UBA6

Summary

UBA6 (ubiquitin like modifier activating enzyme 6, HGNC:25581) is a protein-coding gene on chromosome 4q13.2, encoding Ubiquitin-like modifier-activating enzyme 6 (A0AVT1). Activates ubiquitin 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 ubiquitin-E1 thioester and free AMP. It is a selective cancer dependency (DepMap: 28.5% of cell lines).

Modification of proteins with ubiquitin (UBB; MIM 191339) or ubiquitin-like proteins controls many signaling networks and requires a ubiquitin-activating enzyme (E1), a ubiquitin conjugating enzyme (E2), and a ubiquitin protein ligase (E3). UBE1L2 is an E1 enzyme that initiates the activation and conjugation of ubiquitin-like proteins (Jin et al., 2007 [PubMed 17597759]).

Source: NCBI Gene 55236 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability (Limited, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 179 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 28.5% of screened cell lines
• MANE Select transcript: NM_018227

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25581
Approved symbol	UBA6
Name	ubiquitin like modifier activating enzyme 6
Location	4q13.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10808
Ensembl gene	ENSG00000033178
Ensembl biotype	protein_coding
OMIM	611361
Entrez	55236

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 12 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000322244, ENST00000420827, ENST00000429659, ENST00000505673, ENST00000506571, ENST00000514261, ENST00000907528, ENST00000907529, ENST00000907530, ENST00000907531, ENST00000928864, ENST00000928865, ENST00000928866, ENST00000928867, ENST00000968080

RefSeq mRNA: 1 — MANE Select: NM_018227 NM_018227

CCDS: CCDS3516

Canonical transcript exons

ENST00000322244 — 33 exons

Exon	Start	End
ENSE00001072369	67645938	67646016
ENSE00001072371	67631857	67631908
ENSE00001072372	67663139	67663215
ENSE00001072374	67630466	67630535
ENSE00001072375	67638943	67639124
ENSE00001072376	67649068	67649211
ENSE00001072377	67629071	67629142
ENSE00001072379	67635453	67635558
ENSE00001072381	67663885	67663947
ENSE00001072384	67624994	67625187
ENSE00001072387	67626360	67626477
ENSE00001072390	67646724	67646791
ENSE00001072398	67624126	67624253
ENSE00001072400	67634242	67634322
ENSE00001072402	67644698	67644778
ENSE00001072404	67641151	67641228
ENSE00001072405	67631708	67631771
ENSE00001072406	67633345	67633473
ENSE00001072414	67634429	67634518
ENSE00001243252	67662189	67662255
ENSE00001243352	67612652	67619132
ENSE00001855693	67701049	67701155
ENSE00003460822	67677611	67677722
ENSE00003469797	67673697	67673777
ENSE00003469903	67665189	67665292
ENSE00003482368	67681563	67681591
ENSE00003487135	67678439	67678533
ENSE00003497321	67668551	67668674
ENSE00003556852	67622831	67622925
ENSE00003591198	67696645	67696707
ENSE00003604201	67670470	67670592
ENSE00003606841	67623135	67623222
ENSE00003661558	67682119	67682213

Expression profiles

Bgee: expression breadth ubiquitous, 270 present calls, max score 94.19.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 34.9148 / max 283.3774, expressed in 1821 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
52314	34.9148	1821

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	94.19	gold quality
oocyte	CL:0000023	94.17	gold quality
epithelium of nasopharynx	UBERON:0001951	93.45	gold quality
calcaneal tendon	UBERON:0003701	92.85	gold quality
gingival epithelium	UBERON:0001949	92.62	gold quality
germinal epithelium of ovary	UBERON:0001304	92.51	gold quality
gingiva	UBERON:0001828	92.40	gold quality
mucosa of paranasal sinus	UBERON:0005030	92.29	gold quality
endothelial cell	CL:0000115	91.84	gold quality
ventricular zone	UBERON:0003053	91.73	gold quality
corpus callosum	UBERON:0002336	91.66	gold quality
oral cavity	UBERON:0000167	91.64	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.48	gold quality
cauda epididymis	UBERON:0004360	91.26	gold quality
stromal cell of endometrium	CL:0002255	91.04	gold quality
ganglionic eminence	UBERON:0004023	90.92	gold quality
secondary oocyte	CL:0000655	90.81	gold quality
cortical plate	UBERON:0005343	90.55	gold quality
esophagus squamous epithelium	UBERON:0006920	90.21	gold quality
amniotic fluid	UBERON:0000173	90.18	gold quality
tonsil	UBERON:0002372	90.15	gold quality
palpebral conjunctiva	UBERON:0001812	89.96	gold quality
Brodmann (1909) area 23	UBERON:0013554	89.90	gold quality
cartilage tissue	UBERON:0002418	89.37	gold quality
islet of Langerhans	UBERON:0000006	88.44	gold quality
endometrium	UBERON:0001295	88.31	gold quality
colonic epithelium	UBERON:0000397	88.17	gold quality
jejunal mucosa	UBERON:0000399	88.06	gold quality
buccal mucosa cell	CL:0002336	87.45	gold quality
bone marrow cell	CL:0002092	87.22	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.53
E-CURD-97	no	915.17

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

170 targeting UBA6, 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-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3065-5P	99.97	71.56	3281

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 28.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 14)

• UBE1L2 is a novel E1 enzyme specific for ubiquitin (PMID:17580310)
• Human Uba6 and Ube1 have distinct preferences for E2 charging in vitro, and their specificity depends in part on their C-terminal ubiquitin-fold domains, which recruit E2s (PMID:17597759)
• The identification of an E1-like protein, termed E1-L2, that activates both ubiquitin and another ubiquitin-like protein, FAT10, is reported. (PMID:17889673)
• Ubiquitin-like modifier activating enzyme 6 activates not only ubiquitin, but also the ubiquitin-like modifier FAT10[review] (PMID:18353650)
• Data indicate the potential role of cytokine-induced FAT10 expression in regulating Uba6 pathways. (PMID:22427669)
• Diminished ubiquitylation phenotype observed in enteropathogenic Escherichia coli infected cells corresponds to a strong reduction in the abundance of both Ube1 and Uba6. (PMID:22999844)
• Interstitial microdeletions including the chromosome band 4q13.2 and the UBA6 gene as possible causes of intellectual disability and behavior disorder. (PMID:26284580)
• this study revealed a novel function of LMO2 involving in the regulatory hierarchy of UBA6-USE1-FAT10ylation pathway by targeting the E1 enzyme UBA6. (PMID:27569286)
• Polyubiquitination and proteasomal degradation of ezrin and CUGBP1 require Uba6, but not Uba1, and that Uba6 is involved in the control of ezrin localization and epithelial morphogenesis. These data suggest that distinctive substrate pools exist for Uba1 and Uba6 that reflect non-redundant biological roles for Uba6. (PMID:28134249)
• These findings demonstrate that UBA6 and BIRC6 negatively regulate autophagy by limiting the availability of LC3B. (PMID:31692446)
• Ubiquitination-activating enzymes UBE1 and UBA6 regulate ubiquitination and expression of cardiac sodium channel Nav1.5. (PMID:32315024)
• Down-regulation of UBA6 exacerbates brain injury by inhibiting the activation of Notch signaling pathway to promote cerebral cell apoptosis in rat acute cerebral infarction model. (PMID:32497710)
• UBA6 and NDFIP1 regulate the degradation of ferroportin. (PMID:34320783)
• UBA6 Inhibition Accelerates Lysosomal TRPML1 Depletion and Exosomal Secretion in Lung Cancer Cells. (PMID:38474091)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	uba6	ENSDARG00000080019
mus_musculus	Uba6	ENSMUSG00000035898
rattus_norvegicus	Uba6	ENSRNOG00000021931

Paralogs (9): UBA5 (ENSG00000081307), MOCS3 (ENSG00000124217), UBA2 (ENSG00000126261), UBA1 (ENSG00000130985), SAE1 (ENSG00000142230), UBA3 (ENSG00000144744), NAE1 (ENSG00000159593), UBA7 (ENSG00000182179), ATG7 (ENSG00000197548)

Protein

Protein identifiers

Ubiquitin-like modifier-activating enzyme 6 — A0AVT1 (reviewed: A0AVT1)

Alternative names: Monocyte protein 4, Ubiquitin-activating enzyme E1-like protein 2

All UniProt accessions (3): A0AVT1, H0Y8S8, H0Y9U5

UniProt curated annotations — full annotation on UniProt →

Function. Activates ubiquitin 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 ubiquitin-E1 thioester and free AMP. Specific for ubiquitin, does not activate ubiquitin-like peptides. Also activates UBD/FAT10 conjugation via adenylation of its C-terminal glycine. Differs from UBE1 in its specificity for substrate E2 charging. Does not charge cell cycle E2s, such as CDC34. Essential for embryonic development. Isoform 2 may play a key role in ubiquitin system and may influence spermatogenesis and male fertility.

Subunit / interactions. Forms a thioester with UBD in cells stimulated with tumor necrosis factor-alpha (TNFa) and interferon-gamma (IFNg).

Tissue specificity. Widely expressed. Isoform 2 is predominantly expressed in testis with higher expression in adult testis than in fetal testis.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the ubiquitin-activating E1 family.

Isoforms (4)

UniProt ID	Names	Canonical?
A0AVT1-1	1	yes
A0AVT1-2	2, nUBE1L
A0AVT1-3	3
A0AVT1-4	4

RefSeq proteins (1): NP_060697* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000011	UBQ/SUMO-activ_enz_E1-like	Family
IPR000594	ThiF_NAD_FAD-bd	Domain
IPR018075	UBQ-activ_enz_E1	Family
IPR018965	Ub-activating_enz_E1_C	Domain
IPR019572	UBA_E1_SCCH	Domain
IPR032418	E1_FCCH	Domain
IPR032420	E1_4HB	Domain
IPR035985	Ubiquitin-activating_enz	Homologous_superfamily
IPR038252	UBA_E1_C_sf	Homologous_superfamily
IPR042063	Ubi_acti_E1_SCCH	Homologous_superfamily
IPR042302	E1_FCCH_sf	Homologous_superfamily
IPR042449	Ub-E1_IAD_1	Homologous_superfamily
IPR045886	ThiF/MoeB/HesA	Family

Pfam: PF00899, PF09358, PF10585, PF16190, PF16191

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 (140 total): helix 45, strand 43, binding site 12, sequence conflict 12, mutagenesis site 8, modified residue 6, turn 5, splice variant 5, chain 1, region of interest 1, active site 1, sequence variant 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
7SOL	X-RAY DIFFRACTION	2.25
7PVN	X-RAY DIFFRACTION	2.71
9QH5	ELECTRON MICROSCOPY	3.09
7PYV	X-RAY DIFFRACTION	3.27
9QIC	ELECTRON MICROSCOPY	3.29
9QIV	ELECTRON MICROSCOPY	3.44
9QIM	ELECTRON MICROSCOPY	3.57
9QGW	ELECTRON MICROSCOPY	3.62
9QIG	ELECTRON MICROSCOPY	3.94
9QII	ELECTRON MICROSCOPY	3.99
9QIP	ELECTRON MICROSCOPY	4.15
9QIO	ELECTRON MICROSCOPY	4.22
9QHI	ELECTRON MICROSCOPY	4.27
9QIA	ELECTRON MICROSCOPY	4.38

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A0AVT1-F1	91.67	0.83

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): 625 (glycyl thioester intermediate)

Ligand- & substrate-binding residues (12): 509; 521; 545; 569; 570; 46; 470; 497; 499; 502; 505; 508

Post-translational modifications (6): 1, 54, 301, 544, 729, 737

Mutagenesis-validated functional residues (8):

Position	Phenotype
316	impairs ubiquitin activation and ubd/fat10 conjugation.
320	impairs ubd/fat10 conjugation; when associated with r-324 and r-370.
324	impairs ubd/fat10 conjugation; when associated with k-320 and r-370.
370	impairs ubd/fat10 conjugation; when associated with k-320 and r-324.
601	impairs ubiquitin activation.
616	impairs ubiquitin activation.
625	impairs ubiquitin activation.
934	impairs ubiquitin activation and ubd/fat10 conjugation.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-8866652	Synthesis of active ubiquitin: roles of E1 and E2 enzymes
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-9918485	Dengue Virus Attachment and Entry

MSigDB gene sets: 170 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, WONG_PROTEASOME_GENE_MODULE, chr4q13, WANG_LMO4_TARGETS_DN, GOBP_DNA_DAMAGE_RESPONSE, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, CREB_Q2_01, KEGG_UBIQUITIN_MEDIATED_PROTEOLYSIS, ACEVEDO_LIVER_CANCER_UP, RIGGINS_TAMOXIFEN_RESISTANCE_DN

GO Biological Process (4): ubiquitin-dependent protein catabolic process (GO:0006511), DNA damage response (GO:0006974), protein ubiquitination (GO:0016567), protein modification process (GO:0036211)

GO Molecular Function (8): ubiquitin activating enzyme activity (GO:0004839), ATP binding (GO:0005524), FAT10 activating enzyme activity (GO:0019780), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), protein binding (GO:0005515), ubiquitin-like modifier activating enzyme activity (GO:0008641), ligase activity (GO:0016874)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Protein ubiquitination	1
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
protein ubiquitination	2
ubiquitin-like modifier activating enzyme activity	2
cellular anatomical structure	2
modification-dependent protein catabolic process	1
cellular response to stress	1
protein modification by small protein conjugation	1
protein metabolic process	1
macromolecule modification	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cation binding	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
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

2610 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UBA6	UBD	O15205	955
UBA6	UBE2Z	Q9H832	934
UBA6	UBE2R2	Q712K3	855
UBA6	UBE2K	P27924	749
UBA6	UBE2S	Q16763	747
UBA6	NEDD8	Q15843	682
UBA6	TXNIP	Q9H3M7	633
UBA6	UBB	P02248	614
UBA6	UFM1	P61960	605
UBA6	HLA-F	P30511	572
UBA6	UBE2M	P61081	560
UBA6	NUB1	Q9Y5A7	557
UBA6	UBE3A	P78355	537
UBA6	UBE2N	P61088	523
UBA6	CDC34	P49427	509

IntAct

59 interactions, top by confidence:

A	B	Type	Score
HMBOX1	UBA6	psi-mi:“MI:0915”(physical association)	0.560
UBA6	HMBOX1	psi-mi:“MI:0915”(physical association)	0.560
OR5F1	UBA6	psi-mi:“MI:0914”(association)	0.530
ALDH3B1	UBA6	psi-mi:“MI:0914”(association)	0.530
PLEKHO1	UBA6	psi-mi:“MI:0914”(association)	0.530
SNRNP27	UBA6	psi-mi:“MI:0914”(association)	0.530
FYTTD1	UBA6	psi-mi:“MI:0914”(association)	0.530
CAPN6	UBA6	psi-mi:“MI:0914”(association)	0.530
ECE1	UBA6	psi-mi:“MI:0915”(physical association)	0.370
UBA6	SMAD9	psi-mi:“MI:0915”(physical association)	0.370
UBA6	EIF4A3	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
GTF2E2	UBA6	psi-mi:“MI:0914”(association)	0.350
ARHGAP25	UBA6	psi-mi:“MI:0914”(association)	0.350
RAB2B	UBA6	psi-mi:“MI:0914”(association)	0.350
MYLIP	UBA6	psi-mi:“MI:0914”(association)	0.350
SAR1B	UBA6	psi-mi:“MI:0914”(association)	0.350
LINC01587	UBA6	psi-mi:“MI:0914”(association)	0.350
SPANXN4	UBA6	psi-mi:“MI:0914”(association)	0.350
ANKRD39	UBA6	psi-mi:“MI:0914”(association)	0.350
UBE2L6	UBA6	psi-mi:“MI:0914”(association)	0.350

BioGRID (239): HMBOX1 (Two-hybrid), UBA6 (Affinity Capture-MS), RAD6 (Biochemical Activity), UBE2D2 (Biochemical Activity), UBE2L3 (Biochemical Activity), UBE2L6 (Biochemical Activity), UBE2Z (Biochemical Activity), UBE2Z (Biochemical Activity), UBE2Z (Biochemical Activity), UBA6 (Affinity Capture-MS), UBA6 (Affinity Capture-MS), UBA6 (Affinity Capture-MS), UBA6 (Affinity Capture-MS), UBA6 (Affinity Capture-MS), ATG7 (Co-fractionation)

ESM2 similar proteins: A0AVT1, A3KMX8, A5DLC6, A6H630, A6QXC6, A6ZT79, A7KAI6, G2XR75, I1S0J7, O43069, O94609, P0DI12, P0DI13, P20973, P22178, P22515, P31251, P31252, P38862, P42744, P52495, P79064, P92974, P93028, Q09765, Q13564, Q19360, Q4R3L6, Q54QG9, Q55C16, Q5AWA2, Q5ZIE6, Q6AXB1, Q6CBC3, Q6CXW3, Q6DJA3, Q6NTW6, Q756G8, Q7SXP2, Q8C7R4

Diamond homologs: A0AVT1, A2VE14, A3KMV5, O31619, O42939, O65041, O94609, P20973, P22314, P22515, P31251, P31252, P31254, P31255, P41226, P52495, P92974, P93028, Q02053, Q06624, Q09765, Q18217, Q19360, Q29504, Q54QG9, Q54WI4, Q55C16, Q5R4A0, Q5U300, Q7ZVX6, Q8C7R4, Q8C878, Q8TBC4, Q99344, Q99MI7, Q9DBK7, Q9V6U8, Q9VTE9, A1A4L8, A1CAZ7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
UBA6	“form complex”	“Ub:E1 (UBA6 substrate)”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	132
Likely benign	7
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

5210 predictions. Top by Δscore:

Variant	Effect	Δscore
4:67619028:A:AC	donor_gain	1.0000
4:67619029:C:CC	donor_gain	1.0000
4:67622823:ATACT:A	donor_loss	1.0000
4:67622824:TACTT:T	donor_loss	1.0000
4:67622825:AC:A	donor_loss	1.0000
4:67622829:A:AC	donor_gain	1.0000
4:67622829:A:AT	donor_loss	1.0000
4:67622830:C:CT	donor_gain	1.0000
4:67622830:CG:C	donor_gain	1.0000
4:67622926:C:CC	acceptor_gain	1.0000
4:67622932:G:GC	acceptor_gain	1.0000
4:67622941:C:CT	acceptor_gain	1.0000
4:67623133:A:AC	donor_gain	1.0000
4:67623134:C:CA	donor_gain	1.0000
4:67623136:TTG:T	donor_gain	1.0000
4:67623230:A:T	acceptor_gain	1.0000
4:67624251:AACCT:A	acceptor_loss	1.0000
4:67624252:ACCT:A	acceptor_loss	1.0000
4:67624253:CCTA:C	acceptor_loss	1.0000
4:67624254:C:A	acceptor_loss	1.0000
4:67624255:T:A	acceptor_loss	1.0000
4:67624987:AACTT:A	donor_loss	1.0000
4:67624988:ACTTA:A	donor_loss	1.0000
4:67624989:CTT:C	donor_loss	1.0000
4:67624990:TTACC:T	donor_loss	1.0000
4:67624991:TAC:T	donor_loss	1.0000
4:67624992:A:AC	donor_gain	1.0000
4:67624993:C:CC	donor_gain	1.0000
4:67624993:C:T	donor_loss	1.0000
4:67624993:CCAAG:C	donor_gain	1.0000

AlphaMissense

6968 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:67619085:A:G	L1024P	1.000
4:67631763:A:G	W735R	1.000
4:67631763:A:T	W735R	1.000
4:67641190:G:C	N505K	1.000
4:67641190:G:T	N505K	1.000
4:67619023:A:C	Y1045D	0.999
4:67625028:G:T	A893D	0.999
4:67625046:G:T	A887D	0.999
4:67625101:G:T	R869S	0.999
4:67631761:C:A	W735C	0.999
4:67631761:C:G	W735C	0.999
4:67631898:A:G	L718P	0.999
4:67634440:C:G	A641P	0.999
4:67634443:A:G	W640R	0.999
4:67634443:A:T	W640R	0.999
4:67634469:G:T	P631Q	0.999
4:67634471:A:C	F630L	0.999
4:67634471:A:T	F630L	0.999
4:67634473:A:G	F630L	0.999
4:67634487:C:T	C625Y	0.999
4:67634488:A:G	C625R	0.999
4:67635556:C:G	R580P	0.999
4:67638957:C:A	R574S	0.999
4:67638957:C:G	R574S	0.999
4:67638958:C:A	R574M	0.999
4:67638958:C:G	R574T	0.999
4:67638973:T:A	D569V	0.999
4:67638973:T:G	D569A	0.999
4:67639116:T:A	K521N	0.999
4:67639116:T:G	K521N	0.999

dbSNP variants (sampled 300 via entrez): RS1000066393 (4:67638319 T>C), RS1000070239 (4:67686580 T>A,C,G), RS1000082020 (4:67670824 T>C), RS1000095481 (4:67638589 G>A,T), RS1000110873 (4:67696571 C>A), RS1000165259 (4:67645546 G>A), RS10002740 (4:67686730 T>A,C,G), RS1000275340 (4:67693924 A>G,T), RS1000299129 (4:67612479 G>A), RS1000343464 (4:67664279 T>A,C), RS10003837 (4:67666751 C>T), RS10003945 (4:67654357 G>A), RS1000402786 (4:67626500 T>A,C,G), RS1000442851 (4:67669616 CAA>C,CA,CAAA), RS1000470836 (4:67647688 G>A,C)

Disease associations

OMIM: gene MIM:611361 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability	Limited	Autosomal dominant

Mondo (3): breast ductal adenocarcinoma (MONDO:0005590), autism spectrum disorder (MONDO:0005258), intellectual disability (MONDO:0001071)

Orphanet (1): NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006921_13	Regular attendance at a pub or social club	7.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009592	social interaction measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
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): CHEMBL2321622 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,480 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1231160	PEVONEDISTAT	3	1,480

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

Binding affinities (BindingDB)

7 measured of 14 human assays (14 total across all organisms); most potent 7 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
US9593121, I-02	IC50	1020 nM	US-9593121: Indole substituted pyrrolopyrimidinyl inhibitors of Uba6
US9593121, I-09	IC50	1020 nM	US-9593121: Indole substituted pyrrolopyrimidinyl inhibitors of Uba6
tert-butyl 2-[7-[(1R,3S,4S)-3-hydroxy-4-(sulfamoyloxymethyl)cyclopentyl]pyrrolo[2,3-d]pyrimidin-4-yl]-6-methoxyindole-1-carboxylate	IC50	1020 nM	US-9593121: Indole substituted pyrrolopyrimidinyl inhibitors of Uba6
US9593121, I-11	IC50	1020 nM	US-9593121: Indole substituted pyrrolopyrimidinyl inhibitors of Uba6
US9593121, I-12	IC50	1020 nM	US-9593121: Indole substituted pyrrolopyrimidinyl inhibitors of Uba6
US9593121, I-13	IC50	1020 nM	US-9593121: Indole substituted pyrrolopyrimidinyl inhibitors of Uba6
US9593121, I-14	IC50	1020 nM	US-9593121: Indole substituted pyrrolopyrimidinyl inhibitors of Uba6

ChEMBL bioactivities

10 potent at pChembl≥5 of 10 total, top 10 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.04	IC50	920	nM	CHEMBL2017005
5.99	IC50	1025	nM	CHEMBL6067744
5.99	IC50	1025	nM	CHEMBL6067751
5.99	IC50	1025	nM	CHEMBL5988106
5.99	IC50	1025	nM	CHEMBL6067752
5.99	IC50	1025	nM	CHEMBL6067753
5.99	IC50	1025	nM	CHEMBL6067754
5.99	IC50	1025	nM	CHEMBL6067755
5.75	IC50	1800	nM	CHEMBL2322194
5.75	IC50	1800	nM	PEVONEDISTAT

PubChem BioAssay actives

3 with measured affinity, of 5 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
[(2R,3S,4R,5R)-5-[6-[[(1S)-2,3-dihydro-1H-inden-1-yl]amino]purin-9-yl]-3,4-dihydroxyoxolan-2-yl]methyl sulfamate	727138: Inhibition of UBA6 (unknown origin) in presence of ATP	ic50	0.9200	uM
[(1S,2S,4R)-4-[4-[[(1S)-2,3-dihydro-1H-inden-1-yl]amino]pyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl]methyl sulfamate	1872479: Inhibition of His-tagged UBA6 (unknown origin) expressed in sf9 insect cells	ic50	1.8000	uM
[(1S,2S,4R)-4-[4-[[(1S)-2,3-dihydro-1H-inden-1-yl]amino]-5,6-dihydropyrrolo[2,3-d]pyrimidin-7-yl]-2-hydroxycyclopentyl]methyl sulfamate	727129: Inhibition of UBA6 (unknown origin)	ic50	1.8000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenate	decreases reaction, increases abundance, increases expression, decreases expression	2
Arsenic	increases abundance, increases expression, affects cotreatment	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
beta-methylcholine	affects expression	1
4-phenylbutyric acid	decreases expression	1
chloropicrin	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
torcetrapib	increases expression	1
ICG 001	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	decreases expression	1
LDN 193189	increases expression, affects cotreatment	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
bisphenol AF	increases expression	1
Temozolomide	decreases expression	1
Vorinostat	decreases expression	1
Acetaminophen	decreases expression	1
Cadmium	increases expression	1
Caffeine	increases phosphorylation	1
Cisplatin	decreases expression	1
Dieldrin	increases response to substance	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Furaldehyde	decreases expression, affects cotreatment	1
Ivermectin	decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2328920	Binding	Inhibition of UBA6 (unknown origin)	Exploring a new frontier in cancer treatment: targeting the ubiquitin and ubiquitin-like activating enzymes. — J Med Chem

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E2MY	HAP1 UBA6 (-) 2	Cancer cell line	Male
CVCL_E2MZ	HAP1 UBA6 (-) 3	Cancer cell line	Male
CVCL_E2N0	HAP1 UBA6 (-) 4	Cancer cell line	Male
CVCL_E2N1	HAP1 UBA6 (-) 5	Cancer cell line	Male
CVCL_XU84	HAP1 UBA6 (-) 1	Cancer cell line	Male

Clinical trials (associated diseases)

496 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
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
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
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder