STIM2

Summary

STIM2 (stromal interaction molecule 2, HGNC:19205) is a protein-coding gene on chromosome 4p15.2, encoding Stromal interaction molecule 2 (Q9P246). Plays a role in mediating store-operated Ca(2+) entry (SOCE), a Ca(2+) influx following depletion of intracellular Ca(2+) stores.

This gene is a member of the stromal interaction molecule (STIM) family and likely arose, along with related family member STIM1, from a common ancestral gene. The encoded protein functions to regulate calcium concentrations in the cytosol and endoplasmic reticulum, and is involved in the activation of plasma membrane Orai Ca(2+) entry channels. This gene initiates translation from a non-AUG (UUG) start site. A signal peptide is cleaved from the resulting protein. Multiple transcript variants result from alternative splicing.

Source: NCBI Gene 57620 — RefSeq curated summary.

At a glance

• GWAS associations: 14
• Clinical variants (ClinVar): 122 total
• Druggable target: yes
• MANE Select transcript: NM_020860

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19205
Approved symbol	STIM2
Name	stromal interaction molecule 2
Location	4p15.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000109689
Ensembl biotype	protein_coding
OMIM	610841
Entrez	57620

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 8 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000463501, ENST00000465503, ENST00000467011, ENST00000467087, ENST00000473519, ENST00000477474, ENST00000478049, ENST00000478425, ENST00000494628, ENST00000504511, ENST00000698882

RefSeq mRNA: 3 — MANE Select: NM_020860 NM_001169117, NM_001169118, NM_020860

CCDS: CCDS3440, CCDS54751, CCDS54752

Canonical transcript exons

ENST00000467087 — 12 exons

Exon	Start	End
ENSE00000708838	27007533	27007700
ENSE00000708840	27008764	27009002
ENSE00000708841	27017711	27017984
ENSE00000708842	27022519	27025381
ENSE00000799412	27002927	27003104
ENSE00001759005	27008428	27008528
ENSE00001898575	26860841	26861369
ENSE00003258288	26999232	26999347
ENSE00003401172	26957612	26957726
ENSE00003416974	26995379	26995490
ENSE00003663914	26919504	26919634
ENSE00003786214	27002217	27002394

Expression profiles

Bgee: expression breadth ubiquitous, 246 present calls, max score 96.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.5348 / max 217.0966, expressed in 1684 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47201	3.4163	1225
47197	1.6389	833
47198	1.2119	800
47200	0.6743	359
47204	0.5934	250

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory segment of nasal mucosa	UBERON:0005386	96.95	gold quality
adenohypophysis	UBERON:0002196	94.83	gold quality
right uterine tube	UBERON:0001302	94.66	gold quality
gall bladder	UBERON:0002110	94.62	gold quality
spleen	UBERON:0002106	94.55	gold quality
vermiform appendix	UBERON:0001154	93.66	gold quality
nasal cavity epithelium	UBERON:0005384	93.46	gold quality
pituitary gland	UBERON:0000007	93.24	gold quality
rectum	UBERON:0001052	92.67	gold quality
metanephros cortex	UBERON:0010533	92.29	gold quality
right lobe of thyroid gland	UBERON:0001119	92.28	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.18	gold quality
lymph node	UBERON:0000029	92.06	gold quality
left lobe of thyroid gland	UBERON:0001120	91.90	gold quality
granulocyte	CL:0000094	91.86	gold quality
mucosa of paranasal sinus	UBERON:0005030	91.67	gold quality
body of pancreas	UBERON:0001150	91.59	gold quality
nasal cavity mucosa	UBERON:0001826	91.22	gold quality
right lobe of liver	UBERON:0001114	91.14	gold quality
pancreatic ductal cell	CL:0002079	91.02	gold quality
left ovary	UBERON:0002119	90.93	gold quality
thyroid gland	UBERON:0002046	90.91	gold quality
cortical plate	UBERON:0005343	90.77	gold quality
right ovary	UBERON:0002118	90.73	gold quality
mucosa of transverse colon	UBERON:0004991	90.55	gold quality
small intestine	UBERON:0002108	90.48	gold quality
upper lobe of left lung	UBERON:0008952	90.40	gold quality
leukocyte	CL:0000738	90.15	gold quality
monocyte	CL:0000576	90.08	gold quality
calcaneal tendon	UBERON:0003701	89.80	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-112	yes	38.58
E-CURD-119	yes	24.81
E-ANND-3	yes	8.62

