UBQLN4

Summary

UBQLN4 (ubiquilin 4, HGNC:1237) is a protein-coding gene on chromosome 1q22, encoding Ubiquilin-4 (Q9NRR5). Regulator of protein degradation that mediates the proteasomal targeting of misfolded, mislocalized or accumulated proteins. It is a selective cancer dependency (DepMap: 61.6% of cell lines).

Enables K48-linked polyubiquitin modification-dependent protein binding activity and identical protein binding activity. Involved in DNA damage response; negative regulation of double-strand break repair via homologous recombination; and regulation of catabolic process. Located in several cellular components, including autophagosome; proteasome complex; and site of DNA damage. Part of protein-containing complex.

Source: NCBI Gene 56893 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 74 total — 1 pathogenic
• Cancer dependency (DepMap): dependent in 61.6% of screened cell lines
• MANE Select transcript: NM_020131

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1237
Approved symbol	UBQLN4
Name	ubiquilin 4
Location	1q22
Locus type	gene with protein product
Status	Approved
Aliases	A1U, UBIN, CIP75
Ensembl gene	ENSG00000160803
Ensembl biotype	protein_coding
OMIM	605440
Entrez	56893

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000368309, ENST00000459954, ENST00000472638, ENST00000879792, ENST00000879793, ENST00000932513, ENST00000932514, ENST00000932515

RefSeq mRNA: 2 — MANE Select: NM_020131 NM_001304342, NM_020131

CCDS: CCDS1127

Canonical transcript exons

ENST00000368309 — 11 exons

Exon	Start	End
ENSE00001054591	156050291	156050553
ENSE00001054596	156048501	156048659
ENSE00001075058	156042153	156042236
ENSE00001075059	156043998	156044223
ENSE00001169782	156042774	156042913
ENSE00001741175	156035299	156037130
ENSE00001911612	156053594	156053798
ENSE00003545836	156041485	156041671
ENSE00003635860	156041872	156041987
ENSE00003669454	156051110	156051327
ENSE00003672986	156051706	156051857

Expression profiles

Bgee: expression breadth ubiquitous, 242 present calls, max score 94.62.

FANTOM5 (CAGE): breadth broad, TPM avg 1.0893 / max 27.0833, expressed in 682 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
15061	1.0893	682

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	94.62	gold quality
ganglionic eminence	UBERON:0004023	94.03	gold quality
ventricular zone	UBERON:0003053	93.85	gold quality
gastrocnemius	UBERON:0001388	93.77	gold quality
right frontal lobe	UBERON:0002810	93.72	gold quality
lower esophagus mucosa	UBERON:0035834	93.65	gold quality
anterior cingulate cortex	UBERON:0009835	93.42	gold quality
caudate nucleus	UBERON:0001873	93.37	gold quality
putamen	UBERON:0001874	93.15	gold quality
muscle of leg	UBERON:0001383	93.12	gold quality
prefrontal cortex	UBERON:0000451	92.99	gold quality
tibialis anterior	UBERON:0001385	92.74	silver quality
hindlimb stylopod muscle	UBERON:0004252	92.65	gold quality
nucleus accumbens	UBERON:0001882	92.04	gold quality
Brodmann (1909) area 9	UBERON:0013540	91.61	gold quality
neocortex	UBERON:0001950	91.46	gold quality
amygdala	UBERON:0001876	91.44	gold quality
frontal cortex	UBERON:0001870	91.20	gold quality
apex of heart	UBERON:0002098	91.12	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	91.11	gold quality
body of stomach	UBERON:0001161	91.02	gold quality
endocervix	UBERON:0000458	90.85	gold quality
ectocervix	UBERON:0012249	90.85	gold quality
left uterine tube	UBERON:0001303	90.83	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.73	gold quality
body of pancreas	UBERON:0001150	90.68	gold quality
esophagus mucosa	UBERON:0002469	90.54	gold quality
cerebellar hemisphere	UBERON:0002245	90.45	gold quality
cerebellar cortex	UBERON:0002129	90.39	gold quality
hypothalamus	UBERON:0001898	89.90	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.01

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

128 targeting UBQLN4, 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-6867-5P	100.00	82.21	3464
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
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-5193	100.00	67.26	1744
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-9718	99.94	68.91	918
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

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 61.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 18)

