UBE2A

Summary

UBE2A (ubiquitin conjugating enzyme E2 A, HGNC:12472) is a protein-coding gene on chromosome Xq24, encoding Ubiquitin-conjugating enzyme E2 A (P49459). E2 ubiquitin-conjugating enzyme that accepts ubiquitin from the ubiquitin-activating enzyme E1 and transfers it to a E3 ubiquitin-protein ligase.

The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, and ubiquitin-protein ligases. This gene encodes a member of the E2 ubiquitin-conjugating enzyme family. This enzyme is required for post-replicative DNA damage repair, and may play a role in transcriptional regulation. Mutations in this gene are associated with cognitive disability. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 7319 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic X-linked intellectual disability Nascimento type (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 115 total — 9 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 83
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_003336

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12472
Approved symbol	UBE2A
Name	ubiquitin conjugating enzyme E2 A
Location	Xq24
Locus type	gene with protein product
Status	Approved
Aliases	UBC2, HHR6A, RAD6A, HR6A
Ensembl gene	ENSG00000077721
Ensembl biotype	protein_coding
OMIM	312180
Entrez	7319

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 11 protein_coding, 4 retained_intron, 1 nonsense_mediated_decay

ENST00000346330, ENST00000371558, ENST00000371569, ENST00000469205, ENST00000625379, ENST00000625938, ENST00000628549, ENST00000628734, ENST00000629303, ENST00000630695, ENST00000631185, ENST00000696533, ENST00000696534, ENST00000696539, ENST00000907907, ENST00000919018

RefSeq mRNA: 3 — MANE Select: NM_003336 NM_001282161, NM_003336, NM_181762

CCDS: CCDS14580, CCDS14581, CCDS78500

Canonical transcript exons

ENST00000371558 — 6 exons

Exon	Start	End
ENSE00001711566	119575375	119575400
ENSE00001763448	119581507	119581596
ENSE00003635504	119574901	119574981
ENSE00003743589	119582588	119582676
ENSE00003843518	119583127	119584423
ENSE00003967637	119574563	119574755

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 97.29.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 85.2592 / max 340.9994, expressed in 1828 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197399	69.5118	1824
197398	9.3474	1796
197400	3.3267	1435
197397	3.0733	1651

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	97.29	gold quality
mucosa of transverse colon	UBERON:0004991	97.17	gold quality
placenta	UBERON:0001987	96.85	gold quality
rectum	UBERON:0001052	96.23	gold quality
esophagus squamous epithelium	UBERON:0006920	96.06	gold quality
esophagus mucosa	UBERON:0002469	96.00	gold quality
cervix squamous epithelium	UBERON:0006922	95.99	gold quality
epithelium of nasopharynx	UBERON:0001951	95.97	gold quality
gastrocnemius	UBERON:0001388	95.96	gold quality
heart right ventricle	UBERON:0002080	95.93	gold quality
epithelium of esophagus	UBERON:0001976	95.89	gold quality
cranial nerve II	UBERON:0000941	95.86	gold quality
heart left ventricle	UBERON:0002084	95.75	gold quality
cardiac ventricle	UBERON:0002082	95.72	gold quality
monocyte	CL:0000576	95.68	gold quality
transverse colon	UBERON:0001157	95.68	gold quality
muscle of leg	UBERON:0001383	95.63	gold quality
esophagus	UBERON:0001043	95.62	gold quality
lower esophagus mucosa	UBERON:0035834	95.62	gold quality
mononuclear cell	CL:0000842	95.56	gold quality
squamous epithelium	UBERON:0006914	95.56	gold quality
colonic mucosa	UBERON:0000317	95.53	gold quality
palpebral conjunctiva	UBERON:0001812	95.51	gold quality
leukocyte	CL:0000738	95.48	gold quality
smooth muscle tissue	UBERON:0001135	95.46	gold quality
heart	UBERON:0000948	95.40	gold quality
vermiform appendix	UBERON:0001154	95.40	gold quality
tongue squamous epithelium	UBERON:0006919	95.40	gold quality
popliteal artery	UBERON:0002250	95.36	gold quality
tibial artery	UBERON:0007610	95.36	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	39.12
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR1I2

miRNA regulators (miRDB)