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

186 targeting STIM2, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345

Literature-anchored findings (GeneRIF, showing 40)

• Translation initiation from a non-AUG (UUG) start site. (PMID:11463338)
• STIM proteins function as Ca(2+) store sensors in the signaling pathway connecting Ca(2+) store depletion to Ca(2+) influx. (PMID:16005298)
• STIM2 is an inhibitor of store-operated channel (SOC) activation and plays a coordinated role with STIM1 in controlling SOC-mediated Ca(2+) entry signals. (PMID:16860747)
• STIM2 has two modes of activating CRAC channels: a store-operated mode activated through depletion of ER Ca2+ stores by inositol 1,4,5-trisphosphate and store-independent activation mediated by cell dialysis; both regulated by calmodulin. (PMID:17905723)
• Study places STIM2 at the center of a feedback module that keeps basal cytosolic and endoplasmic reticulum Ca2+ concentrations within tight limits. (PMID:18160041)
• 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)
• distinct oligomerization dynamics of STIM isoforms have evolved to adapt to differential roles in Ca(2+) homeostasis and signaling (PMID:19019825)
• Data demonstrate that cellular levels of STIM1 and STIM2, which are key players in capacitative Ca2+ entry, depend on presenilins. (PMID:19111578)
• results provide evidence for a role of STIM1 protein in the control of Ca2+ influx in neutrophils excluding a STIM2 involvement in this process (PMID:19433064)
• Results show that the 55-amino-acid STIM2 terminus substituted within STIM1 strikingly enhances both Orai1-mediated Ca(2+) entry and constitutive coupling to activate Orai1 channels. (PMID:19487696)
• STIM2 is involved in spatial learning and plays an important role in ischemic-induced neuronal cell death during brain hypoxia. The absence of STIM2 reduces life expectancy in mice by sudden death. (PMID:19843959)
• STIM2 is involved in spatial learning and plays an important role in ischemic-induced neuronal cell death during brain hypoxia. The absence of STIM2 reduces life expectancy in mice by sudden death. (PMID:198439)
• involved in both store-operated calcium entry and cell proliferation (PMID:20172609)
• STIM2 is a necessary partner of STIM1 for excitation-contraction coupling. (PMID:20436167)
• Data suggest that divergent Ca(2+)- and SAM-dependent stabilization of the EF-SAM fold contributes to the disparate regulation of store-operated Ca(2+) entry by STIM1 and STIM2. (PMID:21217057)
• STIM1 and STIM2 are located in the acidic Ca2+ stores and associates with Orai1 upon depletion of the acidic stores in human platelets. (PMID:21321120)
• a new model for STIM2-mediated regulation of ORAI1 in which two distinct proteins, STIM2 and preSTIM2, control store-dependent and store-independent modes of ORAI1 activation. (PMID:21383014)
• Stim1 and Stim2 were increased in brains of chronic epileptic rodents and strongly expressed in hippocampal specimens from medial temporal lobe epilepsy patients. (PMID:21906591)
• Stromal interaction molecule 2 is frequently overexpressed in colorectal tumors and confers a tumor cell growth suppressor phenotype. (PMID:22125164)
• The role of STIM2 in store operated calcium entry and its relevance in cellular physiology. [review] (PMID:22477146)
• It was shown that polyamines regulate intestinal epithelial restitution through TRPC1-mediated Ca2+ signaling by altering the ratio of STIM1 to STIM2. Overexpression of ornithine decarboxylase resulted in increased STIM1 but decreased STIM2 expression. (PMID:22592407)
• Studies indicate that in vertebrates, stromal interaction molecule proteins STIM1 and STIM2 are expressed ubiquitously (PMID:22914293)
• STIM2 regulates store-operated Ca2+ entry as a sensor of mild reductions in ER calcium levels. (PMID:23359669)
• Binding of the lysine rich domains of STIM1 and STIM2 to phosphatidylinositol 4,5 biphosphate rich liposomes depends on their oligomerization. (PMID:24044355)
