RPN1

Summary

RPN1 (ribophorin I, HGNC:10381) is a protein-coding gene on chromosome 3q21.3, encoding Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit 1 (P04843). 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 97.9% 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 forms part of the regulatory subunit of the 26S proteasome and may mediate binding of ubiquitin-like domains to this proteasome.

Source: NCBI Gene 6184 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 97 total — 1 pathogenic
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 97.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_002950

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10381
Approved symbol	RPN1
Name	ribophorin I
Location	3q21.3
Locus type	gene with protein product
Status	Approved
Aliases	OST1
Ensembl gene	ENSG00000163902
Ensembl biotype	protein_coding
OMIM	180470
Entrez	6184

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 12 protein_coding, 4 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000296255, ENST00000476931, ENST00000479113, ENST00000481168, ENST00000490166, ENST00000495462, ENST00000497289, ENST00000497415, ENST00000874292, ENST00000874293, ENST00000874294, ENST00000874295, ENST00000874296, ENST00000916581, ENST00000916582, ENST00000916583, ENST00000916584, ENST00000955675

RefSeq mRNA: 1 — MANE Select: NM_002950 NM_002950

CCDS: CCDS3051

Canonical transcript exons

ENST00000296255 — 10 exons

Exon	Start	End
ENSE00001195724	128619969	128620593
ENSE00001252349	128626733	128626832
ENSE00001252367	128622164	128622409
ENSE00001252373	128625534	128625653
ENSE00001252381	128625874	128626012
ENSE00001252394	128629951	128630143
ENSE00001252422	128650540	128650818
ENSE00002396618	128631948	128632157
ENSE00003635918	128644919	128644983
ENSE00003657174	128637799	128638105

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.25.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 254.5925 / max 1821.6061, expressed in 1828 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
44461	254.5925	1828

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	99.25	gold quality
corpus epididymis	UBERON:0004359	99.01	gold quality
rectum	UBERON:0001052	98.24	gold quality
upper lobe of left lung	UBERON:0008952	98.12	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.10	gold quality
upper lobe of lung	UBERON:0008948	98.05	gold quality
right lung	UBERON:0002167	97.98	gold quality
right lobe of thyroid gland	UBERON:0001119	97.94	gold quality
islet of Langerhans	UBERON:0000006	97.93	gold quality
gall bladder	UBERON:0002110	97.92	gold quality
body of pancreas	UBERON:0001150	97.81	gold quality
left lobe of thyroid gland	UBERON:0001120	97.75	gold quality
smooth muscle tissue	UBERON:0001135	97.69	gold quality
adrenal tissue	UBERON:0018303	97.59	gold quality
thyroid gland	UBERON:0002046	97.55	gold quality
caput epididymis	UBERON:0004358	97.55	gold quality
monocyte	CL:0000576	97.53	gold quality
pericardium	UBERON:0002407	97.47	gold quality
adenohypophysis	UBERON:0002196	97.43	gold quality
mucosa of transverse colon	UBERON:0004991	97.42	gold quality
leukocyte	CL:0000738	97.39	gold quality
mononuclear cell	CL:0000842	97.33	gold quality
granulocyte	CL:0000094	97.30	gold quality
left uterine tube	UBERON:0001303	97.24	gold quality
endocervix	UBERON:0000458	97.23	gold quality
bone marrow cell	CL:0002092	97.21	gold quality
saliva-secreting gland	UBERON:0001044	97.13	gold quality
minor salivary gland	UBERON:0001830	97.11	gold quality
omental fat pad	UBERON:0010414	97.09	gold quality
pituitary gland	UBERON:0000007	97.08	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-88	yes	83.64
E-MTAB-9467	yes	49.26
E-HCAD-4	yes	40.10
E-CURD-122	yes	39.65
E-CURD-46	yes	33.31
E-MTAB-9067	yes	14.57
E-HCAD-1	yes	11.15
E-MTAB-9543	yes	10.73
E-MTAB-8060	no	272.01
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

