SIGMAR1

Summary

SIGMAR1 (sigma non-opioid intracellular receptor 1, HGNC:8157) is a protein-coding gene on chromosome 9p13.3, encoding Sigma non-opioid intracellular receptor 1 (Q99720). Functions in lipid transport from the endoplasmic reticulum and is involved in a wide array of cellular functions probably through regulation of the biogenesis of lipid microdomains at the plasma membrane.

This gene encodes a receptor protein that interacts with a variety of psychotomimetic drugs, including cocaine and amphetamines. The receptor is believed to play an important role in the cellular functions of various tissues associated with the endocrine, immune, and nervous systems. As indicated by its previous name, opioid receptor sigma 1 (OPRS1), the product of this gene was erroneously thought to function as an opioid receptor; it is now thought to be a non-opioid receptor. Mutations in this gene has been associated with juvenile amyotrophic lateral sclerosis 16. Alternative splicing of this gene results in transcript variants encoding distinct isoforms.

Source: NCBI Gene 10280 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive distal spinal muscular atrophy 2 (Strong, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 184 total — 9 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 65
• Druggable target: yes — 148 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005866

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8157
Approved symbol	SIGMAR1
Name	sigma non-opioid intracellular receptor 1
Location	9p13.3
Locus type	gene with protein product
Status	Approved
Aliases	SR-BP1
Ensembl gene	ENSG00000147955
Ensembl biotype	protein_coding
OMIM	601978
Entrez	10280

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 15 protein_coding, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000277010, ENST00000353468, ENST00000378892, ENST00000461426, ENST00000477726, ENST00000478146, ENST00000497006, ENST00000679597, ENST00000680104, ENST00000680244, ENST00000680277, ENST00000680730, ENST00000681409, ENST00000902806, ENST00000902807, ENST00000902808, ENST00000902809, ENST00000902810, ENST00000934985, ENST00000934986, ENST00000966016

RefSeq mRNA: 7 — MANE Select: NM_005866 NM_001282205, NM_001282206, NM_001282207, NM_001282208, NM_001282209, NM_005866, NM_147157

CCDS: CCDS6562, CCDS6563, CCDS94399, CCDS94400, CCDS94401, CCDS94402

Canonical transcript exons

ENST00000277010 — 4 exons

Exon	Start	End
ENSE00000982547	34637220	34637420
ENSE00001189952	34637547	34637787
ENSE00003642931	34634722	34635858
ENSE00003667265	34636997	34637089

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 97.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.4620 / max 242.4320, expressed in 1811 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
100536	37.5242	1809
100537	2.9378	1505

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	97.62	gold quality
stromal cell of endometrium	CL:0002255	96.55	gold quality
liver	UBERON:0002107	95.55	gold quality
right coronary artery	UBERON:0001625	95.14	gold quality
ectocervix	UBERON:0012249	94.92	gold quality
left uterine tube	UBERON:0001303	94.89	gold quality
right adrenal gland	UBERON:0001233	94.88	gold quality
endocervix	UBERON:0000458	94.62	gold quality
right adrenal gland cortex	UBERON:0035827	94.62	gold quality
left adrenal gland	UBERON:0001234	94.61	gold quality
left coronary artery	UBERON:0001626	94.55	gold quality
ventricular zone	UBERON:0003053	94.43	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.43	gold quality
left adrenal gland cortex	UBERON:0035825	94.42	gold quality
mucosa of transverse colon	UBERON:0004991	94.34	gold quality
coronary artery	UBERON:0001621	94.30	gold quality
right ovary	UBERON:0002118	94.13	gold quality
thoracic aorta	UBERON:0001515	94.11	gold quality
adrenal cortex	UBERON:0001235	94.08	gold quality
ascending aorta	UBERON:0001496	94.08	gold quality
body of uterus	UBERON:0009853	94.05	gold quality
aorta	UBERON:0000947	93.97	gold quality
popliteal artery	UBERON:0002250	93.93	gold quality
tibial artery	UBERON:0007610	93.93	gold quality
lower esophagus	UBERON:0013473	93.83	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.82	gold quality
skin of abdomen	UBERON:0001416	93.66	gold quality
descending thoracic aorta	UBERON:0002345	93.63	gold quality
lower esophagus mucosa	UBERON:0035834	93.63	gold quality
skin of leg	UBERON:0001511	93.57	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF4, FOSL2, NR1I2

miRNA regulators (miRDB)

59 targeting SIGMAR1, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-4690-5P	99.65	66.24	813
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-567	99.63	68.57	1219
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4762-5P	99.57	68.54	1424
HSA-MIR-190A-5P	99.54	71.45	933
HSA-MIR-190B-5P	99.54	71.40	925
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-297	99.40	69.58	1418
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-1909-3P	99.03	66.56	1662

Literature-anchored findings (GeneRIF, showing 40)

• Data show that Squid (Sqd) interacts with Hrb27C, and that Ovarian tumor (Otu) cooperates with Hrb27C and Sqd in the oocyte to mediate proper gurken (grk) localization. (PMID:15056611)
• Three proteins (DDP1, Hrp48, and poly(A)-binding protein) are components of the HDE-binding complex and function in translational enhancement (PMID:17890223)
• Hrp48 attenuates Sxl expression to allow for proper notch expression and signaling in wing development (PMID:20351283)
• data provide evidence for a crucial in vivo role of the hnRNP Hrp48 in multiple aspects of axon guidance and branching during nervous system development. (PMID:26313745)
• we observed that Dx together with Hrp48 can regulate Notch signaling in an Sxl-independent manner. In addition, Dx and Hrp48 displayed a synergistic effect on caspase-mediated cell death. Our results suggest that Dx and Hrp48 together negatively regulate Notch signaling in Drosophila melanogaster. (PMID:28396507)
• The data is consistent with a model where Hrp48 inhibits msl-2 translation by targeting eIF3d. (PMID:29635389)
• coexpression of Dx and Hrp48 activates JNK pathway to induce cell death in eye disc of Drosophila melanogaster. (PMID:30597717)
• The role of the heterogeneous nuclear ribonucleoprotein (hnRNP) Hrb27C in regulating lipid storage in the Drosophila fat body. (PMID:31982137)
• REVIEW: Role of the Heterogeneous Nuclear Ribonucleoprotein Hrp48 and Deltex in the Regulation of Notch Signaling (PMID:32072501)
• Novel roles for RNA binding proteins squid, hephaesteus, and Hrb27C in Drosophila oogenesis. (PMID:36308715)
• a variant of SIGMAR1 gene is a protective factor for Alzheimer’s disease (PMID:16319298)
• sigma1 receptor plays a role in proliferation and adhesion of breast cancer cells (PMID:16388898)
• This study establishes a central role for Sig-1R in cell survival and death. (PMID:16472803)
• the present review details the evidences showing that the sigma(1) receptor is a target for neurosteroids in physiological conditions–{REVIEW} (PMID:16945406)
• These results suggest that the effect of cocaine on sigma(1) receptor gene expression in the brain might be indirect and mediated through dopamine-1 receptors. (PMID:16954606)
• These results suggest that HP may irreversibly inactivate sigma(1) receptors in guinea pig and human cells, probably after metabolism to reduced HP. (PMID:17419803)
• No significant differences were observed for the SIGMAR1 allele, genotype, haplotype, and diplotype distributions between a group of Polish patients with late-onset AD, patients with mild cognitive impairment, and a control group. (PMID:17457031)
• Developed an unambiguous assay system for measuring the affinity of ligands to the cloned human sigma(1) receptor. (PMID:17961544)
• sigma-1R overexpression drives sigma agonist-independent dissociation of ANK 220 from IP3R-3, resulting in activation (PMID:18539593)
• Na(+) channels represent a new addition to the large number of voltage-gated ion channels modulated by sigma-receptors (PMID:19279232)
• From this imaging genetics study implicated that the association between Sig-1R gene polymorphism (Gln2Pro) and prefrontal cortical function in schizophrenia. (PMID:19439245)
• Detergent-resistant microdomains determine the localization of sigma-1 receptors to the endoplasmic reticulum-mitochondria junction. (PMID:20053954)
• rs1800866 in SIGMAR1 may play a role in the pathophysiology of major depressive disorder (MDD) in the Japanese population. Also, SIGMAR1 does not play a role in the therapeutic response to SSRI in Japanese MDD patients. (PMID:20178807)
• SIGMAR1 is a causative gene for a familial form of FTLD-MND. (PMID:21031579)
• Suppression of NMDA responses of rat retinal ganglion cells caused by the activation of zeta receptor-1 may be mediated by a distinct intracellular divalent calcium ion-dependent signaling pathway. (PMID:21211548)
• Sigma-1 receptor antagonists, but not agonists, show GTP- and suramin-sensitive high-affinity binding. (PMID:21486275)
• gives evidence Pro carriers more common among pts with schizophrenia, have validly lower activation right PFC comp to pts with Gln/Gln genotype. data imply SIGMAR1 SNP associated w/ increased risk of schz & differential activation of Prefrontal cortex (PMID:21549171)
• SIGMAR1 and APOE interact to influence Alzheimer’s disease severity across ethnic populations. (PMID:21605063)
• Sig1R protein regulates hERG channel expression through a post-translational mechanism in leukemic cells. (PMID:21680736)
• Data indicate that fluorescent sigma(2) ligands show their potential in clarifying the mechanisms of action of sigma(2) receptors. (PMID:21744858)
• This study demonistrated that A mutation in sigma-1 receptor(E102Q ) causes juvenile amyotrophic lateral sclerosis (PMID:21842496)
• These results indicate that Sig-1Rs are transcriptionally upregulated via the PERK/eIF2alpha/ATF4 pathway and ameliolate cell death signaling. (PMID:22079628)
• The sigma-1 receptor plays an important role in modifying the function of transmembrane proteases. (PMID:22322890)
• Sigma1R likely interacts with different domains of Kv ion channel family proteins resulting in distinct modulation of different channels. (PMID:22433979)
• sigma1R may serve as a potential predictive factor for pTNM classification and tumor development in esophageal squamous cell carcinoma. (PMID:22511599)
• Our data demonstrates an association between the SIGMAR1 TT-P variant and the risk for developing Alzheimer’s diseasE (PMID:22561649)
• coding and noncoding variants located in the 3’-UTR region of the SIGMAR1 gene are not the cause of FTLD-MND in our cohort, and more than half of this targeted cohort is genetically explained by C9ORF72 repeat expansions. (PMID:22739338)
• This study demonistrated that association between the SIGMAR1 Gln2Pro polymorphism and schizophrenia in our Japanese population. (PMID:22818711)
• Each set of six transmembrane regions in Nav1.5 likely constitutes a Sig1R binding site, suggesting that the Sig1R interacts with the transmembrane regions of its binding partners. (PMID:22952230)
• Sigma 1 receptor stimulation protects against oxidative damage through suppression of the ER stress responses in the human lens (PMID:23041531)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	sigmar1	ENSDARG00000011418
mus_musculus	Sigmar1	ENSMUSG00000036078
rattus_norvegicus	Sigmar1	ENSRNOG00000014604
caenorhabditis_elegans		WBGENE00021093

Protein

Protein identifiers

Sigma non-opioid intracellular receptor 1 — Q99720 (reviewed: Q99720)

Alternative names: Aging-associated gene 8 protein, SR31747-binding protein, Sigma 1-type opioid receptor

All UniProt accessions (7): Q99720, A0A7P0T9D5, A0A7P0TA12, A0A7P0Z4C2, A2A3U5, B4DR71, Q5T1J1

UniProt curated annotations — full annotation on UniProt →

Function. Functions in lipid transport from the endoplasmic reticulum and is involved in a wide array of cellular functions probably through regulation of the biogenesis of lipid microdomains at the plasma membrane. Involved in the regulation of different receptors it plays a role in BDNF signaling and EGF signaling. Also regulates ion channels like the potassium channel and could modulate neurotransmitter release. Plays a role in calcium signaling through modulation together with ANK2 of the ITP3R-dependent calcium efflux at the endoplasmic reticulum. Plays a role in several other cell functions including proliferation, survival and death. Originally identified for its ability to bind various psychoactive drugs it is involved in learning processes, memory and mood alteration. Necessary for proper mitochondrial axonal transport in motor neurons, in particular the retrograde movement of mitochondria. Plays a role in protecting cells against oxidative stress-induced cell death via its interaction with RNF112.

Subunit / interactions. Homotrimer. Forms a ternary complex with ANK2 and ITPR3. The complex is disrupted by agonists. Interacts with KCNA4. Interacts with KCNA2; cocaine consumption leads to increased interaction. Interacts with RNF112 in an oxidative stress-regulated manner. Interacts with the mu-type opioid receptor OPRM1.

Subcellular location. Nucleus inner membrane. Nucleus outer membrane. Nucleus envelope. Cytoplasmic vesicle. Endoplasmic reticulum membrane. Membrane. Lipid droplet. Cell junction. Cell membrane. Cell projection. Growth cone. Postsynaptic density membrane.

Tissue specificity. Widely expressed with higher expression in liver, colon, prostate, placenta, small intestine, heart and pancreas. Expressed in the retina by retinal pigment epithelial cells. Expressed in alpha-motor neurons.

Disease relevance. Amyotrophic lateral sclerosis 16, juvenile (ALS16) [MIM:614373] A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. The disease is caused by variants affecting the gene represented in this entry. Neuronopathy, distal hereditary motor, autosomal recessive 2 (HMNR2) [MIM:605726] A form of distal hereditary motor neuronopathy, a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs. HMNR2 is characterized by onset of distal muscle weakness and wasting affecting the lower and upper limbs in the first decade. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The C-terminal helices form a flat, hydrophobic surface that is probably tightly associated with the cytosolic surface of the endoplasmic reticulum membrane.

Miscellaneous. Depletion by RNAi inhibits growth and survival signaling cascades and induces cell death. The antagonist rimcazole produces the same effect. Sigma receptors are classified into two subtypes (Sigma-1 and Sigma-2) based on their different pharmacological profile.

Similarity. Belongs to the ERG2 family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q99720-1	1	yes
Q99720-2	2
Q99720-3	3, Sigma-R1A
Q99720-4	4
Q99720-5	5

RefSeq proteins (7): NP_001269134, NP_001269135, NP_001269136, NP_001269137, NP_001269138, NP_005857, NP_671513 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006716	ERG2_sigma1_rcpt-like	Family

Pfam: PF04622

UniProt features (54 total): mutagenesis site 11, strand 10, helix 9, splice variant 6, sequence conflict 5, sequence variant 4, region of interest 3, topological domain 2, site 2, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
5HK1	X-RAY DIFFRACTION	2.51
6DK0	X-RAY DIFFRACTION	2.9
6DJZ	X-RAY DIFFRACTION	3.08
6DK1	X-RAY DIFFRACTION	3.12
5HK2	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99720-F1	93.63	0.85

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): 126 (important for ligand binding); 172 (important for ligand binding)

Mutagenesis-validated functional residues (11):

Position	Phenotype
123	no effect on ligand-binding.
126	reduces ligand-binding. no effect on subcellular localization.
138	no effect on ligand-binding.
144	no effect on ligand-binding.
150	no effect on ligand-binding.
158	no effect on ligand-binding.
163	no effect on ligand-binding.
172	reduces ligand-binding. no effect on subcellular localization.
188	no effect on ligand-binding.
195	no effect on ligand-binding.
213	no effect on ligand-binding.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-9679191	Potential therapeutics for SARS
R-HSA-1643685	Disease
R-HSA-5663205	Infectious disease
R-HSA-9679506	SARS-CoV Infections
R-HSA-9824446	Viral Infection Pathways

MSigDB gene sets: 416 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_RESPONSE_TO_AMINE, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_SYNAPSE_ASSEMBLY, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_ASSOCIATIVE_LEARNING, MORF_BRCA1, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY

GO Biological Process (7): lipid transport (GO:0006869), nervous system development (GO:0007399), regulation of neuron apoptotic process (GO:0043523), protein homotrimerization (GO:0070207), response to alcohol (GO:0097305), regulation of postsynapse assembly (GO:0150052), G protein-coupled opioid receptor signaling pathway (GO:0038003)

GO Molecular Function (4): G protein-coupled opioid receptor activity (GO:0004985), identical protein binding (GO:0042802), protein binding (GO:0005515), signaling receptor activity (GO:0038023)

GO Cellular Component (20): nuclear envelope (GO:0005635), nuclear inner membrane (GO:0005637), nuclear outer membrane (GO:0005640), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), lipid droplet (GO:0005811), cytosol (GO:0005829), postsynaptic density (GO:0014069), membrane (GO:0016020), growth cone (GO:0030426), cytoplasmic vesicle (GO:0031410), anchoring junction (GO:0070161), postsynaptic density membrane (GO:0098839), glutamatergic synapse (GO:0098978), nucleus (GO:0005634), plasma membrane (GO:0005886), cell projection (GO:0042995), synapse (GO:0045202), postsynaptic membrane (GO:0045211), postsynapse (GO:0098794)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
SARS-CoV Infections	1
Disease	1
Viral Infection Pathways	1
Infectious disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
endomembrane system	2
nuclear membrane	2
nuclear outer membrane-endoplasmic reticulum membrane network	2
intracellular membrane-bounded organelle	2
cell junction	2
synapse	2
transport	1
lipid localization	1
system development	1
regulation of apoptotic process	1
neuron apoptotic process	1
protein homooligomerization	1
protein trimerization	1
response to oxygen-containing compound	1
regulation of synapse assembly	1
postsynapse assembly	1
regulation of postsynapse organization	1
G protein-coupled receptor signaling pathway	1
G protein-coupled receptor activity	1
G protein-coupled opioid receptor signaling pathway	1
protein binding	1
binding	1
molecular transducer activity	1
nucleus	1
organelle envelope	1
organelle inner membrane	1
organelle outer membrane	1
organelle membrane	1
endoplasmic reticulum subcompartment	1
intracellular membraneless organelle	1
asymmetric synapse	1
postsynaptic specialization	1
site of polarized growth	1
distal axon	1
intracellular vesicle	1
postsynaptic density	1
postsynaptic membrane	1
postsynaptic specialization membrane	1

Protein interactions and networks

STRING

1684 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SIGMAR1	HSPA5	P11021	992
SIGMAR1	KCNH6	Q9H252	944
SIGMAR1	TMEM97	Q5BJF2	938
SIGMAR1	ITPR1	Q14643	937
SIGMAR1	KCNA4	P22459	913
SIGMAR1	ITPR3	Q14573	910
SIGMAR1	TMBIM4	Q9HC24	876
SIGMAR1	VDAC1	P21796	843
SIGMAR1	ANK2	Q01484	779
SIGMAR1	HSPA9	P30036	754
SIGMAR1	OPRM1	P35372	736
SIGMAR1	STAR	P49675	720
SIGMAR1	VAPB	O95292	710
SIGMAR1	SETX	Q7Z333	690
SIGMAR1	KCNA2	P16389	690

IntAct

139 interactions, top by confidence:

A	B	Type	Score
DRD2	DRD2	psi-mi:“MI:0915”(physical association)	0.770
DRD2	DRD2	psi-mi:“MI:2364”(proximity)	0.770
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
GHSR	GHSR	psi-mi:“MI:0915”(physical association)	0.670
APP	LRPPRC	psi-mi:“MI:0914”(association)	0.580
rep	ATP5MG	psi-mi:“MI:0914”(association)	0.530
ADGRG5	KLRG2	psi-mi:“MI:0914”(association)	0.530
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
CD63	LGALS8	psi-mi:“MI:0914”(association)	0.530
TMEM184A	SLC33A1	psi-mi:“MI:0914”(association)	0.530
TMEM63A	AP3D1	psi-mi:“MI:0914”(association)	0.530
SIGMAR1	NPC1	psi-mi:“MI:0914”(association)	0.530
CXCR4	FANCA	psi-mi:“MI:0914”(association)	0.530
GPR17	IPO8	psi-mi:“MI:0914”(association)	0.530
SLC6A8	ILVBL	psi-mi:“MI:0914”(association)	0.530
DRD2	SIGMAR1	psi-mi:“MI:2364”(proximity)	0.520
DRD2	SIGMAR1	psi-mi:“MI:0403”(colocalization)	0.520
DRD2	SIGMAR1	psi-mi:“MI:0915”(physical association)	0.520
STOM	EI24	psi-mi:“MI:0914”(association)	0.510

BioGRID (170): SIGMAR1 (Affinity Capture-RNA), SIGMAR1 (Affinity Capture-RNA), SIGMAR1 (Co-fractionation), SIGMAR1 (Co-fractionation), SIGMAR1 (Proximity Label-MS), SIGMAR1 (Affinity Capture-MS), SIGMAR1 (Affinity Capture-MS), STOM (Affinity Capture-MS), SIGMAR1 (Affinity Capture-RNA), SIGMAR1 (Affinity Capture-MS), SIGMAR1 (Affinity Capture-MS), SIGMAR1 (Proximity Label-MS), SIGMAR1 (Affinity Capture-MS), KCNH2 (Affinity Capture-Western), SIGMAR1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D8PCB9, A0A1D8PI71, A0A1U8QNM5, A0A345BJQ0, C4R4B3, C4R7Z3, G9N4A5, I1RJD6, I1RT23, O09173, O55242, P25618, P29704, P32352, P32360, P33281, P36596, P78589, P87113, Q00667, Q00912, Q4WHT9, Q4WJU9, Q54DR1, Q54QI4, Q55BU8, Q58DH7, Q5APD4, Q5PXE2, Q5PXE3, Q5RF05, Q5ZL84, Q60492, Q645J3, Q66IM1, Q6DCU6, Q752X9, Q7S4Z6, Q7ZWG9, Q92206

Diamond homologs: A0A1D8PCB9, I1RT23, O55242, P32352, P32360, P33281, P87113, Q4WJU9, Q55BU8, Q58DH7, Q5PXE2, Q5PXE3, Q5ZL84, Q60492, Q645J3, Q66IM1, Q6DCU6, Q7ZWG9, Q92254, Q99720, Q9R0C9

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
ATF4	“up-regulates quantity by expression”	SIGMAR1	“transcriptional regulation”
haloperidol	“down-regulates activity”	SIGMAR1	“chemical inhibition”
(RS)-Ppcc	“up-regulates activity”	SIGMAR1	“chemical activation”
“PB28 dihydrochloride”	“down-regulates activity”	SIGMAR1	“chemical inhibition”
S1RA	“down-regulates activity”	SIGMAR1	“chemical inhibition”
SIGMAR1	“up-regulates quantity by stabilization”	CD274	stabilization
3-(4-Methylphenyl)-5-(1-propyl-3,6-dihydro-2H-pyridin-5-yl)-1,2-oxazole	“down-regulates activity”	SIGMAR1	“chemical inhibition”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 167 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
Class A/1 (Rhodopsin-like receptors)	11	7.5×	9e-05
GPCR ligand binding	9	5.3×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
post-Golgi vesicle-mediated transport	6	42.1×	4e-06
associative learning	5	16.1×	5e-03
amino acid transport	7	14.6×	3e-04
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	6	8.8×	9e-03
positive regulation of cytosolic calcium ion concentration	8	6.2×	8e-03
protein transport	13	3.8×	8e-03
G protein-coupled receptor signaling pathway	14	3.4×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	10
Uncertain significance	72
Likely benign	71
Benign	9

Top pathogenic / likely-pathogenic (19)

Variant ID	HGVS	Classification
1067324	NM_005866.4(SIGMAR1):c.492G>A (p.Trp164Ter)	Pathogenic
209190	NM_005866.4(SIGMAR1):c.283dup (p.Leu95fs)	Pathogenic
2938415	NM_005866.4(SIGMAR1):c.456_471del (p.Val153fs)	Pathogenic
2945263	NM_005866.4(SIGMAR1):c.374C>A (p.Ser125Ter)	Pathogenic
30238	NM_005866.4(SIGMAR1):c.304G>C (p.Glu102Gln)	Pathogenic
3748188	NM_005866.4(SIGMAR1):c.403C>T (p.Gln135Ter)	Pathogenic
3749597	NM_005866.4(SIGMAR1):c.217_220del (p.Val73fs)	Pathogenic
3756143	NM_005866.4(SIGMAR1):c.445+1G>A	Pathogenic
623389	NM_005866.4(SIGMAR1):c.238C>T (p.Gln80Ter)	Pathogenic
1067640	NM_005866.4(SIGMAR1):c.152-2A>T	Likely pathogenic
1285377	NM_005866.4(SIGMAR1):c.109_110del (p.Phe37fs)	Likely pathogenic
1699407	NM_005866.4(SIGMAR1):c.637G>A (p.Glu213Lys)	Likely pathogenic
4278097	NM_005866.4(SIGMAR1):c.672A>G (p.Ter224Trp)	Likely pathogenic
431074	NM_005866.4(SIGMAR1):c.446-25_*40del	Likely pathogenic
431075	NM_005866.4(SIGMAR1):c.561_576del (p.Asp188fs)	Likely pathogenic
4356097	NM_005866.4(SIGMAR1):c.353-2A>G	Likely pathogenic
4526770	NM_005866.4(SIGMAR1):c.446-2A>C	Likely pathogenic
873316	NM_005866.4(SIGMAR1):c.448G>A (p.Glu150Lys)	Likely pathogenic
873317	NM_005866.4(SIGMAR1):c.451A>G (p.Thr151Ala)	Likely pathogenic

SpliceAI

542 predictions. Top by Δscore:

Variant	Effect	Δscore
9:34637215:CTGA:C	donor_loss	1.0000
9:34637216:TGACC:T	donor_loss	1.0000
9:34637217:GACCC:G	donor_loss	1.0000
9:34637218:A:T	donor_loss	1.0000
9:34637265:A:AC	donor_gain	1.0000
9:34637266:C:CC	donor_gain	1.0000
9:34637331:A:AC	donor_gain	1.0000
9:34637332:C:CC	donor_gain	1.0000
9:34637421:C:CA	acceptor_loss	1.0000
9:34637544:CACCA:C	donor_loss	1.0000
9:34637545:A:AC	donor_gain	1.0000
9:34637546:C:CC	donor_gain	1.0000
9:34637546:C:CT	donor_loss	1.0000
9:34637546:CCAG:C	donor_gain	1.0000
9:34637553:A:AC	donor_gain	1.0000
9:34637554:C:CC	donor_gain	1.0000
9:34636993:CCA:C	donor_loss	0.9900
9:34637013:A:AC	donor_gain	0.9900
9:34637014:C:CC	donor_gain	0.9900
9:34637086:CGCC:C	acceptor_gain	0.9900
9:34637088:CC:C	acceptor_gain	0.9900
9:34637089:CC:C	acceptor_gain	0.9900
9:34637090:C:CA	acceptor_loss	0.9900
9:34637090:C:CC	acceptor_gain	0.9900
9:34637091:T:A	acceptor_loss	0.9900
9:34637218:AC:A	donor_gain	0.9900
9:34637219:CC:C	donor_gain	0.9900
9:34637266:CT:C	donor_gain	0.9900
9:34637268:CGG:C	donor_gain	0.9900
9:34637416:CAGCC:C	acceptor_gain	0.9900

AlphaMissense

1418 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:34637331:A:G	W81R	0.999
9:34637331:A:T	W81R	0.999
9:34637050:C:A	G131V	0.998
9:34637056:A:T	I129N	0.998
9:34637251:G:C	F107L	0.998
9:34637251:G:T	F107L	0.998
9:34637253:A:G	F107L	0.998
9:34637267:T:A	E102V	0.998
9:34637329:C:A	W81C	0.998
9:34637329:C:G	W81C	0.998
9:34635721:C:G	D195H	0.997
9:34635752:G:C	F184L	0.997
9:34635752:G:T	F184L	0.997
9:34635754:A:G	F184L	0.997
9:34635799:A:G	W169R	0.997
9:34635799:A:T	W169R	0.997
9:34637036:A:G	W136R	0.997
9:34637036:A:T	W136R	0.997
9:34637089:C:T	G118E	0.997
9:34637249:C:A	G108V	0.997
9:34637378:A:G	L65P	0.997
9:34635720:T:A	D195V	0.996
9:34635788:C:A	E172D	0.996
9:34635788:C:G	E172D	0.996
9:34635797:C:A	W169C	0.996
9:34635797:C:G	W169C	0.996
9:34635814:A:G	W164R	0.996
9:34635814:A:T	W164R	0.996
9:34637034:C:A	W136C	0.996
9:34637034:C:G	W136C	0.996

dbSNP variants (sampled 300 via entrez): RS1000053037 (9:34637597 C>A,T), RS1000729035 (9:34634301 C>A), RS1001693212 (9:34636388 C>T), RS1001724499 (9:34636018 C>A,T), RS1002352384 (9:34634728 A>G), RS1002854090 (9:34635024 C>T), RS1003922114 (9:34638066 T>A), RS1004508514 (9:34634653 AAG>A,AAGAG), RS1005306542 (9:34638226 G>T), RS1005587952 (9:34636625 A>C,G), RS1005618893 (9:34636458 C>T), RS1005959072 (9:34634871 C>G), RS1007466338 (9:34639204 G>T), RS1007487716 (9:34639499 C>T), RS1008182430 (9:34636265 C>G,T)

Disease associations

OMIM: gene MIM:601978 | disease phenotypes: MIM:605726, MIM:614373

GenCC curated gene-disease

Disease	Classification	Inheritance
amyotrophic lateral sclerosis type 16	Strong	Autosomal recessive
autosomal recessive distal spinal muscular atrophy 2	Strong	Autosomal recessive
juvenile amyotrophic lateral sclerosis	Supportive	Autosomal recessive

Mondo (3): autosomal recessive distal spinal muscular atrophy 2 (MONDO:0011585), amyotrophic lateral sclerosis type 16 (MONDO:0013715), juvenile amyotrophic lateral sclerosis (MONDO:0017593)

Orphanet (2): Distal hereditary motor neuropathy, Jerash type (Orphanet:139552), Juvenile amyotrophic lateral sclerosis (Orphanet:300605)

HPO phenotypes

65 total (30 of 65 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000020	Urinary incontinence
HP:0000252	Microcephaly
HP:0000605	Supranuclear gaze palsy
HP:0000639	Nystagmus
HP:0000708	Atypical behavior
HP:0001251	Ataxia
HP:0001263	Global developmental delay
HP:0001264	Spastic diplegia
HP:0001276	Hypertonia
HP:0001288	Gait disturbance
HP:0001300	Parkinsonism
HP:0001317	Abnormal cerebellum morphology
HP:0001324	Muscle weakness
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001348	Brisk reflexes
HP:0001761	Pes cavus
HP:0001765	Hammertoe
HP:0002015	Dysphagia
HP:0002061	Lower limb spasticity
HP:0002072	Chorea
HP:0002167	Abnormal speech pattern
HP:0002169	Clonus
HP:0002179	Opisthotonus
HP:0002425	Anarthria
HP:0002460	Distal muscle weakness
HP:0002483	Bulbar signs
HP:0002505	Loss of ambulation
HP:0002530	Axial dystonia

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C535715	Spinal muscular atrophy, Jerash type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL287 (SINGLE PROTEIN), CHEMBL4524009 (PROTEIN FAMILY)

Molecules with ChEMBL bioactivity

148 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 400,984 (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
CHEMBL103	PROGESTERONE	4	162,141
CHEMBL1065	METHYSERGIDE	4	8,455
CHEMBL1123	DICYCLOMINE	4	8,691
CHEMBL1196	PROPARACAINE	4	12,973
CHEMBL1198	PRAMOXINE	4	10,295
CHEMBL1200406	DIMENHYDRINATE	4	26,424
CHEMBL1200517	DIHYDROERGOTAMINE MESYLATE	4	2,704
CHEMBL1200776	CINACALCET HYDROCHLORIDE	4	1,220
CHEMBL1200809	AZELASTINE HYDROCHLORIDE	4	3,805
CHEMBL1201201	METHAMPHETAMINE	4	28,681
CHEMBL1201203	BENZTROPINE	4	9,334
CHEMBL1201237	LEVOBUNOLOL	4	10,597
CHEMBL1201353	DEXCHLORPHENIRAMINE	4	8,566
CHEMBL1218	RAMELTEON	4	5,217
CHEMBL1231	OXYBUTYNIN	4	15,072
CHEMBL1276308	MIFEPRISTONE	4	30,535
CHEMBL14376	ILOPERIDONE	4	7,878
CHEMBL1490	TRIHEXYPHENIDYL	4	12,556
CHEMBL15023	TRIFLUPERIDOL	4	2,646
CHEMBL1516474	TEGASEROD MALEATE	4
CHEMBL1535	HYDROXYCHLOROQUINE	4
CHEMBL1558	PRAZOSIN HYDROCHLORIDE	4
CHEMBL1615374	VILAZODONE HYDROCHLORIDE	4
CHEMBL1626	CLEMASTINE	4
CHEMBL1628227	DOXEPIN	4
CHEMBL1671	PROPRANOLOL HYDROCHLORIDE	4
CHEMBL1691	BETAXOLOL HYDROCHLORIDE	4
CHEMBL1707	LOPERAMIDE HYDROCHLORIDE	4
CHEMBL1714574	TERCONAZOLE	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 (16 total), top 16:

Ligand	Action	Affinity	Parameter
PD-144418	Antagonist	10.1	pKi
opipramol	Agonist	9.7	pKi
(RS)-PPCC	Agonist	8.8	pKi
NE-100	Antagonist	8.4	pIC50
BD-1063	Antagonist	8.2	pKi
E-52862	Antagonist	7.77	pKi
EST64454	Antagonist	7.66	pKi
1,3-ditolylguanidine	Full agonist	7.45	pKi
fluvoxamine	Binding	7.44	pKi
PRE-084	Agonist	7.4	pIC50
BD-1047	Antagonist	7.4	pIC50
vanoxerine	Binding	7.32	pIC50
pridopidine	Agonist	7.09	pKi
EST73502	Antagonist	6.93	pKi
dextromethorphan	Agonist	6.28	pKi
blarcamesine	Agonist	6.07	pIC50

Binding affinities (BindingDB)

303 measured of 372 human assays (375 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
CHEMBL2023825	IC50	0.27 nM
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
CHEMBL3086334	KI	0.91 nM
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
(R)-3-Cyclohexylmethyl-1,8,8-trimethyl-3-aza-bicyclo[3.2.1]octane	KI	1.1 nM
(S)-3-(4-Cyclohexyl-butyl)-1,8,8-trimethyl-3-aza-bicyclo[3.2.1]octane	KI	1.2 nM
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
(S)-3-Cyclohexylmethyl-1,8,8-trimethyl-3-aza-bicyclo[3.2.1]octane	KI	1.3 nM
(R)-3-(2-Cyclohexyl-ethyl)-1,8,8-trimethyl-3-aza-bicyclo[3.2.1]octane	KI	1.4 nM
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
N-[3-(benzylmethylamino)propyl]-4-tertbutylbenzamide	KI	1.6 nM	US-10179761: Compounds, pharmaceutical composition and their use in treating neurodegenerative diseases
CHEMBL3819489	KI	1.6 nM
US11535596, Compound CNS27-D2	KI	1.6 nM	US-11535596: Analogs of dextromethorphan with balanced receptor activities
(S)-3-(2-Cyclopentyl-ethyl)-1,8,8-trimethyl-3-aza-bicyclo[3.2.1]octane	KI	1.7 nM
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-[(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
N-[3-(benzylmethylamino)propyl]-3-dimethylaminobenzamide	KI	1.9 nM	US-10179761: Compounds, pharmaceutical composition and their use in treating neurodegenerative diseases
CHEMBL2203549	KI	2.1 nM
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
(S)-3-(2-Cyclohexyl-ethyl)-1,8,8-trimethyl-3-aza-bicyclo[3.2.1]octane	KI	2.2 nM
CHEMBL544987	IC50	2.2 nM
CHEMBL3819437	KI	2.4 nM
(S)-3-(3-Cyclohexyl-propyl)-1,8,8-trimethyl-3-aza-bicyclo[3.2.1]octane	KI	2.5 nM
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
N-Adamantan-1-yl-N’-(4-iodo-phenyl)-guanidine	IC50	2.8 nM
CHEMBL3819331	KI	2.8 nM
N-[3-(benzylmethylamino)propyl]-4-bromo-2-fluorobenzamide	KI	2.9 nM	US-10179761: Compounds, pharmaceutical composition and their use in treating neurodegenerative diseases
(S)-3-(2-Cycloheptyl-ethyl)-1,8,8-trimethyl-3-aza-bicyclo[3.2.1]octane	KI	2.9 nM
(S)-3-(2-Cyclooctyl-ethyl)-1,8,8-trimethyl-3-aza-bicyclo[3.2.1]octane	KI	2.9 nM
CHEMBL2023824	IC50	2.9 nM
CHEMBL2204672	IC50	2.9 nM
4-[4-(4-Chloro-phenyl)-4-hydroxy-piperidin-1-yl]-1-(4-fluoro-phenyl)-butan-1-one;propionate(HCl)	KI	2.92 nM
8-[4-(4-fluorophenyl)-4-keto-butyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one	KI	2.94 nM	US-9359372: Hexahydrodibenzo[a,g]quinolizine compound, preparation method thereof, pharmaceutical composition and use thereof
(S)-3-Cyclohexyl-1,8,8-trimethyl-3-aza-bicyclo[3.2.1]octane	KI	3 nM
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
N-Adamantan-1-yl-N’-(4-fluoro-2-methyl-phenyl)-guanidine	IC50	3.2 nM
CHEMBL3819395	KI	3.2 nM
CHEMBL2023823	IC50	3.2 nM
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
(S)-3-(2-Adamantan-2-yl-ethyl)-1,8,8-trimethyl-3-aza-bicyclo[3.2.1]octane	KI	4.3 nM
CLG	IC50	4.5 nM
8-Fluoro-6,11-dimethyl-3-(3-methyl-butyl)-1,2,3,4,5,6-hexahydro-2,6-methano-benzo[d]azocine	KI	4.7 nM
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
N-Adamantan-2-yl-N’-(2-iodo-phenyl)-guanidine; hydrochloride	IC50	5.2 nM

ChEMBL bioactivities

4276 potent at pChembl≥5 of 4327 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	Ki	0.01	nM	FENPROPIMORPH
10.89	Ki	0.013	nM	CHEMBL5432062
10.52	Ki	0.03	nM	CHEMBL3763396
10.44	Ki	0.036	nM	CHEMBL76758
10.40	Ki	0.04	nM	CHEMBL365842
10.30	Ki	0.05	nM	CHEMBL541284
10.28	Ki	0.05248	nM	CHEMBL578825
10.24	Ki	0.05754	nM	CHEMBL570795
10.18	Ki	0.06607	nM	CHEMBL570529
10.15	Ki	0.07	nM	CHEMBL304079
10.10	Ki	0.08	nM	CHEMBL4088272
10.10	Ki	0.08	nM	FENPROPIMORPH
10.05	Ki	0.08913	nM	CHEMBL571418
10.05	Ki	0.09	nM	CHEMBL302087
10.01	Ki	0.09772	nM	CHEMBL572294
9.96	Ki	0.1096	nM	CHEMBL570067
9.89	Ki	0.13	nM	CHEMBL67808
9.85	Ki	0.14	nM	CHEMBL81455
9.77	Ki	0.17	nM	CHEMBL19355
9.77	Ki	0.17	nM	CHEMBL356688
9.74	Ki	0.18	nM	CHEMBL309983
9.72	Ki	0.19	nM	CHEMBL19314
9.70	Ki	0.2	nM	HALOPERIDOL
9.70	Ki	0.2	nM	OPIPRAMOL
9.70	IC50	0.2	nM	CHEMBL542167
9.68	Ki	0.21	nM	HALOPERIDOL
9.68	Ki	0.2089	nM	CHEMBL571659
9.66	Ki	0.22	nM	CHEMBL306133
9.60	Ki	0.25	nM	CHEMBL19544
9.60	IC50	0.2512	nM	CHEMBL553265
9.59	Ki	0.26	nM	CHEMBL20036
9.59	Ki	0.26	nM	CHEMBL142700
9.57	IC50	0.27	nM	CHEMBL2023825
9.57	Ki	0.27	nM	CHEMBL542131
9.55	Ki	0.28	nM	CHEMBL19638
9.54	Ki	0.29	nM	CHEMBL20348
9.54	IC50	0.2884	nM	CHEMBL317029
9.54	Ki	0.29	nM	CHEMBL324392
9.54	IC50	0.29	nM	CHEMBL545477
9.52	Ki	0.3	nM	CHEMBL362699
9.52	Ki	0.3	nM	CHEMBL360351
9.52	Ki	0.3	nM	CHEMBL179648
9.51	Ki	0.31	nM	CHEMBL75878
9.51	Ki	0.31	nM	CHEMBL70807
9.49	Ki	0.32	nM	CHEMBL19315
9.49	IC50	0.3236	nM	CHEMBL540274
9.49	Ki	0.32	nM	CHEMBL342809
9.48	Ki	0.33	nM	HALOPERIDOL
9.47	Ki	0.34	nM	CHEMBL20377
9.47	Ki	0.34	nM	CHEMBL555790

PubChem BioAssay actives

3363 with measured affinity, of 4378 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-cyclohexyl-4-[4-(1,2,3,4-tetrahydronaphthalen-1-yl)butyl]piperazine	203682: In vitro binding affinity at opioid sigma-1 receptor in guinea pig brain membranes by (+)-[3H]pentazocine displacement.	ki	<0.0001	uM
5-(dimethylamino)-2-[6-[5-[4-(4-methylpiperidin-1-yl)butyl]naphthalen-2-yl]oxyhexyl]isoindole-1,3-dione	1948305: Binding affinity to sigma 1 receptor (unknown origin) assessed as inhibition constant	ki	<0.0001	uM
9-benzyl-3-phenyl-1,5-dioxa-9-azaspiro[5.5]undecane	1976006: Binding affinity to S1R (unknown origin)	ki	<0.0001	uM
(2S,6R)-2,6-dimethyl-4-tridecylmorpholine	239347: Affinity for sigma receptor type 1 of guinea pig using [3H]ifenprodil or (+)-[3H]pentazocine radioligand	ki	<0.0001	uM
3-[2-(azepan-1-yl)ethyl]-6-(3-fluoropropyl)-1,3-benzothiazol-2-one	1922160: Binding affinity to sigma 1 receptor (unknown origin)	ki	<0.0001	uM
(2S,6R)-4-[3-(4-tert-butylphenyl)-2-methylpropyl]-2,6-dimethylmorpholine	239347: Affinity for sigma receptor type 1 of guinea pig using [3H]ifenprodil or (+)-[3H]pentazocine radioligand	ki	<0.0001	uM
1-(5,5-diphenylpentyl)-4-methylpiperidine	204635: Binding affinity for Sigma receptor type 1,using 3H-pentazocine as radioligand	ki	0.0001	uM
N-[2-(azepan-1-yl)ethyl]-4-iodo-N-methylbenzenesulfonamide	203689: Inhibition of 3H-pentazocine binding to sigma-1 receptor in guinea pig brain membranes	ki	0.0001	uM
2-(4-phenylpiperidin-1-yl)ethyl 1-(4-nitrophenyl)cyclopentane-1-carboxylate;hydrochloride	203701: Affinity at sigma-1 site by inhibition of 3H-pentazocine (PENT) binding in guinea pig brain	ki	0.0001	uM
2-(1-benzylpiperidin-4-yl)-2,3-dihydrochromen-4-one	444005: Displacement of 3H-pentazocine from sigma1 receptor in human Jurkat cell membrane	ki	0.0001	uM
1-(5,5-diphenylpent-4-enyl)-4-methylpiperidine	204635: Binding affinity for Sigma receptor type 1,using 3H-pentazocine as radioligand	ki	0.0001	uM
1’-benzylspiro[4H-3,1-benzoxathiine-2,4’-piperidine]	444005: Displacement of 3H-pentazocine from sigma1 receptor in human Jurkat cell membrane	ki	0.0001	uM
1’-benzylspiro[4H-1,3-benzodioxine-2,4’-piperidine]	444005: Displacement of 3H-pentazocine from sigma1 receptor in human Jurkat cell membrane	ki	0.0001	uM
1-benzyl-4-(3,4-dihydro-2H-thiochromen-2-yl)piperidine	444005: Displacement of 3H-pentazocine from sigma1 receptor in human Jurkat cell membrane	ki	0.0001	uM
2-(1-benzylpiperidin-4-yl)-2,3-dihydrothiochromen-4-one	444005: Displacement of 3H-pentazocine from sigma1 receptor in human Jurkat cell membrane	ki	0.0001	uM
2-[1-(2-phenylethyl)piperidin-4-yl]-2,3-dihydrochromen-4-one	444005: Displacement of 3H-pentazocine from sigma1 receptor in human Jurkat cell membrane	ki	0.0001	uM
3-(4-methylphenyl)-5-(1-propyl-3,6-dihydro-2H-pyridin-5-yl)-1,2-oxazole	1922166: Binding affinity to human sigma 1 receptor	ki	0.0001	uM
4-methyl-1-(5-phenylpentyl)piperidine	204635: Binding affinity for Sigma receptor type 1,using 3H-pentazocine as radioligand	ki	0.0001	uM
N-[2-(azepan-1-yl)ethyl]-4-bromo-N-methylbenzenesulfonamide	203689: Inhibition of 3H-pentazocine binding to sigma-1 receptor in guinea pig brain membranes	ki	0.0002	uM
1-cyclohexyl-4-(4-naphthalen-1-ylbutyl)piperazine	203682: In vitro binding affinity at opioid sigma-1 receptor in guinea pig brain membranes by (+)-[3H]pentazocine displacement.	ki	0.0002	uM
5-phenyl-N-(2-phenylethyl)pentan-1-amine	203696: Binding affinity against sigma-1 receptor of guinea pig brain membranes using [3H]pentazocine as radioligand	ki	0.0002	uM
N-benzyl-N-methyl-5-phenylpentan-1-amine	203696: Binding affinity against sigma-1 receptor of guinea pig brain membranes using [3H]pentazocine as radioligand	ki	0.0002	uM
1’-benzylspiro[3H-chromene-2,4’-piperidine]-4-one	444005: Displacement of 3H-pentazocine from sigma1 receptor in human Jurkat cell membrane	ki	0.0002	uM
Haloperidol	1449796: Displacement of [3H]-(+)-pentazocine from sigma1 in human MDA-MB-468 cell membranes	ki	0.0002	uM
(2R,4S)-N,N,2-trimethyl-4-phenyl-3,4-dihydro-1H-naphthalen-2-amine;hydrochloride	204435: Binding affinity against sigma receptor from guinea pig brain (minus cerebellum) homogenates, using the novel [3H]-(+/-)-4 as radioligand	ic50	0.0002	uM
N-[2-(azepan-1-yl)ethyl]-2-(3,4-dichlorophenyl)-N-methylethanamine	229194: Displacement of [3H]-(+) -3PPP from sigma receptor in guinea pig brain membranes	ki	0.0002	uM
2-[4-(3-benzo[b][1]benzazepin-11-ylpropyl)piperazin-1-yl]ethanol	239347: Affinity for sigma receptor type 1 of guinea pig using [3H]ifenprodil or (+)-[3H]pentazocine radioligand	ki	0.0002	uM
1-[(2S)-1-(4-chlorophenoxy)propan-2-yl]-4-methylpiperidine;hydrochloride	204632: Inhibition of [3H]pentazocine binding to Sigma receptor type 1 in guinea pig brain membrane without cerebellum	ki	0.0003	uM
tert-butyl N-[4-oxo-4-[4-(3-phenylpropyl)piperazin-1-yl]butyl]carbamate	203684: Binding affinity was tested against sigma-1 receptor in guinea brain membranes.	ki	0.0003	uM
1-benzyl-4-(3,4-dihydro-2H-chromen-2-ylmethyl)piperazine	239105: Inhibitory constant against sigma receptor type 1 using 3 nM [3H]pentazocine	ki	0.0003	uM
1-benzyl-4-(3,4-dihydro-2H-chromen-3-ylmethyl)piperazine	239105: Inhibitory constant against sigma receptor type 1 using 3 nM [3H]pentazocine	ki	0.0003	uM
3-[(4-benzylpiperazin-1-yl)methyl]-3,4-dihydro-2H-naphthalen-1-one	239105: Inhibitory constant against sigma receptor type 1 using 3 nM [3H]pentazocine	ki	0.0003	uM
1-cyclohexyl-4-[(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]piperazine	203682: In vitro binding affinity at opioid sigma-1 receptor in guinea pig brain membranes by (+)-[3H]pentazocine displacement.	ki	0.0003	uM
2-(3,4-dichlorophenyl)-N-methyl-N-(2-pyrrolidin-1-ylethyl)ethanamine	204460: Binding affinity against [3H]-3-PPP labelled sigma sites	ki	0.0003	uM
3-chloro-6-(dimethylamino)-8-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol	203852: The compound was tested for affinity towards sigma-3 receptor	ic50	0.0003	uM
5-phenyl-N-(3-phenylpropyl)pentan-1-amine	203696: Binding affinity against sigma-1 receptor of guinea pig brain membranes using [3H]pentazocine as radioligand	ki	0.0003	uM
5-cyclohexyl-N,N-dimethylpentan-1-amine	203696: Binding affinity against sigma-1 receptor of guinea pig brain membranes using [3H]pentazocine as radioligand	ki	0.0003	uM
N-methyl-5-phenyl-N-propylpentan-1-amine	203696: Binding affinity against sigma-1 receptor of guinea pig brain membranes using [3H]pentazocine as radioligand	ki	0.0003	uM
N-benzyl-5-phenylpentan-1-amine	203696: Binding affinity against sigma-1 receptor of guinea pig brain membranes using [3H]pentazocine as radioligand	ki	0.0003	uM
(1R,13S)-1,13-dimethyl-10-pentyl-10-azatricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-4-ol	229195: Binding affinity against sigma receptor from guinea pig brain, using 3H-3-PPP as radioligand.	ki	0.0003	uM
3-(4-phenylpiperidin-1-yl)propyl 1-(4-nitrophenyl)cyclopentane-1-carboxylate;hydrochloride	203701: Affinity at sigma-1 site by inhibition of 3H-pentazocine (PENT) binding in guinea pig brain	ki	0.0003	uM
(4aR,10bR)-3-cyclohexyl-2,4,4a,5,6,10b-hexahydro-1H-benzo[f]isoquinoline;hydrochloride	204453: In vitro for the binding affinity against sigma receptor by using [3H]DTG as radioligand in guinea pig cerebellum	ic50	0.0003	uM
(6R,8S)-3-chloro-6-(dimethylamino)-8-phenyl-5,6,7,8-tetrahydronaphthalen-2-ol;hydrochloride	204435: Binding affinity against sigma receptor from guinea pig brain (minus cerebellum) homogenates, using the novel [3H]-(+/-)-4 as radioligand	ic50	0.0003	uM
(4aR,10bR)-3-(2-phenylethyl)-2,4,4a,5,6,10b-hexahydro-1H-benzo[f]isoquinoline;hydrochloride	204453: In vitro for the binding affinity against sigma receptor by using [3H]DTG as radioligand in guinea pig cerebellum	ic50	0.0003	uM
1-[2-(3,4-dichlorophenyl)ethyl]-4-propylpiperazine	229195: Binding affinity against sigma receptor from guinea pig brain, using 3H-3-PPP as radioligand.	ki	0.0003	uM
1-[4-[1-adamantyl(phenyl)methyl]phenyl]-4-cyclohexylpiperazine	658997: Displacement of 3Hpentazocine from sigma-1 receptor expressed in human Jurkat cell membranes after 2 hrs by liquid scintillation spectroscopy	ic50	0.0003	uM
2-(3,4-dichlorophenyl)-N-methyl-N-(2-piperidin-1-ylethyl)ethanamine	229194: Displacement of [3H]-(+) -3PPP from sigma receptor in guinea pig brain membranes	ki	0.0003	uM
N-methyl-5-phenyl-N-(2-phenylethyl)pentan-1-amine	203696: Binding affinity against sigma-1 receptor of guinea pig brain membranes using [3H]pentazocine as radioligand	ki	0.0003	uM
1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine	1922168: Displacement of [H3]DTG from sigma 1 receptor (unknown origin) by competition binding assay	ki	0.0004	uM
1-cyclohexyl-4-[3-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine	203682: In vitro binding affinity at opioid sigma-1 receptor in guinea pig brain membranes by (+)-[3H]pentazocine displacement.	ki	0.0004	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
Valproic Acid	increases expression, affects expression, decreases methylation	3
cobaltous chloride	decreases expression	2
ochratoxin A	decreases expression, decreases reaction	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Cyclosporine	decreases expression	2
alpha phellandrene	decreases expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
SK&F 81297	decreases reaction, increases activity, increases phosphorylation, increases reaction, affects binding	1
1-(2-(3,4-dichlorophenyl)ethyl)-4-methylpiperazine	decreases activity	1
1-propyl-5-(3-p-tolylisoxazol-5-yl)-1,2,3,6-tetrahydropyridine	affects binding, decreases activity, decreases reaction, increases activity, increases phosphorylation (+1 more)	1
bardoxolone methyl	decreases reaction, decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
14-deoxy-11,12-didehydroandrographolide	decreases expression	1
SCH 23390	increases phosphorylation, increases reaction, affects binding, decreases reaction, increases activity	1
jinfukang	affects cotreatment, increases expression	1
MT19c compound	decreases expression	1
ferrostatin-1	decreases expression, decreases reaction, increases expression	1
bisphenol AF	increases expression	1
Bortezomib	decreases expression	1
Ursolic Acid	decreases expression, decreases reaction, increases expression	1
Air Pollutants, Occupational	affects expression	1
Benzo(a)pyrene	decreases expression	1
Cadmium	increases abundance, decreases expression	1
Cisplatin	affects cotreatment, increases expression	1
Cocaine	affects binding, decreases reaction, increases activity, increases phosphorylation, increases reaction (+2 more)	1
Ivermectin	decreases expression	1

ChEMBL screening assays

619 unique, capped per target: 610 binding, 5 functional, 3 admet, 1 unclassified

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1032467	Binding	Inhibition of human sigma 1-type opioid receptor at 3 uM	Discovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors. — J Med Chem
CHEMBL1738129	Unclassified	PUBCHEM_BIOASSAY: Late-stage radioligand binding dose response assay to identify inhibitors of NADPH oxidase 1 (NOX1): PDSP screen Ki. (Class of assay: screening) [Related pubchem assays (depositor defined):AID1792, AID1796, AID1823, AID253	PubChem BioAssay data set
CHEMBL4406643	ADMET	Displacement of [3H]-pentazocine from sigma1 receptor (unknown origin) after 90 mins by microbeta scintillation counting method	Discovery, Optimization, and Characterization of ML417: A Novel and Highly Selective D3 Dopamine Receptor Agonist. — J Med Chem

Cellosaurus cell lines

10 cell lines: 5 cancer cell line, 3 induced pluripotent stem cell, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B0XT	Abcam HEK293T SIGMAR1 KO	Transformed cell line	Female
CVCL_B0XU	HeLa SIGMAR1 KO	Cancer cell line	Female
CVCL_D8A9	Ubigene A-549 SIGMAR1 KO	Cancer cell line	Male
CVCL_D8V4	Ubigene HCT 116 SIGMAR1 KO	Cancer cell line	Male
CVCL_D9RL	Ubigene HEK293 SIGMAR1 KO	Transformed cell line	Female
CVCL_E4VA	KOLF2.1J SIGMAR1 2.1kbdel DEL/DEL	Induced pluripotent stem cell	Male
CVCL_E7MD	KOLF2.1J SIGMAR1 E102Q SNV/SNV	Induced pluripotent stem cell	Male
CVCL_E7ME	KOLF2.1J SIGMAR1 E102Q SNV/WT	Induced pluripotent stem cell	Male
CVCL_TL10	HAP1 SIGMAR1 (-) 1	Cancer cell line	Male
CVCL_TL11	HAP1 SIGMAR1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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