PSMD8

Summary

PSMD8 (proteasome 26S subunit, non-ATPase 8, HGNC:9566) is a protein-coding gene on chromosome 19q13.2, encoding 26S proteasome non-ATPase regulatory subunit 8 (P48556). Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. It is a selective cancer dependency (DepMap: 76.7% of cell lines).

The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a non-ATPase subunit of the 19S regulator. A pseudogene has been identified on chromosome 1.

Source: NCBI Gene 5714 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 54 total
• Druggable target: yes — 2 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 76.7% of screened cell lines
• MANE Select transcript: NM_002812

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9566
Approved symbol	PSMD8
Name	proteasome 26S subunit, non-ATPase 8
Location	19q13.2
Locus type	gene with protein product
Status	Approved
Aliases	S14, Nin1p, p31, HIP6, HYPF, Rpn12
Ensembl gene	ENSG00000099341
Ensembl biotype	protein_coding
OMIM	617844
Entrez	5714

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 9 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000215071, ENST00000585598, ENST00000590331, ENST00000591216, ENST00000591250, ENST00000592001, ENST00000592035, ENST00000592561, ENST00000602911, ENST00000700293, ENST00000700294, ENST00000700295, ENST00000700296, ENST00000700297

RefSeq mRNA: 1 — MANE Select: NM_002812 NM_002812

CCDS: CCDS12515

Canonical transcript exons

ENST00000215071 — 7 exons

Exon	Start	End
ENSE00000648417	38380899	38380999
ENSE00001057934	38383253	38383824
ENSE00002851445	38374571	38374961
ENSE00003527338	38376352	38376454
ENSE00003602688	38382117	38382228
ENSE00003661223	38376160	38376232
ENSE00003787051	38379240	38379405

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 99.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 254.0627 / max 1000.9024, expressed in 1828 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175623	250.2803	1828
175628	1.4778	910
175620	1.0197	470
175621	0.7244	413
175622	0.5463	289
175619	0.0141	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	99.15	gold quality
muscle of leg	UBERON:0001383	98.88	gold quality
apex of heart	UBERON:0002098	98.85	gold quality
right atrium auricular region	UBERON:0006631	98.81	gold quality
heart left ventricle	UBERON:0002084	98.78	gold quality
cardiac ventricle	UBERON:0002082	98.72	gold quality
cardiac atrium	UBERON:0002081	98.63	gold quality
stromal cell of endometrium	CL:0002255	98.60	gold quality
right testis	UBERON:0004534	98.57	gold quality
left testis	UBERON:0004533	98.56	gold quality
heart	UBERON:0000948	98.47	gold quality
skin of leg	UBERON:0001511	98.44	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.40	gold quality
muscle organ	UBERON:0001630	98.39	gold quality
islet of Langerhans	UBERON:0000006	98.38	gold quality
skin of abdomen	UBERON:0001416	98.35	gold quality
prefrontal cortex	UBERON:0000451	98.28	gold quality
endometrium epithelium	UBERON:0004811	98.22	gold quality
triceps brachii	UBERON:0001509	98.15	gold quality
omental fat pad	UBERON:0010414	98.11	gold quality
peritoneum	UBERON:0002358	98.10	gold quality
adult organism	UBERON:0007023	98.09	gold quality
adipose tissue of abdominal region	UBERON:0007808	98.09	gold quality
subcutaneous adipose tissue	UBERON:0002190	98.06	gold quality
smooth muscle tissue	UBERON:0001135	98.05	gold quality
zone of skin	UBERON:0000014	98.01	gold quality
adipose tissue	UBERON:0001013	97.97	gold quality
ascending aorta	UBERON:0001496	97.94	gold quality
thoracic aorta	UBERON:0001515	97.94	gold quality
right coronary artery	UBERON:0001625	97.94	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-93593	no	7.29
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): YY1

miRNA regulators (miRDB)