21 targeting RPN1, 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-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-1236-3P	99.94	68.04	1695
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-6126	99.62	68.09	996
HSA-MIR-377-3P	99.37	70.18	1905
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-3154	98.94	66.55	1455
HSA-MIR-4763-5P	98.75	63.89	854
HSA-MIR-3945	98.68	64.21	553
HSA-MIR-3929	98.32	65.58	1026
HSA-MIR-375-3P	97.91	65.12	483
HSA-MIR-7703	97.64	67.00	965
HSA-MIR-342-3P	96.44	67.48	1344
HSA-MIR-4761-3P	96.27	66.26	524

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 97.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 5)

• ribophorin I can regulate the delivery of precursor proteins to the OST complex by capturing substrates and presenting them to the catalytic core. (PMID:18607003)
• Data indicate that malectin functions by forming a complex with ribophorin I. (PMID:22988243)
• These results clearly demonstrate that the association of malectin with ribophorin I is required to capture misfolded alpha1-antitrypsin and direct them to the degradation pathway. (PMID:25451265)
• Study provides evidence that Rpn1-Ser361 is a prevalent phosphosite that is required for proper assembly and activity of the 26S proteasome and identified multiple kinases, including PIM1/2/3, that can phosphorylate Rpn1-S361 and have demonstrated that UBLCP1 is a physiologically relevant phosphatase of this site. Blocking phosphorylation of Rpn1-S361 leads to slowed proliferation and mitochondrial dysfunction. (PMID:31843888)
• Polyubiquitin and ubiquitin-like signals share common recognition sites on proteasomal subunit Rpn1. (PMID:33617881)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rpn1	ENSDARG00000059323
mus_musculus	Rpn1	ENSMUSG00000030062
rattus_norvegicus	Rpn1	ENSRNOG00000046345
drosophila_melanogaster	CG33303	FBGN0053303
caenorhabditis_elegans		WBGENE00020683

Protein

Protein identifiers

Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit 1 — P04843 (reviewed: P04843)

Alternative names: Dolichyl-diphosphooligosaccharide–protein glycosyltransferase 67 kDa subunit, Ribophorin I, Ribophorin-1

All UniProt accessions (3): B7Z4L4, P04843, F8WF32

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 TMEM35A/NACHO.

Subcellular location. Endoplasmic reticulum membrane. Melanosome.

Tissue specificity. Expressed in all tissues tested.

Post-translational modifications. Ubiquitinated by the ECS(ASB11) complex. Ubiquitinated by RNF128, leading to degradation in a proteasome/lysosome-dependent manner. Ufmylated by UFL1 in response to endoplasmic reticulum stress, promoting reticulophagy of endoplasmic reticulum sheets.

Pathway. Protein modification; protein glycosylation.

Similarity. Belongs to the OST1 family.

RefSeq proteins (1): NP_002941* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007676	Ribophorin_I	Family

Pfam: PF04597

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 (57 total): strand 38, helix 9, topological domain 2, modified residue 2, signal peptide 1, chain 1, transmembrane region 1, turn 1, glycosylation site 1, cross-link 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-P04843-F1	90.67	0.78

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 (3): 187, 538, 538

Glycosylation sites (1): 299

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: 216 (showing top): YAGI_AML_WITH_INV_16_TRANSLOCATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_PROTEIN_N_LINKED_GLYCOSYLATION, ENK_UV_RESPONSE_KERATINOCYTE_UP, KEGG_N_GLYCAN_BIOSYNTHESIS, MORF_HDAC1, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, MORF_HDAC2, GHO_ATF5_TARGETS_DN, YY1_Q6, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, REACTOME_ADHERENS_JUNCTIONS_INTERACTIONS, MORF_CTBP1, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, MORF_PRKDC

GO Biological Process (3): protein N-linked glycosylation (GO:0006487), obsolete protein N-linked glycosylation via asparagine (GO:0018279), obsolete protein glycosylation (GO:0006486)

GO Molecular Function (4): RNA binding (GO:0003723), dolichyl-diphosphooligosaccharide-protein glycotransferase activity (GO:0004579), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (9): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), rough endoplasmic reticulum (GO:0005791), cytosol (GO:0005829), oligosaccharyltransferase complex (GO:0008250), membrane (GO:0016020), melanosome (GO:0042470), 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
cytoplasm	2
cellular anatomical structure	2
oligosaccharyltransferase complex	2
glycoprotein biosynthetic process	1
nucleic acid binding	1
oligosaccharyl transferase activity	1
binding	1
catalytic activity	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	1
endoplasmic reticulum membrane	1
membrane protein complex	1
endoplasmic reticulum protein-containing complex	1
transferase complex	1
pigment granule	1

Protein interactions and networks

STRING

2288 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RPN1	RPN2	P04844	999
RPN1	DAD1	P46966	999
RPN1	DDOST	P39656	999
RPN1	STT3A	P46977	993
RPN1	OST4	P0C6T2	992
RPN1	STT3B	Q8TCJ2	967
RPN1	MAGT1	Q9H0U3	834
RPN1	SEC61A1	P38378	824
RPN1	MLEC	Q14165	801
RPN1	TUSC3	Q13454	797
RPN1	ASB11	Q8WXH4	748
RPN1	KRTCAP2	Q8N6L1	734
RPN1	TMEM258	P61165	645
RPN1	MECOM	Q03112	642
RPN1	SEL1L	Q9UBV2	622

IntAct

342 interactions, top by confidence:

A	B	Type	Score
RPN1	SGTA	psi-mi:“MI:0915”(physical association)	0.780
SGTA	RPN1	psi-mi:“MI:0915”(physical association)	0.780
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
STT3B	RPN1	psi-mi:“MI:0915”(physical association)	0.690
RPN1	MLEC	psi-mi:“MI:0915”(physical association)	0.690
RPN1	STT3B	psi-mi:“MI:0915”(physical association)	0.690
MLEC	RPN1	psi-mi:“MI:0915”(physical association)	0.690
UBQLN1	RPN1	psi-mi:“MI:0915”(physical association)	0.670
RPN1	UBQLN1	psi-mi:“MI:0915”(physical association)	0.670
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
UBQLN1	RPN1	psi-mi:“MI:0915”(physical association)	0.560
RPN1	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
STT3A	RPN1	psi-mi:“MI:0915”(physical association)	0.560
RPN1	CAMLG	psi-mi:“MI:0915”(physical association)	0.560
KRTAP1-3	RPN1	psi-mi:“MI:0915”(physical association)	0.560
DDOST	RPN1	psi-mi:“MI:0915”(physical association)	0.560
ILK	HAX1	psi-mi:“MI:0914”(association)	0.530
RPN2	SMPD2	psi-mi:“MI:0914”(association)	0.530
DAD1	RPN1	psi-mi:“MI:0915”(physical association)	0.530

BioGRID (1197): SGTA (Two-hybrid), UBQLN1 (Two-hybrid), RPN1 (Co-localization), RPN1 (Affinity Capture-MS), RPN1 (Affinity Capture-MS), RPN1 (Affinity Capture-MS), RPN1 (Affinity Capture-MS), RPN1 (Affinity Capture-MS), RPN1 (Affinity Capture-MS), RPN1 (Affinity Capture-MS), RPN1 (Affinity Capture-MS), ATP5C1 (Co-fractionation), CANX (Co-fractionation), CCDC47 (Co-fractionation), CLGN (Co-fractionation)

ESM2 similar proteins: A5D8P8, A5PJA8, A6QLP7, A7E2Z9, A9SV59, B5DDX6, E2RQ08, F1QR43, F1R777, F4JVN6, O12940, O18756, O64614, O94923, P04843, P07153, P16967, P43307, P45433, P51571, P53815, Q04499, Q05AW9, Q07984, Q0IHY5, Q0J6P7, Q2M146, Q2TBX5, Q3UFM5, Q4R4T0, Q4R5V2, Q5R4X4, Q5REH6, Q5RFB6, Q5TYV0, Q5ZJT0, Q62186, Q6P7K5, Q7ZV50, Q8BXQ2

Diamond homologs: B9FDT1, E2RQ08, P04843, P07153, Q0DJC5, Q4R4T0, Q54C27, Q5RFB6, Q91YQ5, Q9GMB0, Q9GZH4, Q9SFX3, Q9ZUA0, P80896

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
RPN1	up-regulates	OPRM1	binding
ASB11	“down-regulates quantity by destabilization”	RPN1	polyubiquitination
RPN1	“form complex”	“OST-A complex”	binding
RPN1	“form complex”	“OST-B complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 194 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	5	18.5×	2e-03
Maturation of DENV proteins	8	12.1×	2e-04
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	5	12.0×	9e-03
Maturation of spike protein	6	11.4×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	55
Likely benign	1
Benign	4

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
831903	NC_000003.12:g.(?128480999)(128912627_?)del	Pathogenic

SpliceAI

1515 predictions. Top by Δscore:

Variant	Effect	Δscore
3:128620589:CTCAC:C	acceptor_gain	1.0000
3:128620590:TCAC:T	acceptor_gain	1.0000
3:128620591:CAC:C	acceptor_gain	1.0000
3:128620591:CACC:C	acceptor_gain	1.0000
3:128622160:TTACT:T	donor_loss	1.0000
3:128622161:TA:T	donor_loss	1.0000
3:128622162:A:AC	donor_gain	1.0000
3:128622162:ACT:A	donor_gain	1.0000
3:128622163:C:CT	donor_gain	1.0000
3:128622163:C:G	donor_loss	1.0000
3:128622163:CT:C	donor_gain	1.0000
3:128622163:CTC:C	donor_gain	1.0000
3:128622163:CTCT:C	donor_gain	1.0000
3:128622163:CTCTG:C	donor_gain	1.0000
3:128622221:A:AC	donor_gain	1.0000
3:128622222:C:CC	donor_gain	1.0000
3:128622405:GGATC:G	acceptor_gain	1.0000
3:128622406:GATC:G	acceptor_gain	1.0000
3:128622407:ATC:A	acceptor_gain	1.0000
3:128622408:TC:T	acceptor_gain	1.0000
3:128622409:CC:C	acceptor_gain	1.0000
3:128622410:C:CC	acceptor_gain	1.0000
3:128622410:CTG:C	acceptor_loss	1.0000
3:128625530:GTACC:G	donor_loss	1.0000
3:128625531:TACC:T	donor_loss	1.0000
3:128625532:ACCT:A	donor_loss	1.0000
3:128625649:TGGAC:T	acceptor_gain	1.0000
3:128625650:GGAC:G	acceptor_gain	1.0000
3:128625652:AC:A	acceptor_gain	1.0000
3:128625653:CC:C	acceptor_gain	1.0000

AlphaMissense

3966 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:128625935:C:T	G405D	1.000
3:128625944:T:A	D402V	1.000
3:128625945:C:G	D402H	1.000
3:128625947:A:G	L401P	1.000
3:128626817:A:G	L351P	1.000
3:128630009:C:A	W326C	1.000
3:128630009:C:G	W326C	1.000
3:128630011:A:G	W326R	1.000
3:128630011:A:T	W326R	1.000
3:128630027:G:C	F320L	1.000
3:128630027:G:T	F320L	1.000
3:128630028:A:C	F320C	1.000
3:128630029:A:G	F320L	1.000
3:128630094:C:A	G298V	1.000
3:128630094:C:T	G298D	1.000
3:128630095:C:G	G298R	1.000
3:128630103:T:A	D295V	1.000
3:128630103:T:G	D295A	1.000
3:128630104:C:G	D295H	1.000
3:128630106:C:G	R294P	1.000
3:128630124:G:T	A288D	1.000
3:128632008:G:C	F261L	1.000
3:128632008:G:T	F261L	1.000
3:128632009:A:C	F261C	1.000
3:128632010:A:G	F261L	1.000
3:128632074:C:A	W239C	1.000
3:128632074:C:G	W239C	1.000
3:128632076:A:G	W239R	1.000
3:128632076:A:T	W239R	1.000
3:128632096:C:G	R232P	1.000

