UBQLN2

Summary

UBQLN2 (ubiquilin 2, HGNC:12509) is a protein-coding gene on chromosome Xp11.21, encoding Ubiquilin-2 (Q9UHD9). Plays an important role in the regulation of different protein degradation mechanisms and pathways including ubiquitin-proteasome system (UPS), autophagy and the endoplasmic reticulum-associated protein degradation (ERAD) pathway.

This gene encodes an ubiquitin-like protein (ubiquilin) that shares high degree of similarity with related products in yeast, rat and frog. Ubiquilins contain a N-terminal ubiquitin-like domain and a C-terminal ubiquitin-associated domain. They physically associate with both proteasomes and ubiquitin ligases; and thus, are thought to functionally link the ubiquitination machinery to the proteasome to affect in vivo protein degradation. This ubiquilin has also been shown to bind the ATPase domain of the Hsp70-like Stch protein.

Source: NCBI Gene 29978 — RefSeq curated summary.

At a glance

• Gene–disease (curated): amyotrophic lateral sclerosis type 15 (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 243 total — 3 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 58
• Druggable target: yes
• MANE Select transcript: NM_013444

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12509
Approved symbol	UBQLN2
Name	ubiquilin 2
Location	Xp11.21
Locus type	gene with protein product
Status	Approved
Aliases	Chap1, Dsk2, RIHFB2157, LIC-2, CHAP1/DSK2, PLIC-2, N4BP4, PLIC2
Ensembl gene	ENSG00000188021
Ensembl biotype	protein_coding
OMIM	300264
Entrez	29978

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000338222

RefSeq mRNA: 1 — MANE Select: NM_013444 NM_013444

CCDS: CCDS14374

Canonical transcript exons

ENST00000338222 — 1 exons

Exon	Start	End
ENSE00001368073	56563627	56567868

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 98.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.7432 / max 198.7226, expressed in 1807 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196491	30.6592	1805
196492	2.0840	1231

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar vermis	UBERON:0004720	98.17	gold quality
pons	UBERON:0000988	97.19	gold quality
postcentral gyrus	UBERON:0002581	97.17	gold quality
parietal lobe	UBERON:0001872	97.16	gold quality
endothelial cell	CL:0000115	97.15	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.91	gold quality
pigmented layer of retina	UBERON:0001782	96.89	gold quality
entorhinal cortex	UBERON:0002728	96.77	gold quality
superior vestibular nucleus	UBERON:0007227	96.53	gold quality
seminal vesicle	UBERON:0000998	96.49	gold quality
middle temporal gyrus	UBERON:0002771	96.45	gold quality
visceral pleura	UBERON:0002401	96.20	gold quality
dorsal root ganglion	UBERON:0000044	96.17	gold quality
parietal pleura	UBERON:0002400	96.13	gold quality
ventral tegmental area	UBERON:0002691	96.12	gold quality
superior frontal gyrus	UBERON:0002661	96.07	gold quality
urethra	UBERON:0000057	96.05	gold quality
pericardium	UBERON:0002407	96.04	gold quality
trigeminal ganglion	UBERON:0001675	95.94	gold quality
pleura	UBERON:0000977	95.93	gold quality
inferior vagus X ganglion	UBERON:0005363	95.93	gold quality
substantia nigra pars compacta	UBERON:0001965	95.90	gold quality
cranial nerve II	UBERON:0000941	95.77	gold quality
mucosa of paranasal sinus	UBERON:0005030	95.71	gold quality
CA1 field of hippocampus	UBERON:0003881	95.60	gold quality
lower lobe of lung	UBERON:0008949	95.44	gold quality
substantia nigra pars reticulata	UBERON:0001966	95.36	gold quality
subthalamic nucleus	UBERON:0001906	95.30	gold quality
occipital lobe	UBERON:0002021	95.30	gold quality
oral cavity	UBERON:0000167	95.14	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-36552	no	118.49
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

134 targeting UBQLN2, 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-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548A-5P	99.94	71.27	3482

Literature-anchored findings (GeneRIF, showing 40)

• solution structure of the ubl domain of hPLIC-2 (PMID:11827521)
• hPLIC-2 interferes with the ubiquitin-mediated proteolysis of p53 and interacts with proteasomes (PMID:12972570)
• knockdown of ubiquilin-1 and -2 protein expression by RNAi (RNA interference) increased Pen-2 and nicastrin levels (PMID:15975090)
• Ubiquilin is capable of forming dimers. Dimerization requires the central region of ubiquilin, but not its UBL or the UBA domains. Monomeric ubiquilin is likely to be the active form that is involved in binding presenilin proteins. (PMID:16813565)
• hHR23a and hPLIC2 interact via UBL/UBA domain interactions (PMID:17098253)
• Ubiquitin-like protein PLIC-2 is identified as a negative regulator of G protein-coupled receptor endocytosis. (PMID:18199683)
• siRNA-mediated UBQLN2 depletion made cells more susceptible to starvation-induced cell death. UBQLN2 regulates cell survival during starvation. (PMID:19148225)
• findings link abnormalities in ubiquilin 2 to defects in the protein degradation pathway, abnormal protein aggregation and neurodegeneration, indicating a common pathogenic mechanism that can be exploited for therapeutic intervention (PMID:21857683)
• The results of this study suggested that UBQLN2 gene mutations are rare in French amyotrophic lateral sclerosis. (PMID:22169395)
• Found a pathophysiological link between C9ORF72 expansions and ubiquilin-2 (UBQLN) proteins in amyotrophic lateral sclerosis and frontotemporal lobar degeneration that is associated with a highly characteristic pattern of UBQLN pathology. (PMID:22426854)
• The results of this study support support a causative role of the UBQLN2 gene in the pathogenesis of ALS and suggest that UBQLN2 mutations are rare in the French and French-Canadian population. (PMID:22560112)
• The results of this study suggested that UBQLN2 was not found to be a cause of familial ALS in the Netherlands. (PMID:22676852)
• A novel missense UBQLN2 mutation (c.1460C>T, p.T487I) was identified in 2 apparently unrelated multigenerational amyotrophic lateral sclerosis families with no evidence of frontotemporal dementia. This mutation segregated with the disease. (PMID:22717235)
• No causative mutations within the PXX domain of the UBQLN2 gene are found in familial frontotemoral dementia patients. (PMID:22729385)
• This study reported 3 novel UBQLN2 mutations, accounting for 1.2% (2/161) ALS and 2.2% (1/45) FTD patients, including a patient with pure FTD. (PMID:22892309)
• data support the role of the UBQLN2 gene in the pathogenesis of FALS, being conversely a rare genetic cause in SALS even when complicated by FTD. (PMID:23138764)
• Genetic variations in UBQLN2 in a predominantly Flanders-Belgian cohort of frontotemporal lobar degeneration patients are extremely rare. (PMID:23312802)
• The 4-aminoquinolines were competitive inhibitors of UBQLN2 binding to TDP-43. (PMID:23541532)
• Its mutations related to ALS/FTLD are extremely rare in French FTLD and FTLD-ALS patients. (PMID:23582661)
• results were confirmed by similar findings for ubiquilin-1 and -2 in human brain tissue sections, where accumulation was observed in huntingtin inclusions (PMID:23774650)
• The P506S mutation in UBQLN2 can affect both males and females with frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS). (PMID:23944734)
• Its mutations are not frequent cause of amyotrophic lateral sclerosis in Ireland. (PMID:23973441)
• The dtat of study suggest that UBQLN2 is generally involved in the pathogenesis of ALS. (PMID:24085347)
• no evidence for involvement of ubiquilin 2 in tau pathology (PMID:24086754)
• Causative mutation in the UBQLN2 gene is rare in Korean patients with either familial or sporadic ALS. (PMID:24684794)
• As ubiquilin-2-positive inclusions are identified in brain, this mutant peptide predisposes to protein misfolding and accumulation. (PMID:24771548)
• A single putative mutation of UBQLN2 in a cohort of patients with front temporal lobar degeneration was found. (PMID:25179229)
• Data indicate cognitive deficits in mutant ubiquilin 2 protein UBQLN2P497H transgenic mice. (PMID:25246588)
• ALS-linked mutations in both OPTN and UBQLN2 interfere with the constitution of specific endosomal vesicles, suggesting that the vesicles are involved in protein homeostasis and that these proteins function in common pathological processes. (PMID:25398946)
• ALS-linked mutations in ubiquilin-2 or hnRNPA1 reduce interaction between ubiquilin-2 and hnRNPA1 (PMID:25616961)
• UBQLN2 may be a new molecular target for chemotherapeutics and a useful clinicopathological marker in human osteosarcoma. (PMID:25672654)
• Mutations in UBQLN2 gene cause dominant inheritance of amyotrophic lateral sclerosis due to Defective Proteasome Delivery. (PMID:26075709)
• Results showed that UBQLN2 is selectively recruited to nuclear inclusions in Huntington’s disease but not spinocerebellar ataxia type 3 (PMID:26141599)
• UBQLN2 is specifically expressed in the urine of urothelial carcinoma patients. (PMID:26303000)
• These findings provide a molecular basis for the development of ALS/FTD-associated proteinopathy and establish novel therapeutic targets for ALS. (PMID:26944018)
• Frontotemporal dementia -linked mutations in gene ubiquilin 2 encoding autophagy adaptor proteins , indicate that impaired autophagy might cause Frontotemporal dementia. (PMID:27166223)
• Ubiquilin-2 immunostaining - a new marker as a diagnostic supplement in urine cytology? (PMID:27168037)
• Ubiquilins are a family of chaperones for cytosolically exposed transmembrane domains and use ubiquitin to triage clients for degradation via coordinated intra- and intermolecular interactions. (PMID:27345149)
• The structures of proteasome substrate receptor complexes with the shuttle factors that deliver ubiquitinated proteins to proteasomes have been solved, namely human Rpn13 complexed with PLIC2 and Saccharomyces cerevisiae Rpn1 with Rad23. (PMID:27396824)
• excess UBQLN2 is toxic rather than protective to neurons and that uncontrolled enhancement of UBQLN2 function is involved in UBQLN2 pathogenesis (PMID:27456931)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ubqln2	ENSMUSG00000050148
rattus_norvegicus	Ubqln2	ENSRNOG00000003099
drosophila_melanogaster	CG31528	FBGN0051528