109 targeting UBE2A, 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-513A-5P	100.00	69.77	2465
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 27)

• high resolution backbone structure from nmr (PMID:11885984)
• A single-nucleotide substitution, c.382C–>T in UBE2A, led to a premature UAG stop codon (Q128X). This is the first description of a mutation in a ubiquitin-conjugating enzyme gene as the cause of a human disease. (PMID:16909393)
• Novel missense mutations in the ubiquitination-related gene UBE2A cause a recognizable X-linked mental retardation syndrome (PMID:20412111)
• showed that the function of FA signaling pathway is at least partly mediated through coupling with hRad6/hRad18 signaling (HHR6 pathway) (PMID:20967207)
• UBE2A deficiency syndrome is reported in two male patients. (PMID:21108393)
• RAD6 can form a ternary complex with MDM2 and p53 that contributes to the degradation of p53. (PMID:22083959)
• UBE2A specifically interacts with CDK9, but not CDK2 and is phosphorylated by CDK9 in vitro. (PMID:22592529)
• RNF168, in complex with RAD6A or RAD6B, is activated in the DNA-damage-induced protein ubiquitination cascade. (PMID:23525009)
• RAD6A is a regulator of Parkin-dependent mitophagy plays a critical role in maintaining neuronal function. (PMID:23685073)
• HHR6 and hRad18 can monoubiquitinate FANCD2 at lysine 561 in vitro. This activity may represent a novel stress response pathway. (PMID:24036990)
• This study investigates clinical and molecular data of two unrelated, affected males with chromosome Xq24 deletions encompassing UBE2A. (PMID:25287747)
• RAD6 physically interacts with heterochromatin protein 1alpha and ubiquitinates HP1alpha at residue K154, thereby promoting heterochromatin protein 1alpha degradation through the autophagy pathway (PMID:25384975)
• Results showed KCMF1 C-terminus binds directly to RAD6, whereas N-terminal domains interact with UBR4 and point mutations found in X-linked intellectual disability (XLID) patients specifically lose the interaction with KCMF1 and UBR4. (PMID:25582440)
• Data show that the ubiquitin-conjugating enzyme E2 RAD6A/B-MDM2 ubiquitin ligase machinery regulates anti-silencing function 1A protein (ASF1A) degradation. (PMID:26336826)
• RAD6 promotes proteasome activity and nuclear translocation by enhancing the degradation of PSMF1 and the lamin B receptor. (PMID:28031328)
• RAD6 is upregulated in response to chemotherapy and significantly correlated with expression of ovarian cancer (OC) stem cell signaling genes ALDH1A1 and SOX2 and poor prognosis of OC patients. (PMID:28806395)
• As confirmed by deep sequencing, the c.330G>A substitution in UBE2A was undetectable in genomic DNA from maternal blood cells, suggesting that the recurrent UBE2A deficiency observed in males of this family is caused by a maternal germline mosaicism. (PMID:29283210)
• UBE2A Q93E mutation, which was identified in two brothers with mild intellectual disability, perturbs the UBE2A catalytic microenvironment essential for lysine deprotonation during ubiquitin transfer, thus generating an enzyme that is disabled but not dead. (PMID:30531907)
• UBE2A mutations that are recurrently acquired during chronic myeloid leukemia progression interfere with myeloid differentiation pathways (PMID:30819912)
• These variants constitute the majority of the RAD6B transcriptome in contrast to RAD6A, which was predominantly wild-type. The expression of functional RAD6B variants only in melanomas reveals RAD6B’s molecular heterogeneity and its association with melanoma pathogenesis. (PMID:31683936)
• A novel UBE2A mutation in a Chinese family with X-linked intellectual disability. (PMID:32222108)
• Refinement of the clinical and mutational spectrum of UBE2A deficiency syndrome. (PMID:32415735)
• Delineation of Clinical Manifestations of the Inherited Xq24 Microdeletion Segregating with sXCI in Mothers: Two Novel Cases with Distinct Phenotypes Ranging from UBE2A Deficiency Syndrome to Recurrent Pregnancy Loss. (PMID:32485717)
• A novel missense mutation in the UBE2A gene causes intellectual disability in the large X-linked family. (PMID:33368912)
• The Role of the Reanalysis of Genetic Test Results in the Diagnosis of Dysmorphic Syndrome Caused by Inherited xq24 Deletion including the UBE2A and CXorf56 Genes. (PMID:33673493)
• Redox-sensitive E2 Rad6 controls cellular response to oxidative stress via K63-linked ubiquitination of ribosomes. (PMID:35613580)
• Mutations of Rad6 E2 ubiquitin-conjugating enzymes at alanine-126 in helix-3 affect ubiquitination activity and decrease enzyme stability. (PMID:36162503)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ube2a	ENSDARG00000098466
mus_musculus	Ube2a	ENSMUSG00000016308
rattus_norvegicus	Ube2a	ENSRNOG00000039985