dbSNP variants (sampled 300 via entrez): RS1000006510 (3:128652466 A>G), RS1000061350 (3:128635005 C>T), RS1000073195 (3:128650850 C>G,T), RS1000113445 (3:128635279 G>A), RS1000226161 (3:128632254 C>A,G,T), RS1000413325 (3:128641041 A>C), RS1000559851 (3:128630276 C>A), RS1000616332 (3:128638202 A>G), RS1000638439 (3:128636353 C>G), RS1000692172 (3:128642601 C>A,G), RS1000761330 (3:128641316 A>C), RS1000818395 (3:128644108 C>T), RS1000831554 (3:128620493 G>A), RS1000940872 (3:128620783 T>C), RS1001026675 (3:128649693 C>T)

Disease associations

OMIM: gene MIM:180470 | disease phenotypes: MIM:614038, MIM:614172

GenCC curated gene-disease

Mondo (3): deafness-lymphedema-leukemia syndrome (MONDO:0013540), monocytopenia with susceptibility to infections (MONDO:0013607), hereditary breast ovarian cancer syndrome (MONDO:0003582)

Orphanet (3): GATA2 deficiency spectrum (Orphanet:228423), Deafness-lymphedema-leukemia syndrome (Orphanet:3226), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295697 (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
7.41	Kd	38.76	nM	CHEMBL5653589
7.41	ED50	38.76	nM	CHEMBL5653589
6.89	Kd	129.8	nM	CHEMBL3752910
6.89	ED50	129.8	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 11 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	2149280: Binding affinity to human RPN1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0388	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149280: Binding affinity to human RPN1 incubated for 45 mins by Kinobead based pull down assay	kd	0.1298	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol F	increases expression, affects cotreatment	2
bisphenol A	affects expression, increases expression	2
Caffeine	decreases phosphorylation, increases expression	2
Estradiol	affects cotreatment, increases expression	2
Tunicamycin	increases expression	2
Cyclosporine	increases expression	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
titanium dioxide	decreases expression	1
pyrogallol 1,3-dimethyl ether	increases expression, affects cotreatment, affects localization	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
aflatoxin B2	decreases methylation	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Air Pollutants	increases abundance, affects expression	1
Aspirin	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases reaction, increases abundance, increases palmitoylation	1
Coumestrol	increases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Dexamethasone	affects cotreatment, increases expression	1
Bucladesine	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Folic Acid	decreases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118622	Binding	Binding affinity to RPN1 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02562170	PHASE4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT00673335	PHASE3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	PHASE3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	PHASE3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00253539	PHASE2	COMPLETED	Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer
NCT00305695	PHASE2	COMPLETED	Zoledronate or Observation in Maintaining Bone Mineral Density in Patients Who Are Undergoing Surgery to Remove Both Ovaries
NCT00321633	PHASE2	COMPLETED	Carboplatin or Docetaxel in Treating Women With Metastatic Genetic Breast Cancer
NCT01333748	PHASE2	COMPLETED	Search Allelic Imbalance of Expression of BRCA Genes in Hereditary Risk of Breast and/or Ovarian Cancer
NCT01367639	PHASE2	COMPLETED	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00535119	PHASE1	COMPLETED	Veliparib, Carboplatin, and Paclitaxel in Treating Patients With Advanced Solid Cancer
NCT00892736	PHASE1	COMPLETED	Veliparib in Treating Patients With Malignant Solid Tumors That Do Not Respond to Previous Therapy
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT03832985	EARLY_PHASE1	COMPLETED	Pediatric Reporting of Adult-Onset Genomic Results
NCT00005095	Not specified	RECRUITING	Specimen and Data Study for Ovarian Cancer Early Detection and Prevention
NCT00609505	Not specified	COMPLETED	Telemedicine vs. Face-to-Face Cancer Genetic Counseling
NCT01273909	Not specified	UNKNOWN	Outcomes After Perforator Flap Reconstruction for Breast Reconstruction and/or Lymphedema Treatment
NCT01445275	Not specified	WITHDRAWN	Cost of Cancer Risk Management in Women at Elevated Genetic Risk for Ovarian Cancer Who Participated on GOG-0199
NCT01608074	Not specified	ACTIVE_NOT_RECRUITING	Radical Fimbriectomy for Young BRCA Mutation Carriers
NCT02087592	Not specified	COMPLETED	Feasibility of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02302742	Not specified	RECRUITING	Triple Negative Breast Cancer and Germline Hereditary Breast and Ovarian Cancer Mutation Carrier Registry
NCT02324062	Not specified	COMPLETED	Cancer Genetics Hereditary Cancer Panel Testing
NCT02516540	Not specified	UNKNOWN	Efficacy of Lifestyle Intervention in BRCA1/2 Mutation Carriers
NCT02653105	Not specified	ACTIVE_NOT_RECRUITING	Women at Risk of Breast Cancer and OLFM4
NCT02705924	Not specified	TERMINATED	Impact of a Psychoeducational Intervention on Expectations and Coping in Young Women Exposed to a High HBOC Risk
NCT02760849	Not specified	ACTIVE_NOT_RECRUITING	Surgery in Preventing Ovarian Cancer in Patients With Genetic Mutations
NCT02786147	Not specified	COMPLETED	Identification and Referral of Women at Risk for Hereditary Breast/Ovarian Cancer
NCT02956681	Not specified	COMPLETED	Statewide Communication to Reach Diverse Low Income Women
NCT03015376	Not specified	UNKNOWN	Inherited Susceptible Genes Among Epithelial Ovarian Cancer
NCT03075540	Not specified	COMPLETED	Enhancing At-risk Latina Women’s Use of Genetic Counseling for Hereditary Breast and Ovarian Cancer
NCT03124212	Not specified	RECRUITING	Cascade Genetic Testing for Hereditary Breast/Ovarian Cancer and Lynch Syndrome in Switzerland
NCT03246841	Not specified	ACTIVE_NOT_RECRUITING	Investigation of Tumour Spectrum of Germline Mutations in Breast and Ovarian Cancer Genes.
NCT03294343	Not specified	UNKNOWN	Risk-Reducing Surgeries for Hereditary Ovarian Cancer
NCT03421327	Not specified	COMPLETED	Genetic Risk: Whether, When, and How to Tell Adolescents
NCT03510689	Not specified	COMPLETED	Genetics and Heart Health After Cancer Therapy
NCT03511690	Not specified	COMPLETED	Testing an Intelligent Tutoring System to Enhance Genetic Risk Assessment
NCT03784859	Not specified	COMPLETED	Tissue Expansion in Breast Reconstruction Without Drains
NCT03979612	Not specified	UNKNOWN	Evaluation of the Adhesion to the GENEPY Network
NCT04197856	Not specified	ACTIVE_NOT_RECRUITING	Direct Information to At-risk Relatives
NCT04407611	Not specified	COMPLETED	Scalable Communication Modalities for Returning Genetic Research Results
NCT04508764	Not specified	TERMINATED	Implementation of the Families Accelerating Cascade Testing Toolkit (FACTT) for Hereditary Breast and Ovarian Cancer and Lynch Syndrome