• STIM2 is highly expressed and controls store-operated Ca(2+) entry in human melanoma. The invasive and migratory potential of melanoma cells was reduced upon silencing of STIM2. (PMID:24472175)
• While STIM1 is a full Orai1-agonist, leucine-replacement of this crucial residue in STIM2 endows it with partial agonist properties, which may be critical for limiting Orai1 activation stemming from its enhanced sensitivity to store-depletion (PMID:24492416)
• The higher amplitude of store-operated Ca2+ entry was associated to the over-expression for Stim2, Orai2-3, and TRPC1 while Stim2 levels remained constant and Stim1, Orai1, Orai3, TRPC1 and TRPC4 proteins were over-expressed in primary myelofibrosis. (PMID:24603752)
• the reciprocal shift in transient receptor potential channel 1 (TRPC1) and stromal interaction molecule 2 (STIM2) contributes to Ca2+ remodeling and cancer hallmarks in colorectal carcinoma cells (PMID:25143380)
• Imin channels are regulated by STIM2, TRPC3-containing INS channels are induced by STIM1, and TRPC1-composed Imax channels are activated by both STIM1 and STIM2. (PMID:25533457)
• STIM2 enhances receptor-stimulated Ca(2) signaling by promoting recruitment of STIM1 to the endoplasmic reticulum-plasma membrane junctions. (PMID:25587190)
• STIM2.1 cannot activate Orai1 due to splicing in residues within the channel-activating domain (CAD). STIM2.1 confers a calcium dependent dominant-negative function on both STIM1 and STIM2 (STIM2.2). Affinity of the STIM2.1 calmodulin binding site within the CAD domain is increased compared to STIM2.2. (PMID:25896806)
• These results imply that the splice variant STIM2.1 is an additional player tuning Orai1 activation in vivo. (PMID:25896806)
• STIM2beta does not by itself strongly bind Orai1, it is recruited to Orai1 channels by forming heterodimers with other STIM isoforms. (PMID:26033257)
• What is less clear is how the spatial and temporal spread of intracellular Ca(2+) is shaped and regulated by differential expression of the individual SOCE genes and their splice variants, their heteromeric combinations and pre- and posttranslational modifications. This review focuses on principle mechanisms regulating expression, splicing, and targeting of Ca(2+) release-activated Ca(2+) (CRAC) channels. (PMID:26911279)
• With STIM2 being essential for life, but apparently not for development, newly available data demonstrate a complex and still intriguing behaviour that this review summarizes, updating current knowledge of STIM2 function [review] (PMID:28087881)
• The STIM2 protein play important roles in TGF-beta-induced EMT and these effects are related to both store-operated calcium entry and non-store-operated calcium entry. (PMID:28479254)
• Expression of full-length STIM1 with STIM2 in a 5:1 ratio causes suppression of sustained agonist-induced Ca(2+) oscillations and protects cells from Ca(2+) overload. (PMID:29581306)
• STIM2 is constitutively localized within ER-PM junctions in ER-Ca(2+) store replete cells. STIM2 traps STIM1 and triggers remodeling of STIM1 C terminus, causing STIM1/Orai1 coupling and enhancement of Orai1 function in cells with relatively high ER-[Ca(2+)]. (PMID:29642009)
• Stim2 deletion reduced SOCE by more than 90% in NIH 3T3 cells and abolishes STIM1 translocation to plasma membrane-associated ER membrane junctions. (PMID:29783744)
• Both STIM1 and STIM2 are necessary for cancer cell proliferation, but STIM1 is the dominant endoplasmic reticulum Ca2+ sensor involved in cancer cell migration. (PMID:30317585)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	stim2b	ENSDARG00000001776
danio_rerio	stim2a	ENSDARG00000074867
mus_musculus	Stim2	ENSMUSG00000039156
rattus_norvegicus	Stim2	ENSRNOG00000002956
drosophila_melanogaster	Stim	FBGN0045073
caenorhabditis_elegans		WBGENE00021910

Paralogs (1): STIM1 (ENSG00000167323)

Protein

Protein identifiers

Stromal interaction molecule 2 — Q9P246 (reviewed: Q9P246)

All UniProt accessions (10): Q9P246, A0A1X7SBY3, A0A8V8TMC8, H0Y860, H7C5A5, H7C5C6, H7C5K2, R4GMP0, R4GN82, R4GNC5

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in mediating store-operated Ca(2+) entry (SOCE), a Ca(2+) influx following depletion of intracellular Ca(2+) stores. Functions as a highly sensitive Ca(2+) sensor in the endoplasmic reticulum which activates both store-operated and store-independent Ca(2+)-influx. Regulates basal cytosolic and endoplasmic reticulum Ca(2+) concentrations. Upon mild variations of the endoplasmic reticulum Ca(2+) concentration, translocates from the endoplasmic reticulum to the plasma membrane where it probably activates the Ca(2+) release-activated Ca(2+) (CRAC) channels ORAI1, ORAI2 and ORAI3. May inhibit STIM1-mediated Ca(2+) influx.

Subunit / interactions. Oligomer with STIM1. Interacts with ORAI1.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in all tissues and tumor cell lines examined.

Post-translational modifications. Glycosylated. Phosphorylated predominantly on Ser residues.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9P246-1	1	yes
Q9P246-2	2
Q9P246-3	3

RefSeq proteins (3): NP_001162588, NP_001162589, NP_065911* (*=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
IPR037610	STIM2_SAM	Domain
IPR057835	EF-hand_STIM1/2	Domain

Pfam: PF07647, PF16533, PF25578

UniProt features (50 total): modified residue 9, helix 8, binding site 4, splice variant 4, turn 4, compositionally biased region 3, strand 3, topological domain 2, mutagenesis site 2, sequence conflict 2, domain 2, region of interest 2, signal peptide 1, chain 1, glycosylation site 1, transmembrane region 1, coiled-coil region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2L5Y	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P246-F1	66.17	0.18

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 (4): 80; 82; 84; 91

Post-translational modifications (9): 523, 609, 621, 640, 650, 661, 665, 680, 697

Glycosylation sites (1): 135

Mutagenesis-validated functional residues (2):

Position	Phenotype
80	no effect on inhibitory activity; when associated with a-91.
91	no effect on inhibitory activity; when associated with a-80.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 262 (showing top): GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, MODULE_169, GOBP_POSITIVE_REGULATION_OF_CATION_CHANNEL_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_TRANSPORTER_ACTIVITY, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_TRANSMEMBRANE_TRANSPORT, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, GOBP_POSITIVE_REGULATION_OF_MONOATOMIC_ION_TRANSPORT, SNIJDERS_AMPLIFIED_IN_HEAD_AND_NECK_TUMORS, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P, GOBP_MONOATOMIC_ION_HOMEOSTASIS, GTATGAT_MIR154_MIR487, GOBP_POSITIVE_REGULATION_OF_TRANSPORT, GOBP_REGULATION_OF_TRANSPORT

GO Biological Process (8): store-operated calcium entry (GO:0002115), intracellular calcium ion homeostasis (GO:0006874), activation of store-operated calcium channel activity (GO:0032237), positive regulation of calcium ion transport (GO:0051928), monoatomic ion transport (GO:0006811), calcium ion transport (GO:0006816), regulation of transport (GO:0051049), calcium ion transmembrane transport (GO:0070588)

GO Molecular Function (5): calcium channel regulator activity (GO:0005246), calcium ion binding (GO:0005509), store-operated calcium channel activity (GO:0015279), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (5): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), endomembrane system (GO:0012505), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
calcium ion transport	3
transport	2
calcium channel activity	2
cellular anatomical structure	2
intracellular monoatomic cation homeostasis	1
calcium ion homeostasis	1
positive regulation of store-operated calcium channel activity	1
positive regulation of monoatomic ion transport	1
regulation of calcium ion transport	1
metal ion transport	1
regulation of localization	1
monoatomic cation transmembrane transport	1
ion channel regulator activity	1
metal ion 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
membrane	1
cell periphery	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

1148 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
STIM2	ORAI2	Q96SN7	999
STIM2	ORAI1	Q96D31	999
STIM2	ORAI3	Q9BRQ5	998
STIM2	TRPC1	P48995	937
STIM2	STIM1	Q13586	933
STIM2	TRPC6	Q9Y210	885
STIM2	TRPC3	Q13507	877
STIM2	TRPC4	Q9UBN4	816
STIM2	TRPC5	Q9UL62	758
STIM2	CALM1	P02593	744
STIM2	CCKAR	P32238	736
STIM2	CALML3	P27482	731
STIM2	CALML5	Q9NZT1	731
STIM2	CALML4	Q96GE6	707
STIM2	CALML6	Q8TD86	700
STIM2	PCDH7	O60245	700

IntAct

50 interactions, top by confidence:

A	B	Type	Score
STIM2	STIM1	psi-mi:“MI:0915”(physical association)	0.780
STIM1	STIM2	psi-mi:“MI:0915”(physical association)	0.780
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
STIM2	PRKAB2	psi-mi:“MI:0914”(association)	0.640
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590
INSR	PIK3R2	psi-mi:“MI:2364”(proximity)	0.570
PRKAB2	PRKAB2	psi-mi:“MI:0914”(association)	0.550
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
CALM	STIM2	psi-mi:“MI:0407”(direct interaction)	0.440
PRPF40A	STIM2	psi-mi:“MI:0915”(physical association)	0.370
SH2D3C	TMEM14DP	psi-mi:“MI:0914”(association)	0.350
PRKAA2	DFFA	psi-mi:“MI:0914”(association)	0.350
STIM1	AHSA1	psi-mi:“MI:0914”(association)	0.350
YWHAB	BRAF	psi-mi:“MI:0914”(association)	0.350
YWHAE	DEPDC5	psi-mi:“MI:0914”(association)	0.350
YWHAG	BRAF	psi-mi:“MI:0914”(association)	0.350
ZDHHC12	NBAS	psi-mi:“MI:0914”(association)	0.350
CRLF2	METTL15	psi-mi:“MI:0914”(association)	0.350
PIGH	ILVBL	psi-mi:“MI:0914”(association)	0.350
TMEM106A	TMEM131L	psi-mi:“MI:0914”(association)	0.350
CCDC107	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SFTPC	TMEM131L	psi-mi:“MI:0914”(association)	0.350
ECEL1	ADAM10	psi-mi:“MI:0914”(association)	0.350

BioGRID (195): STIM2 (Co-fractionation), STIM2 (Co-fractionation), STIM2 (Proximity Label-MS), STIM1 (Affinity Capture-MS), BRINP3 (Affinity Capture-MS), PRKAA1 (Affinity Capture-MS), PRKAG2 (Affinity Capture-MS), PRKAG1 (Affinity Capture-MS), PRKAB1 (Affinity Capture-MS), PRKAB2 (Affinity Capture-MS), PRKAA2 (Affinity Capture-MS), MSRB3 (Affinity Capture-MS), SUMF1 (Affinity Capture-MS), CISD2 (Affinity Capture-MS), TMLHE (Affinity Capture-MS)

ESM2 similar proteins: A0A571BF63, A0A8M9QN10, A0JMA8, A1A535, A1A5P5, A1L1K1, A2AVJ5, A7YDW0, B3MJV4, B4MV81, O00443, O08576, O17237, Q0V9V7, Q12923, Q14D04, Q17QK1, Q1LYM3, Q2NKQ1, Q3UGY8, Q59EK9, Q5EB20, Q5JWR5, Q5PQS3, Q5R565, Q5RAY1, Q5TH69, Q5U245, Q5U3W3, Q5XHG1, Q61194, Q61QK6, Q64512, Q6ING4, Q6MZQ0, Q6ZUJ8, Q7Z3E5, Q803Q4, Q80U12, Q8BPQ7

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

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 60 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
Activation of BAD and translocation to mitochondria	5	95.2×	2e-07
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	84.0×	2e-07
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	84.0×	2e-07
Activation of BH3-only proteins	5	62.1×	8e-07
RHO GTPases activate PKNs	5	39.6×	7e-06
Intrinsic Pathway for Apoptosis	5	36.6×	9e-06
Translocation of SLC2A4 (GLUT4) to the plasma membrane	7	27.0×	4e-07
TP53 Regulates Metabolic Genes	7	22.7×	1e-06

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of MAPK cascade	6	8.8×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	100
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3134 predictions. Top by Δscore:

