PSMC2

Summary

PSMC2 (proteasome 26S subunit, ATPase 2, HGNC:9548) is a protein-coding gene on chromosome 7q22.1, encoding 26S proteasome regulatory subunit 7 (P35998). Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. It is a common-essential gene (DepMap: required in 99.5% of cancer 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 one of the ATPase subunits, a member of the triple-A family of ATPases which have a chaperone-like activity. This subunit has been shown to interact with several of the basal transcription factors so, in addition to participation in proteasome functions, this subunit may participate in the regulation of transcription. This subunit may also compete with PSMC3 for binding to the HIV tat protein to regulate the interaction between the viral protein and the transcription complex. Alternative splicing results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 5701 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 39 total — 1 pathogenic
• Regional missense constraint (gnomAD): 3 of 6 regions constrained (≈34% of expected missense variation)
• GTEx eGene: eQTL in 7 tissues, sQTL in 0 (q < 0.05)
• ChEMBL bioactivity: 2 clinical-phase molecules tested; no curated mechanism-of-action drug
• Cancer dependency (DepMap): dependent in 99.5% of screened cell lines (common-essential)
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.27 (highly constrained)
• MANE Select transcript: NM_002803
• Interaction hub: 2,998 STRING partners (top 2% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9548
Approved symbol	PSMC2
Name	proteasome 26S subunit, ATPase 2
Location	7q22.1
Locus type	gene with protein product
Status	Approved
Aliases	MSS1, S7, Nbla10058, RPT1
Ensembl gene	ENSG00000161057
Ensembl biotype	protein_coding
OMIM	154365
Entrez	5701

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 12 protein_coding, 7 retained_intron, 3 nonsense_mediated_decay

MANE Select: ENST00000292644

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1, TSL 2: 1, TSL 3: 2, TSL 5: 1

ENST00000292644, ENST00000425206, ENST00000435765, ENST00000457587, ENST00000460021, ENST00000676908, ENST00000677281, ENST00000677769, ENST00000677943, ENST00000678488, ENST00000678493, ENST00000678587, ENST00000679046, ENST00000679205, ENST00000679250, ENST00000679341, ENST00000864378, ENST00000915465, ENST00001059011, ENST00001059012, ENST00001059013, ENST00001134092

RefSeq mRNA: 2 — MANE Select: NM_002803 NM_001204453, NM_002803

CCDS: CCDS5731

Canonical transcript exons

ENST00000292644 — 12 exons

Exon	Start	End
ENSE00002250553	103347643	103347781
ENSE00003578476	103355694	103355793
ENSE00003620849	103354868	103354949
ENSE00003889056	103362686	103362758
ENSE00003889309	103367413	103367615
ENSE00003890230	103363344	103363439
ENSE00003890548	103366076	103366163
ENSE00003891044	103367713	103367809
ENSE00003891061	103353921	103353958
ENSE00003892422	103364143	103364307
ENSE00003893359	103367897	103369395
ENSE00003895330	103361957	103362088

Expression profiles

Bgee: expression breadth ubiquitous, 302 present calls, max score 98.86.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 93.4468 / max 2038.7012, expressed in 1826 samples.

Highest expression (Bgee): skeletal muscle tissue of biceps brachii, biceps brachii, esophagus squamous epithelium, epithelium of nasopharynx, nasopharynx.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PSMC2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 7 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

7 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	eqtl	1.3e-11	-0.22	7:103344764:C:G
Brain Cerebellar Hemisphere	eqtl	4.9e-03	-0.16	7:103444323:G:A
Breast Mammary Tissue	eqtl	7.3e-03	+0.32	7:103520319:T:C
Thyroid	eqtl	2.9e-02	-0.16	7:104165002:A:G
Esophagus Muscularis	eqtl	3.9e-02	+0.11	7:104131538:T:C
Adipose Subcutaneous	eqtl	4.6e-02	-0.13	7:104243733:T:C
Artery Tibial	eqtl	4.8e-02	+0.06	7:103202553:C:A

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
80283	91.5520	1825
80284	1.8948	1202

Top tissues by expression

showing 100 of 302 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.86	gold quality
biceps brachii	UBERON:0001507	98.78	gold quality
esophagus squamous epithelium	UBERON:0006920	98.78	gold quality
epithelium of nasopharynx	UBERON:0001951	98.70	gold quality
nasopharynx	UBERON:0001728	98.69	gold quality
sperm	CL:0000019	98.60	gold quality
gingival epithelium	UBERON:0001949	98.58	gold quality
gingiva	UBERON:0001828	98.45	gold quality
palpebral conjunctiva	UBERON:0001812	98.39	gold quality
visceral pleura	UBERON:0002401	98.39	gold quality
skin of hip	UBERON:0001554	98.36	gold quality
parietal pleura	UBERON:0002400	98.31	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.31	gold quality
tibia	UBERON:0000979	98.29	gold quality
male germ cell	CL:0000015	98.27	gold quality
pleura	UBERON:0000977	98.27	gold quality
trabecular bone tissue	UBERON:0002483	98.16	gold quality
oral cavity	UBERON:0000167	98.15	gold quality
epithelium of esophagus	UBERON:0001976	98.13	gold quality
diaphragm	UBERON:0001103	98.08	gold quality
eye	UBERON:0000970	98.07	gold quality
heart right ventricle	UBERON:0002080	98.07	gold quality
amniotic fluid	UBERON:0000173	98.06	gold quality
germinal epithelium of ovary	UBERON:0001304	98.06	gold quality
penis	UBERON:0000989	97.96	gold quality
upper leg skin	UBERON:0004262	97.93	gold quality
triceps brachii	UBERON:0001509	97.75	gold quality
mammalian vulva	UBERON:0000997	97.71	gold quality
squamous epithelium	UBERON:0006914	97.68	gold quality
corpus epididymis	UBERON:0004359	97.64	gold quality
cauda epididymis	UBERON:0004360	97.63	gold quality
adult organism	UBERON:0007023	97.63	gold quality
gluteal muscle	UBERON:0002000	97.61	gold quality
bronchial epithelial cell	CL:0002328	97.55	gold quality
synovial joint	UBERON:0002217	97.48	gold quality
hair follicle	UBERON:0002073	97.46	gold quality
body of tongue	UBERON:0011876	97.46	gold quality
tongue squamous epithelium	UBERON:0006919	97.43	gold quality
pons	UBERON:0000988	97.35	gold quality
jejunum	UBERON:0002115	97.35	gold quality
caput epididymis	UBERON:0004358	97.34	gold quality
tendon of biceps brachii	UBERON:0008188	97.33	gold quality
middle temporal gyrus	UBERON:0002771	97.29	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.21	gold quality
decidua	UBERON:0002450	97.20	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.19	gold quality
seminal vesicle	UBERON:0000998	97.04	gold quality
jejunal mucosa	UBERON:0000399	96.99	gold quality
blood vessel layer	UBERON:0004797	96.98	gold quality
pigmented layer of retina	UBERON:0001782	96.96	gold quality
retina	UBERON:0000966	96.93	gold quality
pharyngeal mucosa	UBERON:0000355	96.92	gold quality
tongue	UBERON:0001723	96.84	gold quality
type B pancreatic cell	CL:0000169	96.77	gold quality
epithelium of bronchus	UBERON:0002031	96.66	gold quality
bronchus	UBERON:0002185	96.60	gold quality
renal glomerulus	UBERON:0000074	96.59	gold quality
superficial temporal artery	UBERON:0001614	96.56	gold quality
colonic mucosa	UBERON:0000317	96.49	gold quality
nephron tubule	UBERON:0001231	96.48	gold quality
trigeminal ganglion	UBERON:0001675	96.35	gold quality
metanephric glomerulus	UBERON:0004736	96.34	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.25	gold quality
superior surface of tongue	UBERON:0007371	96.21	gold quality
gastrocnemius	UBERON:0001388	96.19	gold quality
tendon	UBERON:0000043	96.17	gold quality
pericardium	UBERON:0002407	96.10	gold quality
muscle of leg	UBERON:0001383	96.07	gold quality
endometrium epithelium	UBERON:0004811	95.97	gold quality
subthalamic nucleus	UBERON:0001906	95.93	gold quality
muscle organ	UBERON:0001630	95.92	gold quality
skeletal muscle organ	UBERON:0014892	95.92	gold quality
inferior olivary complex	UBERON:0002127	95.89	gold quality
lateral globus pallidus	UBERON:0002476	95.89	gold quality
superior vestibular nucleus	UBERON:0007227	95.89	gold quality
inferior vagus X ganglion	UBERON:0005363	95.86	gold quality
vastus lateralis	UBERON:0001379	95.83	gold quality
mucosa of paranasal sinus	UBERON:0005030	95.83	gold quality
globus pallidus	UBERON:0001875	95.79	gold quality
medial globus pallidus	UBERON:0002477	95.79	gold quality
urethra	UBERON:0000057	95.77	gold quality
islet of Langerhans	UBERON:0000006	95.73	gold quality
dorsal root ganglion	UBERON:0000044	95.73	gold quality
secondary oocyte	CL:0000655	95.69	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.67	gold quality
adrenal tissue	UBERON:0018303	95.67	gold quality
skeletal muscle tissue	UBERON:0001134	95.66	gold quality
placenta	UBERON:0001987	95.63	gold quality
medulla oblongata	UBERON:0001896	95.60	gold quality
choroid plexus epithelium	UBERON:0003911	95.56	gold quality
lower lobe of lung	UBERON:0008949	95.56	gold quality
parotid gland	UBERON:0001831	95.51	gold quality
dorsal plus ventral thalamus	UBERON:0001897	95.50	gold quality
calcaneal tendon	UBERON:0003701	95.42	gold quality
postcentral gyrus	UBERON:0002581	95.25	gold quality
bone marrow	UBERON:0002371	95.18	gold quality
cardia of stomach	UBERON:0001162	95.17	gold quality
pylorus	UBERON:0001166	95.09	gold quality
quadriceps femoris	UBERON:0001377	95.04	gold quality
saphenous vein	UBERON:0007318	95.04	gold quality

Single-cell (SCXA)

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

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

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Caudate putamen	tissue	118.2
Frontal cortex	tissue	117.6
Skeletal muscle	tissue	81.7	high
Pons	tissue	71.8
Tongue	tissue	71.8
Superior colliculi	tissue	66.3
Spinal cord	tissue	65.2
Thalamus	tissue	65.0
Medulla oblongata	tissue	60.7
Cerebral cortex	tissue	59.5	high
Somatosensory cortex	tissue	59.5
Midbrain	tissue	58.5
Putamen	tissue	56.4
Occipital cortex	tissue	56.3
Substantia nigra	tissue	54.3
Liver	tissue	50.7	medium
Motor cortex	tissue	50.6
Prefrontal cortex	tissue	49.0
Periaqueductal gray	tissue	48.4
Hippocampal formation	tissue	48.2
Entorhinal cortex	tissue	48.2
Hypothalamus	tissue	47.4
Retrosplenial and cingulate cortex	tissue	47.1
Basal ganglia	tissue	46.6	high
Septum	tissue	46.4
Temporal cortex	tissue	45.7
Ventral forebrain	tissue	44.6
Retrosplenial cortex	tissue	42.4
Cerebellum	tissue	40.8	high
Thymus	tissue	39.5
Insular cortex	tissue	38.9
Parathyroid gland	tissue	38.8	medium
Kidney	tissue	37.2	high
Amygdala	tissue	34.7
Olfactory bulb	tissue	34.7
Corpus callosum	tissue	34.4
Heart muscle	tissue	33.6	high
Adipose tissue	tissue	32.0	high
Urinary bladder	tissue	32.0	medium
Adrenal gland	tissue	31.7	high
Tonsil	tissue	31.4	high
Choroid plexus	tissue	30.5
Bone marrow	tissue	30.1	medium
Appendix	tissue	29.9	medium
Placenta	tissue	29.0	high
Postcentral gyrus	tissue	28.4
Stomach 1	tissue	27.8	high
Lymph node	tissue	27.7	high
Smooth muscle	tissue	27.6	high
Thyroid gland	tissue	27.3	medium
Ovary	tissue	27.2	medium
Epididymis	tissue	26.2	medium
Skin 1	tissue	26.1	high
Esophagus	tissue	25.6	high
Prostate	tissue	25.5	medium
Seminal vesicle	tissue	24.9	medium
Cervix	tissue	24.6	high
Colon	tissue	24.6	medium
Nucleus accumbens	tissue	24.4
Locus coeruleus	tissue	24.4

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Ventral spinal cord (65.2), Dorsal spinal cord (51.5), Dorsal hippocampus (46.2), Subiculum (44.4), Ventral hippocampus (40.7).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ZNF160

miRNA regulators (miRDB)

Targeting PSMC2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 111 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.274, missense Z 4.63 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000292644 splits into 6 regions with different missense tolerance; 3 are missense-constrained (≈34% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
7:103,347,712–103,354,901	70 / 57.9	1.21	no
7:103,354,902–103,364,156	75 / 185.1	0.41	no
7:103,364,157–103,366,157	26 / 104.7	0.25	yes (p 1.5e-14)
7:103,366,158–103,367,502	0 / 39.6	0.00	yes (p 3.2e-10)
7:103,367,503–103,367,605	10 / 41.0	0.24	yes (p 1.3e-06)
7:103,367,606–103,368,051	60 / 115.8	0.52	no
DepMap (CRISPR cell-line fitness): dependent in 99.5% of screened cell lines, common-essential.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): MFE-280 (-3.057), KLE (-2.436), LOU-NH91 (-2.365), NIH:OVCAR-3 (-2.35), RERF-GC-1B (-2.327), MCF-7 (-2.274), SNU-213 (-2.174), DK-MG (-2.163), SW 1990 (-2.089), RD (-2.078), AM-38 (-2.073), RCC10RGB (-2.056), KASUMI-1 (-2.045), COR-L105 (-2.026), KP-3 (-2.012).

Literature-anchored findings (GeneRIF, showing 9)

• structural determinants for the binding of ubiquitin-like domains to 26s proteasome (PMID:12970176)
• the finding of this study provided the new insight into the mechanism how PSMC2 contribute to osteosarcoma malignancy and further suggested PSMC2 might serve as an attractive potential therapeutic target drug target for osteosarcoma treatment. (PMID:27888613)
• Overexpression of PSMC2 promotes the tumorigenesis and development of human breast cancer via regulating plasminogen activator urokinase (PLAU). (PMID:34244472)
• PSMC2/CCND1 axis promotes development of ovarian cancer through regulating cell growth, apoptosis and migration. (PMID:34294689)
• Knockdown of PSMC2 contributes to suppression of cholangiocarcinoma development by regulating CDK1. (PMID:34499615)
• PSMC2 knockdown inhibits the progression of oral squamous cell carcinoma by promoting apoptosis via PI3K/Akt pathway. (PMID:34979867)
• PSMC2 is overexpressed in glioma and promotes proliferation and anti-apoptosis of glioma cells. (PMID:35287689)
• PSMC2 knockdown exerts an anti-tumor role in nasopharyngeal carcinoma through regulating AKT signaling pathway. (PMID:38123344)
• PSMC2 promotes glioma progression by regulating immune microenvironment and PI3K/AKT/mTOR pathway. (PMID:38569452)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	psmc2	ENSDARG00000020101
mus_musculus	Psmc2	ENSMUSG00000028932
rattus_norvegicus	Psmc2	ENSRNOG00000012026
drosophila_melanogaster	Rpt1	FBGN0028687
caenorhabditis_elegans		WBGENE00004501

Paralogs (5): PSMC4 (ENSG00000013275), PSMC5 (ENSG00000087191), PSMC6 (ENSG00000100519), PSMC1 (ENSG00000100764), PSMC3 (ENSG00000165916)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:109555) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 4 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal gait	1
increased circulating bilirubin level	1
decreased circulating total protein level	1
preweaning lethality, complete penetrance	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Saccharolobus islandicus L.S.2.15	C3MRF1	100.0%	Diamond
Saccharolobus islandicus M.14.25	C3MY47	100.0%	Diamond
Saccharolobus islandicus M.16.27	C3MZI6	100.0%	Diamond
Saccharolobus islandicus Y.G.57.14	C3N7K8	100.0%	Diamond
Saccharolobus islandicus M.16.4	C4KIR6	100.0%	Diamond
Oryza sativa Japonica Group	P0DKJ9	100.0%	Diamond
Bos taurus	P62194	100.0%	Diamond
Sus scrofa	P62197	100.0%	Diamond
Ictidomys tridecemlineatus	P62335	100.0%	Diamond
Macaca fascicularis	Q4R4R0	100.0%	Diamond
Saccharolobus islandicus Y.N.15.51	C3NFW6	99.7%	Diamond
Brassica rapa	O23894	99.5%	Diamond
Pongo abelii	Q5R8D7	99.5%	Diamond
Arabidopsis thaliana	Q9SEI2	99.5%	Diamond
Xenopus laevis	P46472	99.3%	Diamond
Prunus persica	O64982	97.4%	Diamond
Methanosarcina mazei Go1	Q8PY58	97.1%	Diamond
Methanosarcina acetivorans C2A	Q8TI88	97.1%	Diamond
Spinacia oleracea	Q41365	96.9%	Diamond
Manduca sexta	P54814	96.5%	Diamond
Pyrococcus horikoshii OT3	O57940	96.2%	Diamond
Saccharolobus solfataricus P2	Q980M1	96.2%	Diamond
Pyrococcus abyssi GE5	Q9V287	96.2%	Diamond
Methanococcus maripaludis C7	A6VHR1	96.1%	Diamond
Solanum lycopersicum	P54776	94.6%	Diamond
Pyrococcus furiosus DSM 3638	Q8U4H3	93.9%	Diamond
Thermococcus gammatolerans EJ3	C5A6P8	92.8%	Diamond
Thermococcus kodakarensis KOD1	Q5JHS5	92.8%	Diamond
Thermococcus onnurineus NA1	B6YXR2	88.6%	Diamond
Methanococcus vannielii SB	A6UQT3	86.5%	Diamond
Dictyostelium discoideum	P34124	82.5%	Diamond
Schizosaccharomyces pombe 972h-	P41836	81.1%	Diamond
Naegleria fowleri	Q25544	80.2%	Diamond
Saccharomyces cerevisiae S288C	Q01939	77.8%	Diamond
Methanoregula boonei 6A8	A7I8B8	75.1%	Diamond
Haloferax volcanii DS2	D4GUJ7	74.2%	Diamond
Encephalitozoon cuniculi GB-M1	Q8SQK0	73.5%	Diamond
Caenorhabditis briggsae	A8X0L9	72.1%	Diamond
Methanopyrus kandleri AV19	Q8TX03	72.0%	Diamond
Archaeoglobus fulgidus DSM 4304	O28303	71.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
SLC26A5-AS1	ncRNA	101927870
DNAJC2	protein-coding	27000
SLC26A5	protein-coding	375611
RELN	protein-coding	5649
PMPCB	protein-coding	9512
ORC5	protein-coding	5001
LHFPL3	protein-coding	375612
NAPEPLD	protein-coding	222236

Protein

Protein identifiers

26S proteasome regulatory subunit 7 — P35998 (reviewed: P35998)

Alternative names: 26S proteasome AAA-ATPase subunit RPT1, Proteasome 26S subunit ATPase 2

All UniProt accessions (5): P35998, A0A140VK70, A0A7I2YQ68, C9JLS9, C9JX88

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. PSMC2 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.

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, a base containing 6 ATPases including PSMC2 and few additional components. Interacts with NDC80/HEC; this interaction is detected only during M phase. Interacts and SQSTM1. Interacts with PAAF1. Directly interacts with TRIM5. (Microbial infection) Interacts with HIV-1 Tat.

Subcellular location. Cytoplasm.

Post-translational modifications. Monoubiquitinated by RNF181. Phosphorylated. Dephosphorylated by UBLCP1 which impairs PSMC2 ATPase activity and disrupts 26S proteasome assembly.

Induction. Expression is not cell cycle-dependent and occurs throughout the cell cycle.

Similarity. Belongs to the AAA ATPase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P35998-1	1	yes
P35998-2	2

RefSeq proteins (2): NP_001191382, NP_002794* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003593	AAA+_ATPase	Domain
IPR003959	ATPase_AAA_core	Domain
IPR003960	ATPase_AAA_CS	Conserved_site
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR041569	AAA_lid_3	Domain
IPR048723	OB_PRS7	Domain
IPR050221	26S_Proteasome_ATPase	Family

Pfam: PF00004, PF17862, PF21236

UniProt features (68 total): helix 31, strand 20, turn 8, modified residue 2, initiator methionine 1, chain 1, region of interest 1, compositionally biased region 1, binding site 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

showing 30 of 139 structures by resolution:

PDB	Title	Method	Resolution (Å)
9K53	Structure of substrate-engaged human 26S proteasome RP-CP subcomplex in state ED2.1	ELECTRON MICROSCOPY	2.5
8USD	Rpn1/Nub1UBL-focused alignment of the non-substrate-engaged human 26S proteasome	ELECTRON MICROSCOPY	2.7
8USB	Non-substrate-engaged human 26S proteasome with Nub1/FAT10 bound to Rpn1	ELECTRON MICROSCOPY	2.73
9MBP	Substrate-engaged human 26S proteasome bound to midnolin with RPT1 at top of spiral …	ELECTRON MICROSCOPY	2.75
9PDL	Nub1/Fat10-processing human 26S proteasome with Rpt5 at top of spiral staircase (AAA+ …	ELECTRON MICROSCOPY	2.76
9NKG	Structure of substrate engaged MIDN-bound human 26S proteasome, EB-MIDN (Composite map)	ELECTRON MICROSCOPY	2.8
9E8I	Human proteasome in resting state conformation bound to TXNL1 in Forward conformation	ELECTRON MICROSCOPY	2.87
9BV3	M1B Midnolin-Proteasome	ELECTRON MICROSCOPY	2.9
9E8H	Human proteasome in resting state conformation bound to TXNL1 in backward conformation	ELECTRON MICROSCOPY	2.9
9NKF	Structure of human substrate-free 26S proteasome in the presence of ATPgS and …	ELECTRON MICROSCOPY	2.9
9K4J	Structure of substrate-engaged human 26S proteasome RP-CP subcomplex in state EA1.0	ELECTRON MICROSCOPY	2.9
9U3L	Substrate-engaged human 26S proteasome bound to midnolin with RPT2 at top of spiral …	ELECTRON MICROSCOPY	2.91
9NKI	Structure of substrate engaged MIDN-bound human 26S proteasome, EB MIDN_UBL state …	ELECTRON MICROSCOPY	2.94
9PDI	Nub1/Fat10-processing human 26S proteasome with Rpt2 at top of spiral staircase and …	ELECTRON MICROSCOPY	2.98
6MSB	Cryo-EM structures and dynamics of substrate-engaged human 26S proteasome	ELECTRON MICROSCOPY	3
7W37	Structure of USP14-bound human 26S proteasome in state EA1_UBL	ELECTRON MICROSCOPY	3
8CVT	Human 19S-20S proteasome, state SD2	ELECTRON MICROSCOPY	3
9E8G	Nub1/Fat10-processing human 26S proteasome bound to Txnl1 with Rpt5 at top of spiral …	ELECTRON MICROSCOPY	3.01
9PDN	Nub1/Fat10-processing human 26S proteasome with Rpt1 at top of spiral staircase (AAA+ …	ELECTRON MICROSCOPY	3.04
9MBQ	Substrate-engaged human 26S proteasome bound to midnolin with RPT5 at top of spiral …	ELECTRON MICROSCOPY	3.08
7W38	Structure of USP14-bound human 26S proteasome in state EA2.0_UBL	ELECTRON MICROSCOPY	3.1
8USC	Nub1/Fat10-processing human 26S proteasome	ELECTRON MICROSCOPY	3.1
9BV1	M2A Midnolin-Proteasome (translocating)	ELECTRON MICROSCOPY	3.1
9E8O	Nub1/Fat10-processing human 26S proteasome bound to Txnl1 with Rpt2 at top of spiral …	ELECTRON MICROSCOPY	3.1
9K4R	Structure of substrate-engaged human 26S proteasome RP-CP subcomplex in state EB.1	ELECTRON MICROSCOPY	3.1
9VUF	Structure of human proteasome ATPase-CP intermediate assembles with 90min rapaprotin …	ELECTRON MICROSCOPY	3.1
9E8Q	Nub1/Fat10-processing human 26S proteasome with Rpt2 at top of spiral staircase	ELECTRON MICROSCOPY	3.16
9U7R	Substrate-free human 26S proteasome purified by midnolin, 20S proteasome, RPTs and RPN11 …	ELECTRON MICROSCOPY	3.17
6MSD	Cryo-EM structures and dynamics of substrate-engaged human 26S proteasome	ELECTRON MICROSCOPY	3.2
6MSK	Cryo-EM structures and dynamics of substrate-engaged human 26S proteasome	ELECTRON MICROSCOPY	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35998-F1	80.73	0.21

Human Protein Atlas

Protein class: Predicted intracellular proteins, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytoplasmic bodies; cytosol

Antibody reliability (HPA): IH supported · IF supported

Functional residue map

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

Ligand- & substrate-binding residues (1)

Position	Role
216–223	ATP

Post-translational modifications (2)

Type	Positions
N6-acetyllysine	116, 422

Function

Pathways and Gene Ontology

Reactome pathways

58 curated (TAS) of 172; 13 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

showing 60 of 172 pathways:

ID	Pathway	Evidence
R-HSA-5678895	Defective CFTR causes cystic fibrosis ⚕	curated
R-HSA-5362768	Hh mutants are degraded by ERAD ⚕	curated
R-HSA-180585	Vif-mediated degradation of APOBEC3G ⚕	curated
R-HSA-180534	Vpu mediated degradation of CD4 ⚕	curated
R-HSA-382556	ABC-family protein mediated transport	curated
R-HSA-9931269	AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	curated
R-HSA-174154	APC/C:Cdc20 mediated degradation of Securin	curated
R-HSA-174178	APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1	curated
R-HSA-450408	AUF1 (hnRNP D0) binds and destabilizes mRNA	curated
R-HSA-1169091	Activation of NF-kappaB in B cells	curated
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation	curated
R-HSA-68867	Assembly of the pre-replicative complex	curated
R-HSA-4608870	Asymmetric localization of PCP proteins	curated
R-HSA-174084	Autodegradation of Cdh1 by Cdh1:APC/C	curated
R-HSA-349425	Autodegradation of the E3 ubiquitin ligase COP1	curated
R-HSA-69017	CDK-mediated phosphorylation and removal of Cdc6	curated
R-HSA-5607764	CLEC7A (Dectin-1) signaling	curated
R-HSA-174184	Cdc20:Phospho-APC/C mediated degradation of Cyclin A	curated
R-HSA-1236978	Cross-presentation of soluble exogenous antigens (endosomes)	curated
R-HSA-5607761	Dectin-1 mediated noncanonical NF-kB signaling	curated
R-HSA-4641257	Degradation of AXIN	curated
R-HSA-9766229	Degradation of CDH1	curated
R-HSA-4641258	Degradation of DVL	curated
R-HSA-5610780	Degradation of GLI1 by the proteasome	curated
R-HSA-195253	Degradation of beta-catenin by the destruction complex	curated
R-HSA-202424	Downstream TCR signaling	curated
R-HSA-8854050	FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	curated
R-HSA-2871837	FCERI mediated NF-kB activation	curated
R-HSA-69481	G2/M Checkpoints	curated
R-HSA-5610785	GLI3 is processed to GLI3R by the proteasome	curated
R-HSA-9762114	GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	curated
R-HSA-9929356	GSK3B-mediated proteasomal degradation of PD-L1(CD274)	curated
R-HSA-5632684	Hedgehog ‘on’ state	curated
R-HSA-5358346	Hedgehog ligand biogenesis	curated
R-HSA-9020702	Interleukin-1 signaling	curated
R-HSA-9755511	KEAP1-NFE2L2 pathway	curated
R-HSA-5687128	MAPK6/MAPK4 signaling	curated
R-HSA-5676590	NIK–>noncanonical NF-kB signaling	curated
R-HSA-8951664	Neddylation	curated
R-HSA-9974237	Negative Regulation of DNA Double Strand Break Response	curated
R-HSA-6798695	Neutrophil degranulation	curated
R-HSA-68949	Orc1 removal from chromatin	curated
R-HSA-1234176	Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha	curated
R-HSA-8939236	RUNX1 regulates transcription of genes involved in differentiation of HSCs	curated
R-HSA-8948751	Regulation of PTEN stability and activity	curated
R-HSA-5658442	Regulation of RAS by GAPs	curated
R-HSA-8941858	Regulation of RUNX3 expression and activity	curated
R-HSA-350562	Regulation of ornithine decarboxylase (ODC)	curated
R-HSA-187577	SCF(Skp2)-mediated degradation of p27/p21	curated
R-HSA-174113	SCF-beta-TrCP mediated degradation of Emi1	curated
R-HSA-9929491	SPOP-mediated proteasomal degradation of PD-L1(CD274)	curated
R-HSA-2467813	Separation of Sister Chromatids	curated
R-HSA-5668541	TNFR2 non-canonical NF-kB pathway	curated
R-HSA-8852276	The role of GTSE1 in G2/M progression after G2 checkpoint	curated
R-HSA-5689603	UCH proteinases	curated
R-HSA-5689880	Ub-specific processing proteases	curated
R-HSA-69601	Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A	curated
R-HSA-75815	Ubiquitin-dependent degradation of Cyclin D	curated
R-HSA-5619084	ABC transporter disorders ⚕	—
R-HSA-1643685	Disease ⚕	—

MSigDB gene sets: 426 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, REACTOME_DNA_REPLICATION, REACTOME_SIGNALING_BY_NOTCH, MODULE_52, REACTOME_APC_C_CDH1_MEDIATED_DEGRADATION_OF_CDC20_AND_OTHER_APC_C_CDH1_TARGETED_PROTEINS_IN_LATE_MITOSIS_EARLY_G1, REACTOME_INNATE_IMMUNE_SYSTEM, MORF_MBD4, MORF_RAB5A, 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, GOCC_SECRETORY_GRANULE

GO Biological Process (8): osteoblast differentiation (GO:0001649), ubiquitin-dependent protein catabolic process (GO:0006511), response to oxidative stress (GO:0006979), proteasomal protein catabolic process (GO:0010498), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), regulation of proteasomal protein catabolic process (GO:0061136), cellular response to type I interferon (GO:0071357), positive regulation of proteasomal protein catabolic process (GO:1901800)

GO Molecular Function (5): ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), proteasome-activating activity (GO:0036402), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (14): proteasome complex (GO:0000502), P-body (GO:0000932), extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), synaptic vesicle (GO:0008021), proteasome regulatory particle, base subcomplex (GO:0008540), membrane (GO:0016020), proteasome accessory complex (GO:0022624), secretory granule lumen (GO:0034774), cytoplasmic ribonucleoprotein granule (GO:0036464), ficolin-1-rich granule lumen (GO:1904813)

Reactome top-level categories

18 top-level categories:

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
Stabilization of p53	1
Metabolism of polyamines	1
Transport of small molecules	1

GO top-level categories

40 GO namespaces:

Category	Terms
cellular anatomical structure	5
proteasomal protein catabolic process	4
ATP-dependent activity	2
intracellular anatomical structure	2
cytoplasm	2
protein-containing complex	2
ossification	1
cell differentiation	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
response to stress	1
protein catabolic process	1
ubiquitin-dependent protein catabolic process	1
regulation of protein catabolic process	1
response to type I interferon	1
cellular response to cytokine stimulus	1
positive regulation of protein catabolic process	1
regulation of proteasomal protein catabolic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
ribonucleoside triphosphate phosphatase activity	1
polypeptide conformation or assembly isomerase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
intracellular protein-containing complex	1
endopeptidase complex	1
cytoplasmic ribonucleoprotein granule	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
exocytic vesicle	1
presynapse	1
proteasome regulatory particle	1
proteasome complex	1
secretory granule	1
cytoplasmic vesicle lumen	1
ribonucleoprotein granule	1
intracellular organelle lumen	1
ficolin-1-rich granule	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 27 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO term	NS	Evidence
osteoblast differentiation	BP	high-throughput assay
ubiquitin-dependent protein catabolic process	BP	direct assay
cytoplasmic ribonucleoprotein granule	CC	direct assay
cytosol	CC	direct assay
membrane	CC	high-throughput assay
nucleus	CC	high-throughput assay
proteasome complex	CC	direct assay
proteasome-activating activity	MF	direct assay

Protein interactions and networks

STRING

showing 16 of 2,998 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PSMC2	PSMD1	Q99460	771
PSMC2	PSMD2	Q13200	746
PSMC2	PSMC1	P49014	718
PSMC2	PSMD12	O00232	717
PSMC2	PSMC5	P47210	706
PSMC2	PSMD3	O43242	703
PSMC2	PSMB4	P28070	702
PSMC2	PSMB1	P20618	697
PSMC2	PSMD7	P51665	694
PSMC2	PSMD11	O00231	694
PSMC2	PSMD6	Q15008	693
PSMC2	PSMA4	P25789	684
PSMC2	PSMD13	Q9UNM6	680
PSMC2	PSMA3	P25788	674
PSMC2	PSMD4	P55036	670
PSMC2	PSMA1	P25786	670

IntAct

Human interaction partners of PSMC2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

showing 30 of 31 partners by confidence:

Partner	Interaction type	MIscore	Records
PSMD5	physical association	0.960	22
PSMC1	direct interaction	0.890	3
PSMC5	association	0.860	2
PSMD2	physical association	0.840	3
PSMC3	association	0.730	1
PSMD4	physical association	0.670	1
PSMD12	association	0.640	2
KLF11	physical association	0.560	3
NUP58	physical association	0.560	3
OPTN	physical association	0.560	3
RAD23B	physical association	0.560	2
SEM1	association	0.530	2
CDKN1A	physical association	0.490	2
AARSD1	physical association	0.400	1
NDRG1	physical association	0.400	1
RAD23A	physical association	0.400	1
UNC45B	physical association	0.400	1
SKIL	physical association	0.370	1
HERC2	association	0.350	1
PSMD1	association	0.350	1
GH1	physical association	0.000	1
IKBKE	physical association	0.000	1
MPG	physical association	0.000	1
MYZAP	physical association	0.000	1
PAAF1	physical association	0.000	1
PSMC4	physical association	0.000	1
PSMD10	physical association	0.000	1
PSMD13	physical association	0.000	1
PSMD6	physical association	0.000	1
TNIK	physical association	0.000	1

BioGRID (840 interactions; top human partners by supporting records in a sample of 600 records): PSMC1 (Affinity Capture-MS; 20 records), PSMD5 (Two-hybrid; 17 records), PSMC4 (Co-fractionation; 15 records), PSMC3 (Co-fractionation; 12 records), PSMD2 (Co-fractionation; 12 records), PSMD14 (Co-fractionation; 9 records), PSMC5 (Co-fractionation; 8 records), PSMD4 (Co-fractionation; 8 records), PSMC6 (Co-fractionation; 7 records), PSMD10 (Affinity Capture-MS; 7 records), PSMD12 (Co-fractionation; 7 records), ADRM1 (Affinity Capture-MS; 6 records), PSMA7 (Co-fractionation; 6 records), PSMD1 (Co-fractionation; 6 records), PSMD13 (Co-fractionation; 6 records)

SIGNOR signaling

2 signaling interactions:

A	Effect	B	Mechanism
PSMC2	“form complex”	“26S Proteasome”	binding
UBE3A	“down-regulates quantity by destabilization”	PSMC2	ubiquitination

Protein complexes (CORUM) (3)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

3 complexes by size:

Complex	Subunits	Members
★ PA700-20S-PA28 complex	36	PSMA5, PSMD4, PSMD6, PSMD9, PSME1, PSME2, PSMD11, PSMB1, PSMB4, PSMC1, PSMA3, PSMB5, PSMD10, PSMA7, PSMC5, PSMD14, PSMD7, PSMA6, PSMB6, PSMD12, PSMD3, PSMD1, PSMA4, PSMB7, PSMC3, PSMC4, PSMC6, PSMD8, PSMB3, PSMC2, PSMD13, PSMA1, PSMA2, PSMB2, PSMD2, PSMD5
★ 26S proteasome	22	PSMA2, PSMA7, PSMB3, PSMA5, PSMA6, PSMB4, PSMB7, PSMC1, PSMC2, PSMC5, PSMC6, PSMA3, PSMB2, PSMB5, PSMC3, PSMC4, PSMD13, PSMD4, PSMA1, PSMA4, PSMB1, PSMB6
PA700 complex	20	PSMD6, PSMD7, PSMC2, PSMC3, PSMD12, PSMD14, PSMD9, PSMD10, PSMD11, PSMD2, PSMD4, PSMC4, PSMC5, PSMD8, PSMC1, PSMC6, PSMD1, PSMD13, PSMD3, PSMD5

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 31 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
Proteasome assembly	14	105.7×	5e-24
Regulation of activated PAK-2p34 by proteasome mediated degradation	10	103.2×	7e-17
Regulation of ornithine decarboxylase (ODC)	10	100.7×	7e-17
Vpu mediated degradation of CD4	10	98.4×	7e-17
Autodegradation of the E3 ubiquitin ligase COP1	10	98.4×	7e-17
Ubiquitin-dependent degradation of Cyclin D	10	98.4×	7e-17
Cross-presentation of soluble exogenous antigens (endosomes)	10	94.0×	7e-17
Vif-mediated degradation of APOBEC3G	10	94.0×	7e-17

GO biological processes:

GO term	Partners	Fold	FDR
proteasome-mediated ubiquitin-dependent protein catabolic process	14	24.4×	2e-14

Disease & clinical

Genetic variants

Variant evidence for PSMC2: 39 ClinVar records (1 pathogenic / likely pathogenic). Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	18
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (1)

Showing all 1 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1459935	NC_000007.13:g.(?102937907)(103629803_?)del	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore PSMC2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 31 predictions of 530):

Position(s)	Effect	Δscore	Sites
7:103347782	donor_loss	1.0000
7:103354950–103354951	donor_loss	1.0000	5
7:103355692–103355693	acceptor_loss	1.0000	4
7:103355794–103355795	donor_loss	1.0000	5
7:103361955–103361956	acceptor_loss	1.0000	6
7:103362089–103362090	donor_loss	1.0000	5
7:103363330	acceptor_gain	1.0000
7:103363342–103363343	acceptor_loss	1.0000	2
7:103363440	donor_loss	1.0000
7:103363448	donor_gain	1.0000

AlphaMissense

1,946 missense substitutions predicted likely pathogenic (of 2,869 scored), across 391 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M394	9	0.944	0.998
M164	9	0.917	0.995
M299	9	0.912	0.998
M319	9	0.884	0.998
M138	9	0.811	0.969
D275	8	1.000	1.000
D278	8	0.999	1.000
D307	8	0.999	1.000
D328	8	0.997	0.999
F261	8	0.995	1.000
D338	8	0.995	0.999
D83	8	0.994	0.999
F273	8	0.994	0.999
F309	8	0.993	0.999
N322	8	0.993	1.000
F237	8	0.992	1.000
D408	8	0.992	0.998
D158	8	0.975	0.996
D29	8	0.964	0.992
D133	8	0.961	0.989

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	2.94e-10
Colon Adenocarcinoma (validation)	unfavorable	0.000146
Kidney Chromophobe (TCGA)	unfavorable	0.000479

Disease associations

OMIM: gene MIM:154365 | disease phenotypes: MIM:257320, MIM:616436

GenCC curated gene-disease

Mondo (2): Norman-Roberts syndrome (MONDO:0009760), familial temporal lobe epilepsy 7 (MONDO:0014639)

Orphanet (2): Epilepsy with auditory features (Orphanet:101046), Lissencephaly syndrome, Norman-Roberts type (Orphanet:89844)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2364701 (PROTEIN COMPLEX), CHEMBL3831203 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 26,571 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

2 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL325041	BORTEZOMIB	4	13,415
CHEMBL451887	CARFILZOMIB	4	13,156

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (2 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

ChEMBL bioactivities

62 potent at pChembl≥5 of 66 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
7.34	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
5.70	IC50	2000	nM	BORTEZOMIB
5.66	IC50	2170	nM	CHEMBL3237873

PubChem BioAssay actives

61 with measured affinity, of 139 total; 33 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
4-methyl-N-[(2R)-1-[[(2R)-4-methyl-1-[(2S)-2-methyloxiran-2-yl]-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]-4-phenylbutanoyl]amino]pentanamide	2236585: Activation of 26s proteosome (unknown origin)	ic50	0.0034	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
(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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, increases expression	3
sodium arsenite	increases reaction, increases expression, affects binding	2
arsenic disulfide	affects expression, increases expression	2
Arsenic Trioxide	decreases expression, affects cotreatment, increases expression	2
Acetaminophen	decreases expression	2
Arsenic	increases abundance, affects methylation, decreases expression	2
Hydrogen Peroxide	increases expression, affects expression	2
Tretinoin	affects cotreatment, increases expression, decreases expression	2
Valproic Acid	affects expression, increases expression	2
Cadmium Chloride	increases expression, decreases reaction, increases abundance, increases palmitoylation	2
beta-Naphthoflavone	increases expression	2
TAK-243	decreases sumoylation	1
dicrotophos	decreases expression	1
bisphenol A	decreases expression, increases expression	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases expression, decreases reaction	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
trichostatin A	decreases expression	1
arsenite	increases reaction, affects binding	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
sulindac sulfide	decreases expression	1
arsenic trichloride	decreases expression, increases abundance	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	increases expression	1
chromium hexavalent ion	increases expression	1
chloropicrin	increases expression	1
bisphenol B	increases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	decreases expression	1
bromovanin	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	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*

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for PSMC2 across ~30M SureChEMBL compounds — explore on Sugi Predict.