24 targeting PSMD8, 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-6499-3P	99.90	66.38	1212
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-202-5P	99.78	67.65	991
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-653-5P	99.46	67.35	1300
HSA-MIR-5580-5P	99.38	66.96	1139
HSA-MIR-4758-3P	99.12	63.96	869
HSA-MIR-4716-5P	98.82	68.57	1168
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-653-3P	98.31	67.71	1542
HSA-MIR-4443	98.02	66.25	1928
HSA-MIR-22-5P	97.67	68.92	1355
HSA-MIR-3189-5P	97.55	66.71	655
HSA-MIR-4482-5P	97.53	65.68	598
HSA-MIR-6890-3P	97.50	65.71	997
HSA-MIR-5699-5P	97.36	67.03	1014
HSA-MIR-6802-3P	97.29	65.42	613
HSA-MIR-3116	97.07	65.78	1324
HSA-MIR-2861	95.24	65.47	1056

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 76.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 2)

• These findings support the hypothesis that neurodegenerative disorders result primarily from a generic cell dysfunction caused by early misfolded species in the aggregation process. (PMID:16885229)
• PSMD8 can serve as potential biomarker and therapeutic target of the PSMD family in ovarian cancer: based on bioinformatics analysis and in vitro validation. (PMID:37349676)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	psmd8	ENSDARG00000020454
mus_musculus	Psmd8	ENSMUSG00000030591
rattus_norvegicus	Psmd8	ENSRNOG00000037580
drosophila_melanogaster	Rpn12	FBGN0028693
drosophila_melanogaster	Rpn12R	FBGN0036465
caenorhabditis_elegans		WBGENE00004468

Protein

Protein identifiers

26S proteasome non-ATPase regulatory subunit 8 — P48556 (reviewed: P48556)

Alternative names: 26S proteasome regulatory subunit RPN12, 26S proteasome regulatory subunit S14, p31

All UniProt accessions (11): P48556, A0A8V8TPK1, A0A8V8TQ44, A0A8V8TR48, K7EJC1, K7EJR3, K7EK21, K7ENY6, K7ERW6, R4GMR5, V9HW09

UniProt curated annotations — full annotation on UniProt →

Function. Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.

Subunit / interactions. Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD8, a base containing 6 ATPases and few additional components. Interacts with DDI2. Interacts with TASOR.

Similarity. Belongs to the proteasome subunit S14 family.

RefSeq proteins (1): NP_002803* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000717	PCI_dom	Domain
IPR006746	26S_Psome_Rpn12	Family
IPR033464	CSN8_PSD8_EIF3K	Domain

Pfam: PF10075

UniProt features (25 total): helix 15, strand 4, chain 1, domain 1, turn 1, region of interest 1, modified residue 1, cross-link 1

Structure

Experimental structures (PDB)

118 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9K53	ELECTRON MICROSCOPY	2.5
8USB	ELECTRON MICROSCOPY	2.73
9MBP	ELECTRON MICROSCOPY	2.75
9NKG	ELECTRON MICROSCOPY	2.8
9E8I	ELECTRON MICROSCOPY	2.87
9E8H	ELECTRON MICROSCOPY	2.9
9NKF	ELECTRON MICROSCOPY	2.9
9BV3	ELECTRON MICROSCOPY	2.9
9K4J	ELECTRON MICROSCOPY	2.9
9U3L	ELECTRON MICROSCOPY	2.91
9NKI	ELECTRON MICROSCOPY	2.94
6MSB	ELECTRON MICROSCOPY	3
7W37	ELECTRON MICROSCOPY	3
8CVT	ELECTRON MICROSCOPY	3
9E8G	ELECTRON MICROSCOPY	3.01
9MBQ	ELECTRON MICROSCOPY	3.08
7W38	ELECTRON MICROSCOPY	3.1
8USC	ELECTRON MICROSCOPY	3.1
9E8O	ELECTRON MICROSCOPY	3.1
9BV1	ELECTRON MICROSCOPY	3.1
9K4R	ELECTRON MICROSCOPY	3.1
9E8Q	ELECTRON MICROSCOPY	3.16
6MSD	ELECTRON MICROSCOPY	3.2
6MSK	ELECTRON MICROSCOPY	3.2
7W39	ELECTRON MICROSCOPY	3.2
7W3G	ELECTRON MICROSCOPY	3.2
7W3H	ELECTRON MICROSCOPY	3.2
9K4M	ELECTRON MICROSCOPY	3.2
9K4Y	ELECTRON MICROSCOPY	3.2
9K50	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48556-F1	65.77	0.05

