RTN3

Summary

RTN3 (reticulon 3, HGNC:10469) is a protein-coding gene on chromosome 11q13, encoding Reticulon-3 (O95197). May be involved in membrane trafficking in the early secretory pathway.

This gene belongs to the reticulon family of highly conserved genes that are preferentially expressed in neuroendocrine tissues. This family of proteins interact with, and modulate the activity of beta-amyloid converting enzyme 1 (BACE1), and the production of amyloid-beta. An increase in the expression of any reticulon protein substantially reduces the production of amyloid-beta, suggesting that reticulon proteins are negative modulators of BACE1 in cells. Alternatively spliced transcript variants encoding different isoforms have been found for this gene, and pseudogenes of this gene are located on chromosomes 4 and 12.

Source: NCBI Gene 10313 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 169 total
• Druggable target: yes
• MANE Select transcript: NM_001265589

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10469
Approved symbol	RTN3
Name	reticulon 3
Location	11q13
Locus type	gene with protein product
Status	Approved
Aliases	NSPL2, NSPLII, ASYIP, HAP, RTN3-A1
Ensembl gene	ENSG00000133318
Ensembl biotype	protein_coding
OMIM	604249
Entrez	10313

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 29 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000338850, ENST00000339997, ENST00000341307, ENST00000354497, ENST00000356000, ENST00000377819, ENST00000536011, ENST00000537981, ENST00000538995, ENST00000540798, ENST00000542238, ENST00000543123, ENST00000543552, ENST00000545432, ENST00000869708, ENST00000869709, ENST00000869710, ENST00000869711, ENST00000869712, ENST00000869713, ENST00000869714, ENST00000869715, ENST00000918369, ENST00000918370, ENST00000918371, ENST00000918372, ENST00000918373, ENST00000918374, ENST00000961358, ENST00000961359, ENST00000961360, ENST00000961361, ENST00000961362

RefSeq mRNA: 7 — MANE Select: NM_001265589 NM_001265589, NM_001265590, NM_001265591, NM_006054, NM_201428, NM_201429, NM_201430

CCDS: CCDS41664, CCDS58141, CCDS58142, CCDS58143, CCDS8048, CCDS8049, CCDS8050

Canonical transcript exons

ENST00000377819 — 9 exons

Exon	Start	End
ENSE00001093686	63749991	63750198
ENSE00001196662	63752507	63752645
ENSE00001372507	63718702	63721032
ENSE00003458245	63756112	63756170
ENSE00003459869	63704851	63704907
ENSE00003548069	63681500	63681778
ENSE00003550054	63753069	63753138
ENSE00003611915	63753662	63753708
ENSE00003892072	63758156	63759882

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 99.77.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 100.5154 / max 2043.8789, expressed in 1820 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114814	87.4016	1819
114813	9.7789	1673
114812	3.3350	905

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 9	UBERON:0013540	99.77	gold quality
prefrontal cortex	UBERON:0000451	99.76	gold quality
cortical plate	UBERON:0005343	99.56	gold quality
right frontal lobe	UBERON:0002810	99.55	gold quality
anterior cingulate cortex	UBERON:0009835	99.54	gold quality
ganglionic eminence	UBERON:0004023	99.49	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	99.48	gold quality
pons	UBERON:0000988	99.45	gold quality
ventricular zone	UBERON:0003053	99.40	gold quality
hypothalamus	UBERON:0001898	99.37	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	99.36	gold quality
spinal cord	UBERON:0002240	99.30	gold quality
amygdala	UBERON:0001876	99.29	gold quality
cerebellar cortex	UBERON:0002129	99.28	gold quality
cerebellar hemisphere	UBERON:0002245	99.28	gold quality
frontal cortex	UBERON:0001870	99.21	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.18	gold quality
nucleus accumbens	UBERON:0001882	99.17	gold quality
substantia nigra	UBERON:0002038	99.13	gold quality
cerebellum	UBERON:0002037	99.10	gold quality
midbrain	UBERON:0001891	99.09	gold quality
caudate nucleus	UBERON:0001873	99.07	gold quality
putamen	UBERON:0001874	99.06	gold quality
neocortex	UBERON:0001950	99.04	gold quality
superior vestibular nucleus	UBERON:0007227	99.04	gold quality
dorsal root ganglion	UBERON:0000044	98.96	gold quality
oviduct epithelium	UBERON:0004804	98.95	gold quality
corpus callosum	UBERON:0002336	98.83	gold quality
cerebral cortex	UBERON:0000956	98.81	gold quality
medulla oblongata	UBERON:0001896	98.77	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-HCAD-30	yes	2510.45
E-HCAD-35	yes	56.72
E-MTAB-6678	yes	22.91
E-MTAB-9388	yes	14.49
E-MTAB-9801	yes	9.52
E-HCAD-10	yes	4.19
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF6, DDIT3

