OTUD5

Summary

OTUD5 (OTU deubiquitinase 5, HGNC:25402) is a protein-coding gene on chromosome Xp11.23, encoding OTU domain-containing protein 5 (Q96G74). Deubiquitinating enzyme that functions as a negative regulator of the innate immune system. It is a selective cancer dependency (DepMap: 25.2% of cell lines).

This gene encodes a member of the OTU (ovarian tumor) domain-containing cysteine protease superfamily. The OTU domain confers deubiquitinase activity and the encoded protein has been shown to suppress the type I interferon-dependent innate immune response by cleaving the polyubiquitin chain from an essential type I interferon adaptor protein. Cleavage results in disassociation of the adaptor protein from a downstream signaling complex and disruption of the type I interferon signaling cascade. Alternatively spliced transcript variants encoding different isoforms have been described.

Source: NCBI Gene 55593 — RefSeq curated summary.

At a glance

• Gene–disease (curated): multiple congenital anomalies-neurodevelopmental syndrome, X-linked (Strong, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 144 total — 5 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 71
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 25.2% of screened cell lines
• MANE Select transcript: NM_001136157

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25402
Approved symbol	OTUD5
Name	OTU deubiquitinase 5
Location	Xp11.23
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp761A052, DUBA
Ensembl gene	ENSG00000068308
Ensembl biotype	protein_coding
OMIM	300713
Entrez	55593

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 14 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000156084, ENST00000376488, ENST00000396743, ENST00000428668, ENST00000455452, ENST00000481142, ENST00000484499, ENST00000908267, ENST00000908268, ENST00000908269, ENST00000908270, ENST00000931426, ENST00000931427, ENST00000931428, ENST00000951385, ENST00000951386

RefSeq mRNA: 4 — MANE Select: NM_001136157 NM_001136157, NM_001136158, NM_001136159, NM_017602

CCDS: CCDS14313, CCDS48104, CCDS48105

Canonical transcript exons

ENST00000376488 — 9 exons

Exon	Start	End
ENSE00000670807	48934464	48934612
ENSE00000670809	48925847	48926050
ENSE00000670811	48923851	48924052
ENSE00000670813	48923633	48923746
ENSE00001884198	48922024	48923295
ENSE00001912090	48956977	48957607
ENSE00003479529	48944190	48944283
ENSE00003540047	48934954	48935018
ENSE00003665418	48934711	48934867

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 97.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.1744 / max 374.6097, expressed in 1820 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199208	14.0669	1793
199210	6.7505	1735
199215	4.6104	1722
199212	2.1904	1256
199211	1.3372	974
199207	0.7513	224
199209	0.6954	294
199213	0.3394	145
199214	0.2190	64
199204	0.1433	45

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper arm skin	UBERON:0004263	97.00	gold quality
cardiac muscle of right atrium	UBERON:0003379	96.90	silver quality
granulocyte	CL:0000094	96.28	gold quality
nasal cavity epithelium	UBERON:0005384	95.94	silver quality
kidney epithelium	UBERON:0004819	95.73	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.54	gold quality
cerebellar cortex	UBERON:0002129	95.46	gold quality
cerebellar hemisphere	UBERON:0002245	95.46	gold quality
prefrontal cortex	UBERON:0000451	95.41	gold quality
left ovary	UBERON:0002119	95.32	gold quality
right ovary	UBERON:0002118	95.28	gold quality
spleen	UBERON:0002106	95.21	gold quality
right frontal lobe	UBERON:0002810	95.19	gold quality
vena cava	UBERON:0004087	95.18	gold quality
left ventricle myocardium	UBERON:0006566	95.18	silver quality
body of uterus	UBERON:0009853	95.16	gold quality
cerebellum	UBERON:0002037	95.12	gold quality
anterior cingulate cortex	UBERON:0009835	95.07	gold quality
nucleus accumbens	UBERON:0001882	95.05	gold quality
mucosa of stomach	UBERON:0001199	94.99	gold quality
cardia of stomach	UBERON:0001162	94.97	gold quality
popliteal artery	UBERON:0002250	94.95	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.94	gold quality
tibial artery	UBERON:0007610	94.94	gold quality
stromal cell of endometrium	CL:0002255	94.92	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.91	gold quality
left uterine tube	UBERON:0001303	94.89	gold quality
endocervix	UBERON:0000458	94.78	gold quality
right uterine tube	UBERON:0001302	94.73	gold quality
pituitary gland	UBERON:0000007	94.70	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.41
E-GEOD-70580	no	1027.88

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TP53

miRNA regulators (miRDB)

53 targeting OTUD5, 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-4533	100.00	69.48	2758
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6079	99.84	68.54	1170
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-6733-3P	99.54	67.80	1281
HSA-MIR-888-3P	99.53	69.77	1057
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-6828-5P	99.31	69.21	1433

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 25.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 19)

• data identify DUBA as a negative regulator of innate immune responses (PMID:17991829)
• Here the authors show that phosphorylation of the human deubiquitinase DUBA (OTUD5) at a single residue, Ser177, is both necessary and sufficient to activate the enzyme. (PMID:22245969)
• OTUD5 is required for the stabilization and the activation of a p53 response (PMID:24143256)
• Findings have uncovered an apoptotic signaling cascade linking PDCD5, OTUD5, and p53 during genotoxic stress responses. (PMID:25499082)
• OTUD5 localizes to DNA double strand breaks, interacts with UBR5 and represses the RNA Pol II elongation and RNA synthesis. (PMID:30508113)
• OTUD5 is a specific deubiquitinase for Ku80 and is an important and positive regulator of non-homologous end joining repair. (PMID:30980112)
• OTUD5 cooperates with TRIM25 in transcriptional regulation and tumor progression via deubiquitination activity. (PMID:32826889)
• Deubiquitinase OTUD5 is a positive regulator of mTORC1 and mTORC2 signaling pathways. (PMID:33110214)
• An X-linked syndrome with severe neurodevelopmental delay, hydrocephalus, and early lethality caused by a missense variation in the OTUD5 gene. (PMID:33131077)
• Conformational Dynamics of Deubiquitinase A and Functional Implications. (PMID:33417762)
• Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation. (PMID:33523931)
• OTUD5-mediated deubiquitination of YAP in macrophage promotes M2 phenotype polarization and favors triple-negative breast cancer progression. (PMID:33587979)
• Mechanism of OTUD5 in non-small cell lung cancer cell proliferation, invasion, and migration. (PMID:35765958)
• Deubiquitinase OTUD5 modulates mTORC1 signaling to promote bladder cancer progression. (PMID:36085200)
• The Regulation and Double-Edged Roles of the Deubiquitinase OTUD5. (PMID:37190070)
• Hepatocyte Deubiquitinating Enzyme OTUD5 Deficiency is a Key Aggravator for Metabolic Dysfunction-Associated Steatohepatitis by Disturbing Mitochondrial Homeostasis. (PMID:38036082)
• Autophagy of OTUD5 destabilizes GPX4 to confer ferroptosis-dependent kidney injury. (PMID:38110369)
• OTUD5 promotes the growth of hepatocellular carcinoma by deubiquitinating and stabilizing SLC38A1. (PMID:38658981)
• OTUD5 promotes end-joining of deprotected telomeres by promoting ATM-dependent phosphorylation of KAP1[S824]. (PMID:39420004)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	otud5b	ENSDARG00000056840
danio_rerio	otud5a	ENSDARG00000059006
mus_musculus	Otud5	ENSMUSG00000031154
rattus_norvegicus	Otud5	ENSRNOG00000008764
drosophila_melanogaster	Duba	FBGN0036180
caenorhabditis_elegans		WBGENE00015249

Paralogs (5): OTUD6B (ENSG00000155100), OTUD4 (ENSG00000164164), OTUD1 (ENSG00000165312), OTUD3 (ENSG00000169914), OTUD6A (ENSG00000189401)

Protein

Protein identifiers

OTU domain-containing protein 5 — Q96G74 (reviewed: Q96G74)

Alternative names: Deubiquitinating enzyme A

All UniProt accessions (2): Q96G74, H7BZQ3

UniProt curated annotations — full annotation on UniProt →

Function. Deubiquitinating enzyme that functions as a negative regulator of the innate immune system. Has peptidase activity towards ‘Lys-48’- and ‘Lys-63’-linked polyubiquitin chains. Can also cleave ‘Lys-11’-linked ubiquitin chains (in vitro). Acts via TRAF3 deubiquitination and subsequent suppression of type I interferon (IFN) production. Controls neuroectodermal differentiation through cleaving ‘Lys-48’-linked ubiquitin chains to counteract degradation of select chromatin regulators such as ARID1A, HDAC2 and HCF1. Acts as a positive regulator of mTORC1 and mTORC2 signaling following phosphorylation by MTOR: acts by mediating deubiquitination of BTRC, leading to its stability.

Subunit / interactions. Interacts with TRAF3.

Subcellular location. Nucleus.

Tissue specificity. Expressed in various tissues, including the liver and placenta, as well as in peripheral blood leukocytes.

Post-translational modifications. Phosphorylation at Ser-177 is required for deubiquitinating activity. Phosphorylation at Ser-328, Ser-337 and Ser-508 by MTOR promotes its activity.

Disease relevance. Multiple congenital anomalies-neurodevelopmental syndrome, X-linked (MCAND) [MIM:301056] An X-linked recessive, congenital disorder characterized by central nervous system, craniofacial, cardiac, skeletal, and genitourinary anomalies. Clinical features include poor growth, short stature, global developmental delay, impaired intellectual development, microcephaly, hydrocephalus, hypotonia, congenital heart defects, hypospadias, and other variable abnormalities. Brain imaging typically shows ventriculomegaly and thin corpus callosum. The severity of the disorder is highly variable, ranging from death in early infancy to survival into the second or third decade. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by N-ethyl-maleimide (NEM).

Induction. Up-regulated by bacterial lipopolysaccharide (LPS) in bone marrow-derived macrophages.

Miscellaneous. Dubious isoform produced through aberrant splice sites. Dubious isoform produced through aberrant splice sites.

Similarity. Belongs to the peptidase C85 family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q96G74-1	1	yes
Q96G74-2	2
Q96G74-3	3
Q96G74-4	4
Q96G74-5	5

RefSeq proteins (4): NP_001129629, NP_001129630, NP_001129631, NP_060072 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003323	OTU_dom	Domain
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050704	Peptidase_C85-like	Family

Pfam: PF02338

UniProt features (64 total): modified residue 11, helix 10, sequence variant 7, mutagenesis site 7, compositionally biased region 6, region of interest 6, strand 6, splice variant 5, active site 3, chain 1, domain 1, turn 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3PFY	X-RAY DIFFRACTION	1.7
3TMP	X-RAY DIFFRACTION	1.91
3TMO	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96G74-F1	66.15	0.31

Functional residue map

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

Catalytic / active sites (3): 221; 224 (nucleophile); 334

Post-translational modifications (11): 64, 165, 175, 177, 195, 328, 337, 375, 452, 507, 508

Mutagenesis-validated functional residues (7):

Position	Phenotype
177	loss of deubiquitinase activity. abolishes activation by protein kinases.
224	loss of deubiquitinase activity. loss of suppression of ifn production. no effect on nuclear location.
328	reduced phosphorylation. reduced ability to promote stabilization of btrc; when associated with a-337 and a-508.
337	reduced phosphorylation. reduced ability to promote stabilization of btrc; when associated with a-328 and a-508.
508	reduced phosphorylation. reduced ability to promote stabilization of btrc; when associated with a-328 and a-337.
542	loss of ‘k-48’- and ‘k-63’-linked polyubiquitin chain binding. partial loss of traf3 deubiquitination; when associated w
549	loss of ‘k-48’- and ‘k-63’-linked polyubiquitin chain binding. partial loss of traf3 deubiquitination; when associated w