Paralogs (24): UBE2T (ENSG00000077152), UBE2K (ENSG00000078140), CDC34 (ENSG00000099804), UBE2I (ENSG00000103275), UBE2W (ENSG00000104343), UBE2R2 (ENSG00000107341), UBE2S (ENSG00000108106), UBE2B (ENSG00000119048), UBE2G1 (ENSG00000132388), UBE2Z (ENSG00000159202), UBE2J2 (ENSG00000160087), AKTIP (ENSG00000166971), UBE2V2 (ENSG00000169139), UBE2C (ENSG00000175063), UBE2O (ENSG00000175931), UBE2U (ENSG00000177414), UBE2N (ENSG00000177889), UBE2F (ENSG00000184182), UBE2G2 (ENSG00000184787), UBE2H (ENSG00000186591), UBE2J1 (ENSG00000198833), PEDS1 (ENSG00000240849), UBE2V1 (ENSG00000244687), UBE2NL (ENSG00000276380)

Protein

Protein identifiers

Ubiquitin-conjugating enzyme E2 A — P49459 (reviewed: P49459)

Alternative names: E2 ubiquitin-conjugating enzyme A, RAD6 homolog A, Ubiquitin carrier protein A, Ubiquitin-protein ligase A

All UniProt accessions (6): P49459, A0A0D9SEZ6, A0A0D9SF75, A0A0D9SG71, A0A0R4J2E5, A0A8Q3SIL6

UniProt curated annotations — full annotation on UniProt →

Function. E2 ubiquitin-conjugating enzyme that accepts ubiquitin from the ubiquitin-activating enzyme E1 and transfers it to a E3 ubiquitin-protein ligase. In vitro catalyzes ‘Lys-11’, as well as ‘Lys-48’-linked polyubiquitination. Together with the E3 enzyme BRE1 (RNF20 and/or RNF40), plays a role in transcription regulation by catalyzing the monoubiquitination of histone H2B at ‘Lys-120’ to form H2BK120ub1. H2BK120ub1 gives a specific tag for epigenetic transcriptional activation, elongation by RNA polymerase II, telomeric silencing, and is also a prerequisite for H3K4me and H3K79me formation. Involved in mitophagy by acting as a E2 ubiquitin-conjugating enzyme for PRKN. In association with the E3 enzyme UBR4, is involved in N-end rule-dependent protein degradation. In association with the E3 ubiquitin-protein ligase complex SIFI, inhibits the mitochondrial stress response by acting as a E2 ubiquitin-conjugating enzyme for UBR4 and KCMF1.

Subunit / interactions. Interacts with RAD18 and WAC. Interacts with RFPL4A and CCNB1.

Subcellular location. Late endosome. Lysosome.

Post-translational modifications. Phosphorylation at Ser-120 by CDK9 increases activity towards histone H2B.

Disease relevance. Intellectual developmental disorder, X-linked, syndromic, Nascimento-type (MRXSN) [MIM:300860] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRXSN features include dysmorphic facies, hirsutism, skin and nails abnormalities, obesity, speech anomalies and seizures. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the ubiquitin-conjugating enzyme family.

Isoforms (3)

UniProt ID	Names	Canonical?
P49459-1	1	yes
P49459-2	2
P49459-3	3

RefSeq proteins (3): NP_001269090, NP_003327, NP_861427 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000608	UBC	Domain
IPR016135	UBQ-conjugating_enzyme/RWD	Homologous_superfamily
IPR023313	UBQ-conjugating_AS	Active_site
IPR050113	Ub_conjugating_enzyme-E2-like	Family

Pfam: PF00179

Enzyme classification (BRENDA):

• EC 2.3.2.23 — E2 ubiquitin-conjugating enzyme (BRENDA: 20 organisms, 93 substrates, 28 inhibitors, 12 Km, 8 kcat entries)
• EC 2.3.2.24 — (E3-independent) E2 ubiquitin-conjugating enzyme (BRENDA: 5 organisms, 56 substrates, 7 inhibitors, 6 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBIQUITIN-CARRIER-PROTEIN UBC2B]-L-CYSTEINE	0.0001	5
[UBE2W]-S-UBIQUITINYL-L-CYSTEINE	0.2203–0.3014	2
[HISTONE H2A]-L-LYSINE	0.0008–0.0028	2
[HISTONE H2B]-L-LYSINE	0.0015–0.012	2
S-UBIQUITINYL-[E1 UBIQUITIN-ACTIVATING ENZYME]-L	1	1
[UBIQUITIN CARRIER PROTEIN UBC4]-L-CYSTEINE	0.0019	1
[CYTOCHROME C]-L-LYSINE	0.125	1
[HISTONE H3]-L-LYSINE	0.0013	1

UniProt features (32 total): mutagenesis site 7, sequence variant 6, helix 5, strand 5, turn 2, splice variant 2, chain 1, domain 1, sequence conflict 1, active site 1, modified residue 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
6CYO	X-RAY DIFFRACTION	1.85
6CYR	X-RAY DIFFRACTION	2.2
8IEJ	ELECTRON MICROSCOPY	3.12
8BTL	X-RAY DIFFRACTION	3.2
9KQO	ELECTRON MICROSCOPY	3.48

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49459-F1	94.25	0.93

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): 88 (glycyl thioester intermediate)

Post-translational modifications (1): 120

Mutagenesis-validated functional residues (7):

Position	Phenotype
7	impaired ability to transfer ubiquitin to ubr4.
8	impaired ability to transfer ubiquitin to ubr4.
11	impaired ability to transfer ubiquitin to ubr4.
80	abolished ability to transfer ubiquitin to ubr4.
95	impaired ability to transfer ubiquitin to ubr4.
97	impaired ability to transfer ubiquitin to ubr4.
120	abolished ability to transfer ubiquitin to ubr4.

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-8866654	E3 ubiquitin ligases ubiquitinate target proteins
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 455 (showing top): BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_DNA_DAMAGE_TOLERANCE, KAUFFMANN_DNA_REPAIR_GENES, HUMMERICH_SKIN_CANCER_PROGRESSION_DN, GOBP_MACROAUTOPHAGY, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GOBP_PROTEIN_K11_LINKED_UBIQUITINATION, GOBP_REGULATION_OF_CATABOLIC_PROCESS

GO Biological Process (16): G2/M transition of mitotic cell cycle (GO:0000086), protein polyubiquitination (GO:0000209), DNA repair (GO:0006281), DNA damage tolerance (GO:0006301), chromatin remodeling (GO:0006338), ubiquitin-dependent protein catabolic process (GO:0006511), response to UV (GO:0009411), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), protein K48-linked ubiquitination (GO:0070936), protein K11-linked ubiquitination (GO:0070979), positive regulation of mitophagy (GO:1901526), cytoplasmic translation (GO:0002181), chromatin organization (GO:0006325), DNA damage response (GO:0006974), protein ubiquitination (GO:0016567), protein modification by small protein conjugation (GO:0032446)