Paralogs (5): UBQLN1 (ENSG00000135018), UBL7 (ENSG00000138629), UBQLN4 (ENSG00000160803), UBQLNL (ENSG00000175518), UBQLN3 (ENSG00000175520)

Protein

Protein identifiers

Ubiquilin-2 — Q9UHD9 (reviewed: Q9UHD9)

Alternative names: Chap1, DSK2 homolog, Protein linking IAP with cytoskeleton 2, Ubiquitin-like product Chap1/Dsk2

All UniProt accessions (1): Q9UHD9

UniProt curated annotations — full annotation on UniProt →

Function. Plays an important role in the regulation of different protein degradation mechanisms and pathways including ubiquitin-proteasome system (UPS), autophagy and the endoplasmic reticulum-associated protein degradation (ERAD) pathway. Mediates the proteasomal targeting of misfolded or accumulated proteins for degradation by binding (via UBA domain) to their polyubiquitin chains and by interacting (via ubiquitin-like domain) with the subunits of the proteasome. Plays a role in the ERAD pathway via its interaction with ER-localized proteins FAF2/UBXD8 and HERPUD1 and may form a link between the polyubiquitinated ERAD substrates and the proteasome. Involved in the regulation of macroautophagy and autophagosome formation; required for maturation of autophagy-related protein LC3 from the cytosolic form LC3-I to the membrane-bound form LC3-II and may assist in the maturation of autophagosomes to autolysosomes by mediating autophagosome-lysosome fusion. Negatively regulates the endocytosis of GPCR receptors: AVPR2 and ADRB2, by specifically reducing the rate at which receptor-arrestin complexes concentrate in clathrin-coated pits (CCPs).

Subunit / interactions. Homodimer. Forms heterodimer with UBQLN1. Binds UBE3A and BTRC. Interacts with the 19S proteasome subunit. Interacts with C9orf72. Interacts with HNRNPA1 and HNRNPU. Found in a complex with UBQLN1 and MAP1LC3A/B/C. Interacts with EPS15, EPN1 and EPN2. Interacts with HERPUD1. Interacts with RAD23A. Interacts with TARDBP. Interacts (via C-terminus) with FAF2 (via N-terminus). Interacts with UBQLN4. Binds CD47.

Subcellular location. Cytoplasm. Nucleus. Membrane. Cytoplasmic vesicle. Autophagosome.

Post-translational modifications. Degraded during macroautophagy.

Disease relevance. Amyotrophic lateral sclerosis 15, with or without frontotemporal dementia (ALS15) [MIM:300857] A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. Patients with ALS15 may develop frontotemporal dementia. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The ubiquitin-like domain is essential for its inhibitory effect on GPCR endocytosis. Mediates its association with the subunits of the proteasome. The UBA domain is essential for its association with microtubule-associated protein 1 light chain 3 (MAP1LC3). Mediates its association with ubiquitinated substrates. Dimerization is dependent upon the central region of the protein containing the STI1 domains and is independent of its ubiquitin-like and UBA domains.

Induction. Highly expressed in mitotic cells from metaphase to telophase. Expression in non-mitotic cells is very low.

RefSeq proteins (1): NP_038472* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000626	Ubiquitin-like_dom	Domain
IPR006636	STI1_HS-bd	Domain
IPR009060	UBA-like_sf	Homologous_superfamily
IPR015496	Ubiquilin	Family
IPR015940	UBA	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily

Pfam: PF00240, PF00627, PF23195

UniProt features (58 total): repeat 12, sequence variant 12, compositionally biased region 7, domain 6, strand 6, region of interest 5, helix 5, initiator methionine 1, chain 1, modified residue 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
1J8C	SOLUTION NMR
2NBV	SOLUTION NMR
6MUN	SOLUTION NMR
7F7X	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UHD9-F1	62.24	0.03

Functional residue map

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

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis

MSigDB gene sets: 303 (showing top): GOBP_G_PROTEIN_COUPLED_RECEPTOR_INTERNALIZATION, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_REGULATION_OF_AUTOPHAGY, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_VACUOLE_ORGANIZATION, ENK_UV_RESPONSE_KERATINOCYTE_UP, TTTGTAG_MIR520D, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_ENDOCYTOSIS, CREBP1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_VACUOLE_ORGANIZATION

GO Biological Process (10): autophagosome assembly (GO:0000045), ubiquitin-dependent protein catabolic process (GO:0006511), regulation of macroautophagy (GO:0016241), ERAD pathway (GO:0036503), negative regulation of clathrin-dependent endocytosis (GO:1900186), negative regulation of G protein-coupled receptor internalization (GO:1904021), positive regulation of ERAD pathway (GO:1904294), regulation of autophagosome assembly (GO:2000785), autophagy (GO:0006914), negative regulation of transport (GO:0051051)

GO Molecular Function (4): polyubiquitin modification-dependent protein binding (GO:0031593), identical protein binding (GO:0042802), molecular condensate scaffold activity (GO:0140693), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), cytoplasm (GO:0005737), autophagosome (GO:0005776), cytosol (GO:0005829), plasma membrane (GO:0005886), cytoplasmic vesicle (GO:0031410), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Clathrin-mediated endocytosis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	2
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1
autophagosome organization	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
regulation of autophagy	1
macroautophagy	1
proteasomal protein catabolic process	1
response to endoplasmic reticulum stress	1
response to chemical	1
negative regulation of receptor-mediated endocytosis	1
clathrin-dependent endocytosis	1
regulation of clathrin-dependent endocytosis	1
G protein-coupled receptor internalization	1
negative regulation of receptor internalization	1
regulation of G protein-coupled receptor internalization	1
ERAD pathway	1
positive regulation of proteasomal protein catabolic process	1
regulation of ERAD pathway	1
positive regulation of response to endoplasmic reticulum stress	1
autophagosome assembly	1
regulation of vacuole organization	1
regulation of organelle assembly	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
transport	1
negative regulation of biological process	1
regulation of transport	1
modification-dependent protein binding	1
protein binding	1
protein-macromolecule adaptor activity	1
binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

4958 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UBQLN2	HSPA13	P48723	984
UBQLN2	TARDBP	Q13148	943
UBQLN2	OPTN	Q96CV9	939
UBQLN2	FUS	P35637	934
UBQLN2	VCP	P55072	911
UBQLN2	C9orf72	Q96LT7	871
UBQLN2	ADRM1	Q16186	861
UBQLN2	UBE4A	Q14139	857
UBQLN2	PSMD4	P55036	853
UBQLN2	UBE4B	O95155	850
UBQLN2	SOD1	P00441	845
UBQLN2	UBL7	Q96S82	836
UBQLN2	UBE3A	P78355	810
UBQLN2	RAD23A	P54725	801
UBQLN2	STIP1	P31948	796

IntAct

937 interactions, top by confidence:

A	B	Type	Score
ADRM1	UBQLN2	psi-mi:“MI:0407”(direct interaction)	0.710
UBQLN2	HNRNPA1	psi-mi:“MI:0915”(physical association)	0.590
HNRNPA1	UBQLN2	psi-mi:“MI:0407”(direct interaction)	0.590
UBQLN2	HNRNPA1	psi-mi:“MI:0915”(physical association)	0.520
UBQLN2	HNRNPU	psi-mi:“MI:0915”(physical association)	0.510
UBE3A	UBQLN2	psi-mi:“MI:0915”(physical association)	0.490
RPN10	UBQLN2	psi-mi:“MI:0407”(direct interaction)	0.440
UBQLN2		psi-mi:“MI:0915”(physical association)	0.400
UBQLN2	HNRNPA3	psi-mi:“MI:0915”(physical association)	0.370
UBQLN2	yscD	psi-mi:“MI:0915”(physical association)	0.370
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
MAPT	MEX3A	psi-mi:“MI:0914”(association)	0.350
ATXN1		psi-mi:“MI:0914”(association)	0.350
SLC17A2	PSMD11	psi-mi:“MI:0914”(association)	0.350
MTNR1B	UBQLN2	psi-mi:“MI:0915”(physical association)	0.000
PNMA3	UBQLN2	psi-mi:“MI:0915”(physical association)	0.000
PLAAT3	UBQLN2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (977): UBQLN2 (Affinity Capture-MS), UBQLN2 (Affinity Capture-MS), UBQLN2 (Affinity Capture-MS), UBQLN2 (Affinity Capture-MS), UBQLN2 (Affinity Capture-MS), Adrm1 (Reconstituted Complex), PSMC2 (Reconstituted Complex), PSMC1 (Reconstituted Complex), RAD23A (Co-fractionation), RAD23B (Co-fractionation), UBQLN2 (Co-fractionation), UBQLN2 (Co-fractionation), UBQLN2 (Affinity Capture-MS), UBQLN2 (Synthetic Growth Defect), PSMA6 (Affinity Capture-Western)

ESM2 similar proteins: A1CDT9, A1DCU5, A3KMV2, F4JPR7, G5EFF7, O17453, O48726, O74803, P32628, P48510, P54725, P54726, P54727, P54728, P55035, Q0CJ13, Q0U3Y6, Q10169, Q1DNB9, Q1EBV4, Q28DG7, Q29RK4, Q2H085, Q2KIS3, Q2USD7, Q40742, Q4KMA2, Q4WGS4, Q54LV1, Q5AY89, Q5XIR9, Q5ZJI9, Q6NXA9, Q6NYI0, Q7K2G1, Q7S906, Q7ZXQ3, Q84L30, Q84L31, Q84L32

Diamond homologs: A3KPW9, A4IH17, A5D9M6, A7X5R6, C4YP88, D5LXJ0, P05759, P0C016, P0C224, P0C8R3, P0CG47, P0CG48, P0CG49, P0CG50, P0CG51, P0CG53, P0CG54, P0CG55, P0CG60, P0CG61, P0CG62, P0CG63, P0CG64, P0CG65, P0CG66, P0CG67, P0CG68, P0CG69, P0CG70, P0CG71, P0CG72, P0CG73, P0CG74, P0CG75, P0CG76, P0CG77, P0CG78, P0CG79, P0CG80, P0CG81

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
UBQLN2	“down-regulates quantity by destabilization”	TARDBP	binding
UBQLN2	up-regulates	Stress_granules
UBQLN2	down-regulates	Unfolded_Proteins
UBQLN2	“up-regulates quantity by stabilization”	HNRNPA1	binding
UBQLN2	“up-regulates quantity by stabilization”	HNRNPU	binding
UBQLN2	“up-regulates quantity by stabilization”	HNRNPA3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 132 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.

GO biological processes:

GO term	Partners	Fold	FDR
antibacterial humoral response	6	16.7×	6e-04
antimicrobial humoral immune response mediated by antimicrobial peptide	8	10.9×	6e-04
proteasome-mediated ubiquitin-dependent protein catabolic process	11	4.8×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	4
Uncertain significance	157
Likely benign	52
Benign	8

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
29950	NM_013444.4(UBQLN2):c.1490C>A (p.Pro497His)	Pathogenic
29951	NM_013444.4(UBQLN2):c.1489C>T (p.Pro497Ser)	Pathogenic
29952	NM_013444.4(UBQLN2):c.1516C>A (p.Pro506Thr)	Pathogenic
1175827	NM_013444.4(UBQLN2):c.1174A>G (p.Met392Val)	Likely pathogenic
157594	NM_013444.4(UBQLN2):c.1490C>T (p.Pro497Leu)	Likely pathogenic
2630374	NM_013444.4(UBQLN2):c.1517C>T (p.Pro506Leu)	Likely pathogenic
3336842	NM_013444.4(UBQLN2):c.1663C>T (p.Pro555Ser)	Likely pathogenic

SpliceAI

27 predictions. Top by Δscore:

Variant	Effect	Δscore
X:56564048:G:GT	donor_gain	0.6700
X:56563738:GAG:G	donor_gain	0.5300
X:56563829:C:CA	acceptor_gain	0.5300
X:56564262:GGA:G	donor_gain	0.4500
X:56564263:GAG:G	donor_gain	0.4500
X:56563736:CAGAG:C	donor_loss	0.3900
X:56563737:AGAG:A	donor_loss	0.3900
X:56563739:AG:A	donor_loss	0.3900
X:56563740:G:GC	donor_loss	0.3900
X:56563741:G:GG	donor_loss	0.3900
X:56563742:T:C	donor_loss	0.3900
X:56563738:G:GT	donor_gain	0.3600
X:56563743:A:C	donor_loss	0.3600
X:56564262:G:GT	donor_gain	0.3600
X:56563743:AC:A	donor_gain	0.3200
X:56563744:CC:C	donor_gain	0.3200
X:56563833:C:A	acceptor_gain	0.2600
X:56563839:C:CA	acceptor_gain	0.2600
X:56564269:C:G	donor_gain	0.2600
X:56563718:G:T	donor_gain	0.2400
X:56565382:T:TA	acceptor_gain	0.2400
X:56565383:A:AA	acceptor_gain	0.2400
X:56563837:C:A	acceptor_gain	0.2300
X:56564265:G:GG	donor_gain	0.2200
X:56563745:C:G	donor_gain	0.2100
X:56564264:A:AG	donor_gain	0.2100
X:56563983:TG:T	donor_gain	0.2000

AlphaMissense

4124 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:56563983:T:A	V37E	1.000
X:56563987:G:C	K38N	1.000
X:56563987:G:T	K38N	1.000
X:56564047:G:C	K58N	1.000
X:56564047:G:T	K58N	1.000
X:56564094:T:A	L74Q	1.000
X:56564094:T:C	L74P	1.000
X:56564097:T:A	I75N	1.000
X:56564097:T:C	I75T	1.000
X:56564097:T:G	I75S	1.000
X:56564099:T:C	F76L	1.000
X:56564101:T:A	F76L	1.000
X:56564101:T:G	F76L	1.000
X:56564105:G:A	G78R	1.000
X:56564105:G:C	G78R	1.000
X:56564106:G:A	G78E	1.000
X:56564106:G:T	G78V	1.000
X:56564112:T:A	I80N	1.000
X:56564112:T:C	I80T	1.000
X:56564112:T:G	I80S	1.000
X:56564115:T:C	L81S	1.000
X:56564166:T:A	V98D	1.000
X:56564168:C:G	H99D	1.000
X:56564170:C:A	H99Q	1.000
X:56564170:C:G	H99Q	1.000
X:56564172:T:C	L100P	1.000
X:56564175:T:A	V101D	1.000
X:56564445:T:A	V191D	1.000
X:56564586:C:A	A238D	1.000
X:56564831:T:A	W320R	1.000

dbSNP variants (sampled 300 via entrez): RS1000144718 (X:56566584 G>T), RS1000216289 (X:56566126 G>A,T), RS1000551691 (X:56563723 G>T), RS1000716401 (X:56562051 C>A,T), RS1001066189 (X:56561774 T>C), RS1001391381 (X:56566409 A>G,T), RS1001565814 (X:56567697 A>T), RS1001738106 (X:56566034 T>C), RS1001900968 (X:56565247 C>G,T), RS1001930696 (X:56564718 C>A,T), RS1002048756 (X:56567242 C>G), RS1002339016 (X:56563803 T>G), RS1003017831 (X:56568282 G>A,C), RS1003842036 (X:56563375 T>A), RS1004367601 (X:56562781 T>C)

Disease associations

OMIM: gene MIM:300264 | disease phenotypes: MIM:300857

GenCC curated gene-disease

Disease	Classification	Inheritance
amyotrophic lateral sclerosis type 15	Definitive	X-linked
amyotrophic lateral sclerosis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
amyotrophic lateral sclerosis type 15	Definitive	XL

Mondo (3): amyotrophic lateral sclerosis type 15 (MONDO:0010459), vascular dementia (MONDO:0004648), amyotrophic lateral sclerosis (MONDO:0004976)

Orphanet (1): Amyotrophic lateral sclerosis (Orphanet:803)

HPO phenotypes

58 total (30 of 58 shown, HPO-id order):

HPO	Term
HP:0000217	Xerostomia
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000739	Anxiety
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001308	Tongue fasciculations
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001423	X-linked dominant inheritance
HP:0001618	Dysphonia
HP:0001824	Weight loss
HP:0002015	Dysphagia
HP:0002094	Dyspnea
HP:0002145	Frontotemporal dementia
HP:0002171	Gliosis
HP:0002180	Neurodegeneration
HP:0002305	Athetosis
HP:0002307	Drooling
HP:0002313	Spastic paraparesis
HP:0002360	Sleep disturbance
HP:0002380	Fasciculations
HP:0002463	Language impairment
HP:0002878	Respiratory failure
HP:0003202	Skeletal muscle atrophy
HP:0003324	Generalized muscle weakness
HP:0003376	Steppage gait
HP:0003394	Muscle spasm
HP:0003447	Axonal loss

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D015140	Dementia, Vascular	C10.228.140.300.400; C10.228.140.300.510.800.500; C10.228.140.380.230; C10.228.140.695.500; C14.907.137.126.372.500; C14.907.253.560.350.500; F03.615.400.350

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067354 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	affects expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
sodium arsenite	increases expression	1
potassium chromate(VI)	increases expression, affects cotreatment	1
resorcinol	increases expression	1
M-VAC protocol	increases response to substance	1
epigallocatechin gallate	affects cotreatment, increases expression	1
4-chloro-N-((4-(1,1-dimethylethyl)phenyl)methyl)-3-ethyl-1-methyl-1H-pyrazole-5-carboxamide	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
eprenetapopt	affects expression, affects reaction	1
bisphenol S	affects expression	1
LDN 193189	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Vehicle Emissions	increases expression	1
Benzo(a)pyrene	affects methylation	1
Benztropine	decreases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Furaldehyde	affects cotreatment, affects localization, decreases expression	1
Ivermectin	decreases expression	1
Smoke	decreases expression	1
Sodium Chloride	affects cotreatment, affects localization, decreases expression, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652759	Binding	Binding affinity to human UBQLN2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

4 cell lines: 2 induced pluripotent stem cell, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E7N1	KOLF2.1J UBQLN2 P497H SNV/Y	Induced pluripotent stem cell	Male
CVCL_E7N3	KOLF2.1J UBQLN2 P506T SNV/Y	Induced pluripotent stem cell	Male
CVCL_TW09	HAP1 UBQLN2 (-) 1	Cancer cell line	Male
CVCL_TW10	HAP1 UBQLN2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00165763	PHASE4	COMPLETED	Efficacy and Safety of Donepezil Hydrochloride (Aricept) in Vascular Dementia
NCT00847860	PHASE4	COMPLETED	Cilostazol Verse Asprin for Vascular Dementia in Poststroke Patients With White Matter Lesions
NCT00947531	PHASE4	COMPLETED	A Clinical Trial to Evaluate the Safety and Efficacy of 20 ml Cerebrolysin in Patients With Vascular Dementia
NCT00950430	PHASE4	ENROLLING_BY_INVITATION	Imaging of Brain Amyloid Plaques in the Aging Population
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	PHASE3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	PHASE3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial