TMEM97

Summary

TMEM97 (transmembrane protein 97, HGNC:28106) is a protein-coding gene on chromosome 17q11.2, encoding Sigma intracellular receptor 2 (Q5BJF2). Sigma-2 receptor which contributes to ameliorate dysfunctional cellular processes and slow degenerative progression by regulating cell functions including cholesterol biosynthesis/trafficking, membrane trafficking, autophagy, lipid membrane-bound protein trafficking, and recepto….

TMEM97 is a conserved integral membrane protein that plays a role in controlling cellular cholesterol levels (Bartz et al., 2009 [PubMed 19583955]).

Source: NCBI Gene 27346 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 21 total
• Druggable target: yes — 48 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_014573

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28106
Approved symbol	TMEM97
Name	transmembrane protein 97
Location	17q11.2
Locus type	gene with protein product
Status	Approved
Aliases	MAC30, σ2R
Ensembl gene	ENSG00000109084
Ensembl biotype	protein_coding
OMIM	612912
Entrez	27346

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000226230, ENST00000336687, ENST00000582113, ENST00000582384, ENST00000583381

RefSeq mRNA: 1 — MANE Select: NM_014573 NM_014573

CCDS: CCDS11226

Canonical transcript exons

ENST00000226230 — 3 exons

Exon	Start	End
ENSE00000705768	28319200	28319365
ENSE00001350895	28326534	28328685
ENSE00003638227	28325503	28325647

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 98.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 61.1943 / max 1306.5476, expressed in 1792 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160000	58.1139	1783
159997	1.4443	758
159999	0.9072	569
159998	0.7289	466

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	98.23	gold quality
body of pancreas	UBERON:0001150	98.01	gold quality
secondary oocyte	CL:0000655	97.98	gold quality
oocyte	CL:0000023	95.92	gold quality
embryo	UBERON:0000922	95.70	gold quality
pancreas	UBERON:0001264	95.13	gold quality
pylorus	UBERON:0001166	94.88	gold quality
adult organism	UBERON:0007023	94.53	gold quality
ganglionic eminence	UBERON:0004023	94.28	gold quality
pons	UBERON:0000988	93.90	gold quality
upper leg skin	UBERON:0004262	93.84	gold quality
liver	UBERON:0002107	93.79	gold quality
pancreatic ductal cell	CL:0002079	93.52	gold quality
mucosa of urinary bladder	UBERON:0001259	93.06	gold quality
right testis	UBERON:0004534	92.91	gold quality
cardia of stomach	UBERON:0001162	92.68	gold quality
testis	UBERON:0000473	92.54	gold quality
left testis	UBERON:0004533	92.50	gold quality
tendon of biceps brachii	UBERON:0008188	92.08	gold quality
nipple	UBERON:0002030	91.98	gold quality
lower lobe of lung	UBERON:0008949	91.87	gold quality
ventricular zone	UBERON:0003053	91.69	gold quality
epithelial cell of pancreas	CL:0000083	91.50	gold quality
upper arm skin	UBERON:0004263	90.98	gold quality
right lobe of liver	UBERON:0001114	90.78	gold quality
stomach	UBERON:0000945	90.56	gold quality
hair follicle	UBERON:0002073	90.56	gold quality
body of stomach	UBERON:0001161	90.46	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.13	gold quality
endothelial cell	CL:0000115	89.96	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	41.72
E-HCAD-5	yes	39.38
E-ANND-3	yes	23.89
E-GEOD-81547	yes	22.47
E-MTAB-5061	yes	19.57

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

100 targeting TMEM97, 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-3646	100.00	73.56	5283
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-4492	99.87	68.25	3611

Literature-anchored findings (GeneRIF, showing 27)

• MAC30 mRNA and protein expression in normal and cancerous tissue samples of the esophagus, stomach, colon and pancreas (PMID:15375745)
• MAC30 protein may play a role in development of colorectal cancer, and can be considered as a prognostic factor. (PMID:17143516)
• The most up-regulated gene was TMEM97 which encodes a transmembrane protein of unknown function (MAC30). (PMID:18070364)
• expression of MAC30 in the cytoplasm markedly increased from normal oral epithelial cells to primary oral squamous cell carcinoma; MAC30 expression in primary tumors with lymph node metastasis exceeded levels in those without metastasis (PMID:21079401)
• As the tumor penetrated the wall of the colon/rectum, MAC30 mRNA expression notably increased in colorectal tumors with T3+T4 stage compared to tumors with T1+T2 stage. (PMID:22024687)
• Overexpression of MAC30 is associated with non-small-cell lung cancer. (PMID:23229099)
• MAC30 may serve as a new molecular marker to predict the lymph node metastasis and prognosis of patients with epithelial ovarian cancer (PMID:23254963)
• The down-regulation of MAC30 expression efficiently inhibited the proliferation of gastric cancer cells. Furthermore, the mobility of gastric cancer cells was also inhibited by down-regulation of MAC30. (PMID:24853233)
• High expression of TMEM97 is associated with glioma. (PMID:26002575)
• Overexpression of MAC30 is associated with Squamous Cell Carcinomas of the Lung. (PMID:27268655)
• knockdown of TMEM97 also increases levels of residual NPC1 in NPC1-mutant patient fibroblasts and reduces cholesterol storage in an NPC1-dependent manner. Our findings propose TMEM97 inhibition as a novel strategy to increase residual NPC1 levels in cells and a potential therapeutic target for Niemann-Pick type C disease (NP-C). (PMID:27378690)
• MAC30 could be a useful biomarker of tumor differentiation and outcome of patients with non-small cell lung cancer. Overexpression of MAC30 predicts a worse tumor differentiated stage and prognosis in patients with non-small cell lung cancer receiving adjuvant chemotherapy. (PMID:27688262)
• TMEM97 possesses the full suite of molecular properties that define the sigma2 receptor, and Asp29 and Asp56 are essential for ligand recognition (PMID:28559337)
• Study generated a series of sigma1R and sigma2R/Tmem97 agonists and antagonists and tested them for efficacy in the mouse spared nerve injury model. Results show robust antineuropathic pain effects of sigma1R and sigma2R/Tmem97 ligands, demonstrate that sigma2R/Tmem97 is a novel neuropathic pain target, and identify sigma2R/Tmem97 agonist UKH-1114 as a lead molecule for further development. (PMID:28644012)
• we not only confirmed the elevated MAC30 mRNA, but also demonstrated that GC with overexpression of MAC30 resisted to adjuvant platinum-based chemotherapy. (PMID:28972404)
• TMEM97 was found to be overexpressed in prostate cancer, and identified as a novel miR-152 target gene. (PMID:29599847)
• These data indicate that the formation of a ternary complex of LDLR-PGRMC1-TMEM97 is necessary for the rapid internalization of LDL by LDLR. (PMID:30443021)
• The Sigma-2 Receptor/TMEM97, PGRMC1, and LDL Receptor Complex Are Responsible for the Cellular Uptake of Abeta42 and Its Protein Aggregates. (PMID:32572762)
• TMEM97 facilitates the activation of SOCE by downregulating the association of cholesterol to Orai1 in MDA-MB-231 cells. (PMID:33618021)
• Histatin-1 is an endogenous ligand of the sigma-2 receptor. (PMID:34233061)
• Transmembrane protein 97 exhibits oncogenic properties via enhancing LRP6-mediated Wnt signaling in breast cancer. (PMID:34615853)
• Inhibition of MAC30 exerts antitumor effects in nasopharyngeal carcinoma via affecting the Akt/GSK-3beta/beta-catenin pathway. (PMID:35373413)
• TMEM97 is transcriptionally activated by YY1 and promotes colorectal cancer progression via the GSK-3beta/beta-catenin signaling pathway. (PMID:35907137)
• GPCR/endocytosis/ERK signaling/S2R is involved in the regulation of the internalization, mitochondria-targeting and -activating properties of human salivary histatin 1. (PMID:35970844)
• Sigma-2 Receptor Ligand Binding Modulates Association between TSPO and TMEM97. (PMID:37047353)
• Transmembrane protein 97 is a potential synaptic amyloid beta receptor in human Alzheimer’s disease. (PMID:38319380)
• TMEM97 knockdown inhibits 5-fluorouracil resistance by regulating epithelial-mesenchymal transition and ABC transporter expression via inactivating the Akt/mTOR pathway in 5-fluorouracil-resistant colorectal cancer cells. (PMID:38388887)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmem97	ENSDARG00000040553
mus_musculus	Tmem97	ENSMUSG00000037278
rattus_norvegicus	Tmem97	ENSRNOG00000084614

Protein

Protein identifiers

Sigma intracellular receptor 2 — Q5BJF2 (reviewed: Q5BJF2)

Alternative names: Meningioma-associated protein 30, Transmembrane protein 97

All UniProt accessions (4): Q5BJF2, J3KT68, J3KTD1, Q86XC5

UniProt curated annotations — full annotation on UniProt →

Function. Sigma-2 receptor which contributes to ameliorate dysfunctional cellular processes and slow degenerative progression by regulating cell functions including cholesterol biosynthesis/trafficking, membrane trafficking, autophagy, lipid membrane-bound protein trafficking, and receptor stabilization at the cell surface. Forms a ternary complex with PGRMC1 receptor and low density lipoprotein receptor/LDLR at the plasma membrane, which increases LDLR-mediated LDL cholesterol internalization. Decreases lysosomal sterol transporter NPC1 availability to the cell, probably through NPC1-binding, hence controlling lipid transport, including cholesterol and LBPA, outside of late endosome/lysosome. Binds regio- and stereoselective ligand 20(S)-hydroxycholesterol (20(S)-OHC) which enhances TMEM97-NPC1 interaction and decreases TMEM97-PGRMC1 and TMEM97-TSPO interactions, thereby linking OHC binding to cholesterol homeostasis. Also able to bind cholesterol. Binds histatin 1 (Hst 1)/HN1 salivary peptide at the ER membrane, which is critical for increasing mitochondria-ER contacts and stimulating Hst1 wound healing properties. May alter the activity of some cytochrome P450 proteins. Although shows homologies with sterol isomerases (EXPERA domain), not able to catalyze sterol isomerization. However, may act as sensors of these molecules. Acts as a quality control factor in the ER, promoting the proteolytic degradation of nonproductive and extramitochondrial precursor proteins in the ER membrane thus removing them from the ER surface.

Subunit / interactions. Homodimer. Interacts with NPC1; the interaction impairs NPC1-mediated cholesterol transport. Interacts with PGRMC1 and LDLR; the interaction increases LDL internalization. Interacts with histatin 1/HTN1; the interaction induces HTN1-stimulating wound healing. Interacts with TSPO. Forms a complex with TSPO and PGRMC1; the interaction occurs in MIA PaCa-2 cells but not in MCF7 cells.

Subcellular location. Rough endoplasmic reticulum membrane. Nucleus membrane.

Tissue specificity. Widely expressed in normal tissues. Expressed in pancreatic, renal, breast, colon, ovarian surface epithelial (OSE) cells. Highly expressed in various proliferating cancer cells.

Domain organisation. The four transmembrane helices are all kinked owing to the presence of proline residues in each, creating a ligand-binding cavity near the center of the protein. The EXPERA domain doesn’t possess any sterol isomerase catalytic activity.

Induction. Up-regulated in ovarian surface epithelial (OSE) cells with progesterone.

Miscellaneous. Sigma receptors are classified into two subtypes (Sigma-1 and Sigma-2) based on their different pharmacological profile. Sigma-2 receptor is identified by radioligand-binding studies as a binding site with high affinity for di-o-tolylguanidine (DTG) and haloperidol. Binds numerous drugs and highly expressed in various proliferating cancer cells. Potentially useful for cancer diagnostics or as target for anticancer therapeutics or adjuvant anticancer treatment agents. Some exogenous ligands display a neuroprotective effect.

Similarity. Belongs to the TMEM97/sigma-2 receptor family.

RefSeq proteins (1): NP_055388* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR016964	Sigma2_recept	Family
IPR033118	EXPERA	Domain
IPR051987	Sigma-2_receptor-like	Family

Pfam: PF05241

UniProt features (35 total): mutagenesis site 15, topological domain 5, transmembrane region 4, sequence conflict 3, binding site 2, site 2, chain 1, domain 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5BJF2-F1	90.27	0.77

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 (2): 56 (likely important for receptor folding); 150 (important for 20(s)-ohc binding and stereoselectivity)

Ligand- & substrate-binding residues (2): 75; 77

Mutagenesis-validated functional residues (15):

Position	Phenotype
11	decreases dtg binding.
29	abolishes dtg binding.
37	no effect on dtg binding.
42	no effect on dtg binding.
53	no effect on dtg binding.
56	abolishes dtg binding.
61	no effect on dtg binding.
73	no effect on dtg binding.
121	no effect on dtg binding.
122	decreases dtg binding.
135	decreases dtg binding.
139	decreases dtg binding.
170	decreases dtg binding.
171	decreases dtg binding.
172–176	mislocalization to late endosomes and lysosomes.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 294 (showing top): BORCZUK_MALIGNANT_MESOTHELIOMA_UP, HORIUCHI_WTAP_TARGETS_DN, TSENG_IRS1_TARGETS_UP, GOBP_REGULATION_OF_WOUND_HEALING, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, MODULE_255, GOBP_STEROL_HOMEOSTASIS, AAGCCAT_MIR135A_MIR135B, GOBP_GROWTH, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, MODULE_317, MITSIADES_RESPONSE_TO_APLIDIN_DN, KANNAN_TP53_TARGETS_DN, MODULE_16

GO Biological Process (6): regulation of cell growth (GO:0001558), regulation of intracellular lipid transport (GO:0032377), regulation of intracellular cholesterol transport (GO:0032383), cholesterol homeostasis (GO:0042632), positive regulation of wound healing (GO:0090303), positive regulation of lipoprotein transport (GO:0140077)

GO Molecular Function (3): oxysterol binding (GO:0008142), cholesterol binding (GO:0015485), protein binding (GO:0005515)

GO Cellular Component (8): lysosome (GO:0005764), endoplasmic reticulum (GO:0005783), rough endoplasmic reticulum (GO:0005791), plasma membrane (GO:0005886), rough endoplasmic reticulum membrane (GO:0030867), nuclear membrane (GO:0031965), nucleus (GO:0005634), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sterol binding	2
intracellular membrane-bounded organelle	2
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
intracellular lipid transport	1
regulation of lipid transport	1
regulation of intracellular transport	1
intracellular cholesterol transport	1
regulation of cholesterol transport	1
regulation of intracellular sterol transport	1
sterol homeostasis	1
wound healing	1
regulation of wound healing	1
positive regulation of response to wounding	1
lipoprotein transport	1
positive regulation of protein transport	1
regulation of lipoprotein transport	1
alcohol binding	1
binding	1
lytic vacuole	1
cytoplasm	1
endomembrane system	1
endoplasmic reticulum	1
membrane	1
cell periphery	1
endoplasmic reticulum membrane	1
rough endoplasmic reticulum	1
bounding membrane of organelle	1
nucleus	1
nuclear envelope	1
organelle membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1214 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM97	PGRMC1	O00264	985
TMEM97	NPC1	O15118	978
TMEM97	SIGMAR1	Q99720	938
TMEM97	TMBIM4	Q9HC24	830
TMEM97	SREBF2	Q12772	730
TMEM97	LGALS4	P56470	679
TMEM97	MYC	P01106	614
TMEM97	PACC1	Q9H813	566
TMEM97	SIGLEC12	Q96PQ1	519
TMEM97	EGFR	P00533	508
TMEM97	HRH3	Q9Y5N1	495
TMEM97	PGR	P06401	479
TMEM97	BRD2	P25440	476
TMEM97	VTN	P01141	459
TMEM97	TMEM94	Q12767	445

IntAct

215 interactions, top by confidence:

A	B	Type	Score
HLA-DRA	HLA-DRB1	psi-mi:“MI:0914”(association)	0.880
SLC14A2	TMEM97	psi-mi:“MI:0915”(physical association)	0.600
TMEM97	LHFPL5	psi-mi:“MI:0915”(physical association)	0.560
TMEM97	TMX2	psi-mi:“MI:0915”(physical association)	0.560
TMEM97	MRM1	psi-mi:“MI:0915”(physical association)	0.560
TMEM97	SGPL1	psi-mi:“MI:0915”(physical association)	0.560
TMEM97	HSD17B13	psi-mi:“MI:0915”(physical association)	0.560
TMEM97	CGRRF1	psi-mi:“MI:0915”(physical association)	0.560
TMEM97	FXYD3	psi-mi:“MI:0915”(physical association)	0.560
TMEM97		psi-mi:“MI:0915”(physical association)	0.560
TMEM97	TMEM79	psi-mi:“MI:0915”(physical association)	0.560
TMEM97	MFF	psi-mi:“MI:0915”(physical association)	0.560
TMEM97	ASZ1	psi-mi:“MI:0915”(physical association)	0.560
TMEM97	TMEM106C	psi-mi:“MI:0915”(physical association)	0.560
CD74	TMEM97	psi-mi:“MI:0915”(physical association)	0.560
TMEM97	LRRC59	psi-mi:“MI:0915”(physical association)	0.560
FRMD3	TMEM97	psi-mi:“MI:0915”(physical association)	0.560
TMEM97	BCL2L13	psi-mi:“MI:0915”(physical association)	0.560
BIK	TMEM97	psi-mi:“MI:0915”(physical association)	0.560
TMEM97	PDCD1LG2	psi-mi:“MI:0915”(physical association)	0.560
CLDN7	TMEM97	psi-mi:“MI:0915”(physical association)	0.560
TMEM97	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (120): TMEM97 (Affinity Capture-MS), TMEM97 (Affinity Capture-MS), STXBP3 (Affinity Capture-MS), GUK1 (Affinity Capture-MS), TMEM97 (Affinity Capture-MS), TMEM97 (Affinity Capture-MS), TMEM97 (Affinity Capture-MS), TMEM97 (Affinity Capture-MS), STXBP3 (Affinity Capture-MS), GUK1 (Affinity Capture-MS), TMEM97 (Affinity Capture-MS), TMEM97 (Affinity Capture-MS), TMEM97 (Affinity Capture-MS), TMEM97 (Affinity Capture-MS), TMEM97 (Affinity Capture-MS)

ESM2 similar proteins: A2AKM2, A4FUY9, A5D6V4, A7YY55, A8WGS4, Q01685, Q0P5C7, Q15629, Q3T124, Q4R8A8, Q4V8U5, Q5BJF2, Q5GH60, Q5GH61, Q5GH68, Q5HZE5, Q5ND56, Q5NVQ2, Q5R7Z3, Q5U2T1, Q5VWC8, Q5XI41, Q5ZM57, Q60457, Q6DED0, Q6GLX2, Q6GNB5, Q6P4N1, Q6PP77, Q6YWS8, Q7SY06, Q84QC0, Q86X19, Q8CGF5, Q8K0U3, Q8K2C9, Q8N609, Q8QZR0, Q8R000, Q8VZB2

Diamond homologs: Q10255, Q4R8A8, Q5BJF2, Q12155, Q8VD00, Q3MHW7, Q5U3Y7, Q6DFQ5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
“PB28 dihydrochloride”	“up-regulates activity”	TMEM97	“chemical activation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	16
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

614 predictions. Top by Δscore:

Variant	Effect	Δscore
17:28319366:G:GC	donor_loss	1.0000
17:28319367:T:G	donor_loss	1.0000
17:28325501:A:AG	acceptor_gain	1.0000
17:28325502:G:GG	acceptor_gain	1.0000
17:28325571:GTT:G	donor_gain	1.0000
17:28325572:TTT:T	donor_gain	1.0000
17:28326522:T:TA	acceptor_gain	1.0000
17:28325502:GTTT:G	acceptor_gain	0.9900
17:28325502:GTTTA:G	acceptor_gain	0.9900
17:28326527:A:AG	acceptor_gain	0.9900
17:28326530:TCA:T	acceptor_loss	0.9900
17:28326531:CA:C	acceptor_loss	0.9900
17:28326532:A:T	acceptor_loss	0.9900
17:28319366:G:GG	donor_gain	0.9800
17:28325573:T:G	donor_gain	0.9800
17:28326528:C:G	acceptor_gain	0.9800
17:28326532:A:AG	acceptor_gain	0.9800
17:28326533:G:GG	acceptor_gain	0.9800
17:28326533:GGAA:G	acceptor_gain	0.9800
17:28325499:TCA:T	acceptor_loss	0.9700
17:28325500:CA:C	acceptor_loss	0.9700
17:28325501:AGTTT:A	acceptor_loss	0.9700
17:28325570:GGTT:G	donor_gain	0.9700
17:28326744:T:G	acceptor_gain	0.9700
17:28319363:GAG:G	donor_gain	0.9600
17:28326532:AG:A	acceptor_gain	0.9600
17:28326533:GG:G	acceptor_gain	0.9600
17:28326533:GGA:G	acceptor_gain	0.9500
17:28325502:GT:G	acceptor_gain	0.9300
17:28325630:C:G	donor_gain	0.9300

AlphaMissense

1140 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:28325569:T:A	W65R	0.994
17:28325569:T:C	W65R	0.994
17:28325627:C:A	A84E	0.991
17:28319297:A:C	S20R	0.988
17:28319299:C:A	S20R	0.988
17:28319299:C:G	S20R	0.988
17:28325636:C:A	A87D	0.986
17:28326560:G:C	A100P	0.984
17:28326561:C:A	A100E	0.984
17:28326545:T:A	W95R	0.982
17:28326545:T:C	W95R	0.982
17:28325639:T:C	F88S	0.981
17:28326573:C:A	S104Y	0.980
17:28326603:T:A	I114K	0.980
17:28325594:A:T	E73V	0.979
17:28326573:C:T	S104F	0.979
17:28325571:G:C	W65C	0.978
17:28325571:G:T	W65C	0.978
17:28326723:C:G	P154R	0.978
17:28319300:C:G	H21D	0.977
17:28326569:T:G	Y103D	0.977
17:28326681:G:C	R140P	0.977
17:28325590:T:C	C72R	0.976
17:28325638:T:C	F88L	0.975
17:28325640:C:A	F88L	0.975
17:28325640:C:G	F88L	0.975
17:28325609:T:G	L78R	0.974
17:28325609:T:C	L78P	0.973
17:28326600:C:G	P113R	0.973
17:28319291:T:C	F18L	0.972

dbSNP variants (sampled 300 via entrez): RS1000398493 (17:28321281 A>G), RS1000632515 (17:28319976 C>T), RS1000681513 (17:28319664 A>G), RS1002364531 (17:28320842 T>C), RS1002517369 (17:28323512 C>T), RS1003040307 (17:28323790 G>A), RS1004692589 (17:28326419 T>C), RS1004715024 (17:28318019 C>A), RS1004831371 (17:28317684 C>T), RS1005150129 (17:28326208 C>T), RS1006696521 (17:28323065 T>C,G), RS1007156911 (17:28322771 G>A,C,T), RS1008552145 (17:28318370 G>A), RS1008603204 (17:28318200 A>G), RS1010023581 (17:28317380 C>G,T)

Disease associations

OMIM: gene MIM:612912 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002546_2	Osteoprotegerin levels	1.000000e-09
GCST003219_13	Advanced age-related macular degeneration	1.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:1001492	atrophic macular degeneration

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4105907 (SINGLE PROTEIN), CHEMBL4524009 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

48 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 290,363 (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
CHEMBL100116	PENTAZOCINE	4	33,194
CHEMBL1095777	INDACATEROL	4	2,735
CHEMBL1200492	NEFAZODONE HYDROCHLORIDE	4	5,428
CHEMBL1200517	DIHYDROERGOTAMINE MESYLATE	4	2,704
CHEMBL1200776	CINACALCET HYDROCHLORIDE	4	1,220
CHEMBL1200809	AZELASTINE HYDROCHLORIDE	4	3,805
CHEMBL1229211	DOLUTEGRAVIR	4	3,337
CHEMBL1263	SALMETEROL	4	40,383
CHEMBL1516474	TEGASEROD MALEATE	4	1,823
CHEMBL1535	HYDROXYCHLOROQUINE	4	42,638
CHEMBL1615374	VILAZODONE HYDROCHLORIDE	4	432
CHEMBL1626	CLEMASTINE	4	17,590
CHEMBL1633	KETOTIFEN FUMARATE	4	3,954
CHEMBL1671	PROPRANOLOL HYDROCHLORIDE	4	21,811
CHEMBL1691	BETAXOLOL HYDROCHLORIDE	4	6,455
CHEMBL1705	CLONIDINE HYDROCHLORIDE	4	12,746
CHEMBL1707	LOPERAMIDE HYDROCHLORIDE	4	59,532
CHEMBL1722209	TOLTERODINE TARTRATE	4	3,920
CHEMBL190461	CANNABIDIOL	4	26,379
CHEMBL2024517	CARIPRAZINE HYDROCHLORIDE	4	277
CHEMBL2105760	BREXPIPRAZOLE	4
CHEMBL2138684	FROVATRIPTAN SUCCINATE	4
CHEMBL296419	ASTEMIZOLE	4
CHEMBL3039520	LASMIDITAN	4
CHEMBL344159	TOLVAPTAN	4
CHEMBL3545181	TIOTROPIUM BROMIDE	4
CHEMBL398435	TICAGRELOR	4
CHEMBL4164059	PITOLISANT HYDROCHLORIDE	4
CHEMBL500	PINDOLOL	4
CHEMBL54	HALOPERIDOL	4

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: other protein — Sigma receptors

Most potent curated ligand interactions (6 total), top 6:

Ligand	Action	Affinity	Parameter
PB-28	Agonist	8.3	pKi
CT1812	Antagonist	8.07	pKi
1,3-ditolylguanidine	Full agonist	7.4	pKi
vanoxerine	Binding	7.32	pIC50
SM 21	Antagonist	7.2	pIC50
PD-144418	Antagonist	5.86	pKi

Binding affinities (BindingDB)

175 measured of 181 human assays (181 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-[(2R)-4-(3,4-dichlorophenyl)butan-2-yl]-5,6-dimethoxy-1,3-dihydroisoindole	KI	0.44 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
2-[4-(4-fluorophenyl)-2-methylbutan-2-yl]-5,6-dimethoxy-1,3-dihydroisoindole	KI	0.53 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
2-[(2S)-4-(3,4-dichlorophenyl)butan-2-yl]-5,6-dimethoxy-1,3-dihydroisoindole	KI	0.67 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
4-[3-methyl-3-(5-methylsulfonyl-1,3-dihydroisoindol-2-yl)butyl]-2-(2-methylpropoxy)phenol	KI	1.1 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
4-[3-(4-fluoro-1,3-dihydroisoindol-2-yl)-3-methylbutyl]-2-(2-methylpropoxy)phenol	KI	1.3 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
1-cyanoethyl 1-benzyl-5-chloro-3-methylpyrazole-4-carboxylate	KI	1.3 nM	US-20250387403: SELECTIVE SIGMA-2 RECEPTOR LIGANDS AS MODULATORS OF TMEM97
2-[4-(3-methoxyphenyl)-2-methylbutan-2-yl]-5-methylsulfonyl-1,3-dihydroisoindole	KI	1.4 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
2-[(2R)-4-(3,4-dichlorophenyl)butan-2-yl]-1,3-dihydrobenzo[f]isoindole	KI	1.5 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
2-[4-(3,4-dichlorophenyl)butan-2-yl]-1,3-dihydrobenzo[e]isoindole	KI	1.8 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
2-[4-(4-methoxyphenyl)-2-methylbutan-2-yl]-5-methylsulfonyl-1,3-dihydroisoindole	KI	1.8 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
2-[(2R)-4-(3,4-dichlorophenyl)butan-2-yl]-1,3-dihydrobenzo[e]isoindole	KI	1.8 nM	US-9796672: Isoindoline compositions and methods for treating neurodegenerative disease
2-[(2R)-4-(3,4-dichlorophenyl)butan-2-yl]-5-(trifluoromethyl)-1,3-dihydroisoindole	KI	2.2 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
N-(4-chlorophenyl)-2-[(6-methyl-2-nitro-3-pyridinyl)oxy]acetamide	KI	2.3 nM	US-20250387403: SELECTIVE SIGMA-2 RECEPTOR LIGANDS AS MODULATORS OF TMEM97
4-[3-methyl-3-(4-methylsulfonyl-1,3-dihydroisoindol-2-yl)butyl]-2-[(2-methylpropan-2-yl)oxy]phenol	KI	2.6 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
[2-[4-(4-hydroxy-3-methoxyphenyl)-2-methylbutan-2-yl]-1,3-dihydroisoindol-4-yl]-piperazin-1-ylmethanone	KI	2.6 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
5,6-dichloro-2-[(2R)-4-(3,4-dichlorophenyl)butan-2-yl]-1,3-dihydroisoindole	KI	2.7 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
4-fluoro-2-[4-(4-fluorophenyl)-2-methylbutan-2-yl]-1,3-dihydroisoindole	KI	3.2 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
2-[(2R)-4-(3,4-dichlorophenyl)butan-2-yl]-4-fluoro-1,3-dihydroisoindole	KI	3.6 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
5-fluoro-2-[4-(4-fluorophenyl)-2-methylbutan-2-yl]-1,3-dihydroisoindole	KI	3.6 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
3-[(2,6-dichlorophenyl)methoxy]-6-methyl-2-nitropyridine	KI	4.1 nM	US-20250387403: SELECTIVE SIGMA-2 RECEPTOR LIGANDS AS MODULATORS OF TMEM97
N-(3,5-dichlorophenyl)-2-[(6-methyl-2-nitro-3-pyridinyl)oxy]acetamide	KI	4.3 nM	US-20250387403: SELECTIVE SIGMA-2 RECEPTOR LIGANDS AS MODULATORS OF TMEM97
2-(benzimidazol-1-yl)-N-(3,4-dihydro-2H-1,5-benzodioxepin-7-yl)acetamide	KI	4.6 nM	US-20250387403: SELECTIVE SIGMA-2 RECEPTOR LIGANDS AS MODULATORS OF TMEM97
6-methyl-3-[[3-[(6-methyl-2-nitro-3-pyridinyl)oxymethyl]phenyl]methoxy]-2-nitropyridine	KI	4.9 nM	US-20250387403: SELECTIVE SIGMA-2 RECEPTOR LIGANDS AS MODULATORS OF TMEM97
6-[(2R)-4-(3,4-dichlorophenyl)butan-2-yl]-5,7-dihydro-[1,3]dioxolo[4,5-f]isoindole	KI	5 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
6-[4-(4-fluorophenyl)-2-methylbutan-2-yl]-5,7-dihydro-[1,3]dioxolo[4,5-f]isoindole	KI	5.2 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
3-[2-(4-methoxyphenoxy)ethoxy]-6-methyl-2-nitropyridine	KI	5.5 nM	US-20250387403: SELECTIVE SIGMA-2 RECEPTOR LIGANDS AS MODULATORS OF TMEM97
2-[4-[3,4-di(propan-2-yloxy)phenyl]-2-methylbutan-2-yl]-5-fluoro-1,3-dihydroisoindole	KI	6.2 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
[4-[3-methyl-3-(5-methylsulfonyl-1,3-dihydroisoindol-2-yl)butyl]-2-[(2-methylpropan-2-yl)oxy]phenyl] acetate	KI	6.6 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
3-[(5E)-5-[(3-ethoxyphenyl)methylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]propanoic acid	KI	6.8 nM	US-20250387403: SELECTIVE SIGMA-2 RECEPTOR LIGANDS AS MODULATORS OF TMEM97
4-[3-methyl-3-(5-methylsulfonyl-1,3-dihydroisoindol-2-yl)butyl]-2-(trifluoromethoxy)phenol	KI	6.9 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
5-nitro-N-(4-thiophen-2-yl-1,3-thiazol-2-yl)furan-2-carboxamide	KI	7.7 nM	US-20250387403: SELECTIVE SIGMA-2 RECEPTOR LIGANDS AS MODULATORS OF TMEM97
(4-cyclohexylpiperazin-1-yl)-[3-[(3-hydroxypiperidin-1-yl)methyl]imidazo[1,2-a]pyridin-2-yl]methanone	KI	7.9 nM	US-20250387403: SELECTIVE SIGMA-2 RECEPTOR LIGANDS AS MODULATORS OF TMEM97
4-[3-methyl-3-(4-methylsulfonyl-1,3-dihydroisoindol-2-yl)butyl]-2-(trifluoromethoxy)phenol	KI	8.1 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
4-[3-methyl-3-(5-methylsulfonyl-1,3-dihydroisoindol-2-yl)butyl]-2-[(2-methylpropan-2-yl)oxy]phenol	KI	8.5 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
2-methoxy-4-[3-methyl-3-(4-methylsulfonyl-1,3-dihydroisoindol-2-yl)butyl]phenol	KI	8.6 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
N-[2-(2,4-dichlorophenyl)ethyl]-2-[(6-methyl-2-nitro-3-pyridinyl)oxy]acetamide	KI	8.7 nM	US-20250387403: SELECTIVE SIGMA-2 RECEPTOR LIGANDS AS MODULATORS OF TMEM97
6-[(2R)-4-[3,4-di(propan-2-yloxy)phenyl]butan-2-yl]-5,7-dihydro-[1,3]dioxolo[4,5-f]isoindole	KI	8.9 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
4-[3-methyl-3-(5-methylsulfonyl-1,3-dihydroisoindol-2-yl)butyl]-2-propan-2-yloxyphenol	KI	9 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
(2R,11R,12R,13R)-19-chloro-13-methyl-12-phenyl-9-oxa-1,15-diazapentacyclo[11.9.0.02,11.03,8.016,21]docosa-3,5,7,16(21),17,19-hexaene-14,22-dione	KI	9.5 nM	US-20250387403: SELECTIVE SIGMA-2 RECEPTOR LIGANDS AS MODULATORS OF TMEM97
[2-[(3-carbamoylthiophen-2-yl)amino]-2-oxoethyl] 5-nitrofuran-2-carboxylate	KI	10.3 nM	US-20250387403: SELECTIVE SIGMA-2 RECEPTOR LIGANDS AS MODULATORS OF TMEM97
4-[3-(4-fluoro-1,3-dihydroisoindol-2-yl)-3-methylbutyl]-2-propan-2-yloxyphenol	KI	11 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
2-[4-(3,4-dimethoxyphenyl)-2-methylbutan-2-yl]-5-methylsulfonyl-1,3-dihydroisoindole	KI	11 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
N-(4-fluorophenyl)-2-[6-methoxy-3-(4-methylbenzoyl)-4-oxoquinolin-1-yl]acetamide	KI	11 nM	US-20250387403: SELECTIVE SIGMA-2 RECEPTOR LIGANDS AS MODULATORS OF TMEM97
2-[[5-(4-fluorophenyl)-1,3,4-oxadiazol-2-yl]sulfanyl]-N-(6-methoxy-3-pyridinyl)acetamide	KI	11.9 nM	US-20250387403: SELECTIVE SIGMA-2 RECEPTOR LIGANDS AS MODULATORS OF TMEM97
4-fluoro-2-[(2R)-4-(4-fluorophenyl)butan-2-yl]-1,3-dihydroisoindole	KI	12 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
6-[(2R)-4-(4-fluorophenyl)butan-2-yl]-5,7-dihydro-[1,3]dioxolo[4,5-f]isoindole	KI	13 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
4-[3-(5,7-dihydro-[1,3]dioxolo[4,5-f]isoindol-6-yl)-3-methylbutyl]-2-propan-2-yloxyphenol	KI	13 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease
N-butan-2-yl-1-ethyl-6-fluoro-7-[4-(furan-2-carbonyl)piperazin-1-yl]-4-oxoquinoline-3-carboxamide	KI	13.6 nM	US-20250387403: SELECTIVE SIGMA-2 RECEPTOR LIGANDS AS MODULATORS OF TMEM97
3-hydroxy-2-[5-[4-(trifluoromethyl)phenyl]furan-2-yl]-1,2-dihydroquinazolin-4-one	KI	14.7 nM	US-20250387403: SELECTIVE SIGMA-2 RECEPTOR LIGANDS AS MODULATORS OF TMEM97
2-[4-(3,4-dichlorophenyl)-2-methylbutan-2-yl]-5-piperazin-1-yl-1,3-dihydroisoindole	KI	15 nM	US-10207991: Isoindoline compositions and methods for treating neurodegenerative disease

ChEMBL bioactivities

1237 potent at pChembl≥5 of 1240 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.92	Ki	0.12	nM	SIRAMESINE
9.59	Ki	0.26	nM	CHEMBL227126
9.47	Ki	0.34	nM	CHEMBL53325
9.37	Ki	0.43	nM	CHEMBL5426155
9.36	Ki	0.44	nM	CHEMBL4853196
9.28	Ki	0.53	nM	CHEMBL5928382
9.24	Ki	0.58	nM	CHEMBL5278003
9.23	Ki	0.59	nM	CHEMBL4647871
9.17	Ki	0.68	nM	CHEMBL53325
9.17	Ki	0.67	nM	CHEMBL5979974
9.00	Ki	1	nM	CHEMBL5418939
9.00	Ki	1	nM	CHEMBL5395523
8.96	Ki	1.1	nM	CHEMBL6040331
8.92	IC50	1.2	nM	CHEMBL5905454
8.89	Ki	1.3	nM	CHEMBL5960929
8.85	Ki	1.4	nM	CHEMBL6047114
8.82	Ki	1.5	nM	CHEMBL5982604
8.82	IC50	1.5	nM	CHEMBL5911219
8.80	Ki	1.6	nM	CHEMBL332701
8.74	Ki	1.8	nM	CHEMBL5945487
8.74	Ki	1.8	nM	CHEMBL6015644
8.74	Ki	1.8	nM	CHEMBL5991759
8.70	Ki	2	nM	CHEMBL227072
8.70	IC50	2	nM	CHEMBL5951033
8.67	Ki	2.138	nM	CHEMBL3321792
8.66	Ki	2.2	nM	CHEMBL3321792
8.66	Ki	2.2	nM	CHEMBL4577233
8.66	Ki	2.2	nM	CHEMBL5811349
8.65	Ki	2.239	nM	CHEMBL4577233
8.62	IC50	2.4	nM	CHEMBL5752633
8.60	Ki	2.512	nM	CHEMBL53325
8.60	Ki	2.512	nM	CHEMBL4446729
8.59	Ki	2.6	nM	CHEMBL5899919
8.59	Ki	2.6	nM	CHEMBL5744962
8.57	Ki	2.7	nM	CHEMBL4446729
8.57	Ki	2.7	nM	CHEMBL5815237
8.57	Ki	2.7	nM	CHEMBL4165863
8.52	Ki	3	nM	CHEMBL4642427
8.52	Ki	3	nM	CHEMBL5393813
8.50	Ki	3.14	nM	CHEMBL5290452
8.49	Ki	3.2	nM	CHEMBL5946543
8.48	Ki	3.3	nM	CHEMBL4633444
8.46	IC50	3.5	nM	CHEMBL5922874
8.44	Ki	3.6	nM	CHEMBL6056346
8.44	Ki	3.6	nM	CHEMBL5975554
8.43	Ki	3.7	nM	CHEMBL5274616
8.42	Ki	3.8	nM	CHEMBL4590308
8.41	IC50	3.9	nM	CHEMBL6058962
8.41	IC50	3.9	nM	CHEMBL5825785
8.40	Ki	4	nM	CHEMBL5273358

PubChem BioAssay actives

593 with measured affinity, of 815 total; 50 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
1’-[4-[1-(4-fluorophenyl)indol-3-yl]butyl]spiro[1H-2-benzofuran-3,4’-piperidine]	1353759: Binding affinity to sigma-2 receptor (unknown origin)	ki	0.0001	uM
1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine	1353759: Binding affinity to sigma-2 receptor (unknown origin)	ki	0.0003	uM
N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)butyl]-2-(2-(18F)fluoroethoxy)-5-iodo-3-methoxy(18F)benzamide	1353759: Binding affinity to sigma-2 receptor (unknown origin)	ki	0.0003	uM
2-[(2R)-4-(3,4-dichlorophenyl)butan-2-yl]-5,6-dimethoxy-1,3-dihydroisoindole	1780129: Binding affinity to Sigma 2-receptor (unknown origin)	ki	0.0004	uM
1-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)butyl]-3-methylbenzimidazol-2-one	1972118: Binding affinity to sigma2 receptor (unknown origin) assessed as inhibition constant	ki	0.0004	uM
4-benzyl-1-[(2,2-dimethyl-1,3-dithiolan-4-yl)methyl]piperidine;oxalic acid	1655950: Displacement of [3H]-ditolylguanidine from human Sigma 2 receptor by radioligand displacement assay	ki	0.0006	uM
6-[(2E)-3,3-dimethyl-2-[(2E,4E)-5-(1,3,3-trimethylindol-1-ium-2-yl)penta-2,4-dienylidene]indol-1-yl]-N-[1-(4-spiro[1H-2-benzofuran-3,4’-piperidine]-1’-ylbutyl)indol-6-yl]hexanamide iodide	1948320: Binding affinity to sigma 2 receptor in human MCF7 cells assessed as displacement of compound by measuring inhibition constant of DTG incubated for 120 mins by saturation binding assay	ki	0.0006	uM
2-[4-[2-cyclopropyl-5-(3-methyl-1,2-oxazol-5-yl)pyrimidin-4-yl]piperidin-1-yl]-1-morpholin-4-ylethanone	1972125: Displacement of [3H]-1,3-di-O-tolylguanidine from human sigma 2 receptor/TMEM97 transfected in sigma 1 receptor knockout HEK293 cell membranes assessed as inhibition constant measured after 120 mins by microbeta scintillation counting analysis	ki	0.0010	uM
2-[4-[2-ethyl-5-(3-methyl-1,2-oxazol-5-yl)pyrimidin-4-yl]piperidin-1-yl]-1-(2-oxa-8-azaspiro[4.5]decan-8-yl)ethanone	1972125: Displacement of [3H]-1,3-di-O-tolylguanidine from human sigma 2 receptor/TMEM97 transfected in sigma 1 receptor knockout HEK293 cell membranes assessed as inhibition constant measured after 120 mins by microbeta scintillation counting analysis	ki	0.0010	uM
1-[2-[(2R)-1-(3-methoxyphenyl)sulfonylpyrrolidin-2-yl]ethyl]-4-methylpiperidine	1855148: Binding affinity to sigma 2 receptor (unknown origin) assessed as inhibition constant	ki	0.0016	uM
N-[4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)butyl]-2-(2-(18F)fluoroethoxy)-5-methyl(18F)benzamide	1922171: Binding affinity to sigma 2 receptor (unknown origin)	ki	0.0020	uM
3-(4-chlorophenyl)-8-[3-(2-fluorophenyl)sulfanylpropyl]-8-azabicyclo[3.2.1]octan-3-ol	1592019: Displacement [3H]-DTG from sigma 2 receptor (unknown origin) expressed in HEK cell membranes	ki	0.0021	uM
1-(5-chloro-2-pyridinyl)-4-[3-(4-fluorophenyl)sulfanylpropyl]-1,4-diazepane	1592019: Displacement [3H]-DTG from sigma 2 receptor (unknown origin) expressed in HEK cell membranes	ki	0.0022	uM
(NZ)-N-[4-[4-(5-chloro-2-pyridinyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butylidene]hydroxylamine	1592019: Displacement [3H]-DTG from sigma 2 receptor (unknown origin) expressed in HEK cell membranes	ki	0.0025	uM
4-benzyl-1-(1,4-dithiaspiro[4.4]nonan-3-ylmethyl)piperidine;oxalic acid	1655950: Displacement of [3H]-ditolylguanidine from human Sigma 2 receptor by radioligand displacement assay	ki	0.0030	uM
1-(4,4-difluoropiperidin-1-yl)-2-[4-[5-(3-methyl-1,2-oxazol-5-yl)-2-propylpyrimidin-4-yl]piperidin-1-yl]ethanone	1972125: Displacement of [3H]-1,3-di-O-tolylguanidine from human sigma 2 receptor/TMEM97 transfected in sigma 1 receptor knockout HEK293 cell membranes assessed as inhibition constant measured after 120 mins by microbeta scintillation counting analysis	ki	0.0030	uM
6-[(2Z)-3,3-dimethyl-2-[(2E,4E)-5-(1,3,3-trimethylindol-1-ium-2-yl)penta-2,4-dienylidene]indol-1-yl]-N-[6-[3-(4-spiro[1H-2-benzofuran-3,4’-piperidine]-1’-ylbutyl)indol-1-yl]hexyl]hexanamide iodide	1948320: Binding affinity to sigma 2 receptor in human MCF7 cells assessed as displacement of compound by measuring inhibition constant of DTG incubated for 120 mins by saturation binding assay	ki	0.0031	uM
1-benzyl-4-[(2,2-dimethyl-1,3-dithiolan-4-yl)methyl]piperazine;oxalic acid	1655950: Displacement of [3H]-ditolylguanidine from human Sigma 2 receptor by radioligand displacement assay	ki	0.0033	uM
3-[1-(3-phenylpropyl)-3,6-dihydro-2H-pyridin-4-yl]-1H-pyrrolo[2,3-b]pyridine	1922169: Displacement of [H3]DTG from sigma 2 receptor (unknown origin) by competition binding assay	ki	0.0037	uM
3-[4-(azepan-1-yl)butyl]-5-chloro-1,3-benzoxazol-2-one	1596349: Displacement of [3H]-DTG from sigma2 receptor (unknown origin) incubated for 120 mins by scintillation counting method	ki	0.0038	uM
6-[[[(1S)-1-hydroxy-2-methyl-1-phenylpropan-2-yl]amino]methyl]-1-methyl-3,4-dihydroquinolin-2-one	1922169: Displacement of [H3]DTG from sigma 2 receptor (unknown origin) by competition binding assay	ki	0.0040	uM
2-[4-[2-ethyl-5-(3-methyl-1,2-oxazol-5-yl)pyrimidin-4-yl]piperidin-1-yl]-1-piperidin-1-ylethanone	1972125: Displacement of [3H]-1,3-di-O-tolylguanidine from human sigma 2 receptor/TMEM97 transfected in sigma 1 receptor knockout HEK293 cell membranes assessed as inhibition constant measured after 120 mins by microbeta scintillation counting analysis	ki	0.0040	uM
N-(cyclohexylmethyl)-N-methylspiro[cyclohexane-4,1’-isochromene]-1-amine	1587573: Displacement of [3H]-di-o-tolylguanidine from sigma2 receptor in human RT4 cell membranes incubated for 120 mins in the presence of sigma1 receptor ligand (+)-pentazocine by scintillation counting method	ki	0.0046	uM
4-[3-methyl-3-(5-methylsulfonyl-1,3-dihydroisoindol-2-yl)butyl]-2-[(2-methylpropan-2-yl)oxy]phenol	1972125: Displacement of [3H]-1,3-di-O-tolylguanidine from human sigma 2 receptor/TMEM97 transfected in sigma 1 receptor knockout HEK293 cell membranes assessed as inhibition constant measured after 120 mins by microbeta scintillation counting analysis	ki	0.0050	uM
4-benzyl-1-(1,4-dithiaspiro[4.5]decan-3-ylmethyl)piperidine	1981014: Binding affinity to sigma 2 receptor (unknown origin) assessed as inhibition constant	ki	0.0050	uM
2-[4-[2-ethyl-5-(3-methyl-1,2-oxazol-5-yl)pyrimidin-4-yl]piperidin-1-yl]-1-(1,4-oxazepan-4-yl)ethanone	1972125: Displacement of [3H]-1,3-di-O-tolylguanidine from human sigma 2 receptor/TMEM97 transfected in sigma 1 receptor knockout HEK293 cell membranes assessed as inhibition constant measured after 120 mins by microbeta scintillation counting analysis	ki	0.0050	uM
4-[4-(4-chlorophenyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one	1592019: Displacement [3H]-DTG from sigma 2 receptor (unknown origin) expressed in HEK cell membranes	ki	0.0051	uM
1-[3-(4-fluorophenoxy)propyl]-4-phenylpiperazine	1592019: Displacement [3H]-DTG from sigma 2 receptor (unknown origin) expressed in HEK cell membranes	ki	0.0051	uM
[(1R,5R)-9-(6-aminohexyl)-9-azabicyclo[3.3.1]nonan-3-yl] N-(2-methoxy-5-methylphenyl)carbamate	1353759: Binding affinity to sigma-2 receptor (unknown origin)	ki	0.0052	uM
N-(cyclohexylmethyl)-N-methylspiro[3,4-dihydroisochromene-1,4’-cyclohexane]-1’-amine	1587573: Displacement of [3H]-di-o-tolylguanidine from sigma2 receptor in human RT4 cell membranes incubated for 120 mins in the presence of sigma1 receptor ligand (+)-pentazocine by scintillation counting method	ki	0.0055	uM
1-(4-chlorophenyl)-4-[3-(4-fluorophenoxy)propyl]-1,4-diazepane	1592019: Displacement [3H]-DTG from sigma 2 receptor (unknown origin) expressed in HEK cell membranes	ki	0.0059	uM
2-[4-[5-(3-methyl-1,2-oxazol-5-yl)-2-(trifluoromethyl)pyrimidin-4-yl]piperidin-1-yl]-1-morpholin-4-ylethanone	1972125: Displacement of [3H]-1,3-di-O-tolylguanidine from human sigma 2 receptor/TMEM97 transfected in sigma 1 receptor knockout HEK293 cell membranes assessed as inhibition constant measured after 120 mins by microbeta scintillation counting analysis	ki	0.0060	uM
4-benzyl-1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]piperidine;oxalic acid	1655950: Displacement of [3H]-ditolylguanidine from human Sigma 2 receptor by radioligand displacement assay	ki	0.0062	uM
1’-benzylspiro[3,4-dihydrothiochromene-2,4’-piperidine]	1976007: Binding affinity to S2R (unknown origin)	ki	0.0064	uM
N-(cyclohexylmethyl)spiro[cyclohexane-4,1’-isochromene]-1-amine	1587573: Displacement of [3H]-di-o-tolylguanidine from sigma2 receptor in human RT4 cell membranes incubated for 120 mins in the presence of sigma1 receptor ligand (+)-pentazocine by scintillation counting method	ki	0.0067	uM
2-[[5-[3-(4-cyclohexylpiperazin-1-yl)propyl]-5,6,7,8-tetrahydronaphthalen-1-yl]oxy]-5-(dimethylamino)isoindole-1,3-dione	1948306: Binding affinity to sigma 2 receptor (unknown origin) assessed as inhibition constant	ki	0.0069	uM
(4-fluorophenyl)methyl (1R,8S)-5-[4-(3-fluoropropyl)piperazin-1-yl]-9-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-9-carboxylate	2132259: Displacement of 3H-ditolylguanidine from human sigma 2 receptor transfected in human HEK293T cells assessed as inhibition constant in presence of (+)-pentazocine by radioligand competition binding assay	ki	0.0069	uM
N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-(methylamino)benzamide	1763013: Displacement of [3H]DTG from sigma2 receptor(unknown origin)	ki	0.0072	uM
3-[4-(azepan-1-yl)butyl]-5-chloro-1,3-benzothiazol-2-one	1596349: Displacement of [3H]-DTG from sigma2 receptor (unknown origin) incubated for 120 mins by scintillation counting method	ki	0.0076	uM
N-(cyclohexylmethyl)-1-methoxy-N-methylspiro[1H-2-benzofuran-3,4’-cyclohexane]-1’-amine	1587573: Displacement of [3H]-di-o-tolylguanidine from sigma2 receptor in human RT4 cell membranes incubated for 120 mins in the presence of sigma1 receptor ligand (+)-pentazocine by scintillation counting method	ki	0.0076	uM
[9-(10-aminodecyl)-9-azabicyclo[3.3.1]nonan-3-yl] N-(2-methoxy-5-methylphenyl)carbamate	1922169: Displacement of [H3]DTG from sigma 2 receptor (unknown origin) by competition binding assay	ki	0.0077	uM
benzyl 5-(4-propylpiperazin-1-yl)-9-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-9-carboxylate	1907475: Displacement of 3H-ditolylguanidine from human sigma 2 receptor/TMEM97 transfected in human HEK293T cells assessed as inhibition constant in presence of (+)-pentazocine by radioligand competition binding assay	ki	0.0079	uM
2-[3-(azepan-1-yl)propylsulfanyl]-5-chloro-1,3-benzothiazole	1596349: Displacement of [3H]-DTG from sigma2 receptor (unknown origin) incubated for 120 mins by scintillation counting method	ki	0.0079	uM
4-[4-(5-chloro-2-pyridinyl)-1,4-diazepan-1-yl]-1-(4-fluorophenyl)butan-1-one	1592019: Displacement [3H]-DTG from sigma 2 receptor (unknown origin) expressed in HEK cell membranes	ki	0.0079	uM
N-(cyclohexylmethyl)spiro[3,4-dihydroisochromene-1,4’-cyclohexane]-1’-amine	1587573: Displacement of [3H]-di-o-tolylguanidine from sigma2 receptor in human RT4 cell membranes incubated for 120 mins in the presence of sigma1 receptor ligand (+)-pentazocine by scintillation counting method	ki	0.0080	uM
benzyl (1R,8S)-5-[4-(3-methoxypropyl)piperazin-1-yl]-9-azatricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene-9-carboxylate	2132261: Binding affinity to sigma 2 receptor (unknown origin) assessed as inhibition constant	ki	0.0080	uM
3-(4-chlorophenyl)-8-[3-(3-fluorophenyl)sulfanylpropyl]-8-azabicyclo[3.2.1]octan-3-ol	1592019: Displacement [3H]-DTG from sigma 2 receptor (unknown origin) expressed in HEK cell membranes	ki	0.0081	uM
4-benzyl-1-(1,4-dithiaspiro[4.6]undecan-3-ylmethyl)piperidine;oxalic acid	1655950: Displacement of [3H]-ditolylguanidine from human Sigma 2 receptor by radioligand displacement assay	ki	0.0081	uM
2-[[1-[2-(4-fluorophenyl)-2-oxoethyl]piperidin-4-yl]methyl]-3H-isoindol-1-one	1922169: Displacement of [H3]DTG from sigma 2 receptor (unknown origin) by competition binding assay	ki	0.0082	uM
N-[4-(4-benzylpiperidin-1-yl)butyl]-4-nitro-3-(trifluoromethyl)aniline	1467942: Displacement of [3H]-DTG from sigma 2 receptor (unknown origin) after 120 mins by liquid scintillation counting method	ki	0.0084	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	5
bisphenol A	affects expression, decreases expression, affects cotreatment, decreases methylation, increases expression	4
sodium arsenite	increases expression, decreases expression	4
Tetrachlorodibenzodioxin	affects expression, decreases expression	4
bisphenol S	increases expression, decreases methylation, affects cotreatment	2
(+)-JQ1 compound	decreases expression	2
Acetaminophen	decreases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Doxorubicin	decreases expression, affects response to substance	2
Estradiol	increases expression	2
Nickel	decreases expression	2
Rotenone	increases expression	2
Tretinoin	decreases expression	2
Aflatoxin B1	decreases expression, decreases methylation	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
alpha phellandrene	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	increases activity, increases expression, affects binding	1
dodecyldimethylamine oxide	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	increases expression, affects cotreatment	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
lead chloride	affects cotreatment, increases expression	1
cupric chloride	decreases expression	1
hydroquinone	decreases expression	1
cadmium sulfate	affects cotreatment, increases expression	1
diallyl trisulfide	decreases expression	1
M-VAC protocol	increases response to substance	1
epigallocatechin gallate	increases expression	1

ChEMBL screening assays

200 unique, capped per target: 197 binding, 3 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4022868	Binding	Displacement of [3H]-DTG from sigma 2 receptor (unknown origin) after 120 mins by liquid scintillation counting method	Novel Sigma Receptor Ligand-Nitric Oxide Photodonors: Molecular Hybrids for Double-Targeted Antiproliferative Effect. — J Med Chem
CHEMBL4406644	ADMET	Displacement of [3H]-DTG from sigma 2 receptor (unknown origin) measured after 90 mins by microbeta counting analysis	Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist. — J Med Chem

Cellosaurus cell lines

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

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

Cellosaurus	Name	Category	Sex
CVCL_B3JQ	Abcam HEK293T TMEM97 KO	Transformed cell line	Female
CVCL_D9UH	Ubigene HEK293 TMEM97 KO	Transformed cell line	Female
CVCL_E2M8	HAP1 TMEM97 (-) 1	Cancer cell line	Male
CVCL_E2M9	HAP1 TMEM97 (-) 2	Cancer cell line	Male
CVCL_E2MA	HAP1 TMEM97 (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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