GO Molecular Function (9): ubiquitin-protein transferase activity (GO:0004842), ATP binding (GO:0005524), ubiquitin protein ligase binding (GO:0031625), ubiquitin binding (GO:0043130), ubiquitin conjugating enzyme activity (GO:0061631), nucleotide binding (GO:0000166), protein binding (GO:0005515), transferase activity (GO:0016740), ubiquitin-like protein transferase activity (GO:0019787)

GO Cellular Component (7): chromatin (GO:0000785), nucleoplasm (GO:0005654), lysosome (GO:0005764), late endosome (GO:0005770), cytosol (GO:0005829), HULC complex (GO:0033503), endosome (GO:0005768)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Protein ubiquitination	2
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein ubiquitination	2
DNA metabolic process	2
DNA damage response	2
protein polyubiquitination	2
mitotic cell cycle	1
mitotic cell cycle phase transition	1
cell cycle G2/M phase transition	1
DNA replication	1
chromatin organization	1
modification-dependent protein catabolic process	1
response to light stimulus	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
mitophagy	1
positive regulation of macroautophagy	1
regulation of mitophagy	1
positive regulation of autophagy of mitochondrion	1
translation	1
cellular component organization	1
cellular response to stress	1
protein modification by small protein conjugation	1
protein modification by small protein conjugation or removal	1
ubiquitin-like protein transferase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ubiquitin-like protein ligase binding	1
ubiquitin-like protein binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein conjugating enzyme activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
aminoacyltransferase activity	1
catalytic activity, acting on a protein	1
chromosome	1
nuclear lumen	1
lytic vacuole	1
endosome	1

Protein interactions and networks

STRING

4226 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UBE2A	RAD18	Q9NS91	987
UBE2A	UBR1	Q8IWV7	890
UBE2A	UBA1	P22314	884
UBE2A	RNF20	Q5VTR2	828
UBE2A	RNF40	O75150	819
UBE2A	UBR2	Q8IWV8	817
UBE2A	UBE2V2	Q15819	788
UBE2A	LTN1	O94822	767
UBE2A	UBA7	P41226	727
UBE2A	UBE3A	P78355	721
UBE2A	CUL4B	Q13620	715
UBE2A	ARIH1	Q9Y4X5	684
UBE2A	MCTS1	Q9ULC4	649
UBE2A	NTAQ1	Q96HA8	612
UBE2A	PSMD11	O00231	610

IntAct

108 interactions, top by confidence:

A	B	Type	Score
LLGL2	PRKCI	psi-mi:“MI:0914”(association)	0.890
RNF20	RNF40	psi-mi:“MI:0220”(ubiquitination reaction)	0.820
UBE2A	SDCBP	psi-mi:“MI:0915”(physical association)	0.720
SDCBP	UBE2A	psi-mi:“MI:0915”(physical association)	0.720
UBE2A	RAD18	psi-mi:“MI:0915”(physical association)	0.660
CASP6	UBE2A	psi-mi:“MI:0915”(physical association)	0.560
CHAT	UBE2A	psi-mi:“MI:0915”(physical association)	0.560
UBE2A	EIF2S3	psi-mi:“MI:0915”(physical association)	0.560
UBE2A	ERN1	psi-mi:“MI:0915”(physical association)	0.560
UBE2A	FGFR3	psi-mi:“MI:0915”(physical association)	0.560
FKBP1A	UBE2A	psi-mi:“MI:0915”(physical association)	0.560
GRIN2C	UBE2A	psi-mi:“MI:0915”(physical association)	0.560
UBE2A	GSN	psi-mi:“MI:0915”(physical association)	0.560
HMOX2	UBE2A	psi-mi:“MI:0915”(physical association)	0.560
HSPA2	UBE2A	psi-mi:“MI:0915”(physical association)	0.560
LAMP2	UBE2A	psi-mi:“MI:0915”(physical association)	0.560
RAN	UBE2A	psi-mi:“MI:0915”(physical association)	0.560
UBE2A		psi-mi:“MI:0915”(physical association)	0.560
DNALI1	UBE2A	psi-mi:“MI:0915”(physical association)	0.560
KLF11	UBE2A	psi-mi:“MI:0915”(physical association)	0.560
NUP58	UBE2A	psi-mi:“MI:0915”(physical association)	0.560
OPTN	UBE2A	psi-mi:“MI:0915”(physical association)	0.560
RAPGEF4	UBE2A	psi-mi:“MI:0915”(physical association)	0.560
UBQLN1	UBE2A	psi-mi:“MI:0915”(physical association)	0.560
PRPF40A	UBE2A	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (325): UBE2A (Reconstituted Complex), UBE2A (Reconstituted Complex), UBE2A (Affinity Capture-Western), UBE2A (Biochemical Activity), UBE2A (Two-hybrid), CBX5 (Affinity Capture-Western), UBE2A (Affinity Capture-Western), UBE2A (Co-localization), UBE2A (Reconstituted Complex), UBE2A (Biochemical Activity), CBX5 (Reconstituted Complex), UBE2A (Biochemical Activity), UBE2B (Affinity Capture-MS), UBC (Affinity Capture-MS), RAD18 (Affinity Capture-MS)

ESM2 similar proteins: O09181, P0CS16, P0CS17, P23566, P25153, P34477, P40984, P42746, P49459, P50623, P52484, P52493, P56616, P63146, P63147, P63148, P63149, P63279, P63280, P63281, P63282, P63283, P78717, Q28CQ4, Q2EF73, Q32P99, Q32PA5, Q42551, Q4WLA7, Q54XS6, Q553F3, Q58FS2, Q6BU36, Q6CUD9, Q6FR76, Q6Y1Z4, Q7ZY08, Q8LGF7, Q94A97, Q95017

Diamond homologs: A1L3K1, A5PKP9, A7SE05, B3MQV3, B3NWW9, B4H9W2, B4IF39, B4JKB7, B4L7V4, B4MA02, B4N208, B4Q2J2, B4R6G1, B5DFI8, B5DKM4, C1C3R6, C3Z724, D3ZDK2, O13685, O74196, O74810, P0CS16, P0CS17, P15731, P15732, P25153, P25865, P25866, P25867, P35128, P35129, P35130, P35131, P35132, P35133, P35134, P35135, P42745, P42746, P43102

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
CDK1	up-regulates	UBE2A	phosphorylation
CDK2	up-regulates	UBE2A	phosphorylation
UBE2A	up-regulates	PCNA	ubiquitination
“Ub:E1 (UBA1 substrate)”	“up-regulates activity”	UBE2A	ubiquitination
“Ub:E1 (UBA6 substrate)”	“up-regulates activity”	UBE2A	ubiquitination
CDK9	“up-regulates activity”	UBE2A	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 58 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
ubiquitin-dependent protein catabolic process	7	9.4×	2e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — DLBCLNOS.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	13
Uncertain significance	37
Likely benign	19
Benign	2

Top pathogenic / likely-pathogenic (22)

Variant ID	HGVS	Classification
2138710	NM_003336.4(UBE2A):c.328C>G (p.Gln110Glu)	Pathogenic
29993	NM_003336.4(UBE2A):c.32G>A (p.Arg11Gln)	Pathogenic
3254933	NM_003336.4(UBE2A):c.126-2A>G	Pathogenic
392902	NM_003336.4(UBE2A):c.126-1G>A	Pathogenic
437188	NM_003336.4(UBE2A):c.67G>A (p.Gly23Arg)	Pathogenic
452557	NM_003336.4(UBE2A):c.125+2T>C	Pathogenic
625798	GRCh37/hg19 Xq24(chrX:118714474-118718137)	Pathogenic
985531	NM_003336.4(UBE2A):c.108G>A (p.Trp36Ter)	Pathogenic
9922	NM_003336.4(UBE2A):c.382C>T (p.Gln128Ter)	Pathogenic
1333497	NM_003336.4(UBE2A):c.421_422del (p.Val141fs)	Likely pathogenic
1700138	NM_003336.4(UBE2A):c.28A>C (p.Met10Leu)	Likely pathogenic
2572051	NM_003336.4(UBE2A):c.439C>T (p.Gln147Ter)	Likely pathogenic
3061895	NM_003336.4(UBE2A):c.330+1del	Likely pathogenic
3775532	NM_003336.4(UBE2A):c.330+1G>C	Likely pathogenic
4849266	NM_003336.4(UBE2A):c.260dup (p.Cys88fs)	Likely pathogenic
520743	NM_003336.4(UBE2A):c.2T>G (p.Met1Arg)	Likely pathogenic
520791	NM_003336.4(UBE2A):c.1A>G (p.Met1Val)	Likely pathogenic
559652	NM_003336.4(UBE2A):c.373del (p.Gln125fs)	Likely pathogenic
804078	NM_003336.4(UBE2A):c.31_42del (p.Asp12_Arg15del)	Likely pathogenic
915473	NM_003336.4(UBE2A):c.299ATG[1] (p.Asp101del)	Likely pathogenic
915474	NM_003336.4(UBE2A):c.242-3_244del	Likely pathogenic
976781	NM_003336.4(UBE2A):c.330+1G>A	Likely pathogenic

SpliceAI

2145 predictions. Top by Δscore:

Variant	Effect	Δscore
X:119539786:CAGC:C	acceptor_gain	1.0000
X:119541323:CTCA:C	donor_loss	1.0000
X:119541324:TCAC:T	donor_loss	1.0000
X:119541325:CA:C	donor_loss	1.0000
X:119541326:A:AC	donor_gain	1.0000
X:119541326:A:C	donor_loss	1.0000
X:119541326:AC:A	donor_gain	1.0000
X:119541326:ACCAG:A	donor_gain	1.0000
X:119541327:C:CC	donor_gain	1.0000
X:119541327:CC:C	donor_gain	1.0000
X:119541327:CCA:C	donor_gain	1.0000
X:119541327:CCAG:C	donor_gain	1.0000
X:119541327:CCAGC:C	donor_gain	1.0000
X:119541416:TCCCT:T	acceptor_gain	1.0000
X:119541417:CCCT:C	acceptor_gain	1.0000
X:119541417:CCCTC:C	acceptor_gain	1.0000
X:119541418:CCT:C	acceptor_gain	1.0000
X:119541418:CCTC:C	acceptor_gain	1.0000
X:119541419:CT:C	acceptor_gain	1.0000
X:119541419:CTC:C	acceptor_gain	1.0000
X:119541420:TC:T	acceptor_loss	1.0000
X:119541420:TCT:T	acceptor_gain	1.0000
X:119541421:C:A	acceptor_gain	1.0000
X:119541421:C:CC	acceptor_gain	1.0000
X:119541421:C:CG	acceptor_loss	1.0000
X:119542501:TTA:T	donor_loss	1.0000
X:119542502:TAC:T	donor_loss	1.0000
X:119542503:A:AC	donor_gain	1.0000
X:119542503:ACAG:A	donor_gain	1.0000
X:119542503:ACAGC:A	donor_gain	1.0000

AlphaMissense

1008 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:119582606:T:A	I87K	1.000
X:119582632:T:A	W96R	1.000
X:119582632:T:C	W96R	1.000
X:119582634:G:C	W96C	1.000
X:119582634:G:T	W96C	1.000
X:119574737:T:A	L9H	0.999
X:119574933:G:A	G26E	0.999
X:119574962:T:A	W36R	0.999
X:119574962:T:C	W36R	0.999
X:119574969:C:A	A38E	0.999
X:119574981:G:A	G42E	0.999
X:119581519:T:C	L55P	0.999
X:119581542:T:C	Y63H	0.999
X:119581558:C:A	P68H	0.999
X:119581564:T:A	V70D	0.999
X:119581570:T:C	F72S	0.999
X:119581587:C:G	H78D	0.999
X:119581588:A:G	H78R	0.999
X:119581591:C:A	P79Q	0.999
X:119581595:T:A	N80K	0.999
X:119581595:T:G	N80K	0.999
X:119582588:T:A	V81D	0.999
X:119582600:G:T	G85V	0.999
X:119582606:T:G	I87R	0.999
X:119582608:T:C	C88R	0.999
X:119582609:G:A	C88Y	0.999
X:119582610:T:G	C88W	0.999
X:119582612:T:C	L89P	0.999
X:119582615:A:T	D90V	0.999
X:119582618:T:A	I91K	0.999

dbSNP variants (sampled 300 via entrez): RS1000779701 (X:119577144 C>CA), RS1001668924 (X:119580317 C>G), RS1001763656 (X:119579780 C>G,T), RS1002249118 (X:119579310 C>A,G), RS1002309733 (X:119578375 A>G), RS1002737239 (X:119584776 A>G), RS1002865083 (X:119575546 G>C), RS1003109963 (X:119580822 A>C), RS1003196209 (X:119574444 C>T), RS1003349158 (X:119575169 G>T), RS1003656050 (X:119577329 G>A,C), RS1003867017 (X:119573265 T>C,G), RS1003898107 (X:119572912 T>G), RS1004265717 (X:119582960 A>G), RS1005125061 (X:119582474 A>T)

Disease associations

OMIM: gene MIM:312180 | disease phenotypes: MIM:300860

GenCC curated gene-disease

Disease	Classification	Inheritance
syndromic X-linked intellectual disability Nascimento type	Definitive	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
syndromic X-linked intellectual disability Nascimento type	Definitive	XL

Mondo (2): syndromic X-linked intellectual disability Nascimento type (MONDO:0010461), intellectual disability (MONDO:0001071)

Orphanet (2): X-linked intellectual disability, Nascimento type (Orphanet:163956), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

83 total (30 of 83 shown, HPO-id order):

HPO	Term
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000076	Vesicoureteral reflux
HP:0000085	Horseshoe kidney
HP:0000154	Wide mouth
HP:0000233	Thin vermilion border
HP:0000256	Macrocephaly
HP:0000272	Malar flattening
HP:0000283	Broad face
HP:0000316	Hypertelorism
HP:0000336	Prominent supraorbital ridges
HP:0000348	High forehead
HP:0000365	Hearing impairment
HP:0000400	Macrotia
HP:0000430	Underdeveloped nasal alae
HP:0000470	Short neck
HP:0000475	Broad neck
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000519	Developmental cataract
HP:0000582	Upslanted palpebral fissure
HP:0000664	Synophrys
HP:0000718	Aggressive behavior
HP:0000722	Compulsive behaviors
HP:0000750	Delayed speech and language development
HP:0000958	Dry skin
HP:0001007	Hirsutism
HP:0001249	Intellectual disability
HP:0001250	Seizure

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001889_4	Brain connectivity	2.000000e-10

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
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: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, increases expression	3
Acetaminophen	increases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Benzo(a)pyrene	affects methylation, affects cotreatment, affects expression, increases methylation	2
Tobacco Smoke Pollution	increases expression	2
Valproic Acid	affects expression, increases methylation	2
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
beta-lapachone	increases expression	1
1,2,5,6-dibenzanthracene	affects cotreatment, affects expression	1
4-hydroxy-2-nonenal	decreases expression	1
dibenzo(a,l)pyrene	affects expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
nickel acetate	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
jinfukang	decreases expression	1
Ascorbic Acid	affects cotreatment, decreases expression	1
Aspirin	increases expression	1
Berberine	decreases expression	1
Cadmium	affects expression	1
Cannabidiol	increases expression	1
Catechin	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Hydrogen Peroxide	decreases expression	1
Ivermectin	increases expression	1
Methyl Methanesulfonate	increases expression	1
Nickel	decreases expression	1
Ozone	affects expression, increases abundance	1
Phthalic Acids	increases methylation	1

Cellosaurus cell lines

4 cell lines: 2 cancer cell line, 1 transformed cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B3KI	Abcam HEK293T UBE2A KO	Transformed cell line	Female
CVCL_C6SD	RCPCMi009-A-1	Induced pluripotent stem cell	Male
CVCL_TV46	HAP1 UBE2A (-) 1	Cancer cell line	Male
CVCL_TV47	HAP1 UBE2A (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

197 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
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
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders