rattus_norvegicus	Stim1	ENSRNOG00000020425
drosophila_melanogaster	Stim	FBGN0045073
caenorhabditis_elegans		WBGENE00021910

Paralogs (1): STIM2 (ENSG00000109689)

Protein

Protein identifiers

Stromal interaction molecule 1 — Q13586 (reviewed: Q13586)

All UniProt accessions (20): A0A8V8TMF0, A0A8V8TMG1, A0A8V8TMG5, Q13586, A0A8V8TMX0, A0A8V8TNW0, A0A8V8TNW5, A0A8V8TP73, A0A8V8TP78, E9PIQ8, E9PJ19, E9PMB4, E9PN27, E9PNJ4, E9PR07, E9PR09, E9PRE4, E9PRZ7, G0XQ39, H0YDB2

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a Ca(2+) sensor that gates 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. Plays a role in mediating store-operated Ca(2+) entry (SOCE), a Ca(2+) influx following depletion of intracellular Ca(2+) stores. Upon Ca(2+) depletion, translocates from the endoplasmic reticulum to the plasma membrane where it activates CRAC channel pore-forming subunits ORA1, ORA2 and ORAI3 to generate sustained and oscillatory Ca(2+) entry. Involved in enamel formation.

Subunit / interactions. Monomer in the presence of Ca(2+); it oligomerizes in absence of Ca(2+). Forms homooligomers and heterooligomers with STIM2. Interacts with pore-forming subunits of CRAC channels, ORAI1, ORAI2 and ORAI3; this interaction is potentiated upon Ca(2+) store depletion. Interacts (via the transmembrane region and the SOAR/CAD domain) with SPPL3; the interaction promotes the binding of STIM1 to ORAI1. Interacts (via the SOAR/CAD domain) with ORAI1. Interacts with MAPRE1; probably required for targeting to the growing microtubule plus ends. Interacts with CRACR2A/EFCAB4B; the interaction is direct and takes place in absence of Ca(2+). Forms a complex with CRACR2A/EFCAB4B and ORAI1 at low concentration of Ca(2+), the complex dissociates at elevated Ca(2+) concentrations. Interacts with SARAF, promoting a slow inactivation of STIM1-dependent SOCE activity, possibly by facilitating the deoligomerization of STIM1. Interacts with EFHB; the interaction takes place upon Ca(2+)-store depletion and inhibits the association with SARAF. Interacts with ASPH (isoform 8). Interacts with SLC35G1; intracellular Ca(2+)-dependent. May interact with ATP1A1, ATP2A2, ATP2B1, ATP2B4, KPNB1 and XPO1; through SLC35G1. Interacts with TMEM203. Interacts with STIMATE, promoting STIM1 conformational switch. Interacts with TMEM178A. Interacts with CASQ1 (via C-terminal end and preferentially with the monomeric form); this interaction increases in response to a depletion of intracellular Ca(2+), decreases both STIM1 aggregation and clustering, interaction of STIM1 with ORAI1 and store-operated Ca(2+) entry (SOCE) activity. Interacts with ADCY8.

Subcellular location. Cell membrane. Endoplasmic reticulum membrane. Cytoplasm. Cytoskeleton. Sarcoplasmic reticulum.

Tissue specificity. Ubiquitously expressed in various human primary cells and tumor cell lines.

Post-translational modifications. Glycosylation is required for cell surface expression. Phosphorylated predominantly on Ser residues.

Disease relevance. Immunodeficiency 10 (IMD10) [MIM:612783] An immune disorder characterized by recurrent infections, impaired activation and proliferative response of T-cells, decreased T-cell production of cytokines, lymphadenopathy, and normal lymphocytes counts and serum immunoglobulin levels. Additional features include thrombocytopenia, autoimmune hemolytic anemia, myopathy, partial iris hypoplasia, hepatosplenomegaly and defective enamel dentition. The disease is caused by variants affecting the gene represented in this entry. Myopathy, tubular aggregate, 1 (TAM1) [MIM:160565] 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. They may occur in a variety of circumstances, including inherited myopathies, alcohol- and drug-induced myopathies, exercise-induced cramps or muscle weakness. The disease is caused by variants affecting the gene represented in this entry. Stormorken syndrome (STRMK) [MIM:185070] A rare autosomal dominant disease characterized by mild bleeding tendency, thrombocytopathy, thrombocytopenia, mild anemia, asplenia, tubular aggregate myopathy, miosis, headache, and ichthyosis. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The microtubule tip localization signal (MtLS) motif; mediates interaction with MAPRE1 and targeting to the growing microtubule plus ends. The EF-hand domain is responsible for Ca(2+) sensitivity. It consists of a canonical helix-loop-helix EF motif (alpha1beta1alpha2; EF-hand 1) paired to a second helix-loop-helix EF motif (alpha3beta2alpha4; EF-hand 2). EF-hand 1 binds Ca(2+) whereas EF-hand 2 mediates the interactions with SAM domain. The sterile alpha motif (SAM) domain folds into a characteristic 5-helix bundle (alpha6-alpha10) which interacts with the EF-hand pairs enabling concerted folding and stability of EF-hand and SAM domains. The STIM1 Orai-activating region/CRAC-activating domain (SOAR/CAD) directly interacts with ORAI1 subunits and mediates CRAC channel gating. The polybasic Lys-rich region (residues 672-685) functionally interacts with the Pro-rich region of ORAI1 (residues 3-47) and regulates CRAC channel gating at negative membrane potentials.

Miscellaneous. Transfection of STIM1 into cells derived from a rhabdoid tumor and from a rhabdomyosarcoma that do not express detectable levels of STIM1 can induce cell death, suggesting a possible role in the control of rhabdomyosarcomas and rhabdoid tumors.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13586-1	1	yes
Q13586-2	2

RefSeq proteins (19): NP_001264890, NP_001264891, NP_001369495, NP_001369496, NP_001369497, NP_001369498, NP_001369499, NP_001369500, NP_001369501, NP_001369502, NP_001369503, NP_001369504, NP_001369505, NP_001369506, NP_001369507, NP_001369508, NP_001369509, NP_001369510, NP_003147 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001660	SAM	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR032393	SOAR_STIM1/2	Domain
IPR037608	STIM1/2	Family
IPR037609	STIM1_SAM	Domain
IPR057835	EF-hand_STIM1/2	Domain

Pfam: PF07647, PF16533, PF25578

UniProt features (111 total): mutagenesis site 27, modified residue 18, helix 17, sequence variant 14, region of interest 5, compositionally biased region 5, binding site 5, domain 3, turn 2, topological domain 2, glycosylation site 2, splice variant 2, sequence conflict 2, strand 2, signal peptide 1, chain 1, coiled-coil region 1, short sequence motif 1, transmembrane region 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
3TEQ	X-RAY DIFFRACTION	1.9
4O9B	X-RAY DIFFRACTION	2.6
2K60	SOLUTION NMR
2MAJ	SOLUTION NMR
2MAK	SOLUTION NMR
6YEL	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13586-F1	68.81	0.22

Functional residue map

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

Ligand- & substrate-binding residues (5): 76; 78; 80; 82; 87

Post-translational modifications (18): 257, 504, 512, 517, 519, 521, 523, 524, 567, 575, 602, 608, 618, 621, 628, 660, 665, 668

Glycosylation sites (2): 131, 171

Mutagenesis-validated functional residues (27):

Position	Phenotype
76	increases ca(2+) influx even when ca(2+) stores are not depleted. promotes constitutive activation of the ca2+ release-a
78	increases ca(2+) influx even when ca(2+) stores are not depleted.
87	increases ca(2+) influx through activation of crac channels, even when ca(2+) stores are not depleted.
108	constitutive localization in punctae at the cell membrane and constitutive activation of crac channels; when associated
110	constitutive localization in punctae at the cell membrane and constitutive activation of crac channels; when associated
131	impairs orai1 arc channel currents; when associated with q-171.
171	impairs orai1 arc channel currents; when associated with q-131.
195	constitutive localization in punctae at the cell membrane and constitutive activation of crac channels.
258	promotes constitutive activation of the ca2+ release-activated ca2+ (crac) channel.
318–322	constitutive activation of crac channels.
324	reduces activation of crac channels.
347	impairs orai1 crac channel gating; when associated with a-348. impairs the interaction and clustering with orai1 in punc
347	abolishes colocalization with orai1 and activation of crac channels.
348	impairs orai1 crac channel gating; when associated with a-347. impairs the interaction and clustering with orai1 in punc
351	abolishes colocalization with orai1 and activation of crac channels.
361–362	abolishes activation of crac channels.
380	constitutive activation of crac channels.
382–386	abolishes activation of crac channels.
383	abolishes activation of crac channels.
475	decreases fast ca(2+)-dependent inactivation of orai3 channels; when associated with a-476, a-478, a-479.
476	decreases fast ca(2+)-dependent inactivation of orai3 channels; when associated with a-475, a-478, a-479.
478	decreases fast ca(2+)-dependent inactivation of orai3 channels; when associated with a-475, a-476, a-479.
479	decreases fast ca(2+)-dependent inactivation of orai3 channels; when associated with a-475, a-476, a-478.
481	decreases fast ca(2+)-dependent inactivation of orai3 channels; when associated with a-482 and a-483.
482	decreases fast ca(2+)-dependent inactivation of orai3 channels; when associated with a-481 and a-483.

Function

Pathways and Gene Ontology

Reactome pathways

11 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
R-HSA-109582	Hemostasis
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-397014	Muscle contraction
R-HSA-418346	Platelet homeostasis
R-HSA-418360	Platelet calcium homeostasis
R-HSA-5576891	Cardiac conduction
R-HSA-983705	Signaling by the B Cell Receptor (BCR)

MSigDB gene sets: 453 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, MYOGENIN_Q6, GOBP_POSITIVE_REGULATION_OF_CATION_CHANNEL_ACTIVITY, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, AAGTCCA_MIR422B_MIR422A, GCANCTGNY_MYOD_Q6, GOBP_POSITIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_POSITIVE_REGULATION_OF_LYASE_ACTIVITY, TGACCTY_ERR1_Q2, MOTAMED_RESPONSE_TO_ANDROGEN_DN, GOBP_TOOTH_MINERALIZATION, CAGCTG_AP4_Q5

GO Biological Process (12): store-operated calcium entry (GO:0002115), detection of calcium ion (GO:0005513), intracellular calcium ion homeostasis (GO:0006874), activation of store-operated calcium channel activity (GO:0032237), positive regulation of adenylate cyclase activity (GO:0045762), positive regulation of angiogenesis (GO:0045766), regulation of calcium ion transport (GO:0051924), enamel mineralization (GO:0070166), regulation of store-operated calcium entry (GO:2001256), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), regulation of transport (GO:0051049)

GO Molecular Function (7): protease binding (GO:0002020), calcium channel regulator activity (GO:0005246), calcium ion binding (GO:0005509), identical protein binding (GO:0042802), microtubule plus-end binding (GO:0051010), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (12): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), microtubule (GO:0005874), plasma membrane (GO:0005886), cortical endoplasmic reticulum (GO:0032541), sarcoplasmic reticulum membrane (GO:0033017), plasma membrane raft (GO:0044853), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), endomembrane system (GO:0012505), membrane (GO:0016020), sarcoplasmic reticulum (GO:0016529)

Reactome top-level categories

Rollup of top-8 pathways:

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

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
calcium ion transport	2
transport	2
plasma membrane	2
detection of chemical stimulus	1
response to calcium ion	1
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
positive regulation of store-operated calcium channel activity	1
adenylate cyclase activity	1
positive regulation of cyclase activity	1
regulation of adenylate cyclase activity	1
positive regulation of lyase activity	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
regulation of metal ion transport	1
tooth mineralization	1
amelogenesis	1
store-operated calcium entry	1
regulation of calcium ion transport	1
metal ion transport	1
regulation of localization	1
enzyme binding	1
calcium channel activity	1
ion channel regulator activity	1
metal ion binding	1
protein binding	1
microtubule binding	1
binding	1
cation binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
membrane	1

Protein interactions and networks

STRING

2286 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
STIM1	ORAI2	Q96SN7	999
STIM1	TRPC1	P48995	999
STIM1	ORAI1	Q96D31	999
STIM1	ORAI3	Q9BRQ5	998
STIM1	TRPC5	Q9UL62	973
STIM1	TRPC6	Q9Y210	971
STIM1	TRPC4	Q9UBN4	971
STIM1	TRPC3	Q13507	956
STIM1	CACNA1C	Q13936	949
STIM1	STIM2	Q9P246	933
STIM1	CRACR2A	Q9BSW2	922
STIM1	ITPR1	Q14643	904
STIM1	ITPR3	Q14573	894
STIM1	SARAF	Q96BY9	889
STIM1	PDIA3	P30101	826

IntAct

263 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
STIM1	STIM1	psi-mi:“MI:2364”(proximity)	0.910
STIM1	STIM1	psi-mi:“MI:0407”(direct interaction)	0.910
STX18	NBAS	psi-mi:“MI:0914”(association)	0.810
STIM2	STIM1	psi-mi:“MI:0915”(physical association)	0.780
STIM1	STIM2	psi-mi:“MI:0915”(physical association)	0.780
YWHAG	STIM1	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710

BioGRID (525): STIM1 (Affinity Capture-MS), STIM1 (Affinity Capture-MS), STIM1 (Affinity Capture-MS), STIM1 (Affinity Capture-MS), STIM1 (Co-fractionation), STIM1 (Proximity Label-MS), STIM1 (Proximity Label-MS), STIM1 (Proximity Label-MS), STIM1 (Proximity Label-MS), STIM1 (Proximity Label-MS), STIM1 (Proximity Label-MS), STIM1 (Proximity Label-MS), STIM1 (Affinity Capture-MS), STIM1 (Affinity Capture-MS), STIM1 (Affinity Capture-MS)

ESM2 similar proteins: A0MZ67, A1L260, A2AMM0, A2VDA9, A4IGC3, A5PJI6, A9C3W3, B1PRL5, B9EKI3, O35711, O35867, O54724, O76878, O94876, O95810, P34609, P55326, P70302, P83093, P84903, P85125, Q0IIE0, Q13586, Q29EP6, Q32PN7, Q58CP9, Q5BKX8, Q5FWS6, Q63918, Q66H98, Q674X7, Q69ZS8, Q69ZZ6, Q6NZI2, Q6P0R8, Q6P402, Q7T019, Q8CJ96, Q8K2Q9, Q8MJK1

Diamond homologs: P70302, P83093, P83094, P84903, Q13586, Q58CP9, Q9P246, G5EF60

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
CDK1	down-regulates	STIM1	phosphorylation
MAPK1	up-regulates	STIM1	phosphorylation
FAM20C	“up-regulates activity”	STIM1	phosphorylation
PAK1	“up-regulates activity”	STIM1	phosphorylation
PRKAG2	“down-regulates activity”	STIM1	phosphorylation
PRKAB1	“down-regulates activity”	STIM1	phosphorylation
PRKAA1	“down-regulates activity”	STIM1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 154 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	37.7×	2e-06
Activation of BAD and translocation to mitochondria	5	35.6×	1e-05
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	31.4×	2e-05
Signaling by ERBB2 ECD mutants	5	31.4×	2e-05
GRB2 events in ERBB2 signaling	5	29.6×	2e-05
SHC1 events in ERBB2 signaling	6	26.7×	7e-06
Signaling by ERBB2 TMD/JMD mutants	6	26.7×	7e-06
Signaling by ERBB2 KD Mutants	6	23.7×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
peptidyl-tyrosine phosphorylation	8	24.2×	5e-07
cell surface receptor protein tyrosine kinase signaling pathway	14	17.5×	7e-11
positive regulation of fibroblast proliferation	5	10.6×	1e-02
protein autophosphorylation	10	10.4×	9e-06
MAPK cascade	9	9.9×	6e-05
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	15	8.5×	2e-07
positive regulation of MAPK cascade	13	7.5×	5e-06
intracellular protein localization	9	6.8×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	14
Uncertain significance	404
Likely benign	283
Benign	42

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
132887	NM_001382567.1(STIM1):c.910C>T (p.Arg304Trp)	Pathogenic
1365102	NM_001382567.1(STIM1):c.869_887del (p.Ile290fs)	Pathogenic
1371047	NC_000011.9:g.(?3988762)(4113028_?)del	Pathogenic
143191	NM_001382567.1(STIM1):c.343A>T (p.Ile115Phe)	Pathogenic
1457776	NM_001382567.1(STIM1):c.1189del (p.Ala397fs)	Pathogenic
1459002	NC_000011.9:g.(?4076736)(4076887_?)del	Pathogenic
2683800	NM_001382567.1(STIM1):c.216C>G (p.His72Gln)	Pathogenic
2928208	NM_001382567.1(STIM1):c.1463T>A (p.Leu488Ter)	Pathogenic
30540	NM_001382567.1(STIM1):c.970-1G>A	Pathogenic
3061748	NM_001382567.1(STIM1):c.1453del (p.Val485fs)	Pathogenic
3752806	NM_001382567.1(STIM1):c.757C>T (p.Arg253Ter)	Pathogenic
375471	NM_001382567.1(STIM1):c.221T>C (p.Leu74Pro)	Pathogenic
3755531	NM_001382567.1(STIM1):c.30G>A (p.Trp10Ter)	Pathogenic
3756856	NM_001382567.1(STIM1):c.1437_1444dup (p.Glu482fs)	Pathogenic
3763455	NM_001382567.1(STIM1):c.325C>T (p.His109Tyr)	Pathogenic
41464	NM_001382567.1(STIM1):c.1285C>T (p.Arg429Cys)	Pathogenic
41481	NM_001382567.1(STIM1):c.251A>G (p.Asp84Gly)	Pathogenic
41482	NM_001382567.1(STIM1):c.325C>A (p.His109Asn)	Pathogenic
4711	NM_001382567.1(STIM1):c.381dup (p.Glu128fs)	Pathogenic
572186	NM_001382567.1(STIM1):c.1452del (p.Ile484fs)	Pathogenic
643831	NM_001382567.1(STIM1):c.700_707del (p.Asn234fs)	Pathogenic
832877	NC_000011.10:g.(?4059271)(4059406_?)del	Pathogenic
1476711	NM_001382567.1(STIM1):c.386-1G>A	Likely pathogenic
1679390	NM_001382567.1(STIM1):c.1403del (p.Pro468fs)	Likely pathogenic
1703798	NM_001382567.1(STIM1):c.563A>G (p.Gln188Arg)	Likely pathogenic
189363	NM_001382567.1(STIM1):c.239A>C (p.Asn80Thr)	Likely pathogenic
2020521	NM_001382567.1(STIM1):c.270+2T>C	Likely pathogenic
2090235	NM_001382567.1(STIM1):c.1568-1G>T	Likely pathogenic
2091216	NM_001382567.1(STIM1):c.792-1G>A	Likely pathogenic
2424636	NC_000011.9:g.(?4045083)(4045237_?)dup	Likely pathogenic

SpliceAI

3518 predictions. Top by Δscore:

Variant	Effect	Δscore
11:3967546:A:AG	acceptor_gain	1.0000
11:3967547:C:G	acceptor_gain	1.0000
11:3967547:CACA:C	acceptor_loss	1.0000
11:3967547:CACAG:C	acceptor_gain	1.0000
11:3967548:A:AG	acceptor_gain	1.0000
11:3967548:ACAGA:A	acceptor_gain	1.0000
11:3967549:C:G	acceptor_gain	1.0000
11:3967549:CAG:C	acceptor_gain	1.0000
11:3967550:A:AG	acceptor_gain	1.0000
11:3967550:AG:A	acceptor_gain	1.0000
11:3967551:G:GG	acceptor_gain	1.0000
11:3967551:GA:G	acceptor_gain	1.0000
11:3967551:GAG:G	acceptor_gain	1.0000
11:3967551:GAGT:G	acceptor_gain	1.0000
11:3967551:GAGTT:G	acceptor_gain	1.0000
11:3967678:ATGAG:A	donor_gain	1.0000
11:3967679:TGAG:T	donor_gain	1.0000
11:3967680:GAG:G	donor_gain	1.0000
11:3967680:GAGG:G	donor_gain	1.0000
11:3967681:AGG:A	donor_loss	1.0000
11:3967683:G:GA	donor_loss	1.0000
11:3967683:G:GG	donor_gain	1.0000
11:4023868:TGCA:T	acceptor_loss	1.0000
11:4023869:GCAGT:G	acceptor_loss	1.0000
11:4023871:A:AG	acceptor_gain	1.0000
11:4023872:G:GG	acceptor_gain	1.0000
11:4023872:GTTC:G	acceptor_gain	1.0000
11:4055523:C:G	acceptor_gain	1.0000
11:4055524:A:AG	acceptor_gain	1.0000
11:4055525:G:GA	acceptor_gain	1.0000

AlphaMissense

4754 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:3967674:A:C	S88R	1.000
11:3967676:T:A	S88R	1.000
11:3967676:T:G	S88R	1.000
11:4023873:T:C	F91L	1.000
11:4023874:T:C	F91S	1.000
11:4023874:T:G	F91C	1.000
11:4023875:C:A	F91L	1.000
11:4023875:C:G	F91L	1.000
11:4023889:T:C	L96P	1.000
11:4023961:T:C	L120P	1.000
11:4023972:T:A	W124R	1.000
11:4023972:T:C	W124R	1.000
11:4055534:T:A	W132R	1.000
11:4055534:T:C	W132R	1.000
11:4055558:T:A	W140R	1.000
11:4055558:T:C	W140R	1.000
11:4055560:G:C	W140C	1.000
11:4055560:G:T	W140C	1.000
11:4055562:T:C	L141P	1.000
11:4055580:T:C	L147P	1.000
11:4059286:C:A	A168D	1.000
11:4059352:T:C	L190P	1.000
11:4059358:T:C	L192P	1.000
11:4059363:G:C	A194P	1.000
11:4059367:T:C	L195P	1.000
11:4059381:T:C	F200L	1.000
11:4059383:T:A	F200L	1.000
11:4059383:T:G	F200L	1.000
11:4070079:G:C	G223R	1.000
11:4070080:G:A	G223D	1.000

dbSNP variants (sampled 300 via entrez): RS1000009373 (11:3907615 C>T), RS1000017062 (11:3902789 G>A), RS1000024984 (11:3878422 T>C), RS1000029858 (11:3902619 C>T), RS1000040984 (11:4004130 A>G), RS1000060044 (11:3962822 T>A,C), RS1000068189 (11:3990981 C>T), RS1000075225 (11:3943899 C>T), RS1000076688 (11:3957404 C>G,T), RS1000084105 (11:4041351 G>A), RS1000099248 (11:3997732 T>C), RS1000108120 (11:4089041 G>A), RS1000108685 (11:4004310 G>T), RS1000116166 (11:4014898 G>A), RS1000128073 (11:3912886 T>A,C)

Disease associations

OMIM: gene MIM:605921 | disease phenotypes: MIM:160565, MIM:185070, MIM:612783, MIM:615577, MIM:609500

GenCC curated gene-disease

Disease	Classification	Inheritance
myopathy, tubular aggregate, 1	Definitive	Autosomal dominant
combined immunodeficiency due to STIM1 deficiency	Strong	Autosomal recessive
Stormorken syndrome	Strong	Autosomal dominant
tubular aggregate myopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
tubular aggregate myopathy	Definitive	AD
combined immunodeficiency due to STIM1 deficiency	Definitive	AR

Mondo (7): tubular aggregate myopathy (MONDO:0008051), Stormorken syndrome (MONDO:0008497), combined immunodeficiency due to STIM1 deficiency (MONDO:0013008), myopathy, tubular aggregate, 1 (MONDO:0024531), immunodeficiency, common variable, 10 (MONDO:0014260), myopathy, autophagic vacuolar, infantile-onset (MONDO:0012286), migraine disorder (MONDO:0005277)

Orphanet (4): Combined immunodeficiency due to CRAC channel dysfunction (Orphanet:169090), Tubular aggregate myopathy (Orphanet:2593), Combined immunodeficiency due to STIM1 deficiency (Orphanet:317430), Stormorken-Sjaastad-Langslet syndrome (Orphanet:3204)

HPO phenotypes

91 total (30 of 91 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000100	Nephrotic syndrome
HP:0000322	Short philtrum
HP:0000348	High forehead
HP:0000403	Recurrent otitis media
HP:0000421	Epistaxis
HP:0000448	Prominent nose
HP:0000490	Deeply set eye
HP:0000544	External ophthalmoplegia
HP:0000601	Hypotelorism
HP:0000615	Abnormal pupil morphology
HP:0000616	Miosis
HP:0000662	Nyctalopia
HP:0000705	Amelogenesis imperfecta
HP:0000790	Hematuria
HP:0000966	Hypohidrosis
HP:0000978	Bruising susceptibility
HP:0000979	Purpura
HP:0001252	Hypotonia
HP:0001371	Flexion contracture
HP:0001744	Splenomegaly
HP:0001746	Asplenia
HP:0001872	Abnormality of thrombocytes
HP:0001873	Thrombocytopenia
HP:0001890	Autoimmune hemolytic anemia
HP:0001892	Abnormal bleeding
HP:0001903	Anemia
HP:0001928	Abnormality of coagulation

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST004599_16	Mean platelet volume	5.000000e-11
GCST004616_84	Platelet distribution width	8.000000e-11
GCST005982_6	Calcium levels	1.000000e-08
GCST009391_1178	Metabolite levels	5.000000e-06
GCST010725_20	Malaria	4.000000e-69
GCST010725_33	Malaria	2.000000e-67
GCST010725_51	Malaria	1.000000e-55
GCST011956_47	Systemic lupus erythematosus	2.000000e-12
GCST012052_3	Waist circumference	5.000000e-08
GCST012052_4	Waist circumference	5.000000e-08
GCST012098_1	Disruptive behavior disorder and attention deficit hyperactivity disorder	3.000000e-10
GCST90002379_87	Basophil count	1.000000e-13
GCST90002380_99	Basophil percentage of white cells	2.000000e-12
GCST90002384_278	Hemoglobin	9.000000e-10
GCST90002392_556	Mean corpuscular volume	2.000000e-09
GCST90002395_72	Mean platelet volume	4.000000e-28
GCST90002396_451	Mean reticulocyte volume	1.000000e-09
GCST90002397_557	Mean spheric corpuscular volume	4.000000e-11
GCST90002401_176	Platelet distribution width	5.000000e-14

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0007984	platelet component distribution width
EFO:0004838	calcium measurement
EFO:0010454	adenosine monophosphate measurement
EFO:0005090	basophil count
EFO:0007992	basophil percentage of leukocytes
EFO:0004509	hemoglobin measurement
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008881	Migraine Disorders	C10.228.140.546.399.750
C557827	Immune dysfunction with T-cell inactivation due to calcium entry defect 2 (supp.)
C566108	Stormorken Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (5): CHEMBL3832644 (PROTEIN COMPLEX), CHEMBL4296083 (PROTEIN COMPLEX), CHEMBL4296084 (PROTEIN COMPLEX), CHEMBL4888450 (PROTEIN COMPLEX), CHEMBL4888461 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 7,832 (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
CHEMBL973	TERIFLUNOMIDE	4	7,575
CHEMBL4753998	ZEGOCRACTIN	2	257

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

PharmGKB variants

5 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1561876	RRM1, STIM1	3	2.75	1	cladribine;cytarabine
rs2898950	RRM1, STIM1	3	1.75	1	cladribine;cytarabine
rs11030918	RRM1, STIM1	3	3.00	1	gemcitabine;Platinum compounds
rs12806698	RRM1, STIM1	3	3.00	2	gemcitabine;Platinum compounds
rs7126100	STIM1		0.00	0

ChEMBL bioactivities

51 potent at pChembl≥5 of 51 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.12	IC50	76	nM	CHEMBL4868242
6.92	IC50	119	nM	ZEGOCRACTIN
6.64	IC50	228	nM	CHEMBL3403742
6.52	IC50	300	nM	CHEMBL101896
6.44	IC50	361	nM	CHEMBL4753023
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
6.07	IC50	851	nM	CHEMBL4761656
6.06	IC50	866	nM	CHEMBL4799904
6.05	IC50	895	nM	ZEGOCRACTIN
6.00	IC50	1000	nM	CHEMBL4863881
5.92	IC50	1198	nM	CHEMBL4750981
5.79	IC50	1621	nM	CHEMBL4742227
5.75	IC50	1790	nM	CHEMBL4742960
5.54	IC50	2900	nM	CHEMBL4177187
5.51	IC50	3100	nM	CHEMBL4162062
5.40	IC50	4000	nM	CHEMBL4570175
5.37	IC50	4300	nM	TERIFLUNOMIDE
5.36	IC50	4400	nM	CHEMBL4172741
5.31	IC50	4900	nM	CHEMBL4162723

PubChem BioAssay actives

24 with measured affinity, of 175 total; 20 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2,6-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
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
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
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
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
2,6-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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Lead	affects response to substance, increases transport, decreases reaction, increases import, affects expression (+1 more)	3
bisphenol F	increases expression, affects cotreatment	2
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	2
Acrolein	affects cotreatment, increases oxidation, increases abundance	2
Benzo(a)pyrene	increases expression, increases methylation	2
Ozone	affects cotreatment, increases oxidation, increases abundance	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	affects cotreatment, increases expression	1
titanium dioxide	decreases methylation	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression, decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
aflatoxin B2	decreases methylation	1
usnic acid	increases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
(+)-JQ1 compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Ethanol	increases expression, affects response to substance	1
Benztropine	decreases expression	1
Caffeine	affects phosphorylation	1
Calcium	affects abundance	1
Clozapine	decreases expression	1

ChEMBL screening assays

35 unique, capped per target: 33 binding, 1 functional, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
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
CHEMBL3734545	Binding	Inhibition of recombinant human STIM1/Orai1 expressed in HEK293 cells assessed as inhibition of peak basal signal after 30 mins by fluo4-AM dye-based 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

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_XT93	HAP1 STIM1 (-) 1	Cancer cell line	Male
CVCL_XT94	HAP1 STIM1 (-) 2	Cancer cell line	Male
CVCL_XT95	HAP1 STIM1 (-) 3	Cancer cell line	Male
CVCL_XT96	HAP1 STIM1 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00174395	PHASE4	COMPLETED	A Trial to Study of the Effects of Eletriptan 40mg on Mild vs Moderate to Severe Pain Intensity of Migraine
NCT00208065	PHASE4	COMPLETED	Evaluation of Histamine, CGRP and VIP as Markers for Activation of Trigeminal and Parasympathetic Nerve Fibers
NCT00210496	PHASE4	COMPLETED	Potential Impact (Benefit) of Preventative Treatment With Topamax on the Effectiveness of Axert in the Acute Treatment of Migraine
NCT00210509	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Almotriptan Versus Placebo in the Treatment of Migraine Headache
NCT00212810	PHASE4	COMPLETED	Evaluation of the Effectiveness of Topiramate in Preventing the Transformation From Episodic Migraine to Chronic Daily Headache.
NCT00212823	PHASE4	COMPLETED	The Effectiveness of Almotriptan Malate (AXERT®) 12.5 Milligrams When Taken at the Onset of Migraine Pain
NCT00216736	PHASE4	COMPLETED	Oral Dexamethasone for Treatment of Migraine
NCT00259636	PHASE4	WITHDRAWN	Zonisamide for Fibromyalgia & Migraine
NCT00259649	PHASE4	COMPLETED	Prospective Survey of Menstrual Migraine & Prevention With Eletriptan
NCT00297375	PHASE4	COMPLETED	A Study Comparing the Effectiveness and Safety of ULTRACET® (Tramadol HCl/Acetaminophen) Versus Placebo for the Treatment of Acute Pain From a Migraine Headache
NCT00335777	PHASE4	COMPLETED	A Research Study Examining Migranal and Skin Sensitivity in Subjects With Migraine
NCT00363506	PHASE4	UNKNOWN	American Migraine Prevention Study
NCT00364806	PHASE4	COMPLETED	Prochlorperazine vs Metoclopramide
NCT00391755	PHASE4	TERMINATED	A Double-Blind Placebo-Controlled Trial of Rozerem in Migraine Headaches
NCT00397254	PHASE4	COMPLETED	Two Rizatriptan Prescribing Portions for Treatment of Migraine
NCT00443352	PHASE4	COMPLETED	A Research Study Examining The Use Of Duloxetine In The Prevention Of Migraine Headache
NCT00449787	PHASE4	COMPLETED	Comparing Naproxen to Sumatriptan for Emergency Headache Patients
NCT00632385	PHASE4	COMPLETED	Efficacy and Safety of Eletriptan for the Treatment of Migraine in Patients Not Satisfied With Rizatriptan Therapy
NCT00634985	PHASE4	COMPLETED	Safety and Efficacy of Eletriptan for the Treatment of Migraine in Subjects Unsuccessfully Treated With Nonsteroidal Anti-inflammatory Drugs
NCT00637286	PHASE4	COMPLETED	ZAP, US. Zomig for Appropriate for Primary Care
NCT00753311	PHASE4	COMPLETED	Rizatriptan in Acute Treatment of Migraine in Patients With Unilateral Trigeminal-autonomic Symptoms.
NCT00792636	PHASE4	COMPLETED	A Study to Determine the Effect of Sumatriptan and Naproxen Sodium Combination Tablet, Sumatriptan Tablet, and Naproxen Sodium Tablet on Blood Pressure When Treating Migraine Headaches That Occur During a 6-month Period
NCT00799045	PHASE4	COMPLETED	Clopidogrel For the Prevention of New Onset Migraine Headache Following Transcatheter Closure of Atrial Septal Defects
NCT00812214	PHASE4	COMPLETED	Treatment of Insomnia in Migraineurs
NCT00846495	PHASE4	COMPLETED	Pilot Study to Compare Frovatriptan vs. Topiramate for Prevention of Migraine
NCT00893737	PHASE4	COMPLETED	Completeness of Response Following Treatment With Treximet™ for Migraine
NCT00910689	PHASE4	COMPLETED	Drug and Non-Drug Treatment Of Severe Migraine
NCT00915473	PHASE4	COMPLETED	Greater Occipital Nerve Block for Migraine Prophylaxis
NCT01016834	PHASE4	COMPLETED	Evaluation of Treatment Satisfaction and Preference for Sumavel DosePro in the Treatment of Migraine
NCT01057160	PHASE4	COMPLETED	Rizatriptan 10 MG RPD in the Treatment of Acute Migraine
NCT01060111	PHASE4	COMPLETED	An Efficacy and Tolerability Study of Topiramate in Participants With Migraine
NCT01071096	PHASE4	COMPLETED	Calcitonin Gene-related Peptide Levels in Chronic Migraine
NCT01071317	PHASE4	COMPLETED	Trial of Comprehensive Migraine Intervention
NCT01090050	PHASE4	COMPLETED	Treximet in the Treatment of Chronic Migraine
NCT01138150	PHASE4	COMPLETED	Ictal and Interictal Inflammatory Markers in Migraine
NCT01211145	PHASE4	COMPLETED	Zomig - Treatment of Acute Migraine Headache in Adolescents
NCT01267864	PHASE4	COMPLETED	Valproate Versus Ketorolac Versus Metoclopramide
NCT01300546	PHASE4	COMPLETED	Treximet Trademark (TM) in the Prevention and Modification of Disease Progression in Migraine
NCT01319825	PHASE4	UNKNOWN	Preventive Treatment of Episodic and Chronic Migraine
NCT01332864	PHASE4	COMPLETED	Effect of Osteopathic Manipulative Treatment for Patients With Chronic Headache