UBA5

Summary

UBA5 (ubiquitin like modifier activating enzyme 5, HGNC:23230) is a protein-coding gene on chromosome 3q22.1, encoding Ubiquitin-like modifier-activating enzyme 5 (Q9GZZ9). E1-like enzyme which specifically catalyzes the first step in ufmylation. It is a selective cancer dependency (DepMap: 60.9% of cell lines).

This gene encodes a member of the E1-like ubiquitin-activating enzyme family. This protein activates ubiquitin-fold modifier 1, a ubiquitin-like post-translational modifier protein, via the formation of a high-energy thioester bond. Alternative splicing results in multiple transcript variants. A pseudogene of this gene has been identified on chromosome 1.

Source: NCBI Gene 79876 — RefSeq curated summary.

At a glance

• Gene–disease (curated): genetic developmental and epileptic encephalopathy (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 42 total — 8 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 75
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 60.9% of screened cell lines
• MANE Select transcript: NM_024818

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23230
Approved symbol	UBA5
Name	ubiquitin like modifier activating enzyme 5
Location	3q22.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ23251
Ensembl gene	ENSG00000081307
Ensembl biotype	protein_coding
OMIM	610552
Entrez	79876

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 11 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000264991, ENST00000356232, ENST00000464068, ENST00000464101, ENST00000468022, ENST00000468227, ENST00000469158, ENST00000473651, ENST00000480955, ENST00000489361, ENST00000493720, ENST00000494112, ENST00000494238, ENST00000505777, ENST00000683741, ENST00000967272, ENST00000967273

RefSeq mRNA: 5 — MANE Select: NM_024818 NM_001320210, NM_001321238, NM_001321239, NM_024818, NM_198329

CCDS: CCDS3076, CCDS3077

Canonical transcript exons

ENST00000356232 — 12 exons

Exon	Start	End
ENSE00001078116	132665984	132666073
ENSE00001078120	132672050	132672177
ENSE00001949991	132660329	132660698
ENSE00001952871	132676443	132679794
ENSE00003458957	132670965	132671049
ENSE00003463269	132671777	132671881
ENSE00003510354	132675817	132675923
ENSE00003511827	132665823	132665868
ENSE00003576033	132675248	132675383
ENSE00003681767	132675605	132675680
ENSE00003789728	132668818	132668927
ENSE00003791037	132670198	132670284

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 97.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.3331 / max 332.3969, expressed in 1816 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38639	23.6294	1814
38636	1.7454	983
38637	0.6663	413
38638	0.4648	251
38641	0.4453	197
38640	0.3762	138
38635	0.0057	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	97.58	gold quality
right adrenal gland	UBERON:0001233	95.28	gold quality
right adrenal gland cortex	UBERON:0035827	95.21	gold quality
adrenal tissue	UBERON:0018303	95.14	gold quality
left adrenal gland	UBERON:0001234	95.12	gold quality
left adrenal gland cortex	UBERON:0035825	95.03	gold quality
pancreas	UBERON:0001264	94.90	gold quality
parotid gland	UBERON:0001831	94.88	gold quality
adenohypophysis	UBERON:0002196	94.82	gold quality
pituitary gland	UBERON:0000007	94.61	gold quality
adrenal gland	UBERON:0002369	94.35	gold quality
adrenal cortex	UBERON:0001235	94.34	gold quality
calcaneal tendon	UBERON:0003701	94.29	gold quality
saliva-secreting gland	UBERON:0001044	94.22	gold quality
minor salivary gland	UBERON:0001830	94.02	gold quality
secondary oocyte	CL:0000655	93.76	gold quality
metanephros cortex	UBERON:0010533	93.56	gold quality
right uterine tube	UBERON:0001302	93.50	gold quality
left lobe of thyroid gland	UBERON:0001120	92.93	gold quality
right lobe of thyroid gland	UBERON:0001119	92.91	gold quality
body of stomach	UBERON:0001161	92.90	gold quality
cortical plate	UBERON:0005343	92.74	gold quality
rectum	UBERON:0001052	92.66	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.65	gold quality
left ovary	UBERON:0002119	92.56	gold quality
right atrium auricular region	UBERON:0006631	92.51	gold quality
thyroid gland	UBERON:0002046	92.48	gold quality
right lobe of liver	UBERON:0001114	92.47	gold quality
right ovary	UBERON:0002118	92.45	gold quality
mouth mucosa	UBERON:0003729	92.40	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