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 (2): 106, 297

Function

Pathways and Gene Ontology

Reactome pathways

67 pathways

ID	Pathway
R-HSA-1169091	Activation of NF-kappaB in B cells
R-HSA-1234176	Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha
R-HSA-1236974	ER-Phagosome pathway
R-HSA-1236978	Cross-presentation of soluble exogenous antigens (endosomes)
R-HSA-174084	Autodegradation of Cdh1 by Cdh1:APC/C
R-HSA-174113	SCF-beta-TrCP mediated degradation of Emi1
R-HSA-174154	APC/C:Cdc20 mediated degradation of Securin
R-HSA-174178	APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1
R-HSA-174184	Cdc20:Phospho-APC/C mediated degradation of Cyclin A
R-HSA-180534	Vpu mediated degradation of CD4
R-HSA-180585	Vif-mediated degradation of APOBEC3G
R-HSA-187577	SCF(Skp2)-mediated degradation of p27/p21
R-HSA-195253	Degradation of beta-catenin by the destruction complex
R-HSA-202424	Downstream TCR signaling
R-HSA-211733	Regulation of activated PAK-2p34 by proteasome mediated degradation
R-HSA-2467813	Separation of Sister Chromatids
R-HSA-2871837	FCERI mediated NF-kB activation
R-HSA-349425	Autodegradation of the E3 ubiquitin ligase COP1
R-HSA-350562	Regulation of ornithine decarboxylase (ODC)
R-HSA-382556	ABC-family protein mediated transport
R-HSA-450408	AUF1 (hnRNP D0) binds and destabilizes mRNA
R-HSA-4608870	Asymmetric localization of PCP proteins
R-HSA-4641257	Degradation of AXIN
R-HSA-4641258	Degradation of DVL
R-HSA-5358346	Hedgehog ligand biogenesis
R-HSA-5362768	Hh mutants are degraded by ERAD
R-HSA-5607761	Dectin-1 mediated noncanonical NF-kB signaling
R-HSA-5607764	CLEC7A (Dectin-1) signaling
R-HSA-5610780	Degradation of GLI1 by the proteasome
R-HSA-5610783	Degradation of GLI2 by the proteasome

MSigDB gene sets: 381 (showing top): REACTOME_DNA_REPLICATION, REACTOME_SIGNALING_BY_NOTCH, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, REACTOME_APC_C_CDH1_MEDIATED_DEGRADATION_OF_CDC20_AND_OTHER_APC_C_CDH1_TARGETED_PROTEINS_IN_LATE_MITOSIS_EARLY_G1, REACTOME_INNATE_IMMUNE_SYSTEM, FAELT_B_CLL_WITH_VH_REARRANGEMENTS_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, KEGG_PROTEASOME, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, MODULE_151, ENK_UV_RESPONSE_KERATINOCYTE_UP

GO Biological Process (2): proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), proteolysis (GO:0006508)

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

GO Cellular Component (8): proteasome complex (GO:0000502), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), proteasome regulatory particle (GO:0005838), proteasome regulatory particle, lid subcomplex (GO:0008541), proteasome accessory complex (GO:0022624), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-18 pathways:

Category	Pathways
Antigen processing-Cross presentation	2
APC/C-mediated degradation of cell cycle proteins	2
Host Interactions of HIV factors	2
Downstream signaling events of B Cell Receptor (BCR)	1
Cellular response to hypoxia	1
Regulation of APC/C activators between G1/S and early anaphase	1
APC/C:Cdc20 mediated degradation of mitotic proteins	1
APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint	1
Cyclin E associated events during G1/S transition	1
Cyclin A:Cdk2-associated events at S phase entry	1
Signaling by WNT	1
TCR signaling	1
Regulation of Apoptosis	1
Mitotic Anaphase	1
Fc epsilon receptor (FCERI) signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein-containing complex	3
cellular anatomical structure	2
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
protein metabolic process	1
binding	1
intracellular protein-containing complex	1
endopeptidase complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
proteasome accessory complex	1
proteasome regulatory particle	1
proteasome complex	1
intracellular anatomical structure	1
cellular_component	1

Protein interactions and networks

STRING

3038 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PSMD8	PSMD12	O00232	997
PSMD8	PSMD14	O00487	997
PSMD8	PSMD3	O43242	997
PSMD8	PSMD13	Q9UNM6	997
PSMD8	PSMD11	O00231	996
PSMD8	PSMD6	Q15008	996
PSMD8	PSMD7	P51665	994
PSMD8	SEM1	Q6ZVN7	982
PSMD8	NOB1	Q9ULX3	966
PSMD8	ADRM1	Q16186	956
PSMD8	PSMD4	P55036	948
PSMD8	NINJ1	Q92982	939
PSMD8	UCHL5	Q9Y5K5	882
PSMD8	PSMD1	Q99460	874
PSMD8	PSMC4	P43686	872

IntAct

134 interactions, top by confidence:

A	B	Type	Score
UCHL5	PSMD11	psi-mi:“MI:0914”(association)	0.840
PSMD10	PSMD11	psi-mi:“MI:0914”(association)	0.800
PSMD13	PSMD11	psi-mi:“MI:0914”(association)	0.750
PSMD4	PSMD11	psi-mi:“MI:0914”(association)	0.750
PSMD7	PSMD11	psi-mi:“MI:0914”(association)	0.730
PSMD11	PSMD12	psi-mi:“MI:0915”(physical association)	0.730
PSMB2	PSMD11	psi-mi:“MI:0914”(association)	0.730
PSMD2	PSMD11	psi-mi:“MI:0914”(association)	0.730
PSMC5	PSMD11	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
PSMC4	PSMD11	psi-mi:“MI:0914”(association)	0.670
PSMD14	PSMD11	psi-mi:“MI:0914”(association)	0.650
PSMB3	PSMD11	psi-mi:“MI:0914”(association)	0.640
PSMD5	PSMD12	psi-mi:“MI:0914”(association)	0.640
	PMPCB	psi-mi:“MI:0914”(association)	0.640
ADRM1	PSMD11	psi-mi:“MI:0914”(association)	0.640
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
PSMD8	SHC3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (382): PSMD8 (Affinity Capture-MS), PSMD8 (Affinity Capture-Western), PSMD8 (Affinity Capture-MS), PSMD7 (Affinity Capture-MS), DVL2 (Affinity Capture-MS), PSMD8 (Affinity Capture-MS), PSMD8 (Affinity Capture-MS), PSMD8 (Affinity Capture-MS), PSMD8 (Affinity Capture-MS), PSMD8 (Affinity Capture-MS), PSMD8 (Affinity Capture-MS), HEATR1 (Co-fractionation), NLRP13 (Co-fractionation), PSMA1 (Co-fractionation), PSMA2 (Co-fractionation)

ESM2 similar proteins: A0JMA8, A1A5P5, A1YVX4, A2VDN5, A3KMI0, A4QP73, B7PXE3, D4A6D7, E7F187, O94513, P0C624, P41229, P41230, P48556, P50524, Q05AS3, Q14738, Q17DK2, Q28653, Q294E0, Q2KI89, Q38JA7, Q3SYT7, Q5F3R2, Q5RE15, Q5U245, Q5XUN4, Q5ZK92, Q6AZT2, Q6DKK2, Q6NW58, Q6PGC1, Q719N1, Q7Z3E5, Q7Z478, Q80Y84, Q8CC21, Q9BY66, Q9CX56, Q9D1P2

Diamond homologs: P02889, P32496, P48556, Q23449, Q3SYT7, Q5RE15, Q9CX56, Q9FHY0, Q9SGW3, P50524

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PSMD8	“form complex”	“26S Proteasome”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 109 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
Ubiquitin-dependent degradation of Cyclin D	17	62.7×	5e-25
Proteasome assembly	22	62.3×	1e-32
Regulation of activated PAK-2p34 by proteasome mediated degradation	16	61.9×	4e-24
Regulation of ornithine decarboxylase (ODC)	16	60.4×	6e-24
Cross-presentation of soluble exogenous antigens (endosomes)	17	59.9×	8e-25
Vpu mediated degradation of CD4	16	59.0×	8e-24
Autodegradation of the E3 ubiquitin ligase COP1	16	59.0×	8e-24
GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	17	58.6×	1e-24

GO biological processes:

GO term	Partners	Fold	FDR
proteasome-mediated ubiquitin-dependent protein catabolic process	24	13.5×	6e-18

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	40
Likely benign	2
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1292 predictions. Top by Δscore:

Variant	Effect	Δscore
19:38376228:GGCCC:G	donor_gain	1.0000
19:38376229:GCCC:G	donor_gain	1.0000
19:38376229:GCCCG:G	donor_gain	1.0000
19:38376233:G:GG	donor_gain	1.0000
19:38376347:CACAG:C	acceptor_loss	1.0000
19:38376350:A:AC	acceptor_loss	1.0000
19:38376350:A:AG	acceptor_gain	1.0000
19:38376350:AG:A	acceptor_gain	1.0000
19:38376350:AGGT:A	acceptor_gain	1.0000
19:38376351:G:GA	acceptor_gain	1.0000
19:38376351:GG:G	acceptor_gain	1.0000
19:38376351:GGT:G	acceptor_gain	1.0000
19:38376351:GGTG:G	acceptor_gain	1.0000
19:38376351:GGTGA:G	acceptor_gain	1.0000
19:38376450:TACAA:T	donor_gain	1.0000
19:38376452:CAA:C	donor_gain	1.0000
19:38376454:AG:A	donor_loss	1.0000
19:38376455:G:GG	donor_gain	1.0000
19:38379231:C:G	acceptor_gain	1.0000
19:38379235:CACA:C	acceptor_loss	1.0000
19:38379238:A:AG	acceptor_gain	1.0000
19:38379238:AG:A	acceptor_gain	1.0000
19:38379238:AGG:A	acceptor_gain	1.0000
19:38379239:G:A	acceptor_loss	1.0000
19:38379239:G:GT	acceptor_gain	1.0000
19:38379239:GG:G	acceptor_gain	1.0000
19:38379239:GGG:G	acceptor_gain	1.0000
19:38379239:GGGA:G	acceptor_gain	1.0000
19:38379358:GACA:G	donor_gain	1.0000
19:38379402:GCAA:G	donor_gain	1.0000

AlphaMissense

2262 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:38376361:T:C	L148P	1.000
19:38376369:G:T	G151W	1.000
19:38376370:G:A	G151E	1.000
19:38376373:C:A	A152D	1.000
19:38376408:T:C	F164L	1.000
19:38376410:C:A	F164L	1.000
19:38376410:C:G	F164L	1.000
19:38376429:C:T	L171F	1.000
19:38376430:T:A	L171H	1.000
19:38376430:T:C	L171P	1.000
19:38379280:G:C	G193R	1.000
19:38379281:G:A	G193D	1.000
19:38379281:G:T	G193V	1.000
19:38379284:T:C	L194P	1.000
19:38379290:T:C	L196P	1.000
19:38379293:T:C	L197P	1.000
19:38379299:T:C	L199P	1.000
19:38379302:T:A	L200Q	1.000
19:38379302:T:C	L200P	1.000
19:38379314:G:C	R204P	1.000
19:38379325:T:C	F208L	1.000
19:38379326:T:C	F208S	1.000
19:38379326:T:G	F208C	1.000
19:38379327:C:A	F208L	1.000
19:38379327:C:G	F208L	1.000
19:38379328:C:A	H209N	1.000
19:38379328:C:G	H209D	1.000
19:38379330:C:A	H209Q	1.000
19:38379330:C:G	H209Q	1.000
19:38379342:G:C	E213D	1.000

dbSNP variants (sampled 300 via entrez): RS1000158263 (19:38375171 A>G), RS1000594222 (19:38376479 T>C,G), RS1000758919 (19:38376681 G>A), RS1001307795 (19:38377163 C>T), RS1001683632 (19:38384158 T>C), RS1001795944 (19:38377713 T>C), RS1002040680 (19:38383901 C>A), RS1002315143 (19:38375831 C>T), RS1002326866 (19:38382035 G>A,T), RS1002920045 (19:38380776 A>G), RS1002992091 (19:38381096 G>C), RS1003840896 (19:38374729 G>A), RS1004212875 (19:38379146 C>A,G), RS1004243948 (19:38378859 A>G), RS1004679874 (19:38372939 C>A)

Disease associations

OMIM: gene MIM:617844 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010242_111	HDL cholesterol levels	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2364701 (PROTEIN COMPLEX), CHEMBL3831217 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

2 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 25,628 (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
CHEMBL325041	BORTEZOMIB	4	13,120
CHEMBL451887	CARFILZOMIB	4	12,508

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

ChEMBL bioactivities

66 potent at pChembl≥5 of 67 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.62	IC50	2.4	nM	BORTEZOMIB
8.59	IC50	2.56	nM	BORTEZOMIB
8.57	IC50	2.7	nM	CHEMBL3237863
8.47	IC50	3.4	nM	CHEMBL6143686
8.41	IC50	3.9	nM	CHEMBL3237862
8.39	IC50	4.1	nM	CHEMBL3237864
8.39	IC50	4.1	nM	CHEMBL3237867
8.32	IC50	4.8	nM	CHEMBL3237873
8.29	IC50	5.1	nM	CHEMBL3237865
8.24	IC50	5.7	nM	CHEMBL3237866
8.24	IC50	5.7	nM	CHEMBL3237860
8.23	IC50	5.9	nM	CHEMBL3237868
8.15	IC50	7	nM	BORTEZOMIB
8.15	IC50	7.1	nM	CHEMBL3237870
8.15	IC50	7.14	nM	BORTEZOMIB
8.12	IC50	7.5	nM	CHEMBL3237871
8.11	IC50	7.7	nM	CHEMBL3237874
8.11	IC50	7.8	nM	CHEMBL3237869
8.07	IC50	8.6	nM	CARFILZOMIB
7.54	IC50	29	nM	CHEMBL3237861
7.47	Kd	34.09	nM	CHEMBL5653589
7.47	ED50	34.09	nM	CHEMBL5653589
7.34	IC50	46	nM	CHEMBL3237867
7.27	IC50	54	nM	CHEMBL3237872
7.12	IC50	75	nM	CHEMBL3237865
7.12	IC50	76	nM	CHEMBL3237866
6.96	IC50	110	nM	CHEMBL3262766
6.92	IC50	120	nM	CHEMBL3237864
6.92	IC50	120	nM	BORTEZOMIB
6.89	IC50	130	nM	CHEMBL3237869
6.85	IC50	140	nM	CHEMBL3237862
6.82	IC50	150	nM	CHEMBL3237863
6.77	IC50	170	nM	CHEMBL3237873
6.77	IC50	170	nM	CHEMBL3262765
6.72	IC50	190	nM	CHEMBL3262758
6.68	IC50	210	nM	CHEMBL3237870
6.66	IC50	220	nM	CHEMBL3262756
6.60	IC50	250	nM	CHEMBL3237868
6.47	IC50	340	nM	CHEMBL3262752
6.47	IC50	340	nM	CHEMBL3262755
6.44	IC50	360	nM	CHEMBL3262757
6.42	IC50	380	nM	CHEMBL3262754
6.36	IC50	440	nM	CHEMBL3262753
6.30	IC50	500	nM	CHEMBL3237872
6.20	IC50	630	nM	CHEMBL3262762
6.02	IC50	950	nM	CHEMBL3262761
6.00	IC50	1000	nM	CHEMBL3237871
5.96	IC50	1100	nM	CHEMBL3237862
5.85	IC50	1400	nM	BELACTOSIN A
5.84	IC50	1440	nM	BELACTOSIN A

PubChem BioAssay actives

62 with measured affinity, of 137 total; 34 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
Bortezomib	1985684: Inhibition of 26S proteasome (unknown origin)	ic50	0.0024	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0027	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[3-phenylmethoxy-2-(phenylmethoxymethyl)propyl]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0039	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[5-phenylmethoxy-4-(phenylmethoxymethyl)pentyl]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0041	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[5-phenylmethoxy-4-(phenylmethoxymethyl)pentyl]pentanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0041	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-(4-phenylmethoxybutyl)butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0048	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[3-phenylmethoxy-2-(phenylmethoxymethyl)propyl]pentanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0051	uM
(2S)-2-acetamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]pentanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0057	uM
benzyl N-[(2S)-1-[[(2R)-1-[(1R,2S)-2-[[(2R,3S)-3-[(2S)-butan-2-yl]-4-oxooxetane-2-carbonyl]amino]cyclopropyl]-4-phenylbutan-2-yl]amino]-1-oxopropan-2-yl]carbamate	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0057	uM
(2S)-2-[(2,5-dichlorobenzoyl)amino]-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0059	uM
(2S)-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]-2-(pyrazine-2-carbonylamino)butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0071	uM
(2S)-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]-2-[(6-phenylpyridine-2-carbonyl)amino]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0075	uM
[(1R)-1-[[(2S)-2-acetamido-4-oxo-4-[[3-phenylmethoxy-2-(phenylmethoxymethyl)propyl]amino]butanoyl]amino]-3-methylbutyl]boronic acid	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0077	uM
(2S)-2-benzamido-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]-N’-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0078	uM
Carfilzomib	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.0086	uM
(2R,3S)-3-[(2S)-butan-2-yl]-4-oxo-N-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]oxetane-2-carboxamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0290	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149131: Binding affinity to human PSMD8 incubated for 45 mins by Kinobead based pull down assay	kd	0.0341	uM
(2S)-2-acetamido-N’-methyl-N-[(1R)-3-methyl-1-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.02,6]decan-4-yl]butyl]butanediamide	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	0.0540	uM
N-[(1R)-3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]naphthalene-2-carboxamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.1100	uM
N-[(1R)-3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]-4-(trifluoromethyl)benzamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.1700	uM
N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]naphthalene-2-carboxamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.1900	uM
N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]-4-(trifluoromethyl)benzamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.2200	uM
N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]pyridine-3-carboxamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.3400	uM
4-methoxy-N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]benzamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.3400	uM
4-cyano-N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]benzamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.3600	uM
4-fluoro-N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]benzamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.3800	uM
N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]benzamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.4400	uM
N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]oxane-4-carboxamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.6300	uM
N-[3-[[(2S)-1-[[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-oxo-1-phenylpropyl]thiophene-2-carboxamide	1141825: Inhibition of chymotrypsin-like enzyme activity of purified human 20S proteasome using Suc-Leu-Leu-Val-Tyr-AMC as substrate by fluorescence method	ic50	0.9500	uM
(2S)-2-[[(2S)-2-aminopropanoyl]amino]-3-[(1S,2S)-2-[[(2R,3S)-3-[(2S)-butan-2-yl]-4-oxooxetane-2-carbonyl]amino]cyclopropyl]propanoic acid	1128229: Inhibition of chymotrypsin-like activity of human 20S proteasome using Suc-LLVY-AMC as substrate	ic50	1.4000	uM
(2S)-2-acetamido-N-[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]-N’-[4-phenylmethoxy-3-(phenylmethoxymethyl)butyl]butanediamide	1152964: Inhibition of chymotrypsin-like of human 20S proteasome using chromophoric Suc-LLVY-AMC as substrate after 60 mins by fluorescence assay	ic50	2.3000	uM
N-[3-(2-oxo-1,3,4-oxathiazol-5-yl)phenyl]acetamide	1137840: Inhibition of chymotrypsin-like activity of 26S proteasome in intact human Karpas 1106p cells assessed as substrate hydrolysis using Suc-LLVY-(D)-aminoluciferin as substrate after 3 hrs by cell-based Proteasome-Glo assay	ec50	4.2000	uM
(2S)-2-acetamido-N-[(2S)-4-methyl-1-[(2R)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]-N’-(4-phenylmethoxybutyl)butanediamide	1152964: Inhibition of chymotrypsin-like of human 20S proteasome using chromophoric Suc-LLVY-AMC as substrate after 60 mins by fluorescence assay	ic50	5.7000	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149131: Binding affinity to human PSMD8 incubated for 45 mins by Kinobead based pull down assay	kd	8.8986	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	3
sodium arsenite	increases expression	2
Arsenic	affects methylation, decreases expression, increases abundance	2
Dronabinol	decreases expression	2
Aflatoxin B1	increases expression, increases methylation	2
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
sodium arsenate	decreases expression	1
salinomycin	decreases expression	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
cobaltous chloride	increases expression	1
tetrabromobisphenol A	decreases expression	1
ochratoxin A	increases expression	1
arsenic trichloride	decreases expression, increases abundance	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases expression	1
CGP 52608	affects binding, increases reaction	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	increases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants, Occupational	affects expression	1
Vehicle Emissions	increases expression	1
Benzo(a)pyrene	affects methylation	1

ChEMBL screening assays

27 unique, capped per target: 27 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3222879	Binding	Inhibition of human 20S proteasome using Suc-LLVY-AMC as substrate preincubated for 30 mins followed by substrate addition measured after 90 mins by fluorescence assay	Oxathiazole-2-one derivative of bortezomib: Synthesis, stability and proteasome inhibition activity — Medchemcomm

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3F5	Abcam HEK293T PSMD8 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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