RPN2

Summary

RPN2 (ribophorin II, HGNC:10382) is a protein-coding gene on chromosome 20q11.23, encoding Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit 2 (P04844). Subunit of the oligosaccharyl transferase (OST) complex that catalyzes the initial transfer of a defined glycan (Glc(3)Man(9)GlcNAc(2) in eukaryotes) from the lipid carrier dolichol-pyrophosphate to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypep…. It is a common-essential gene (DepMap: required in 90.7% of cancer cell lines).

This gene encodes a type I integral membrane protein found only in the rough endoplasmic reticulum. The encoded protein is part of an N-oligosaccharyl transferase complex that links high mannose oligosaccharides to asparagine residues found in the Asn-X-Ser/Thr consensus motif of nascent polypeptide chains. This protein is similar in sequence to the yeast oligosaccharyl transferase subunit SWP1. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 6185 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 270 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 90.7% of screened cell lines (common-essential)
• MANE Select transcript: NM_002951

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10382
Approved symbol	RPN2
Name	ribophorin II
Location	20q11.23
Locus type	gene with protein product
Status	Approved
Aliases	SWP1, RPNII, RIBIIR, RPN-II
Ensembl gene	ENSG00000118705
Ensembl biotype	protein_coding
OMIM	180490
Entrez	6185

Gene structure

Transcript identifiers

Ensembl transcripts: 38 — 36 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000237530, ENST00000373622, ENST00000373632, ENST00000437329, ENST00000456102, ENST00000456400, ENST00000462163, ENST00000470352, ENST00000705448, ENST00000892620, ENST00000892621, ENST00000892622, ENST00000892623, ENST00000892624, ENST00000892625, ENST00000892626, ENST00000892627, ENST00000892628, ENST00000892629, ENST00000892630, ENST00000892631, ENST00000892632, ENST00000892633, ENST00000892634, ENST00000892635, ENST00000892636, ENST00000892637, ENST00000892638, ENST00000892639, ENST00000892640, ENST00000914582, ENST00000914583, ENST00000914584, ENST00000914585, ENST00000947422, ENST00000947423, ENST00000947424, ENST00000947425

RefSeq mRNA: 9 — MANE Select: NM_002951 NM_001135771, NM_001324299, NM_001324301, NM_001324302, NM_001324303, NM_001324304, NM_001324305, NM_001324306, NM_002951

CCDS: CCDS13291, CCDS46599

Canonical transcript exons

ENST00000237530 — 17 exons

Exon	Start	End
ENSE00001369190	37179330	37179369
ENSE00001598422	37223878	37223969
ENSE00001599516	37207273	37207449
ENSE00001632894	37203885	37203960
ENSE00001642702	37199050	37199225
ENSE00001658808	37229973	37230059
ENSE00001741053	37213760	37213865
ENSE00001742400	37225688	37225802
ENSE00001747005	37232296	37232391
ENSE00001770516	37204767	37204901
ENSE00001776667	37228550	37228744
ENSE00003482342	37184180	37184373
ENSE00003520078	37236580	37236709
ENSE00003528590	37234020	37234095
ENSE00003786166	37210047	37210165
ENSE00003993553	37198397	37198492
ENSE00003993554	37241303	37241619

Expression profiles

Bgee: expression breadth ubiquitous, 303 present calls, max score 99.54.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 108.2967 / max 644.2339, expressed in 1823 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
184468	85.4378	1823
184467	17.3654	1799
184466	5.0538	1667
184474	0.4238	205
184473	0.0159	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	99.54	gold quality
pylorus	UBERON:0001166	99.42	gold quality
placenta	UBERON:0001987	99.36	gold quality
pericardium	UBERON:0002407	99.33	gold quality
ileal mucosa	UBERON:0000331	99.32	gold quality
stromal cell of endometrium	CL:0002255	99.12	gold quality
islet of Langerhans	UBERON:0000006	99.12	gold quality
caput epididymis	UBERON:0004358	99.10	gold quality
pancreatic ductal cell	CL:0002079	99.08	gold quality
trachea	UBERON:0003126	99.08	gold quality
cardia of stomach	UBERON:0001162	99.02	gold quality
nasal cavity epithelium	UBERON:0005384	99.02	gold quality
superior surface of tongue	UBERON:0007371	99.00	gold quality
seminal vesicle	UBERON:0000998	98.98	gold quality
tongue squamous epithelium	UBERON:0006919	98.97	gold quality
tibia	UBERON:0000979	98.90	gold quality
renal medulla	UBERON:0000362	98.86	gold quality
epithelium of nasopharynx	UBERON:0001951	98.86	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	98.84	gold quality
nasopharynx	UBERON:0001728	98.84	gold quality
ventricular zone	UBERON:0003053	98.83	gold quality
smooth muscle tissue	UBERON:0001135	98.80	gold quality
cauda epididymis	UBERON:0004360	98.77	gold quality
decidua	UBERON:0002450	98.74	gold quality
bone marrow cell	CL:0002092	98.72	gold quality
lower lobe of lung	UBERON:0008949	98.72	gold quality
mammary duct	UBERON:0001765	98.71	gold quality
pharyngeal mucosa	UBERON:0000355	98.70	gold quality
nasal cavity mucosa	UBERON:0001826	98.70	gold quality
pigmented layer of retina	UBERON:0001782	98.69	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	88.04
E-MTAB-9467	yes	60.09
E-CURD-122	yes	44.08
E-HCAD-4	yes	39.54
E-HCAD-1	yes	32.24
E-CURD-46	yes	20.03
E-HCAD-9	yes	14.64
E-HCAD-13	yes	12.34
E-MTAB-7606	no	2358.54
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

42 targeting RPN2, 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-513A-5P	100.00	69.77	2465
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-6733-3P	99.54	67.80	1281
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-4318	99.38	66.94	1505
HSA-MIR-422A	99.18	65.83	550
HSA-MIR-4686	98.77	66.87	964
HSA-MIR-6776-5P	98.54	67.43	1304
HSA-MIR-378A-3P	98.43	66.10	548
HSA-MIR-378B	98.43	65.36	573
HSA-MIR-378C	98.43	66.10	548

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 90.7% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 27)

• RPN2 gene confers docetaxel resistance in breast cancer. (PMID:18724378)
• S-glutathionylation of Rpn2 is a contributory mechanism for H2O2-induced inhibition of 26 S proteasomal function (PMID:19549781)
• Data show that the decay of metabolically labeled p53 follows biphasic kinetics, while 20 S proteasome executes the first phase by default, and the second phase requires the 26 S proteasome. (PMID:19617345)
• Rpn13 binding to the proteasome scaffolding protein hRpn2/S1 abrogates its interdomain interactions, thus activating hRpn13 for ubiquitin binding. (PMID:20471946)
• Furthermore, our study reveals that high expression of RPN2 and concomitant accumulation of mtp53 were associated with cancer tissues in a small cohort of metastatic breast cancer patients. (PMID:23959174)
• Of the total, the deregulation of several genes (CDK1, CDK2, CDK4, MCM2, MCM3, MCM4, EIF3a and RPN2) were potentially associated with disease development and progression. (PMID:24386425)
• these results indicated that high glycosylation of CD63 by RPN2 is implicated in clinical outcomes in breast cancer patients (PMID:24884960)
• Data suggest that RPN2 is involved in the regulation of lethal cancer phenotypes and represents a promising new target for RNAi-based medicine against non-small cell lung cancer. (PMID:25595901)
• RPN2 expression correlates with gastric adenocarcinoma cell invasion and shows promise as a new prognostic factor in human gastric adenocarcinoma (PMID:28035352)
• Rpn13-Rpn2 complex structural analysis shows that RA190 targets hRpn13 and Uch37 through parallel mechanisms and at proteasomes, RA190-inactivated Uch37 cannot disassemble hRpn13-bound ubiquitin chains (PMID:28598414)
• These findings indicated a novel pathway of tumor-promoting activity by RPN2 in colorectal cancer (CRC), with significant implications for unraveling the tumorigenesis of CRC. (PMID:29749494)
• RPN2 potentiated P-gp- and ABCG2-mediated MDR via activating MEK/ERK pathway in GC (PMID:30710584)
• Findings indicate increased oligosaccharyltransferase complex subunit (non-catalytic) ribophorin-2 (RPN2) expression in esophageal cancer tissues and cell lines. (PMID:30940778)
• reveals specific interactions with positively charged side chains in RPN13 that explain how phosphorylation increases binding affinity without inducing conformational change (PMID:31064842)
• Overexpression of RPN2 promotes osteogenic differentiation of hBMSCs through the JAK/STAT3 pathway. (PMID:31743606)
• Knockdown of circNFIX inhibits progression of glioma in vitro and in vivo by increasing miR-378e and decreasing RPN2, providing a novel mechanism for understanding the pathogenesis of glioma. (PMID:31888753)
• An Extended Conformation for K48 Ubiquitin Chains Revealed by the hRpn2:Rpn13:K48-Diubiquitin Structure. (PMID:32160516)
• Overexpression of RPN2 suppresses radiosensitivity of glioma cells by activating STAT3 signal transduction. (PMID:32404045)
• Ribophorin II is upregulated in myelodysplastic syndromes and prevents apoptosis and cell cycle progression. (PMID:32447991)
• MicroRNA422a functions as a tumor suppressor in glioma by regulating the Wnt/betacatenin signaling pathway via RPN2. (PMID:33000268)
• RPN2 is targeted by miR-181c and mediates glioma progression and temozolomide sensitivity via the wnt/beta-catenin signaling pathway. (PMID:33087705)
• Overexpression of ribophorin II is required for viability of nasopharyngeal cancer cells by regulating JAK1/STAT3 activation. (PMID:34184962)
• Epigenetically-regulated RPN2 gene influences lymphocyte activation and is involved in pathogenesis of rheumatoid arthritis. (PMID:34740730)
• Sevoflurane represses the progression of glioma by the regulation of circ_0037655/miR-130a-5p/RPN2 axis. (PMID:35032276)
• Ribophorin II promotes the epithelial-mesenchymal transition and aerobic glycolysis of laryngeal squamous cell carcinoma via regulating reactive oxygen species-mediated Phosphatidylinositol-3-Kinase/Protein Kinase B activation. (PMID:35156537)
• The N(6)-methyladenosine-mediated lncRNA WEE2-AS1 promotes glioblastoma progression by stabilizing RPN2. (PMID:36168628)
• RPN2 in cancer: An overview. (PMID:36621657)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rpn2	ENSDARG00000009724
mus_musculus	Rpn2	ENSMUSG00000027642
rattus_norvegicus	Rpn2	ENSRNOG00000007492
drosophila_melanogaster	OstDelta	FBGN0034277
caenorhabditis_elegans	ostd-1	WBGENE00019693

Protein

Protein identifiers

Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit 2 — P04844 (reviewed: P04844)

Alternative names: Dolichyl-diphosphooligosaccharide–protein glycosyltransferase 63 kDa subunit, RIBIIR, Ribophorin II, Ribophorin-2

All UniProt accessions (6): A0A994J5J1, P04844, H0Y5M1, Q5JYR3, Q5JYR4, Q5JYR7

UniProt curated annotations — full annotation on UniProt →

Function. Subunit of the oligosaccharyl transferase (OST) complex that catalyzes the initial transfer of a defined glycan (Glc(3)Man(9)GlcNAc(2) in eukaryotes) from the lipid carrier dolichol-pyrophosphate to an asparagine residue within an Asn-X-Ser/Thr consensus motif in nascent polypeptide chains, the first step in protein N-glycosylation. N-glycosylation occurs cotranslationally and the complex associates with the Sec61 complex at the channel-forming translocon complex that mediates protein translocation across the endoplasmic reticulum (ER). All subunits are required for a maximal enzyme activity.

Subunit / interactions. Component of the oligosaccharyltransferase (OST) complex. OST exists in two different complex forms which contain common core subunits RPN1, RPN2, OST48, OST4, DAD1 and TMEM258, either STT3A or STT3B as catalytic subunits, and form-specific accessory subunits. STT3A complex assembly occurs through the formation of 3 subcomplexes. Subcomplex 1 contains RPN1 and TMEM258, subcomplex 2 contains the STT3A-specific subunits STT3A, DC2/OSTC, and KCP2 as well as the core subunit OST4, and subcomplex 3 contains RPN2, DAD1, and OST48. The STT3A complex can form stable complexes with the Sec61 complex or with both the Sec61 and TRAP complexes. Interacts with DDI2. Interacts with TMEM35A/NACHO.

Subcellular location. Endoplasmic reticulum. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in all tissues tested.

Pathway. Protein modification; protein glycosylation.

Similarity. Belongs to the SWP1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P04844-1	1	yes
P04844-2	2

RefSeq proteins (9): NP_001129243, NP_001311228, NP_001311230, NP_001311231, NP_001311232, NP_001311233, NP_001311234, NP_001311235, NP_002942* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008814	Swp1	Family
IPR055373	Ribophorin_II_N	Domain
IPR055374	Ribophorin_II_3rd	Domain
IPR055375	Ribophorin_II_2nd	Domain
IPR056790	Ribophorin_II_C	Domain

Pfam: PF05817, PF23860, PF23861, PF25147

Enzyme classification (BRENDA):

• EC 2.4.99.18 — dolichyl-diphosphooligosaccharide-protein glycotransferase (BRENDA: 84 organisms, 135 substrates, 28 inhibitors, 38 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

29 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
TYR-ASN-LEU-THR-SER-VAL	0.05–0.6	3
ACETYL-ASN-ALA-THR	0.08–0.143	2
ALA-LEU-GLN-ASN-ALA-THR-ARG	0.3–0.358	2
ASN-ALA-THR	0.56–2.09	2
DIPHENYL-ALA-LEU-GLU-ASN-ALA-THR-ARG-NH2	0.072–0.23	2
TYR-GLN-SER-ASN-SER-THR-MET	0.08–0.127	2
AC-ASN-ALA-THR-NH2	2	1
AC-ASN-LEU-THR-NH2	1	1
ACETYL-ASN-LYS-THR	0.278	1
ACETYL-DFNAT-(4-NITROPHENYLALANINE)-NH2	0.0009	1
ACETYL-DFNVT-(4-NITROPHENYLALANINE)-NH2	0.0012	1
ACETYL-DQNAT-(4-NITROPHENYLALANINE)-NH2	0.0008	1
ACETYL-DVNAS-(4-NITROPHENYLALANINE)-NH2	0.003	1
ACETYL-DVNAT-(4-NITROPHENYLALANINE)-NH2	0.0011	1
ACETYL-DVNVT-(4-NITROPHENYLALANINE)-NH2	0.0014	1

UniProt features (41 total): strand 15, sequence conflict 7, topological domain 4, transmembrane region 3, helix 3, splice variant 2, turn 2, signal peptide 1, chain 1, cross-link 1, sequence variant 1, glycosylation site 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
9N9J	ELECTRON MICROSCOPY	3.2
6S7O	ELECTRON MICROSCOPY	3.5
6S7T	ELECTRON MICROSCOPY	3.5
8PN9	ELECTRON MICROSCOPY	3.61
9YGY	ELECTRON MICROSCOPY	4.1
8B6L	ELECTRON MICROSCOPY	7.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P04844-F1	89.49	0.73

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 (1): 154

Glycosylation sites (1): 106

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-1799339	SRP-dependent cotranslational protein targeting to membrane
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-9694548	Maturation of spike protein
R-HSA-9768727	Regulation of CDH1 posttranslational processing and trafficking to plasma membrane
R-HSA-9918432	Maturation of DENV proteins
R-HSA-9931295	PD-L1(CD274) glycosylation and translocation to plasma membrane
R-HSA-1643685	Disease
R-HSA-392499	Metabolism of proteins
R-HSA-5663205	Infectious disease
R-HSA-597592	Post-translational protein modification
R-HSA-72766	Translation
R-HSA-9679506	SARS-CoV Infections
R-HSA-9694516	SARS-CoV-2 Infection
R-HSA-9694635	Translation of Structural Proteins
R-HSA-9772573	Late SARS-CoV-2 Infection Events
R-HSA-9824446	Viral Infection Pathways

MSigDB gene sets: 250 (showing top): HONMA_DOCETAXEL_RESISTANCE, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_10, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_PROTEIN_N_LINKED_GLYCOSYLATION, BOYAULT_LIVER_CANCER_SUBCLASS_G2, KEGG_N_GLYCAN_BIOSYNTHESIS, HSIAO_HOUSEKEEPING_GENES, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, MARTINEZ_RB1_TARGETS_UP, FREAC3_01, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, KLEIN_PRIMARY_EFFUSION_LYMPHOMA_UP, MORI_SMALL_PRE_BII_LYMPHOCYTE_DN, SCHLOSSER_SERUM_RESPONSE_DN

GO Biological Process (3): protein N-linked glycosylation (GO:0006487), protein modification process (GO:0036211), obsolete protein glycosylation (GO:0006486)

GO Molecular Function (2): dolichyl-diphosphooligosaccharide-protein glycotransferase activity (GO:0004579), protein binding (GO:0005515)

GO Cellular Component (7): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), oligosaccharyltransferase complex (GO:0008250), membrane (GO:0016020), nuclear body (GO:0016604), oligosaccharyltransferase complex A (GO:0160226), oligosaccharyltransferase complex B (GO:0160227)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Metabolism of proteins	2
Translation	1
Post-translational protein modification	1
Translation of Structural Proteins	1
Regulation of CDH1 Expression and Function	1
Dengue Virus Genome Translation and Replication	1
Regulation of PD-L1(CD274) Post-translational modification	1
Disease	1
Viral Infection Pathways	1
SARS-CoV Infections	1
Late SARS-CoV-2 Infection Events	1
SARS-CoV-2 Infection	1
Infectious disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
oligosaccharyltransferase complex	2
glycoprotein biosynthetic process	1
protein metabolic process	1
macromolecule modification	1
oligosaccharyl transferase activity	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
endoplasmic reticulum membrane	1
membrane protein complex	1
endoplasmic reticulum protein-containing complex	1
transferase complex	1
cellular anatomical structure	1
nucleoplasm	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1732 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RPN2	RPN1	P04843	999
RPN2	DDOST	P39656	999
RPN2	DAD1	P46966	999
RPN2	OST4	P0C6T2	993
RPN2	STT3A	P46977	982
RPN2	STT3B	Q8TCJ2	949
RPN2	MAGT1	Q9H0U3	810
RPN2	TUSC3	Q13454	802
RPN2	KRTCAP2	Q8N6L1	730
RPN2	UBQLN2	Q9UHD9	649
RPN2	TMEM258	P61165	642
RPN2	SEC61A1	P38378	597
RPN2	BNIP3	Q12983	585
RPN2	UBQLN1	Q9UMX0	549
RPN2	SSR1	P43307	539

IntAct

221 interactions, top by confidence:

A	B	Type	Score
TUSC3	RPN2	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
MLEC	RPN1	psi-mi:“MI:0915”(physical association)	0.690
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
STT3A	RPN1	psi-mi:“MI:0914”(association)	0.560
LRRC15	TCAF2	psi-mi:“MI:0914”(association)	0.560
RPN2	SMPD2	psi-mi:“MI:0914”(association)	0.530
VSIG8	RPN2	psi-mi:“MI:0914”(association)	0.530
DAD1	RPN1	psi-mi:“MI:0915”(physical association)	0.530
	XPO1	psi-mi:“MI:0914”(association)	0.530
RPN1	APBB1	psi-mi:“MI:0914”(association)	0.530
POMK	RPN2	psi-mi:“MI:0915”(physical association)	0.500
ESR1		psi-mi:“MI:0914”(association)	0.460
LTK	PIK3R2	psi-mi:“MI:0914”(association)	0.420
NDRG1	RPN2	psi-mi:“MI:0915”(physical association)	0.400
RPN2	LTB4R2	psi-mi:“MI:0915”(physical association)	0.370
RPN2	SMO	psi-mi:“MI:0915”(physical association)	0.370
RPN2	RHOA	psi-mi:“MI:0915”(physical association)	0.370
RPN2	RCHY1	psi-mi:“MI:0915”(physical association)	0.370
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350
JUN		psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350

BioGRID (1082): RPN2 (Affinity Capture-MS), RPN2 (Affinity Capture-MS), RPN2 (Affinity Capture-MS), RPN2 (Affinity Capture-MS), DDOST (Co-fractionation), DDX39B (Co-fractionation), HSP90B1 (Co-fractionation), IPO9 (Co-fractionation), KDSR (Co-fractionation), PC (Co-fractionation), RPN1 (Co-fractionation), RPN2 (Co-fractionation), RPN2 (Co-fractionation), RPN2 (Co-fractionation), RPN2 (Co-fractionation)

ESM2 similar proteins: A0A8I3NGV2, A2VE47, A4IG72, A7E2V1, D3Z2R5, F1PCT7, O43909, P02786, P04844, P25235, P57716, Q07891, Q0VCN6, Q28120, Q28DV7, Q2V905, Q5R9Q9, Q5RBM1, Q5RDH6, Q5XIA1, Q5ZJH2, Q5ZL00, Q62351, Q64255, Q6DDX8, Q6NZ07, Q7TMC8, Q8BXQ2, Q8C7X2, Q8CGU6, Q8K224, Q8N766, Q8N961, Q8R553, Q8VCM8, Q8VDL4, Q92542, Q969N2, Q969V3, Q99JH7

Diamond homologs: F1PCT7, P04844, P25235, P91390, Q3SZI6, Q5RBM1, Q9DBG6, Q9GL01, Q54HG9, Q5N7W3

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
RPN2	“form complex”	“OST-A complex”	binding
RPN2	“form complex”	“OST-B complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 213 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
PD-L1(CD274) glycosylation and translocation to plasma membrane	9	32.7×	2e-09
Maturation of spike protein	10	18.6×	2e-08
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	7	16.4×	3e-05
Maturation of DENV proteins	11	16.3×	2e-08
Asparagine N-linked glycosylation	12	5.0×	7e-04

GO biological processes:

GO term	Partners	Fold	FDR
obsolete protein N-linked glycosylation via asparagine	10	37.9×	5e-11
protein N-linked glycosylation	10	14.8×	8e-07
learning or memory	7	9.5×	2e-03
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	12	5.3×	1e-03
negative regulation of apoptotic process	20	3.9×	9e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	122
Likely benign	75
Benign	38

Top pathogenic / likely-pathogenic (0)

SpliceAI

3172 predictions. Top by Δscore:

Variant	Effect	Δscore
20:37184373:GGTAA:G	donor_loss	1.0000
20:37184374:G:T	donor_loss	1.0000
20:37184375:T:A	donor_loss	1.0000
20:37198396:GAAA:G	acceptor_gain	1.0000
20:37199223:GGC:G	donor_gain	1.0000
20:37199224:GC:G	donor_gain	1.0000
20:37199224:GCG:G	donor_gain	1.0000
20:37199226:G:GG	donor_gain	1.0000
20:37204756:T:TA	acceptor_gain	1.0000
20:37204760:AT:A	acceptor_gain	1.0000
20:37204761:T:G	acceptor_gain	1.0000
20:37204761:T:TA	acceptor_gain	1.0000
20:37204762:G:A	acceptor_gain	1.0000
20:37204763:GCA:G	acceptor_loss	1.0000
20:37204765:A:AG	acceptor_gain	1.0000
20:37204765:A:T	acceptor_loss	1.0000
20:37204765:AG:A	acceptor_gain	1.0000
20:37204766:G:A	acceptor_loss	1.0000
20:37204766:G:GA	acceptor_gain	1.0000
20:37204766:GG:G	acceptor_gain	1.0000
20:37204766:GGA:G	acceptor_gain	1.0000
20:37204766:GGAC:G	acceptor_gain	1.0000
20:37204766:GGACC:G	acceptor_gain	1.0000
20:37204898:GGAG:G	donor_gain	1.0000
20:37204899:GAG:G	donor_gain	1.0000
20:37204899:GAGG:G	donor_gain	1.0000
20:37204900:AGGT:A	donor_loss	1.0000
20:37204902:G:C	donor_loss	1.0000
20:37204903:T:G	donor_loss	1.0000
20:37207268:TTCA:T	acceptor_loss	1.0000

AlphaMissense

4117 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:37228557:T:A	V436D	0.999
20:37228563:T:C	L438P	0.999
20:37228736:T:A	W496R	0.999
20:37228736:T:C	W496R	0.999
20:37223924:T:C	L380P	0.998
20:37228602:C:A	A451D	0.998
20:37234077:T:C	F579L	0.998
20:37234079:T:A	F579L	0.998
20:37234079:T:G	F579L	0.998
20:37236676:G:A	G617D	0.998
20:37225801:A:C	Q433P	0.997
20:37228553:T:C	F435L	0.997
20:37228555:T:A	F435L	0.997
20:37228555:T:G	F435L	0.997
20:37228560:G:C	R437P	0.997
20:37228638:T:C	L463P	0.997
20:37228707:G:A	G486E	0.997
20:37232302:T:C	F530L	0.997
20:37232304:C:A	F530L	0.997
20:37232304:C:G	F530L	0.997
20:37234020:T:A	W560R	0.997
20:37234020:T:C	W560R	0.997
20:37234086:G:A	G582R	0.997
20:37234086:G:C	G582R	0.997
20:37236654:G:C	G610R	0.997
20:37225802:G:C	Q433H	0.996
20:37225802:G:T	Q433H	0.996
20:37228595:T:C	F449L	0.996
20:37228597:T:A	F449L	0.996
20:37228597:T:G	F449L	0.996

dbSNP variants (sampled 300 via entrez): RS1000016490 (20:37227746 T>A,C), RS1000030106 (20:37234748 A>G,T), RS1000078970 (20:37192459 C>G), RS1000235443 (20:37179254 C>A,T), RS1000236045 (20:37208369 C>T), RS1000263920 (20:37208524 T>C,G), RS1000283913 (20:37211467 CA>C), RS1000328675 (20:37198991 G>A), RS1000361617 (20:37205469 G>A), RS1000394261 (20:37205266 G>A), RS1000437805 (20:37214376 C>G,T), RS1000474134 (20:37180838 C>T), RS1000496038 (20:37191237 G>A), RS1000552526 (20:37234855 A>AT), RS1000553011 (20:37223744 A>G)

Disease associations

OMIM: gene MIM:180490 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): congenital disorder of glycosylation (MONDO:0015286)

Orphanet (1): Congenital disorder of glycosylation (Orphanet:137)

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000461_10	Hippocampal atrophy	6.000000e-06
GCST005026_14	Initial pursuit acceleration in psychotic disorders	2.000000e-08
GCST008839_36	Height	6.000000e-23
GCST90000025_648	Appendicular lean mass	2.000000e-21
GCST90014243_5	Kawasaki disease	3.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005039	hippocampal atrophy
EFO:0008434	initial pursuit acceleration
EFO:0004980	appendicular lean mass

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D018981	Congenital Disorders of Glycosylation	C16.320.565.202.125; C18.452.648.202.125

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725139 (SINGLE PROTEIN)

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.22	Kd	60.29	nM	CHEMBL5653589
7.22	ED50	60.29	nM	CHEMBL5653589
6.06	Kd	873.7	nM	CHEMBL3752910
6.06	ED50	873.7	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 10 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149281: Binding affinity to human RPN2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0603	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149281: Binding affinity to human RPN2 incubated for 45 mins by Kinobead based pull down assay	kd	0.8737	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	3
Valproic Acid	decreases methylation, increases expression	3
Cyclosporine	increases expression	2
bisphenol F	increases expression	1
2,4,6-tribromophenol	decreases expression	1
decabromobiphenyl ether	decreases expression	1
sodium arsenite	affects cotreatment, increases expression	1
tetrabromobisphenol A	decreases expression	1
abrine	decreases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol AF	increases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	increases expression	1
Catechin	affects cotreatment, decreases expression	1
Clozapine	decreases expression	1
Dimethyl Sulfoxide	increases expression	1
Diuron	decreases expression	1
Doxorubicin	increases expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Lead	decreases expression	1
Phenobarbital	affects expression	1
Ribonucleotides	affects binding	1
T-2 Toxin	decreases expression	1
Testosterone	decreases expression	1
Tobacco Smoke Pollution	increases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652323	Binding	Binding affinity to human RPN2 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

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07572825	PHASE1	NOT_YET_RECRUITING	Assessing the Safety and Tolerability of NMN in DHDDS-CDG
NCT02089789	Not specified	RECRUITING	Clinical and Basic Investigations Into Known and Suspected Congenital Disorders of Glycosylation
NCT02503267	Not specified	UNKNOWN	Incidence and Consequences of Disorders of Glycosylation in Patients With Conotruncal and Septal Heart Defects
NCT02955264	Not specified	COMPLETED	Using D-Galactose as a Food Supplement in Congenital Disorders of Glycosylation
NCT03250728	Not specified	COMPLETED	Role of the Endothelium in Stroke-like Episode Among CDG Patients
NCT03560570	Not specified	COMPLETED	Study of Hemostasis in Patients With Congenital Disorder of Glycosylation
NCT04198987	Not specified	COMPLETED	Dietary Monosaccharide Supplementation in Patients With Congenital Disorders of Glycosylation
NCT04199000	Not specified	RECRUITING	Clinical and Basic Investigations Into Congenital Disorders of Glycosylation
NCT04201067	Not specified	COMPLETED	Large-Scale Metabolomic Profiling for the Diagnosis of Inborn Errors of Metabolism