miRNA regulators (miRDB)

70 targeting RTN3, 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-4682	100.00	68.89	1258
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-636	99.80	69.58	1500
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-26A-1-3P	99.64	66.81	788
HSA-MIR-26A-2-3P	99.64	66.82	786
HSA-MIR-2113	99.58	71.22	1521
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-486-3P	99.51	66.82	1901

Literature-anchored findings (GeneRIF, showing 40)

• The ASYIP protein co-localizes with ASY in the endoplasmic reticulum. Characterization of the ASYIP gene helps to clarify ASY-induced apoptosis or Nogo-involved inhibition of neuronal regeneration in the central nervous system. (PMID:12811824)
• RTN3 isoforms may contribute, by as yet unknown mechanisms, to neuronal survival and plasticity (PMID:15350194)
• apoptosis-inducing protein, HAP, induces bacterial cell death [HAP, homolog of ASY protein] (PMID:15560370)
• These results suggest that RTN3 plays a role in membrane trafficking in the early secretory pathway. (PMID:16054885)
• All the results indicate that both the mitochondria and the endoplasmic reticulum (ER) are involved in apoptosis caused by HAP overexpression, and suggest that HAP overexpression may initiate an ER overload response (EOR). (PMID:16847569)
• Results describe the mapping of interaction domains mediating binding between BACE1 and RTN3/Nogo proteins. (PMID:16979658)
• Endoplasmic reticulum, ER-bound RTN3 protein recruited endogenous FADD to the ER membrane and subsequently initiated caspase-8 cascade, including activation of caspase-8, processing of Bid and release of cytochrome c from mitochondria. (PMID:17031492)
• These findings indicate that RTN3 is directly involved in the endoplasmic reticulum-constituents trafficking events through dually acting as an essential and important ER-stress sensor, and a trigger for the Bcl-2 translocation. (PMID:17191123)
• In normal HeLa cells, ectopic overexpressed Bcl-2 reduced the cell apoptosis induced by overexpressed RTN3. results suggest that RTN3 could bind with Bcl-2 and mediate its accumulation in mitochondria, which modulate the anti-apoptotic activity of Bcl-2. (PMID:17379544)
• the membrane topology of RTN3 has an effect on binding of RTN3 to BACE1 (PMID:17699523)
• These results show that RTN3 is primarily expressed in pyramidal neurones of the human cerebral cortex and that no clear difference of RTN3 immunoreactivity is observable between control and Alzheimer’s disease brains. (PMID:19284479)
• the disordered C-terminus of RTN3 is able to interact with FADD via a novel mode previously unobserved for FADD. (PMID:19364499)
• Elevated levels of RTN3 in transgenic RTN3 mice lead to an imbalance in the axonal transport of RTN3, which results in the accumulation of RTN3 in swollen neurites. (PMID:19386906)
• RTN3 mutants w/o the N-terminal or C-terminal or loop domain bound BACE1 like wild-type & reduced Abeta40/42 secretion. Mutants of the the 1st or 2d potential transmembrane domains bound BACE1 but failed to inhibit Abeta secretion. (PMID:19405102)
• CRELD1 could partly change the localization of RTN3 from the endoplasmic reticulum to the plasma membrane and modulate the apoptotic activity of RTN3 through binding with it. (PMID:19521671)
• common genetic variation in the BACE1-interacting proteins, RTN3 an PPIL2, does not influence platelet b-secretase activity or susceptibility to Alzheimer’s disease in this population. (PMID:19669607)
• we examined reticulon-3 expression in cases of Alzheimer’s disease, Parkinson’s disease, and diffuse Lewy body disease (PMID:20374499)
• Reticulons, the only molecular so far to participate in all three apoptosis signaling pathways, may be a novel player in the progress of atherosclerosis. (PMID:20717916)
• we hypothesis that RTN3 may participate in the continuous process of circulating monocyte recruitment in atherosclerosis. (PMID:21964562)
• This study demonistrated that Reduction of beta-amyloid accumulation by reticulon 3. (PMID:22742855)
• successful prevention of imunoreactive dystrophic neurites formation should be initiated before RTN3 aggregation (PMID:23407961)
• Authors demonstrated that the second transmembrane region of RTN3 competed for, and bound to, the AH2 domain of hepatitis C virus NS4B, thus abolishing NS4B self-interaction and leading to the downregulation of viral replication. (PMID:24898729)
• In Alzheimer’s disease transgenic mouse models, RTN3 deficiency facilitates amyloid deposition. (PMID:25319692)
• RTN 3 interacts with the N-terminal domain of EV71 2C, which is crucial for replication of viral RNA. [Review] (PMID:26164948)
• These results suggested that RTN3 modulates primordial germ cell migration through interaction with, and regulation of, CXCR4. (PMID:27070582)
• RTN3 was critical for EGFR-nonclathrin endocytosis (NCE), promoting the creation of plasma membrane - endoplasmic reticulum contact sites that were required for the formation and/or maturation of NCE invaginations. (PMID:28495747)
• This study demonstrated that higher intrahepatic RTN3 levels were independently associated with higher intrahepatic HCV viral loads and genotype 1 in HCV-related hepatocellular carcinoma (PMID:28551625)
• Here, the authors identified reticulon 3 (RTN3) as a specific receptor for the degradation of endoplasmic reticulum tubules. None of the other reticulon family members have the ability to induce fragmentation of endoplasmic reticulum tubules during starvation. (PMID:28617241)
• RTN3 is abundantly enriched in dystrophic neurites that surround amyloid plaques found in the brains of Alzheimer’s disease (AD) patients and mouse models. RTN3 deficiency causes elevation of BACE1 protein levels, while RTN1 deficiency shows no obvious effects on BACE1 due to compensation by elevated RTN3 expression. These results suggested that RTN3 has more prominent role in AD pathogenesis. (PMID:28733667)
• Overexpression of RTN3 T39 M in cultured neurons led to impaired axonal transport of BACE1. The variants found in this study are likely genetic modifiers for RTN3-mediated formation of neuritic plaques in Alzheimer’s disease (AD). (PMID:29356939)
• RTN3 has roles in inducing obesity and hypertriglyceridemia. (PMID:29716941)
• RTN3 regulates very low density lipoprotein (VLDL) secretion by controlling VLDL transport vesicle-mediated endoplasmic reticulum-to-Golgi transport of nascent VLDL. (PMID:29756473)
• We also find that RTN3 participates in the clearance of other mutant prohormone aggregates. Together, these results identify a series of substrates of RTN3-mediated ER-phagy, highlighting RTN3 in the disposal of pathogenic prohormone aggregates. (PMID:31176671)
• Reticulon-3 modulates the incorporation of replication competent hepatitis C virus molecules for release inside infectious exosomes. (PMID:32941510)
• Role of VAMP7-Dependent Secretion of Reticulon 3 in Neurite Growth. (PMID:33357422)
• Reticulon-3 Promotes Endosome Maturation at ER Membrane Contact Sites. (PMID:33434526)
• LINC02288 promotes chondrocyte apoptosis and inflammation through miR-374a-3p targeting RTN3. (PMID:33491257)
• The Implication of Reticulons (RTNs) in Neurodegenerative Diseases: From Molecular Mechanisms to Potential Diagnostic and Therapeutic Approaches. (PMID:33924890)
• RTN3 inhibits RIG-I-mediated antiviral responses by impairing TRIM25-mediated K63-linked polyubiquitination. (PMID:34313226)
• Loss of RTN3 phenocopies chronic kidney disease and results in activation of the IGF2-JAK2 pathway in proximal tubular epithelial cells. (PMID:35596061)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rtn3	ENSDARG00000091348
mus_musculus	Rtn3	ENSMUSG00000024758
rattus_norvegicus	Rtn3	ENSRNOG00000021202
drosophila_melanogaster	Rtnl2	FBGN0015831
drosophila_melanogaster	Rtnl1	FBGN0053113

Paralogs (4): RTN4 (ENSG00000115310), RTN2 (ENSG00000125744), RTN1 (ENSG00000139970), PRR18 (ENSG00000176381)

Protein

Protein identifiers

Reticulon-3 — O95197 (reviewed: O95197)

Alternative names: Homolog of ASY protein, Neuroendocrine-specific protein-like 2, Neuroendocrine-specific protein-like II

All UniProt accessions (5): B7Z4M1, O95197, F5GWG7, F5H617, F5H891

UniProt curated annotations — full annotation on UniProt →

Function. May be involved in membrane trafficking in the early secretory pathway. Inhibits BACE1 activity and amyloid precursor protein processing. May induce caspase-8 cascade and apoptosis. May favor BCL2 translocation to the mitochondria upon endoplasmic reticulum stress. Induces the formation of endoplasmic reticulum tubules. Also acts as an inflammation-resolving regulator by interacting with both TRIM25 and RIGI, subsequently impairing RIGI ‘Lys-63’-linked polyubiquitination leading to IRF3 and NF-kappa-B inhibition. (Microbial infection) Plays a positive role in viral replication and pathogenesis of enteroviruses.

Subunit / interactions. Homodimer. Interacts with ATL1. Interacts with RTN4. Isoform 3 interacts with BACE1, BACE2, BCL2 and FADD. Interacts with ATL2. Interacts with TMEM33. Interacts with ZFYVE27 and with KIF5A in a ZFYVE27-dependent manner. Interacts with RIGI. Interacts with TRIM25. (Microbial infection) Interacts with Coxsackievirus A16, enterovirus 71 and poliovirus P2C proteins. (Microbial infection) Interacts with West Nile virus protein NS4A.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus membrane.

Tissue specificity. Isoform 3 is widely expressed, with highest levels in brain, where it is enriched in neuronal cell bodies from gray matter (at protein level). Three times more abundant in macula than in peripheral retina. Isoform 1 is expressed at high levels in brain and at low levels in skeletal muscle. Isoform 2 is only found in melanoma.

Induction. By endoplasmic reticulum stress (at protein level). Up-regulated and self-aggregates upon RNA viral infection.

Isoforms (7)

UniProt ID	Names	Canonical?
O95197-1	1, A1, A4b	yes
O95197-2	2, A2, A3b
O95197-3	3, B1, A1
O95197-4	4, B2, A2
O95197-5	5
O95197-6	6
O95197-7	7

RefSeq proteins (7): NP_001252518, NP_001252519, NP_001252520, NP_006045, NP_958831, NP_958832, NP_958833 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003388	Reticulon	Domain
IPR046964	RTN1-4	Family

Pfam: PF02453

UniProt features (42 total): modified residue 11, splice variant 6, region of interest 5, compositionally biased region 5, topological domain 4, intramembrane region 3, sequence variant 2, initiator methionine 1, chain 1, sequence conflict 1, helix 1, turn 1, domain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
7BRU	X-RAY DIFFRACTION	2.15

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95197-F1	43.42	0.08

Functional residue map

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

Post-translational modifications (11): 2, 30, 229, 243, 246, 283, 316, 453, 649, 650, 735

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-8849932	Synaptic adhesion-like molecules
R-HSA-9918487	Dengue Virus Genome Translation and Replication
R-HSA-112316	Neuronal System
R-HSA-6794362	Protein-protein interactions at synapses

MSigDB gene sets: 244 (showing top): RORA1_01, GOBP_NEUROGENESIS, TGACCTY_ERR1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT, COLIN_PILOCYTIC_ASTROCYTOMA_VS_GLIOBLASTOMA_UP, GGGTGGRR_PAX4_03, GOBP_NEGATIVE_REGULATION_OF_AMIDE_METABOLIC_PROCESS, chr11q13, SP1_Q2_01, GOBP_MACROAUTOPHAGY, PATIL_LIVER_CANCER, GOBP_REGULATION_OF_AMYLOID_PRECURSOR_PROTEIN_CATABOLIC_PROCESS, AP1_Q4_01, MODULE_239, RAMALHO_STEMNESS_DN

GO Biological Process (9): apoptotic process (GO:0006915), brain development (GO:0007420), vesicle-mediated transport (GO:0016192), neuron differentiation (GO:0030182), reticulophagy (GO:0061709), endoplasmic reticulum tubular network organization (GO:0071786), endoplasmic reticulum tubular network formation (GO:0071787), negative regulation of amyloid-beta formation (GO:1902430), endoplasmic reticulum tubular network membrane organization (GO:1990809)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (10): Golgi membrane (GO:0000139), obsolete extracellular space (GO:0005615), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), neuron projection (GO:0043005), membrane (GO:0016020), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Protein-protein interactions at synapses	1
Dengue Virus Infection	1
Neuronal System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endoplasmic reticulum tubular network organization	2
cytoplasm	2
endomembrane system	2
intracellular membrane-bounded organelle	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
central nervous system development	1
animal organ development	1
head development	1
transport	1
cellular process	1
cell differentiation	1
generation of neurons	1
macroautophagy	1
endoplasmic reticulum organization	1
cellular component assembly	1
amyloid-beta formation	1
regulation of amyloid-beta formation	1
negative regulation of amyloid precursor protein catabolic process	1
endoplasmic reticulum membrane organization	1
binding	1
Golgi apparatus	1
bounding membrane of organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
asymmetric synapse	1
postsynaptic specialization	1
plasma membrane bounded cell projection	1
cellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

1612 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RTN3	BACE1	P56817	860
RTN3	RETREG1	Q9H6L5	823
RTN3	SEC62	Q99442	819
RTN3	CCPG1	Q9ULG6	776
RTN3	ATL3	Q6DD88	768
RTN3	REEP5	Q00765	749
RTN3	TEX264	Q9Y6I9	729
RTN3	GABARAPL2	P60520	713
RTN3	F5GZY7	F5GZY7	707
RTN3	ATL1	Q8WXF7	683
RTN3	NUS1	Q96E22	678
RTN3	ATL2	Q8NHH9	651
RTN3	BACE2	Q9Y5Z0	634
RTN3	RTN4	Q9NQC3	599
RTN3	APP	P05067	592

IntAct

114 interactions, top by confidence:

A	B	Type	Score
RTN3	RTN4	psi-mi:“MI:0915”(physical association)	0.750
PTPN9	RTN3	psi-mi:“MI:0915”(physical association)	0.740
RTN3	PTPN9	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
RTN3	CERT1	psi-mi:“MI:0915”(physical association)	0.670
CERT1	RTN3	psi-mi:“MI:0915”(physical association)	0.670
FPR2	ARL6IP5	psi-mi:“MI:0914”(association)	0.640
RTN3	CDIPT	psi-mi:“MI:0915”(physical association)	0.560
RTN3		psi-mi:“MI:0915”(physical association)	0.560
RTN3	SNX1	psi-mi:“MI:0915”(physical association)	0.560
RTN3	PTPN9	psi-mi:“MI:0915”(physical association)	0.560
PPP2R3C	RTN3	psi-mi:“MI:0915”(physical association)	0.560
	RTN3	psi-mi:“MI:0915”(physical association)	0.560
SNX1	RTN3	psi-mi:“MI:0915”(physical association)	0.560
RTN3	PPP2R3C	psi-mi:“MI:0915”(physical association)	0.560
CDIPT	RTN3	psi-mi:“MI:0915”(physical association)	0.560
RTN3	RTN3	psi-mi:“MI:0915”(physical association)	0.550
RTN3	GPR35	psi-mi:“MI:0915”(physical association)	0.550

BioGRID (248): RTN3 (Two-hybrid), RTN3 (Two-hybrid), RTN3 (Two-hybrid), CDIPT (Two-hybrid), PPP2R3C (Two-hybrid), ZNF391 (Two-hybrid), RTN3 (Two-hybrid), RTN3 (Two-hybrid), FAM160A2 (Two-hybrid), RTN4 (Two-hybrid), RTN3 (Two-hybrid), PLEKHF2 (Two-hybrid), RTN3 (Two-hybrid), RTN3 (Two-hybrid), RTN3 (Two-hybrid)

ESM2 similar proteins: A2ARZ3, A4FU69, A4IH95, A5WUN7, A6H5Y1, A7MC64, D3Z8E6, E9Q309, O75969, O95197, P11137, P15146, P20357, P86839, Q01613, Q0P5X5, Q16799, Q2M2Z5, Q2T9M9, Q498L0, Q52KN3, Q53TS8, Q5IS59, Q5MY90, Q5RHB5, Q5SW79, Q5T5Y3, Q5VT06, Q62394, Q64548, Q6A065, Q6DFV7, Q6RJR6, Q6ZQ06, Q6ZVD7, Q76I76, Q7TS75, Q8BYM7, Q8BZJ8, Q8C5W0

Diamond homologs: A7MC64, O70622, O75298, O95197, Q08D83, Q16799, Q28D16, Q4FZ58, Q4FZ76, Q5IS59, Q5J6M8, Q5MY90, Q5RBL9, Q64548, Q68EW1, Q6IFY7, Q6RJR6, Q6WN19, Q8K0T0, Q99P72, Q9ES97, Q9JK11, Q9NQC3, Q56X72, Q6DR04, Q8LDS3, Q6NPD8, Q9SH59

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 93 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
Sphingolipid de novo biosynthesis	5	23.4×	7e-04
COPI-dependent Golgi-to-ER retrograde traffic	6	10.9×	3e-03
SLC-mediated transmembrane transport	7	6.8×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
intra-Golgi vesicle-mediated transport	5	31.4×	1e-04
endoplasmic reticulum organization	6	30.1×	4e-05
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	6	24.1×	7e-05
endoplasmic reticulum to Golgi vesicle-mediated transport	7	11.3×	4e-04
protein transport	11	5.8×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	143
Likely benign	13
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1857 predictions. Top by Δscore:

Variant	Effect	Δscore
11:63681775:GCGG:G	donor_gain	1.0000
11:63681777:GG:G	donor_gain	1.0000
11:63681777:GGGTA:G	donor_loss	1.0000
11:63681778:GG:G	donor_gain	1.0000
11:63681779:G:GA	donor_loss	1.0000
11:63681779:G:GG	donor_gain	1.0000
11:63714055:GCTTA:G	donor_gain	1.0000
11:63749989:A:AG	acceptor_gain	1.0000
11:63749990:G:GA	acceptor_gain	1.0000
11:63749990:GT:G	acceptor_gain	1.0000
11:63749990:GTGCA:G	acceptor_gain	1.0000
11:63750199:G:GG	donor_gain	1.0000
11:63752481:AT:A	acceptor_gain	1.0000
11:63752482:T:G	acceptor_gain	1.0000
11:63752501:T:TA	acceptor_gain	1.0000
11:63753710:T:A	donor_loss	1.0000
11:63756109:A:G	acceptor_gain	1.0000
11:63756110:A:G	acceptor_gain	1.0000
11:63756111:G:GG	acceptor_gain	1.0000
11:63756166:GAAAA:G	donor_gain	1.0000
11:63756171:G:GG	donor_gain	1.0000
11:63681774:TGCGG:T	donor_gain	0.9900
11:63681775:GCGGG:G	donor_gain	0.9900
11:63681780:T:G	donor_loss	0.9900
11:63721028:CTCAG:C	donor_loss	0.9900
11:63721029:TCAG:T	donor_loss	0.9900
11:63721030:CAGGT:C	donor_loss	0.9900
11:63721031:AG:A	donor_loss	0.9900
11:63721032:GGTAA:G	donor_loss	0.9900
11:63721033:G:T	donor_loss	0.9900

AlphaMissense

6787 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:63750080:A:C	S874R	0.999
11:63750082:T:A	S874R	0.999
11:63750082:T:G	S874R	0.999
11:63750089:A:C	S877R	0.999
11:63750091:T:A	S877R	0.999
11:63750091:T:G	S877R	0.999
11:63750134:A:C	S892R	0.999
11:63750136:C:A	S892R	0.999
11:63750136:C:G	S892R	0.999
11:63753084:T:A	W965R	0.999
11:63753084:T:C	W965R	0.999
11:63750156:T:A	V899D	0.998
11:63750164:G:C	A902P	0.998
11:63753102:G:C	G971R	0.998
11:63753679:A:C	S989R	0.998
11:63753681:T:A	S989R	0.998
11:63753681:T:G	S989R	0.998
11:63750120:T:C	L887P	0.997
11:63753070:T:C	L960P	0.997
11:63753073:C:A	A961D	0.997
11:63753103:G:A	G971D	0.997
11:63750111:T:C	L884P	0.996
11:63753088:T:C	L966P	0.996
11:63753127:T:C	L979P	0.996
11:63753692:T:A	V993D	0.996
11:63750069:T:C	L870P	0.995
11:63750105:T:C	L882P	0.995
11:63753100:T:A	V970D	0.995
11:63753102:G:T	G971C	0.995
11:63753105:G:C	A972P	0.995

dbSNP variants (sampled 300 via entrez): RS1000018794 (11:63698501 C>T), RS1000029911 (11:63705233 A>G,T), RS1000034711 (11:63735455 G>A,C,T), RS1000067106 (11:63691965 C>T), RS1000071214 (11:63698117 G>C), RS1000091075 (11:63748200 C>T), RS1000242428 (11:63741591 C>G), RS1000306710 (11:63699298 T>C,G), RS1000377497 (11:63711592 TTCGTTC>T), RS1000416771 (11:63691634 T>G), RS1000435797 (11:63722032 A>T), RS1000461191 (11:63680957 T>C,G), RS1000468180 (11:63699152 T>C,G), RS1000476198 (11:63741546 C>A), RS1000487927 (11:63701104 G>A,T)

Disease associations

OMIM: gene MIM:604249 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066992 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.69	Kd	20.58	nM	CHEMBL5653589
7.69	ED50	20.58	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149327: Binding affinity to human RTN3 incubated for 45 mins by Kinobead based pull down assay	kd	0.0206	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases abundance, affects expression, affects cotreatment, increases methylation, decreases expression	4
trichostatin A	affects cotreatment, decreases expression	3
Valproic Acid	affects expression, decreases expression, increases expression	3
sodium arsenite	increases expression	2
cobaltous chloride	increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
Acetaminophen	affects response to substance, increases expression	2
Cyclosporine	increases expression	2
FR900359	decreases phosphorylation	1
ginger extract	increases abundance, affects cotreatment, affects expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction, increases reaction	1
tetrabromobisphenol A	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
K 7174	increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Decitabine	decreases expression, affects reaction	1
Sunitinib	increases expression	1
Fulvestrant	increases methylation, affects cotreatment	1
Benzo(a)pyrene	decreases expression	1
Caffeine	decreases phosphorylation	1
Dimethyl Sulfoxide	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652369	Binding	Binding affinity to human RTN3 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3GE	Abcam HEK293T RTN3 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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