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5689896	Ovarian tumor domain proteases
R-HSA-936440	Negative regulators of DDX58/IFIH1 signaling

MSigDB gene sets: 372 (showing top): REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, RNGTGGGC_UNKNOWN, WANG_CLIM2_TARGETS_UP, REACTOME_INNATE_IMMUNE_SYSTEM, TGCGCANK_UNKNOWN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_POSITIVE_REGULATION_OF_TOR_SIGNALING, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_NEGATIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GGGTGGRR_PAX4_03, GOBP_PROTEIN_MODIFICATION_BY_SMALL_PROTEIN_REMOVAL, FERREIRA_EWINGS_SARCOMA_UNSTABLE_VS_STABLE_DN, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS

GO Biological Process (13): proteolysis (GO:0006508), neural crest cell differentiation (GO:0014033), protein deubiquitination (GO:0016579), negative regulation of type I interferon production (GO:0032480), response to lipopolysaccharide (GO:0032496), regulation of immune response (GO:0050776), protein K63-linked deubiquitination (GO:0070536), protein K48-linked deubiquitination (GO:0071108), negative regulation of canonical Wnt signaling pathway (GO:0090090), positive regulation of TORC1 signaling (GO:1904263), positive regulation of TORC2 signaling (GO:1904515), negative regulation of cytokine production (GO:0001818), cell differentiation (GO:0030154)

GO Molecular Function (7): cysteine-type deubiquitinase activity (GO:0004843), K63-linked deubiquitinase activity (GO:0061578), deubiquitinase activity (GO:0101005), K48-linked deubiquitinase activity (GO:1990380), peptidase activity (GO:0008233), cysteine-type peptidase activity (GO:0008234), hydrolase activity (GO:0016787)

GO Cellular Component (2): nucleus (GO:0005634), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Deubiquitination	1
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
deubiquitinase activity	3
protein deubiquitination	2
positive regulation of TOR signaling	2
protein metabolic process	1
mesenchymal cell differentiation	1
stem cell differentiation	1
cysteine-type deubiquitinase activity	1
protein modification by small protein removal	1
negative regulation of cytokine production	1
regulation of type I interferon production	1
type I interferon production	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
regulation of immune system process	1
immune response	1
regulation of response to stimulus	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
TORC1 signaling	1
regulation of TORC1 signaling	1
TORC2 signaling	1
regulation of TORC2 signaling	1
cytokine production	1
regulation of cytokine production	1
negative regulation of gene expression	1
negative regulation of multicellular organismal process	1
cellular developmental process	1
cysteine-type peptidase activity	1
ubiquitin-like protein peptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
intracellular membrane-bounded organelle	1
cytoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1248 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OTUD5	TRAF3	Q13114	903
OTUD5	TBK1	Q9UHD2	858
OTUD5	ZUP1	Q96AP4	821
OTUD5	UBR5	O95071	782
OTUD5	IKBKE	Q14164	736
OTUD5	OTUB1	Q96FW1	733
OTUD5	OTUB2	Q96DC9	672
OTUD5	IRF3	Q14653	668
OTUD5	TANK	Q92844	668
OTUD5	OTUD7B	Q6GQQ9	652
OTUD5	OTUD6B	Q8N6M0	650
OTUD5	CYLD	Q9NQC7	647
OTUD5	USP11	P51784	630
OTUD5	TRAF6	Q9Y4K3	630
OTUD5	OTULIN	Q96BN8	626

IntAct

27 interactions, top by confidence:

A	B	Type	Score
gag	PDCD6IP	psi-mi:“MI:0915”(physical association)	0.710
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
TRIM35	MTA2	psi-mi:“MI:0914”(association)	0.530
TNFAIP3	UBB	psi-mi:“MI:0914”(association)	0.530
OTUD5		psi-mi:“MI:0915”(physical association)	0.520
	OTUD5	psi-mi:“MI:0915”(physical association)	0.520
KSR1	FBLL1	psi-mi:“MI:0914”(association)	0.350
KSR1	DDX39A	psi-mi:“MI:0914”(association)	0.350
KSR1	FAM168B	psi-mi:“MI:0914”(association)	0.350
KSR1		psi-mi:“MI:0914”(association)	0.350
MAD2L2		psi-mi:“MI:0914”(association)	0.350
OTUD5	TP53	psi-mi:“MI:0914”(association)	0.350
USP11	PRRC2B	psi-mi:“MI:0914”(association)	0.350
rep	VWA8	psi-mi:“MI:0914”(association)	0.350
LIN28A	MEX3A	psi-mi:“MI:0914”(association)	0.350
LIN28A	AGPS	psi-mi:“MI:0914”(association)	0.350
hspa1a_hspa1b_human-1	SHTN1	psi-mi:“MI:0914”(association)	0.350
HSPA2	HGS	psi-mi:“MI:0914”(association)	0.350
RABGEF1	GAK	psi-mi:“MI:0914”(association)	0.350
GRN	COX6B1	psi-mi:“MI:0914”(association)	0.350
OTUD7A	OTUD7B	psi-mi:“MI:0914”(association)	0.350
MAB21L3	AHCYL1	psi-mi:“MI:0914”(association)	0.350
OTUD5		psi-mi:“MI:0915”(physical association)	0.000
metG	OTUD5	psi-mi:“MI:0915”(physical association)	0.000
ARPC3	OTUD5	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (110): OTUD5 (Affinity Capture-RNA), OTUD5 (Affinity Capture-MS), OTUD5 (Affinity Capture-Western), PDCD5 (Affinity Capture-Western), TP53 (Affinity Capture-Western), PDCD5 (Co-localization), TP53 (Co-localization), OTUD5 (Two-hybrid), OTUD5 (Reconstituted Complex), OTUD5 (Reconstituted Complex), OTUD5 (Affinity Capture-MS), OTUD5 (Affinity Capture-MS), OTUD5 (Affinity Capture-MS), OTUD5 (Affinity Capture-MS), OTUD5 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2JUG7, A1YER5, A1YFY1, A2T6X5, B2DD29, C0HBT3, O08629, O15156, O15169, O35730, O60307, O95343, P0C0T2, P28702, P28704, P29353, P50241, P98083, Q06587, Q0IHB0, Q13263, Q2V2M9, Q2YDU3, Q3U1V8, Q3U2S4, Q4KMP7, Q5DU25, Q5JU85, Q5PRF9, Q5R7W7, Q5RBI7, Q5RJI5, Q5TJF3, Q5TJF7, Q62233, Q62318, Q66J69, Q68DC2, Q6MGB6, Q6ZRS2

Diamond homologs: B2RRE7, F4K3M6, P10383, Q01804, Q08BW0, Q2YDU3, Q3U2S4, Q5T2D3, Q640H3, Q6GL44, Q7ZX21, Q96G74, Q9D8C3, Q9NP73, Q9XIP2, Q5VV17, Q9CUB6, Q9LZF7, Q9VR20, Q9SGA5, O80949, Q0V869, Q54P70, Q8LBW2

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
OTUD5	“down-regulates activity”	TRAF3	deubiquitination
CSNK2A1	“up-regulates activity”	OTUD5	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 34 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
Ovarian tumor domain proteases	5	58.0×	7e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	5
Uncertain significance	66
Likely benign	9
Benign	1

Top pathogenic / likely-pathogenic (10)

Variant ID	HGVS	Classification
1174501	NM_001136157.2(OTUD5):c.1477C>T (p.Gln493Ter)	Pathogenic
996322	NM_001136157.2(OTUD5):c.598G>A (p.Glu200Lys)	Pathogenic
996323	NM_001136157.2(OTUD5):c.1465G>A (p.Gly489Ser)	Pathogenic
996324	NM_001136157.2(OTUD5):c.1040T>C (p.Leu347Pro)	Pathogenic
996326	NM_001136157.2(OTUD5):c.1195C>T (p.Arg399Trp)	Pathogenic
2204087	NM_001136157.2(OTUD5):c.1543C>T (p.Arg515Trp)	Likely pathogenic
2629974	NM_001136157.2(OTUD5):c.1100C>T (p.Ser367Leu)	Likely pathogenic
3374739	NM_001136157.2(OTUD5):c.863T>C (p.Met288Thr)	Likely pathogenic
4820347	NM_001136157.2(OTUD5):c.1544G>T (p.Arg515Leu)	Likely pathogenic
635108	NC_000023.11:g.48930034_48935858del	Likely pathogenic

SpliceAI

1143 predictions. Top by Δscore:

Variant	Effect	Δscore
X:48923291:CAGAC:C	acceptor_gain	1.0000
X:48923292:AGACC:A	acceptor_loss	1.0000
X:48923293:GACCT:G	acceptor_loss	1.0000
X:48923296:C:CG	acceptor_loss	1.0000
X:48923296:CTG:C	acceptor_gain	1.0000
X:48923297:T:G	acceptor_loss	1.0000
X:48923304:C:CT	acceptor_gain	1.0000
X:48923847:TGAC:T	donor_loss	1.0000
X:48923849:ACCTG:A	donor_loss	1.0000
X:48924053:C:CC	acceptor_gain	1.0000
X:48925844:CACCT:C	donor_loss	1.0000
X:48925845:A:T	donor_loss	1.0000
X:48925846:C:T	donor_loss	1.0000
X:48925846:CCTGG:C	donor_gain	1.0000
X:48926046:GCAAA:G	acceptor_gain	1.0000
X:48926047:CAAA:C	acceptor_gain	1.0000
X:48926047:CAAAC:C	acceptor_gain	1.0000
X:48926048:AAA:A	acceptor_gain	1.0000
X:48926049:AA:A	acceptor_gain	1.0000
X:48926051:C:CC	acceptor_gain	1.0000
X:48926054:C:CT	acceptor_gain	1.0000
X:48926055:A:T	acceptor_gain	1.0000
X:48934462:ACC:A	donor_gain	1.0000
X:48934463:CCC:C	donor_gain	1.0000
X:48934706:AGTAC:A	donor_loss	1.0000
X:48934707:GTACC:G	donor_loss	1.0000
X:48934722:TGG:T	donor_gain	1.0000
X:48934731:T:TA	donor_gain	1.0000
X:48934863:TTCAT:T	acceptor_gain	1.0000
X:48934864:TCAT:T	acceptor_gain	1.0000

AlphaMissense

3668 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:48923245:A:G	S549P	1.000
X:48923251:C:G	A547P	1.000
X:48923253:A:G	L546P	1.000
X:48925897:A:G	W410R	1.000
X:48925897:A:T	W410R	1.000
X:48925902:A:G	L408P	1.000
X:48925906:A:C	Y407D	1.000
X:48925908:G:A	S406F	1.000
X:48925909:A:G	S406P	1.000
X:48925914:C:G	R404P	1.000
X:48925917:G:T	A403D	1.000
X:48925918:C:G	A403P	1.000
X:48925923:T:G	Q401P	1.000
X:48925932:A:T	I398N	1.000
X:48925936:C:G	A397P	1.000
X:48925944:G:A	T394I	1.000
X:48925948:C:G	A393P	1.000
X:48925952:C:A	W391C	1.000
X:48925952:C:G	W391C	1.000
X:48925954:A:G	W391R	1.000
X:48925954:A:T	W391R	1.000
X:48925956:T:A	D390V	1.000
X:48925956:T:C	D390G	1.000
X:48925957:C:G	D390H	1.000
X:48925959:G:A	T389I	1.000
X:48925963:C:G	A388P	1.000
X:48925965:C:G	R387P	1.000
X:48925970:C:A	K385N	1.000
X:48925970:C:G	K385N	1.000
X:48925974:T:A	D384V	1.000

dbSNP variants (sampled 300 via entrez): RS1000003761 (X:48955532 T>C), RS1000190544 (X:48931585 C>A,T), RS1000201639 (X:48923079 A>G), RS1000252690 (X:48923460 C>T), RS1000551282 (X:48950004 C>G), RS1000698951 (X:48940673 A>G), RS1000899943 (X:48949710 G>A), RS1000960802 (X:48956679 G>A), RS1001165160 (X:48931293 A>G), RS1001252083 (X:48925334 C>T), RS1001503356 (X:48951276 C>A,G,T), RS1001597199 (X:48933136 C>T), RS1001694185 (X:48942910 T>C), RS1001961755 (X:48958950 C>A,G), RS1002191839 (X:48935853 C>T)

Disease associations

OMIM: gene MIM:300713 | disease phenotypes: MIM:301056, MIM:300894

GenCC curated gene-disease

Disease	Classification	Inheritance
multiple congenital anomalies-neurodevelopmental syndrome, X-linked	Strong	X-linked
multiple congenital anomalies/dysmorphic syndrome	Moderate	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
multiple congenital anomalies-neurodevelopmental syndrome, X-linked	Moderate	XL

Mondo (5): multiple congenital anomalies-neurodevelopmental syndrome, X-linked (MONDO:0025351), intellectual disability (MONDO:0001071), ependymoma (MONDO:0016698), neurodegeneration with brain iron accumulation 5 (MONDO:0010476), multiple congenital anomalies/dysmorphic syndrome (MONDO:0019042)

Orphanet (3): Ependymoma (Orphanet:251636), Beta-propeller protein-associated neurodegeneration (Orphanet:329284), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

71 total (30 of 71 shown, HPO-id order):

HPO	Term
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000076	Vesicoureteral reflux
HP:0000081	Duplicated collecting system
HP:0000126	Hydronephrosis
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000278	Retrognathia
HP:0000280	Coarse facial features
HP:0000307	Pointed chin
HP:0000316	Hypertelorism
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000506	Telecanthus
HP:0000540	Hypermetropia
HP:0000609	Optic nerve hypoplasia
HP:0000639	Nystagmus
HP:0000668	Hypodontia
HP:0000729	Autistic behavior
HP:0001007	Hirsutism
HP:0001162	Postaxial hand polydactyly
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D004806	Ependymoma	C04.557.465.625.600.380.290; C04.557.470.670.380.290; C04.557.580.625.600.380.290
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5291522 (SINGLE PROTEIN)

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
Air Pollutants	affects expression, increases abundance, increases expression	2
Cadmium Chloride	increases expression	2
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	decreases expression	1
sodium arsenite	increases expression	1
coumarin	increases phosphorylation	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
Grape Seed Proanthocyanidins	decreases expression, affects cotreatment	1
eprenetapopt	affects expression, affects reaction	1
licochalcone B	increases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Caffeine	decreases phosphorylation	1
Catechin	affects cotreatment, decreases expression	1
Doxorubicin	decreases expression	1
Methotrexate	decreases expression	1
Ozone	affects expression, increases abundance	1
Phthalic Acids	increases methylation	1
Quercetin	decreases phosphorylation	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	increases expression	1
Urethane	increases expression	1
Zinc	increases expression	1
Aflatoxin B1	decreases methylation	1
Particulate Matter	increases abundance, 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
CHEMBL5251178	Binding	Inhibition of OTUD5 (unknown origin) using ubiquitin rhodamine 110 as substrate at 1 to 10 uM by DUBprofiler fluorometric assay	Discovery and Characterization of BAY-805, a Potent and Selective Inhibitor of Ubiquitin-Specific Protease USP21. — J Med Chem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TB75	HAP1 OTUD5 (-) 1	Cancer cell line	Male
CVCL_TB76	HAP1 OTUD5 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00517959	PHASE3	UNKNOWN	SCRT Versus Conventional RT in Children and Young Adults With Low Grade and Benign Brain Tumors
NCT01096368	PHASE3	COMPLETED	Maintenance Chemotherapy or Observation Following Induction Chemotherapy and Radiation Therapy in Treating Patients With Newly Diagnosed Ependymoma
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00003479	PHASE2	TERMINATED	Antineoplaston Therapy in Treating Patients With Ependymoma
NCT00520936	PHASE2	COMPLETED	A Study of Pemetrexed in Children With Recurrent Cancer
NCT00840047	PHASE2	ACTIVE_NOT_RECRUITING	Methionine PET/CT Studies In Patients With Cancer
NCT01088035	PHASE2	TERMINATED	Carboplatin as a Radiosensitizer in Treating Childhood Ependymoma
NCT01247922	PHASE2	TERMINATED	Single-agent Erlotinib in Patients Previously Treated With Oral Etoposide in Protocol OSI-774-205
NCT01288235	PHASE2	COMPLETED	Proton Radiotherapy for Pediatric Brain Tumors Requiring Partial Brain Irradiation
NCT01295944	PHASE2	COMPLETED	Carboplatin and Bevacizumab for Recurrent Ependymoma
NCT01356290	PHASE2	RECRUITING	Antiangiogenic Therapy for Children With Recurrent Medulloblastoma, Ependymoma, ATRT and Rare CNS Tumors
NCT01836549	PHASE2	TERMINATED	Imetelstat Sodium in Treating Younger Patients With Recurrent or Refractory Brain Tumors
NCT02125786	PHASE2	ACTIVE_NOT_RECRUITING	A Trial of Surgery and Fractionated Re-Irradiation for Recurrent Ependymoma
NCT02689336	PHASE2	WITHDRAWN	Erlotinib in Combination With Temozolomide in Treating Relapsed/Recurrent/Refractory Pediatric Solid Tumors
NCT03095248	PHASE2	TERMINATED	Trial of Selumetinib in Patients With Neurofibromatosis Type II Related Tumors
NCT03155620	PHASE2	ACTIVE_NOT_RECRUITING	Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
NCT03173950	PHASE2	COMPLETED	Immune Checkpoint Inhibitor Nivolumab in People With Recurrent Select Rare CNS Cancers
NCT03194906	PHASE2	COMPLETED	Memantine for Prevention of Cognitive Late Effects in Pediatric Patients Receiving Cranial Radiation Therapy for Localized Brain Tumors
NCT03210714	PHASE2	ACTIVE_NOT_RECRUITING	Erdafitinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With FGFR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213652	PHASE2	ACTIVE_NOT_RECRUITING	Ensartinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial)
NCT03213665	PHASE2	COMPLETED	Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)
NCT03213678	PHASE2	COMPLETED	Samotolisib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213704	PHASE2	ACTIVE_NOT_RECRUITING	Larotrectinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With NTRK Fusions (A Pediatric MATCH Treatment Trial)
NCT03220035	PHASE2	COMPLETED	Vemurafenib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With BRAF V600 Mutations (A Pediatric MATCH Treatment Trial)
NCT03233204	PHASE2	COMPLETED	Olaparib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Defects in DNA Damage Repair Genes (A Pediatric MATCH Treatment Trial)
NCT03526250	PHASE2	COMPLETED	Palbociclib in Treating Patients With Relapsed or Refractory Rb Positive Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Activating Alterations in Cell Cycle Genes (A Pediatric MATCH Treatment Trial)
NCT03698994	PHASE2	ACTIVE_NOT_RECRUITING	Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial)
NCT03727841	PHASE2	TERMINATED	Marizomib for Recurrent Low-Grade and Anaplastic Supratentorial, Infratentorial, and Spinal Cord Ependymoma
NCT04049669	PHASE2	ACTIVE_NOT_RECRUITING	Pediatric Trial of Indoximod With Chemotherapy and Radiation for Relapsed Brain Tumors or Newly Diagnosed DIPG
NCT04195555	PHASE2	ACTIVE_NOT_RECRUITING	Ivosidenib in Treating Patients With Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With IDH1 Mutations (A Pediatric MATCH Treatment Trial)
NCT04284774	PHASE2	ACTIVE_NOT_RECRUITING	Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial
NCT04320888	PHASE2	ACTIVE_NOT_RECRUITING	Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediatric MATCH Treatment Trial