• A novel connexin43-interacting protein, CIP75, which belongs to the UbL-UBA protein family, regulates the turnover of connexin43 (PMID:18079109)
• Co-immunoprecipitation confirmed the binding of small hydrophobic (SH) protein of mumps virus and ubiquilin 4 and demonstrates that a truncated protein fragment corresponding to amino acids 136-270 of ubiquilin 4 was sufficient for interaction. (PMID:20702650)
• although CIP75 can interact with ubiquitinated cellular proteins, its interaction with Cx43 and stimulation of Cx43 proteasomal degradation does not require the ubiquitination of Cx43. (PMID:20940304)
• Targeting of Ubqln1 to autophagosomes requires the Ubqln4 UBL domain and the Ubqln1 UBA domain. (PMID:23459205)
• results suggested that CIP75 is essential for the interaction of Cx43 and the proteasome, but that alternate compensatory mechanisms exist to supplement the degradation normally facilitated by CIP75 (PMID:24256120)
• UBQLN4 recognizes not only the defective model substrate but also a pool of endogenous defective proteins that were induced by the depletion of the SRP54 subunit of the signal recognition particle. (PMID:27113755)
• Here, the authors present a novel variant in UBQLN4 that is associated with ALS and show that its expression compromises motor axon morphogenesis in mouse motor neurons and in zebrafish. (PMID:28463112)
• UBQLN4, APP, CTNNB1, SHBG, and COL1A1 might be involved in the development of nonalcoholic fatty liver disease, and are proposed as the potential markers for predicting the development of this condition (PMID:28796060)
• results suggest that ubiquitinated proteins are exported from the nucleus to the cytosol in the UBIN-POST complex-dependent manner for the maintenance of nuclear protein homeostasis. (PMID:29666234)
• UBQLN4 may induce cell cycle arrest and apoptosis via activation of the ERK pathway and upregulation of cyclin D1 in GES-1 cells. (PMID:29807370)
• Findings not only establish the anti-tumor potential of Ubqln4 in gastric cancer but also reveal a role for Ubqln4 in regulation of the cell cycle and cellular senescence via stabilizing p21. (PMID:29899380)
• UBQLN4 therefore curtails HRR activity through removal of MRE11 from damaged chromatin. (PMID:30612738)
• Ubqln4 Facilitates Endoplasmic Reticulum-to-Cytosol Escape of a Nonenveloped Virus during Infection. (PMID:32161173)
• Angiogenesis-Centered Molecular Cross-Talk in Amyotrophic Lateral Sclerosis Survival: Mechanistic Insights. (PMID:32558493)
• Regulation of MRE11A by UBQLN4 leads to cisplatin resistance in patients with esophageal squamous cell carcinoma. (PMID:33605536)
• Genomic Amplification of UBQLN4 Is a Prognostic and Treatment Resistance Factor. (PMID:36291176)
• Ubiquilin-4 induces immune escape in gastric cancer by activating the notch signaling pathway. (PMID:37702916)
• UBQLN4 promotes the proliferation and invasion of non-small cell lung cancer cell by regulating PI3K/AKT pathway. (PMID:38969831)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ubqln4	ENSDARG00000052975
mus_musculus	Ubqln4	ENSMUSG00000008604
rattus_norvegicus	Ubqln4	ENSRNOG00000019933
drosophila_melanogaster	CG31528	FBGN0051528

Paralogs (5): UBQLN1 (ENSG00000135018), UBL7 (ENSG00000138629), UBQLNL (ENSG00000175518), UBQLN3 (ENSG00000175520), UBQLN2 (ENSG00000188021)

Protein

Protein identifiers

Ubiquilin-4 — Q9NRR5 (reviewed: Q9NRR5)

Alternative names: Ataxin-1 interacting ubiquitin-like protein, Ataxin-1 ubiquitin-like-interacting protein A1U, Connexin43-interacting protein of 75 kDa

All UniProt accessions (2): Q9NRR5, B4DZF6

UniProt curated annotations — full annotation on UniProt →

Function. Regulator of protein degradation that mediates the proteasomal targeting of misfolded, mislocalized or accumulated proteins. Acts by binding polyubiquitin chains of target proteins via its UBA domain and by interacting with subunits of the proteasome via its ubiquitin-like domain. Key regulator of DNA repair that represses homologous recombination repair: in response to DNA damage, recruited to sites of DNA damage following phosphorylation by ATM and acts by binding and removing ubiquitinated MRE11 from damaged chromatin, leading to MRE11 degradation by the proteasome. MRE11 degradation prevents homologous recombination repair, redirecting double-strand break repair toward non-homologous end joining (NHEJ). Specifically recognizes and binds mislocalized transmembrane-containing proteins and targets them to proteasomal degradation. Collaborates with DESI1/POST in the export of ubiquitinated proteins from the nucleus to the cytoplasm. Also plays a role in the regulation of the proteasomal degradation of non-ubiquitinated GJA1. Acts as an adapter protein that recruits UBQLN1 to the autophagy machinery. Mediates the association of UBQLN1 with autophagosomes and the autophagy-related protein LC3 (MAP1LC3A/B/C) and may assist in the maturation of autophagosomes to autolysosomes by mediating autophagosome-lysosome fusion.

Subunit / interactions. Homooligomer. Binds signal sequences of proteins that are targeted to the endoplasmic reticulum. Interacts (via UBA domain) with GJA1 (not ubiquitinated) and with ubiquitin; both compete for the same binding site. Interacts (via UBA domain) with ubiquitin and with polyubiquitin chains. Interacts (via ubiquitin-like domain) with PSMD2 and PSMD4, regulatory subunits of the 26S proteasome. Interacts with ATXN1/SCA1; interaction with ATXN1 inhibits polyubiquitination of UBQLN4 and interferes with PSMD4 binding. Interacts with HERPUD1. Interacts (via ubiquitin-like domain) with UBQLN1 (via UBA domain). Interacts with UBQLN2. Interacts (via STI1 1 and 2 domains) with MAP1LC3A/B/C. Interacts with BAG6. Interacts with MRE11 (when ubiquitinated); interaction with ubiquitinated MRE11 leads to MRE11 removal from chromatin. Interacts with DESI1/POST; leading to nuclear export. Interacts with BCL2A1 and BCL2L10. (Microbial infection) Interacts with Mumps virus protein SH.

Subcellular location. Nucleus. Cytoplasm. Chromosome. Endoplasmic reticulum. Perinuclear region. Cytoplasmic vesicle. Autophagosome.

Tissue specificity. Highly expressed in pancreas, kidney, skeletal muscle, heart and throughout the brain, and at lower levels in placenta, lung and liver.

Post-translational modifications. Phosphorylated by ATM at Ser-318 in response to DNA damage, leading to localization in the nucleus and recruitment to sites of DNA damage. Ubiquitinated; this does not lead to proteasomal degradation. May undergo both ‘Lys-48’- and ‘Lys-63’-linked polyubiquitination.

Disease relevance. Amyotrophic lateral sclerosis (ALS) [MIM:105400] 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. Disease susceptibility is associated with variants affecting the gene represented in this entry. Defects in UBQLN4 are the cause of the UBQLN4 deficiency syndrome (UBDS). Patients display intellectual impairment, growth retardation, microcephaly, facial dysmorphism, hearing loss, ataxia and anemia. Cells display genomic instability characterized by hypersensitivity to genotoxic agents, leading to enhanced apoptotic cell death in response to DNA damage.

Induction. Up-regulated in aggressive tumors: expression is significantly increased in stage 3 and 4 neuroblastomas, compared to stage 1 disease.

Miscellaneous. May be a potential prognostic marker in cancer patients.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NRR5-1	1	yes
Q9NRR5-2	2

RefSeq proteins (2): NP_001291271, NP_064516* (*=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
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily

Pfam: PF00240, PF00627, PF23195

UniProt features (32 total): compositionally biased region 7, domain 6, modified residue 4, sequence variant 3, region of interest 3, cross-link 2, splice variant 2, mutagenesis site 2, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NRR5-F1	62.18	0.01

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 (6): 98, 144, 287, 318, 23, 62

Mutagenesis-validated functional residues (2):

Position	Phenotype
55	loss of interaction with ubqln1.
318	abolishes phosphorylation by atm in response to dna damage and impaired ability to regulate dna repair.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 154 (showing top): GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_DNA_REPAIR, GOBP_NEGATIVE_REGULATION_OF_DNA_RECOMBINATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, AACYNNNNTTCCS_UNKNOWN, GOBP_REGULATION_OF_DOUBLE_STRAND_BREAK_REPAIR_VIA_HOMOLOGOUS_RECOMBINATION, TAL1ALPHAE47_01, GOBP_REGULATION_OF_DNA_REPAIR, GOBP_MACROAUTOPHAGY, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_AUTOPHAGY, MARTINEZ_RB1_TARGETS_UP

GO Biological Process (10): DNA repair (GO:0006281), ubiquitin-dependent protein catabolic process (GO:0006511), autophagy (GO:0006914), DNA damage response (GO:0006974), regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032434), negative regulation of autophagosome maturation (GO:1901097), negative regulation of double-strand break repair via homologous recombination (GO:2000042), cellular response to stress (GO:0033554), regulation of proteasomal protein catabolic process (GO:0061136), regulation of cellular response to stress (GO:0080135)

GO Molecular Function (4): polyubiquitin modification-dependent protein binding (GO:0031593), K48-linked polyubiquitin modification-dependent protein binding (GO:0036435), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (14): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), autophagosome (GO:0005776), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), cytoplasmic vesicle (GO:0031410), protein-containing complex (GO:0032991), perinuclear region of cytoplasm (GO:0048471), site of DNA damage (GO:0090734), chromosome (GO:0005694), endoplasmic reticulum (GO:0005783), nuclear proteasome complex (GO:0031595), cytosolic proteasome complex (GO:0031597)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoplasm	4
cellular response to stress	2
intracellular membrane-bounded organelle	2
nuclear lumen	2
proteasome complex	2
DNA metabolic process	1
DNA damage response	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
regulation of proteasomal protein catabolic process	1
regulation of ubiquitin-dependent protein catabolic process	1
negative regulation of macroautophagy	1
negative regulation of protein-containing complex disassembly	1
autophagosome maturation	1
regulation of autophagosome maturation	1
double-strand break repair via homologous recombination	1
regulation of double-strand break repair via homologous recombination	1
negative regulation of DNA recombination	1
negative regulation of double-strand break repair	1
response to stress	1
cellular response to stimulus	1
proteasomal protein catabolic process	1
regulation of protein catabolic process	1
regulation of cellular process	1
regulation of response to stress	1
modification-dependent protein binding	1
polyubiquitin modification-dependent protein binding	1
protein binding	1
binding	1
intracellular anatomical structure	1
vacuole	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
intracellular vesicle	1

Protein interactions and networks

STRING

4302 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UBQLN4	ATXN1	P54253	989
UBQLN4	PSMD4	P55036	858
UBQLN4	HSPA13	P48723	827
UBQLN4	HSPA4	P34932	738
UBQLN4	RNF114	Q9Y508	736
UBQLN4	TARDBP	Q13148	667
UBQLN4	GJA1	P17302	631
UBQLN4	SLC35F6	Q8N357	603
UBQLN4	FBXO6	Q9NRD1	600
UBQLN4	FAF2	Q96CS3	591
UBQLN4	UBE3A	P78355	588
UBQLN4	RBM17	Q96I25	577
UBQLN4	EPS15	P42566	573
UBQLN4	STIP1	P31948	570
UBQLN4	PQBP1	O60828	567

IntAct

265 interactions, top by confidence:

A	B	Type	Score
STK25	STRN	psi-mi:“MI:0914”(association)	0.900
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
UBQLN1	UBQLN4	psi-mi:“MI:0915”(physical association)	0.720
UBQLN4	UBQLN1	psi-mi:“MI:0915”(physical association)	0.720
UBQLN4	UBQLN1	psi-mi:“MI:0403”(colocalization)	0.720
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
UBQLN4	UBQLN4	psi-mi:“MI:0915”(physical association)	0.680
DYNLL2	BLTP3B	psi-mi:“MI:0914”(association)	0.640
UBQLN4	ATXN1	psi-mi:“MI:0915”(physical association)	0.590
UBQLN4	ATXN1	psi-mi:“MI:0403”(colocalization)	0.590
ATXN1	UBQLN4	psi-mi:“MI:0915”(physical association)	0.590
UBQLN4	MAP1LC3A	psi-mi:“MI:0403”(colocalization)	0.570
MAP1LC3A	UBQLN4	psi-mi:“MI:0407”(direct interaction)	0.570
UBQLN4	MAP1LC3A	psi-mi:“MI:0915”(physical association)	0.570
UBQLN1		psi-mi:“MI:0914”(association)	0.560
PRPF40A	UBQLN4	psi-mi:“MI:0915”(physical association)	0.550
TMEM31	PSMD11	psi-mi:“MI:0914”(association)	0.530
KDELR1	TRAFD1	psi-mi:“MI:0914”(association)	0.530
MSRB2	BLTP3B	psi-mi:“MI:0914”(association)	0.530
ZMYM4	ILVBL	psi-mi:“MI:0914”(association)	0.530
UBQLN4	FKBP2	psi-mi:“MI:0915”(physical association)	0.510
UBQLN4	MLLT6	psi-mi:“MI:0915”(physical association)	0.510
UBQLN4	PDLIM7	psi-mi:“MI:0915”(physical association)	0.510

BioGRID (318): UBQLN4 (Two-hybrid), UBC (Reconstituted Complex), ASNS (Co-fractionation), RAD23A (Co-fractionation), RAD23B (Co-fractionation), UBQLN4 (Affinity Capture-MS), UBQLN4 (Affinity Capture-MS), GJA5 (Reconstituted Complex), GJC1 (Reconstituted Complex), GJA1 (Reconstituted Complex), UBQLN4 (Affinity Capture-Western), UBQLN4 (Affinity Capture-Western), GJB1 (Affinity Capture-Western), BAG6 (Affinity Capture-Western), UBQLN4 (Two-hybrid)

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: A3KMV2, A3KPW9, A4IH17, A5D9M6, A7X5R6, D5LXJ0, G1SK22, G5EFF7, O14399, O65381, O74803, P0C030, P0C031, P0C032, P0C073, P0C273, P0C275, P0C276, P0CG47, P0CG48, P0CG49, P0CG50, P0CG51, P0CG53, P0CG54, P0CG55, P0CG60, P0CG61, P0CG62, P0CG64, P0CG65, P0CG66, P0CG67, P0CG68, P0CG69, P0CH28, P0DXC2, P15357, P16709, P18101

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
ATM	“up-regulates activity”	UBQLN4	phosphorylation
UBQLN4	“up-regulates activity”	MRE11	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	57
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
4537401	NM_020131.5(UBQLN4):c.976C>T (p.Arg326Ter)	Pathogenic

SpliceAI

1945 predictions. Top by Δscore:

Variant	Effect	Δscore
1:156037012:G:C	donor_gain	1.0000
1:156041482:TACC:T	donor_loss	1.0000
1:156041483:A:T	donor_loss	1.0000
1:156041484:C:CA	donor_loss	1.0000
1:156041500:T:TA	donor_gain	1.0000
1:156041985:CAT:C	acceptor_gain	1.0000
1:156041987:TCT:T	acceptor_loss	1.0000
1:156041988:C:CC	acceptor_gain	1.0000
1:156041988:C:T	acceptor_loss	1.0000
1:156041991:G:GC	acceptor_gain	1.0000
1:156042149:TCA:T	donor_loss	1.0000
1:156042150:CA:C	donor_loss	1.0000
1:156042151:A:AC	donor_gain	1.0000
1:156042152:C:CC	donor_gain	1.0000
1:156042152:CCTG:C	donor_gain	1.0000
1:156042233:TCAT:T	acceptor_gain	1.0000
1:156042234:CATC:C	acceptor_gain	1.0000
1:156042770:ATACC:A	donor_loss	1.0000
1:156042771:TAC:T	donor_loss	1.0000
1:156042772:A:C	donor_loss	1.0000
1:156042909:CATCC:C	acceptor_gain	1.0000
1:156042910:ATCC:A	acceptor_gain	1.0000
1:156042911:TCC:T	acceptor_gain	1.0000
1:156042912:CC:C	acceptor_gain	1.0000
1:156042912:CCC:C	acceptor_gain	1.0000
1:156042913:CC:C	acceptor_gain	1.0000
1:156042914:C:CC	acceptor_gain	1.0000
1:156042925:C:CT	acceptor_gain	1.0000
1:156042926:G:T	acceptor_gain	1.0000
1:156048656:TTGT:T	acceptor_gain	1.0000

AlphaMissense

3941 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:156037000:A:G	L595P	1.000
1:156037012:G:T	A591D	1.000
1:156037013:C:G	A591P	1.000
1:156037027:C:A	G586V	1.000
1:156037027:C:T	G586E	1.000
1:156037028:C:A	G586W	1.000
1:156037037:C:G	A583P	1.000
1:156037042:A:G	L581P	1.000
1:156037042:A:T	L581Q	1.000
1:156037046:C:G	A580P	1.000
1:156037051:A:G	L578P	1.000
1:156037071:G:C	F571L	1.000
1:156037071:G:T	F571L	1.000
1:156037072:A:C	F571C	1.000
1:156037072:A:G	F571S	1.000
1:156037073:A:C	F571V	1.000
1:156037073:A:G	F571L	1.000
1:156037075:C:A	G570V	1.000
1:156037075:C:T	G570D	1.000
1:156037076:C:A	G570C	1.000
1:156037076:C:G	G570R	1.000
1:156037087:A:G	L566P	1.000
1:156037087:A:T	L566H	1.000
1:156037096:A:G	L563P	1.000
1:156044125:C:A	W333C	1.000
1:156044125:C:G	W333C	1.000
1:156044127:A:G	W333R	1.000
1:156044127:A:T	W333R	1.000
1:156048511:G:T	A297D	1.000
1:156048545:A:C	Y286D	1.000

dbSNP variants (sampled 300 via entrez): RS1000033686 (1:156046141 C>T), RS1000286210 (1:156032463 A>G), RS1000305713 (1:156038581 C>A,T), RS1000549353 (1:156054436 C>T), RS1000555633 (1:156053153 G>A,T), RS1000893115 (1:156030862 G>T), RS1000905891 (1:156037415 G>A), RS1000919977 (1:156038519 T>C), RS1000961145 (1:156052402 C>G), RS1001034282 (1:156044473 C>A), RS1001108747 (1:156044018 T>C), RS1001166498 (1:156045913 T>C), RS1001377079 (1:156039143 C>T), RS1001649573 (1:156030910 T>A), RS1001713114 (1:156044147 C>T)

Disease associations

OMIM: gene MIM:605440 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001725_35	Inflammatory bowel disease	6.000000e-11
GCST004131_70	Inflammatory bowel disease	6.000000e-08
GCST004132_44	Crohn’s disease	2.000000e-07
GCST007294_124	Body fat distribution (trunk fat ratio)	8.000000e-35
GCST007294_3	Body fat distribution (trunk fat ratio)	6.000000e-21
GCST007294_50	Body fat distribution (trunk fat ratio)	1.000000e-15
GCST007295_17	Body fat distribution (leg fat ratio)	3.000000e-13
GCST007295_37	Body fat distribution (leg fat ratio)	7.000000e-17
GCST007295_72	Body fat distribution (leg fat ratio)	1.000000e-28
GCST007325_8	General risk tolerance (MTAG)	7.000000e-09
GCST008129_6	Body mass index	2.000000e-13

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004341	body fat distribution
EFO:0008579	risk-taking behaviour
EFO:0004340	body mass index

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects expression, increases expression	2
Tobacco Smoke Pollution	increases expression, increases methylation	2
aristolochic acid I	increases expression	1
dicrotophos	increases expression	1
beta-lapachone	increases expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects 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
ICG 001	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Arsenic	affects methylation	1
Caffeine	decreases phosphorylation	1
Cuprizone	decreases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Formaldehyde	increases expression	1
Haloperidol	decreases expression	1
Ivermectin	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Thiram	decreases expression	1
Cyclosporine	decreases methylation	1
Aflatoxin B1	increases methylation	1
Genistein	increases expression	1

Cellosaurus cell lines

6 cell lines: 5 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9VC	Ubigene HEK293 UBQLN4 KO	Transformed cell line	Female
CVCL_DX12	HAP1 UBQLN4 (-) 1	Cancer cell line	Male
CVCL_DX13	HAP1 UBQLN4 (-) 2	Cancer cell line	Male
CVCL_DX65	HAP1 UBQLN1 (-) UBQLN4 (-) 1	Cancer cell line	Male
CVCL_DX66	HAP1 UBQLN1 (-) UBQLN4 (-) 2	Cancer cell line	Male
CVCL_E1DX	Ubigene U2OS UBQLN4 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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