76 targeting UBA5, 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-1277-5P	100.00	73.95	5056
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-4658	99.77	64.94	514
HSA-MIR-548O-3P	99.74	69.30	2228

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 60.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 24)

• UBE1DC1 greatly activated SUMO2 in the nucleus or transferred activated-SUMO2 to nucleus after it conjugated SUMO2 in the cytoplasm. (PMID:18442052)
• Studies reveal structural features of UBA5 that further understanding of the enzyme reaction mechanism and provide insight into the evolution of ubiquitin activation. (PMID:20368332)
• Crystallization of Uba5 residues 57-363 was performed at 277 K using PEG 3350 as the precipitant, and crystals optimized by microseeding diffracted to 2.95 A resolution, with unit-cell parameters a=b=97.66, c=144.83 A, alpha=beta=90, gamma=120 degrees . (PMID:24915089)
• binding of ATP to Uba5 approximately Ufm1 thioester was required for efficient transfer of Ufm1 from Uba5 to Ufc1 via transthiolation. (PMID:24966333)
• Uba5 residues 364-404 were demonstrated to be necessary for the transthiolation of Ufm1 to Ufc1, and Uba5 381-404 was identified to be the minimal region for Ufc1 recognition (PMID:25084390)
• The study of UBA5-R246X revealed a dramatically decreased half-life and loss of UFM1 activation due to the absence of the catalytic cysteine Cys250. (PMID:26872069)
• study provides important structural and functional insights into the interaction between UBA5 and Ub-like modifiers, improving the understanding of the biology of the ufmylation pathway. (PMID:26929408)
• Biallelic Variants in UBA5 Link Dysfunctional UFM1 Ubiquitin-like Modifier Pathway to Severe Infantile-Onset Encephalopathy (PMID:27545674)
• clinical, biochemical, and experimental findings support our finding of UBA5 mutations as a pathophysiological cause for early-onset encephalopathies due to abnormal protein ufmylation (PMID:27545681)
• These findings explicitly elucidate the role of UBA5 dimerization in UFM1 activation. (PMID:27653677)
• UFM1 His 70 resembles UBA5 His336 and enters a negatively charged pocked on the other UFM1 molecule. (PMID:28360427)
• Heterozygous mutations in the UBA5 gene in two sisters with early-onset epileptic encephalopathy . (PMID:28965491)
• Likely pathogenic variants were identified in SOX5 gene, not previously associated with epilepsy, and UBA5, a recently associated with epilepsy gene (PMID:29286531)
• results make a connection between the binding of UFM1 to UBA5 and the latter’s affinity to ATP, so we propose a novel mechanism for the regulation of ATP’s binding to E1. (PMID:29295865)
• our results further demonstrate the importance of post-translational modifications such as the addition of an ubiquitin-fold modifier 1 (UFM1) to target proteins (ufmylation) for normal neuronal networks activity, and reveal that the dysfunction of the ubiquitous UBA5 protein is a cause of EME. (PMID:29663568)
• Hemizygous UBA5 missense mutation was identified in a patient with infantile-onset encephalopathy, acquired microcephaly, small cerebellum, movement disorder and severe neurodevelopmental delay. (PMID:29902590)
• Stimulates transfer of UFM1 from UBA5 to the E2, UFC1. (PMID:30412706)
• An atypical LIR motif within UBA5 (ubiquitin like modifier activating enzyme 5) interacts with GABARAP proteins and mediates membrane localization of UBA5. (PMID:30990354)
• A homozygous UBA5 pathogenic variant causes a fatal congenital neuropathy. (PMID:32179706)
• Homozygous UBA5 Variant Leads to Hypomyelination with Thalamic Involvement and Axonal Neuropathy. (PMID:33853163)
• A Concerted Action of UBA5 C-Terminal Unstructured Regions Is Important for Transfer of Activated UFM1 to UFC1. (PMID:34299007)
• Structure and dynamics of UBA5-UFM1 complex formation showing new insights in the UBA5 activation mechanism. (PMID:34508858)
• Structural basis for UFM1 transfer from UBA5 to UFC1. (PMID:34588452)
• Allelic strengths of encephalopathy-associated UBA5 variants correlate between in vivo and in vitro assays. (PMID:38079206)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	uba5	ENSDARG00000063588
mus_musculus	Uba5	ENSMUSG00000032557
rattus_norvegicus	Uba5	ENSRNOG00000011027
drosophila_melanogaster	Uba5	FBGN0030305
caenorhabditis_elegans	uba-5	WBGENE00020184

Paralogs (9): UBA6 (ENSG00000033178), MOCS3 (ENSG00000124217), UBA2 (ENSG00000126261), UBA1 (ENSG00000130985), SAE1 (ENSG00000142230), UBA3 (ENSG00000144744), NAE1 (ENSG00000159593), UBA7 (ENSG00000182179), ATG7 (ENSG00000197548)

Protein

Protein identifiers

Ubiquitin-like modifier-activating enzyme 5 — Q9GZZ9 (reviewed: Q9GZZ9)

Alternative names: ThiFP1, UFM1-activating enzyme, Ubiquitin-activating enzyme E1 domain-containing protein 1

All UniProt accessions (8): Q9GZZ9, A0A804HJ86, C9J0F6, C9J5W5, C9JRV9, D6RJC9, E7EQ61, E7EWE1

UniProt curated annotations — full annotation on UniProt →

Function. E1-like enzyme which specifically catalyzes the first step in ufmylation. Activates UFM1 by first adenylating its C-terminal glycine residue with ATP, and thereafter linking this residue to the side chain of a cysteine residue in E1, yielding a UFM1-E1 thioester and free AMP. Activates UFM1 via a trans-binding mechanism, in which UFM1 interacts with distinct sites in both subunits of the UBA5 homodimer. Trans-binding also promotes stabilization of the UBA5 homodimer, and enhances ATP-binding. Transfer of UFM1 from UBA5 to the E2-like enzyme UFC1 also takes place using a trans mechanism. Ufmylation plays a key role in various processes, such as ribosome recycling, response to DNA damage, interferon response or reticulophagy (also called ER-phagy). Ufmylation is essential for erythroid differentiation of both megakaryocytes and erythrocytes.

Subunit / interactions. Homodimer; homodimerization is required for UFM1 activation. Interacts (via UIS motif) with UFM1; binds UFM1 via a trans-binding mechanism in which UFM1 interacts with distinct sites in both subunits of the UBA5 homodimer. Interacts (via C-terminus) with UFC1. Interacts (via UIS motif) with GABARAPL2 and, with lower affinity, with GABARAP and GABARAPL1.

Subcellular location. Cytoplasm. Nucleus. Endoplasmic reticulum membrane. Golgi apparatus.

Tissue specificity. Widely expressed.

Disease relevance. Developmental and epileptic encephalopathy 44 (DEE44) [MIM:617132] A form of epileptic encephalopathy, a heterogeneous group of severe early-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. DEE44 transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry. Spinocerebellar ataxia, autosomal recessive, 24 (SCAR24) [MIM:617133] A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR24 patients manifest gait instability and speech difficulties with onset in childhood. Clinical features include gait and limb ataxia, dysarthria, nystagmus, cataracts, and cerebellar atrophy on brain imaging. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The UFC1-binding sequence (UFC) motif mediates interaction with UFC1. The linker region is required to activate the active site of UFC1: it region moves next to active site of UFC1 to reduce the amount of water molecules in the vicinity of UFC1’s active site and thereby elevate the nucleophilic activity of UFC1 active site. The UFM1-interacting sequence (UIS) motif mediates interaction with both UFM1 and LC3/GABARAP proteins (GABARAP, GABARAPL1 and GABARAPL2). The N-terminus (1-56) contributes to the transfer of UFM1 from UBA5 to UFC1.

Similarity. Belongs to the ubiquitin-activating E1 family. UBA5 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9GZZ9-1	1, UBE1DC1A	yes
Q9GZZ9-2	2, UBE1DC1B

RefSeq proteins (5): NP_001307139, NP_001308167, NP_001308168, NP_079094, NP_938143 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000594	ThiF_NAD_FAD-bd	Domain
IPR029752	D-isomer_DH_CS1	Conserved_site
IPR035985	Ubiquitin-activating_enz	Homologous_superfamily
IPR045886	ThiF/MoeB/HesA	Family

Pfam: PF00899

Enzyme classification (BRENDA):

• EC 6.2.1.45 — E1 ubiquitin-activating enzyme (BRENDA: 12 organisms, 35 substrates, 23 inhibitors, 28 Km, 30 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0047–0.208	11
UBIQUITIN	0.0002–0.029	11
UBIQUITIN CARRIER PROTEIN E2	0.0001	5
OREGON GREEN-LABELED UBIQUITIN	0.0002	1

UniProt features (72 total): mutagenesis site 18, helix 13, strand 12, binding site 9, sequence variant 8, modified residue 3, short sequence motif 2, turn 2, chain 1, region of interest 1, splice variant 1, active site 1, sequence conflict 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
5IAA	X-RAY DIFFRACTION	1.85
7NW1	X-RAY DIFFRACTION	1.95
3H8V	X-RAY DIFFRACTION	2
5IA8	X-RAY DIFFRACTION	2
5L95	X-RAY DIFFRACTION	2.1
6H77	X-RAY DIFFRACTION	2.1
3GUC	X-RAY DIFFRACTION	2.25
5HKH	X-RAY DIFFRACTION	2.55
7NVK	X-RAY DIFFRACTION	2.65
6H78	X-RAY DIFFRACTION	2.7
6H8C	SOLUTION NMR
7OVC	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9GZZ9-F1	86.98	0.67

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 (1): 250 (glycyl thioester intermediate)

Ligand- & substrate-binding residues (9): 226; 229; 303; 308; 83; 104; 127; 150; 184

Post-translational modifications (3): 45, 358, 393

Mutagenesis-validated functional residues (18):

Position	Phenotype
188	abolished ability to activate ufm1.
215–217	abolished ability to activate ufm1.
230–233	abolished interaction with ufm1.
250	abolished ability to activate ufm1.
250	forms a stable intermediate complex.
271	impaired ability to activate ufm1 via a trans-binding mechanism.
290	impaired homodimerization and ability to activate ufm1 via a trans-binding mechanism.
336	impaired ability to activate ufm1.
341	abolished interaction with ufm1 and gabarapl2.
342	decreased interaction with ufm1 without affecting interaction with gabarapl2.
343–345	impaired ability to activate ufm1.
343	abolished interaction with ufm1 and decreased interaction with gabarapl2.
345	abolished interaction with ufm1 and decreased interaction with gabarapl2.
346	abolished interaction with ufm1 and decreased interaction with gabarapl2.
372	strongly decreased ability to transfer ufm1 to ufc1.
372	does not affect ability to transfer ufm1 to ufc1.
397	abolished interaction with ufc1.
401	abolished interaction with ufc1.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-9918485	Dengue Virus Attachment and Entry

MSigDB gene sets: 292 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_MONOCYTE_UP, GOBP_MYELOID_CELL_HOMEOSTASIS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_CELLULAR_RESPONSE_TO_LIPID, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_ERYTHROCYTE_HOMEOSTASIS, GOBP_REGULATION_OF_INTRACELLULAR_STEROID_HORMONE_RECEPTOR_SIGNALING_PATHWAY, GOBP_MACROAUTOPHAGY, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_REGULATION_OF_INTRACELLULAR_ESTROGEN_RECEPTOR_SIGNALING_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS

GO Biological Process (9): erythrocyte differentiation (GO:0030218), megakaryocyte differentiation (GO:0030219), regulation of type II interferon production (GO:0032649), regulation of intracellular estrogen receptor signaling pathway (GO:0033146), response to endoplasmic reticulum stress (GO:0034976), neuromuscular process (GO:0050905), reticulophagy (GO:0061709), protein ufmylation (GO:0071569), protein K69-linked ufmylation (GO:1990592)

GO Molecular Function (8): ATP binding (GO:0005524), zinc ion binding (GO:0008270), protein homodimerization activity (GO:0042803), UFM1 activating enzyme activity (GO:0071566), nucleotide binding (GO:0000166), protein binding (GO:0005515), ubiquitin-like modifier activating enzyme activity (GO:0008641), metal ion binding (GO:0046872)

GO Cellular Component (7): nucleus (GO:0005634), cytoplasm (GO:0005737), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), cytosol (GO:0005829), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Class I MHC mediated antigen processing & presentation	1
Dengue Virus Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	3
cellular anatomical structure	3
cytoplasm	3
myeloid cell differentiation	2
endomembrane system	2
erythrocyte homeostasis	1
regulation of cytokine production	1
type II interferon production	1
estrogen receptor signaling pathway	1
regulation of intracellular steroid hormone receptor signaling pathway	1
cellular response to stress	1
nervous system process	1
macroautophagy	1
protein modification by small protein conjugation	1
protein polyufmylation	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transition metal ion binding	1
identical protein binding	1
protein dimerization activity	1
ubiquitin-like modifier activating enzyme activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
ligase activity, forming carbon-sulfur bonds	1
catalytic activity, acting on a protein	1
ATP-dependent activity	1
cation binding	1
intracellular anatomical structure	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1

Protein interactions and networks

STRING

2256 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UBA5	UFM1	P61960	995
UBA5	UFC1	Q9Y3C8	990
UBA5	UFL1	O94874	934
UBA5	UFSP2	Q9NUQ7	902
UBA5	DDRGK1	Q96HY6	844
UBA5	UFSP1	Q6NVU6	815
UBA5	UBA3	Q8TBC4	808
UBA5	UBE2M	P61081	793
UBA5	GABARAPL2	P60520	786
UBA5	CDK5RAP3	Q96JB5	711
UBA5	F5GZY7	F5GZY7	634
UBA5	TXNIP	Q9H3M7	624
UBA5	NEDD8	Q15843	615
UBA5	URM1	Q9BTM9	590
UBA5	NAE1	Q13564	553

IntAct

72 interactions, top by confidence:

A	B	Type	Score
UBA5	GABARAPL2	psi-mi:“MI:0915”(physical association)	0.950
GABARAPL2	UBA5	psi-mi:“MI:0915”(physical association)	0.950
UBA5	GABARAPL2	psi-mi:“MI:0407”(direct interaction)	0.950
GABARAPL2	UBA5	psi-mi:“MI:2364”(proximity)	0.950
UBA5	GABARAPL2	psi-mi:“MI:0914”(association)	0.950
UBA5	UFM1	psi-mi:“MI:0915”(physical association)	0.890
UBA5	UFM1	psi-mi:“MI:0914”(association)	0.890
GABARAPL2	IPO5	psi-mi:“MI:0914”(association)	0.690
UBA5	GABARAPL1	psi-mi:“MI:0407”(direct interaction)	0.660
GABARAPL1	UBA5	psi-mi:“MI:0915”(physical association)	0.660
FGL1	LCMT2	psi-mi:“MI:0914”(association)	0.640
UBA5	GPA2	psi-mi:“MI:0915”(physical association)	0.560
UBA5	GABARAP	psi-mi:“MI:0407”(direct interaction)	0.540
UBA5	MAP1LC3B	psi-mi:“MI:0407”(direct interaction)	0.540
UBA5	MAP1LC3C	psi-mi:“MI:0407”(direct interaction)	0.540
UBA5	GABARAP	psi-mi:“MI:0915”(physical association)	0.540
MAP1LC3B	UBA5	psi-mi:“MI:0915”(physical association)	0.540
MAP1LC3C	UBA5	psi-mi:“MI:0915”(physical association)	0.540
UBA5	GAPDHS	psi-mi:“MI:0914”(association)	0.530
PECR	LCN1	psi-mi:“MI:0914”(association)	0.530
PNMA1	ACTB	psi-mi:“MI:0914”(association)	0.530

BioGRID (172): UBA5 (Two-hybrid), UBA5 (Affinity Capture-MS), UBA5 (Affinity Capture-MS), UBA5 (Affinity Capture-MS), UBA5 (Affinity Capture-MS), UBA5 (Affinity Capture-MS), UBA5 (Affinity Capture-MS), UBA5 (Two-hybrid), UBA5 (Two-hybrid), UBA5 (Co-fractionation), UBA5 (Two-hybrid), UBA5 (Affinity Capture-MS), GOLGA1 (Affinity Capture-MS), HSPE1 (Affinity Capture-MS), IPP (Affinity Capture-MS)

ESM2 similar proteins: A5DDF4, A7MAZ3, A8XEQ8, B0WQV1, B3NUC9, B4GYC7, B4IK21, B4JIY0, B4L1K2, B4M357, B4NDE5, B4PYA4, B4R345, B9VJ80, C3YZ51, D1GY43, F4JY24, O13861, O23034, O60264, O82486, O89042, P06625, P08240, P09884, P33609, P36101, P40991, P91430, Q0J7Y8, Q14562, Q17DT0, Q29HT0, Q3KQ23, Q3MHE8, Q54C02, Q5M7A4, Q5R8X4, Q6FPQ3, Q6GLG7

Diamond homologs: A1A4L8, A1CAZ7, A1DED8, A2BDX3, A2R3H4, A3ACF3, A3LQF9, A4RPM5, A4TGR3, A5DMB6, A5DSR2, A5GFZ6, A6ZT19, A7F582, A7FNW5, A7MAZ3, A7THV5, A8GKU1, A8WRE3, A9R4D5, B0W377, B0WQV1, B0Y0P7, B1JHY9, B2K5W3, B3LSM6, B3MLX7, B4FAT0, B4GKQ3, B4HYP0, B4JBC4, B4KI53, B4LRB9, B4N7R4, B4NXF7, B4PYA4, B4R345, B5DS72, B5VK45, B6TNK6

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 62 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
Macroautophagy	6	16.5×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
autophagosome maturation	6	36.3×	4e-06
mitophagy	5	27.4×	1e-04
autophagosome assembly	6	23.2×	4e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	9
Uncertain significance	5
Likely benign	14
Benign	1

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1048516	NM_024818.6(UBA5):c.761T>C (p.Leu254Pro)	Pathogenic
1459503	NC_000003.11:g.(?132379382)(133191429_?)del	Pathogenic
1686286	NM_024818.6(UBA5):c.1A>G (p.Met1Val)	Pathogenic
2426894	NC_000003.11:g.(?132387642)(132389148_?)del	Pathogenic
265746	NM_024818.6(UBA5):c.164G>A (p.Arg55His)	Pathogenic
265748	NM_024818.6(UBA5):c.181C>T (p.Arg61Ter)	Pathogenic
4526087	NC_000003.11:g.(?132379172)(132398639_?)del	Pathogenic
870956	NM_024818.6(UBA5):c.1131+2T>C	Pathogenic
1251993	NM_024818.6(UBA5):c.199G>T (p.Asp67Tyr)	Likely pathogenic
1325326	NM_024818.6(UBA5):c.204T>G (p.Tyr68Ter)	Likely pathogenic
1501581	NM_024818.6(UBA5):c.407+1G>T	Likely pathogenic
2500792	NM_024818.6(UBA5):c.280A>G (p.Arg94Gly)	Likely pathogenic
265752	NM_024818.6(UBA5):c.778G>A (p.Val260Met)	Likely pathogenic
3773977	NM_024818.6(UBA5):c.758G>C (p.Ser253Thr)	Likely pathogenic
4755518	NM_024818.6(UBA5):c.724_725del (p.Lys242fs)	Likely pathogenic
4845701	NM_024818.4:c.-823C>A	Likely pathogenic
489201	NM_024818.6(UBA5):c.684G>A (p.Ala228=)	Likely pathogenic

SpliceAI

2001 predictions. Top by Δscore:

Variant	Effect	Δscore
3:132665820:A:AG	acceptor_gain	1.0000
3:132665820:AAGCC:A	acceptor_gain	1.0000
3:132665821:A:G	acceptor_gain	1.0000
3:132665822:G:GG	acceptor_gain	1.0000
3:132667100:G:GG	donor_gain	1.0000
3:132668816:A:AG	acceptor_gain	1.0000
3:132668817:G:GA	acceptor_gain	1.0000
3:132668891:GAT:G	donor_gain	1.0000
3:132670192:TCTTA:T	acceptor_loss	1.0000
3:132670193:CTTA:C	acceptor_loss	1.0000
3:132670194:TTA:T	acceptor_loss	1.0000
3:132670195:TAG:T	acceptor_loss	1.0000
3:132670196:A:AG	acceptor_gain	1.0000
3:132670196:A:T	acceptor_loss	1.0000
3:132670197:G:C	acceptor_loss	1.0000
3:132670197:G:GG	acceptor_gain	1.0000
3:132670197:GGAAC:G	acceptor_gain	1.0000
3:132670280:ATAAG:A	donor_loss	1.0000
3:132670281:TAAGG:T	donor_loss	1.0000
3:132670282:AAGG:A	donor_loss	1.0000
3:132670285:GTA:G	donor_loss	1.0000
3:132670286:T:A	donor_loss	1.0000
3:132670963:A:AG	acceptor_gain	1.0000
3:132670964:G:GG	acceptor_gain	1.0000
3:132670964:GT:G	acceptor_gain	1.0000
3:132670964:GTA:G	acceptor_gain	1.0000
3:132671045:ATACA:A	donor_gain	1.0000
3:132671046:TACA:T	donor_gain	1.0000
3:132671046:TACAG:T	donor_loss	1.0000
3:132671047:ACA:A	donor_gain	1.0000

AlphaMissense

2681 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:132666030:G:A	G85D	1.000
3:132666041:G:C	A89P	1.000
3:132666042:C:A	A89D	1.000
3:132668856:T:A	N112K	1.000
3:132668856:T:G	N112K	1.000
3:132668862:T:A	N114K	1.000
3:132668862:T:G	N114K	1.000
3:132668864:G:C	R115T	1.000
3:132668865:A:C	R115S	1.000
3:132668865:A:T	R115S	1.000
3:132668900:A:T	K127I	1.000
3:132668901:A:C	K127N	1.000
3:132668901:A:T	K127N	1.000
3:132671013:T:G	C181W	1.000
3:132671017:G:C	D183H	1.000
3:132671018:A:C	D183A	1.000
3:132671018:A:G	D183G	1.000
3:132671018:A:T	D183V	1.000
3:132671019:C:A	D183E	1.000
3:132671019:C:G	D183E	1.000
3:132672120:C:A	A252D	1.000
3:132672122:A:C	S253R	1.000
3:132672124:T:A	S253R	1.000
3:132672124:T:G	S253R	1.000
3:132660697:A:C	S54R	0.999
3:132665823:C:A	S54R	0.999
3:132665823:C:G	S54R	0.999
3:132665824:C:A	R55S	0.999
3:132665824:C:G	R55G	0.999
3:132665824:C:T	R55C	0.999

dbSNP variants (sampled 300 via entrez): RS1000006782 (3:132660511 G>A,C), RS1000090183 (3:132654518 C>G), RS1000110172 (3:132653659 C>T), RS1000196645 (3:132666210 G>A), RS1000500461 (3:132652562 A>T), RS1000615417 (3:132658805 A>G), RS1000626486 (3:132674380 G>A), RS1000672720 (3:132673075 A>G), RS1000723486 (3:132665575 G>A), RS1000795121 (3:132666549 C>G,T), RS1001056126 (3:132659931 G>A), RS1001122 (3:132652934 C>G,T), RS1001170387 (3:132655919 A>C,G), RS1001455855 (3:132669887 T>C), RS1001637780 (3:132680289 C>G)

Disease associations

OMIM: gene MIM:610552 | disease phenotypes: MIM:617132, MIM:256100, MIM:617133

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 44	Strong	Autosomal recessive
spinocerebellar ataxia, autosomal recessive 24	Moderate	Autosomal recessive
undetermined early-onset epileptic encephalopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
genetic developmental and epileptic encephalopathy	Definitive	AR

Mondo (4): developmental and epileptic encephalopathy, 44 (MONDO:0014933), nephronophthisis (MONDO:0019005), spinocerebellar ataxia, autosomal recessive 24 (MONDO:0014934), undetermined early-onset epileptic encephalopathy (MONDO:0018614)

Orphanet (1): Nephronophthisis (Orphanet:655)

HPO phenotypes

75 total (30 of 75 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000298	Mask-like facies
HP:0000348	High forehead
HP:0000494	Downslanted palpebral fissures
HP:0000504	Abnormality of vision
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000546	Retinal degeneration
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000666	Horizontal nystagmus
HP:0000668	Hypodontia
HP:0000708	Atypical behavior
HP:0000717	Autism
HP:0000737	Irritability
HP:0000750	Delayed speech and language development
HP:0000817	Reduced eye contact
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001265	Hyporeflexia
HP:0001268	Mental deterioration
HP:0001272	Cerebellar atrophy
HP:0001273	Abnormal corpus callosum morphology
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST010699_54	Brain morphology (min-P)	5.000000e-08
GCST010701_80	Cortical surface area (MOSTest)	5.000000e-09
GCST010702_60	Subcortical volume (MOSTest)	6.000000e-12
GCST010703_12	Brain morphology (MOSTest)	9.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2016429 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	2
Valproic Acid	increases expression, decreases methylation	2
Cyclosporine	increases expression, affects cotreatment	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases expression, decreases reaction	1
decabromobiphenyl ether	increases expression	1
methylparaben	increases expression	1
tetrabromobisphenol A	increases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
nefazodone	affects cotreatment, increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
pentabrominated diphenyl ether 100	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1
bisphenol S	increases expression	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Air Pollutants	increases abundance, decreases expression	1
Benzo(a)pyrene	increases expression	1
Caffeine	decreases phosphorylation	1
Chenodeoxycholic Acid	affects cotreatment, increases expression	1
Deoxycholic Acid	affects cotreatment, increases expression	1
Estradiol	decreases expression	1
Glycochenodeoxycholic Acid	affects cotreatment, increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2019634	Binding	Inhibition of human recombinant UBA5 assessed as inhibition of UCF1-UFM1 complex formation at 10 uM after 1.5 hrs by Western blot analysis	Identification of NAE Inhibitors Exhibiting Potent Activity in Leukemia Cells: Exploring the Structural Determinants of NAE Specificity. — ACS Med Chem Lett

Cellosaurus cell lines

6 cell lines: 3 finite cell line, 3 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D2ZS	GM28856	Finite cell line	Female
CVCL_D2ZT	GM28954	Transformed cell line	Female
CVCL_D2ZU	GM28858	Finite cell line	Male
CVCL_D2ZV	GM28953	Transformed cell line	Male
CVCL_D2ZW	GM28857	Finite cell line	Male
CVCL_D2ZX	GM28942	Transformed cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01022957	Not specified	COMPLETED	Nephronophthisis : Clinical and Genetic Study
NCT01401998	Not specified	RECRUITING	ARPKD Database Study
NCT04874909	Not specified	COMPLETED	Classification, Functional Stratification and Biomarkers in Ciliopathy (CILLICORIRCM)
NCT05286632	Not specified	COMPLETED	KidneYou - Innovative Digital Therapy
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases
NCT06648044	Not specified	RECRUITING	Research of Therapeutic Targets in the Frame of Nephronophthisis and Renal Associated Ciliopathies