Variant	Effect	Δscore
4:26919500:TCA:T	acceptor_loss	1.0000
4:26919501:CAG:C	acceptor_loss	1.0000
4:26919502:A:AG	acceptor_gain	1.0000
4:26919502:A:G	acceptor_loss	1.0000
4:26919503:G:GA	acceptor_gain	1.0000
4:26919503:GA:G	acceptor_gain	1.0000
4:26919503:GAT:G	acceptor_gain	1.0000
4:26919503:GATC:G	acceptor_gain	1.0000
4:26919503:GATCC:G	acceptor_gain	1.0000
4:26919624:A:T	donor_gain	1.0000
4:26919628:TGATG:T	donor_gain	1.0000
4:26919632:G:GT	donor_gain	1.0000
4:26919632:GAA:G	donor_gain	1.0000
4:26919633:AAGT:A	donor_loss	1.0000
4:26919634:AGTA:A	donor_loss	1.0000
4:26919635:G:GG	donor_gain	1.0000
4:26919635:GTAGG:G	donor_loss	1.0000
4:26919636:TA:T	donor_loss	1.0000
4:26957608:A:AG	acceptor_gain	1.0000
4:26957609:T:G	acceptor_gain	1.0000
4:26957610:A:AG	acceptor_gain	1.0000
4:26957611:G:GT	acceptor_gain	1.0000
4:26957611:GT:G	acceptor_gain	1.0000
4:26957611:GTT:G	acceptor_gain	1.0000
4:26957611:GTTC:G	acceptor_gain	1.0000
4:26957611:GTTCA:G	acceptor_gain	1.0000
4:26957723:GAAG:G	donor_gain	1.0000
4:26957724:AAGGT:A	donor_loss	1.0000
4:26957725:AGGT:A	donor_loss	1.0000
4:26957727:G:GG	donor_gain	1.0000

AlphaMissense

4918 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:26957612:T:C	F95L	1.000
4:26957614:C:A	F95L	1.000
4:26957614:C:G	F95L	1.000
4:26957711:T:A	W128R	1.000
4:26957711:T:C	W128R	1.000
4:26995411:T:A	W144R	1.000
4:26995411:T:C	W144R	1.000
4:26995433:T:C	L151P	1.000
4:26999303:T:C	L194P	1.000
4:27002280:G:A	G230D	1.000
4:27002292:C:A	A234D	1.000
4:27002363:G:C	A258P	1.000
4:27002376:T:C	L262P	1.000
4:27002937:G:C	A272P	1.000
4:27003024:G:C	A301P	1.000
4:27007542:G:C	A331P	1.000
4:27007546:T:C	L332P	1.000
4:27007554:G:C	A335P	1.000
4:27007603:T:A	L351H	1.000
4:27007603:T:C	L351P	1.000
4:27007611:T:A	W354R	1.000
4:27007611:T:C	W354R	1.000
4:27007615:T:A	L355H	1.000
4:27007615:T:C	L355P	1.000
4:27007618:A:C	Q356P	1.000
4:27007624:C:A	T358K	1.000
4:27007624:C:G	T358R	1.000
4:27007624:C:T	T358I	1.000
4:27007626:C:G	H359D	1.000
4:27007627:A:C	H359P	1.000

dbSNP variants (sampled 300 via entrez): RS1000009444 (4:26991225 A>G), RS1000057179 (4:27003553 C>T), RS1000085504 (4:26902739 A>C,G), RS1000087515 (4:27016505 G>A), RS1000144855 (4:26861689 G>T), RS1000158773 (4:26960759 A>G), RS1000180039 (4:26873146 T>C), RS1000184171 (4:27002815 G>T), RS1000191790 (4:26890396 A>G), RS1000205020 (4:26984995 G>A), RS1000231829 (4:26915192 T>C), RS1000236381 (4:26872811 G>A), RS1000254030 (4:26985264 C>T), RS10002654 (4:26955142 T>A,C), RS1000279291 (4:26956533 T>G)

Disease associations

OMIM: gene MIM:610841 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST001179_5	Plasma omega-3 polyunsaturated fatty acid levels (docosapentaenoic acid)	6.000000e-07
GCST001762_290	Obesity-related traits	8.000000e-06
GCST002658_1	Hirschsprung disease	2.000000e-06
GCST002663_9	Superior frontal gyrus grey matter volume	8.000000e-07
GCST002685_8	Refractive astigmatism	1.000000e-06
GCST003992_2	Photic sneeze reflex	6.000000e-11
GCST004029_32	Angiotensin-converting enzyme inhibitor intolerance	1.000000e-06
GCST005351_8	Carboplatin disposition in epthelial ovarian cancer	7.000000e-06
GCST006630_60	Diastolic blood pressure	2.000000e-20
GCST007325_70	General risk tolerance (MTAG)	5.000000e-10
GCST007327_13	Smoking status (ever vs never smokers)	2.000000e-08
GCST007327_8	Smoking status (ever vs never smokers)	2.000000e-08
GCST007576_225	Chronotype	3.000000e-08
GCST009391_1411	Metabolite levels	9.000000e-06

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0006809	docosapentaenoic acid measurement
EFO:0003939	energy intake
EFO:0006516	superior frontal gyrus grey matter volume measurement
EFO:0007887	autosomal dominant compelling helio-ophthalmic outburst syndrome
EFO:0005325	response to angiotensin-converting enzyme inhibitor
EFO:0006336	diastolic blood pressure
EFO:0008579	risk-taking behaviour
EFO:0004318	smoking behavior
EFO:0008328	chronotype measurement
EFO:0005132	5-HIAA measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296084 (PROTEIN COMPLEX)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.54	IC50	2900	nM	CHEMBL4177187
5.31	IC50	4900	nM	CHEMBL4162723

PubChem BioAssay actives

2 with measured affinity, of 2 total; 2 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
ethyl 1-[4-(2,3,3-trichloroprop-2-enoylamino)phenyl]-5-(trifluoromethyl)pyrazole-4-carboxylate	1363557: Inhibition of STIM1/STIM2/Orai1 (unknown origin) expressed in mouse BV2 cells assessed as reduction of store-operated calcium entry at 100 uM preincubated for 30 mins followed by tBhQ, mediated Ca2+ depletion and re-addition measured for 600 secs by Fluo-4 AM-based fluorometric assay	ic50	2.9000	uM
3-[1-[4-[4-ethoxycarbonyl-5-(trifluoromethyl)pyrazol-1-yl]phenyl]triazol-4-yl]benzoic acid	1363554: Inhibition of STIM1/STIM2/Orai1 (unknown origin) expressed in mouse BV2 cells assessed as induction of store-operated calcium entry by measuring residual activity preincubated for 30 mins followed by tBhQ, mediated Ca2+ depletion and re-addition measured for 600 secs by Fluo-4 AM-based fluorometric assay	ic50	4.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	4
bisphenol A	decreases expression, affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
methylmercuric chloride	decreases expression	1
beta-lapachone	decreases expression	1
coumarin	decreases phosphorylation	1
pentanal	decreases expression	1
abrine	decreases expression	1
(+)-JQ1 compound	increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	decreases expression	1
Bortezomib	decreases expression	1
Acetaminophen	increases expression	1
Arsenic	affects methylation	1
Atrazine	decreases expression	1
Benzo(a)pyrene	decreases expression	1
Caffeine	decreases phosphorylation	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Hydrogen Peroxide	increases expression	1
Indomethacin	increases expression, affects cotreatment	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Quercetin	affects expression	1
Thimerosal	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Aflatoxin B1	decreases methylation	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4158681	Binding	Inhibition of STIM1/STIM2/Orai1 (unknown origin) expressed in mouse BV2 cells assessed as induction of store-operated calcium entry by measuring residual activity preincubated for 30 mins followed by tBhQ, mediated Ca2+ depletion and re-add	Pyrtriazoles, a Novel Class of Store-Operated Calcium Entry Modulators: Discovery, Biological Profiling, and in Vivo Proof-of-Concept Efficacy in Acute Pancreatitis. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1Z7	Abcam A-549 STIM2 KO	Cancer cell line	Male
CVCL_D2D9	Abcam HCT 116 STIM2 KO	Cancer cell line	Male
CVCL_D2P9	Abcam THP-1 STIM2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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