UBE4A

Summary

UBE4A (ubiquitination factor E4A, HGNC:12499) is a protein-coding gene on chromosome 11q23.3, encoding Ubiquitin conjugation factor E4 A (Q14139). Ubiquitin-protein ligase that probably functions as an E3 ligase in conjunction with specific E1 and E2 ligases.

This gene encodes a member of the U-box ubiquitin ligase family. The encoded protein is involved in multiubiquitin chain assembly and plays a critical role in chromosome condensation and separation through the polyubiquitination of securin. Autoantibodies against the encoded protein may be markers for scleroderma and Crohn’s disease. A pseudogene of this gene is located on the long arm of chromosome 3. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 9354 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with hypotonia and gross motor and speech delay (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 124 total — 3 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 11
• Druggable target: yes
• MANE Select transcript: NM_001204077

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12499
Approved symbol	UBE4A
Name	ubiquitination factor E4A
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Aliases	UBOX2, UFD2, KIAA0126, E4
Ensembl gene	ENSG00000110344
Ensembl biotype	protein_coding
OMIM	603753
Entrez	9354

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 10 protein_coding

ENST00000252108, ENST00000431736, ENST00000545354, ENST00000857052, ENST00000857053, ENST00000857054, ENST00000911347, ENST00000911348, ENST00000911349, ENST00000911350

RefSeq mRNA: 2 — MANE Select: NM_001204077 NM_001204077, NM_004788

CCDS: CCDS55790, CCDS8396

Canonical transcript exons

ENST00000252108 — 20 exons

Exon	Start	End
ENSE00001111757	118359600	118359674
ENSE00001111758	118390657	118390804
ENSE00001111759	118386438	118386612
ENSE00001111760	118389725	118389905
ENSE00001111762	118392738	118392895
ENSE00001111763	118365040	118365201
ENSE00001111766	118384635	118384735
ENSE00001111769	118384832	118384945
ENSE00001129539	118382589	118382776
ENSE00001129546	118381391	118381523
ENSE00001129557	118376574	118376694
ENSE00001129561	118374896	118375229
ENSE00001129566	118373494	118373685
ENSE00001129572	118373086	118373288
ENSE00001129585	118371514	118371666
ENSE00001129591	118369423	118369535
ENSE00001129595	118368631	118368804
ENSE00001620123	118396314	118399211
ENSE00001680501	118372507	118372666
ENSE00003576197	118379446	118379750

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 98.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.8918 / max 476.3244, expressed in 1818 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
116993	45.7787	1818
116994	0.1131	48

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	98.20	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.07	gold quality
middle temporal gyrus	UBERON:0002771	97.78	gold quality
parietal pleura	UBERON:0002400	97.28	gold quality
visceral pleura	UBERON:0002401	97.28	gold quality
pleura	UBERON:0000977	97.23	gold quality
pons	UBERON:0000988	97.09	gold quality
upper leg skin	UBERON:0004262	97.04	gold quality
trigeminal ganglion	UBERON:0001675	96.96	gold quality
superior vestibular nucleus	UBERON:0007227	96.79	gold quality
inferior vagus X ganglion	UBERON:0005363	96.73	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.65	gold quality
jejunal mucosa	UBERON:0000399	96.64	gold quality
medulla oblongata	UBERON:0001896	96.63	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	96.60	gold quality
substantia nigra pars compacta	UBERON:0001965	96.54	gold quality
dorsal root ganglion	UBERON:0000044	96.47	gold quality
subthalamic nucleus	UBERON:0001906	96.46	gold quality
corpus epididymis	UBERON:0004359	96.44	gold quality
skin of hip	UBERON:0001554	96.42	gold quality
pylorus	UBERON:0001166	96.35	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.26	gold quality
dorsal plus ventral thalamus	UBERON:0001897	96.23	gold quality
postcentral gyrus	UBERON:0002581	96.08	gold quality
globus pallidus	UBERON:0001875	96.05	gold quality
medial globus pallidus	UBERON:0002477	96.05	gold quality
germinal epithelium of ovary	UBERON:0001304	96.03	gold quality
tibia	UBERON:0000979	96.00	gold quality
caput epididymis	UBERON:0004358	96.00	gold quality
parietal lobe	UBERON:0001872	95.98	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.32

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

175 targeting UBE4A, 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-340-5P	100.00	72.50	4437
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-548AB	99.95	71.31	3488
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

Literature-anchored findings (GeneRIF, showing 9)

• UBE4A is expressed in different tissues in a pattern that seems to be dependent from cell type and cell cycle and that UBE4A might have a specific role in different biochemical processes other than ubiquitination, including growth or differentiation. (PMID:15019985)
• In these studies, we define Ufd2 (a novel E4 polyubiquitylating enzyme) as a new autoantigen in scleroderma, and show that it regulates chromosome condensation and separation during mitosis in human cells. (PMID:15611659)
• UBE4A was over-expressed in ovarian serous cystadenocarcinoma tissues, suggesting that the activity of ubiquitin-proteasome system is enhanced in ovarian cancer. (PMID:17553343)
• Identified an intestinal cDNA clone encoding ubiquitination factor E4A (UBE4A), a U-box-type ubiquitin-protein ligase. The prevalence of anti-UBE4A IgG in patients with CD was significantly higher than that in patients with UC or healthy controls (PMID:18069675)
• Ectopic overexpression of UBE4A, but not UBE3C, in cells was downregulated in vitro migration and invasion in these cells. Cumulatively, our data reveals a novel post-translational regulatory mechanism of regulating ILEI1 expression, a protein required for metastatic progression in prostate cancer cells (PMID:27862841)
• UBE4A’s recruitment to sites of DNA damage is dependent on primary E3 ligases in the DDR and promotes enhancement and sustainment of K48- and K63-linked ubiquitin chains at these sites. This step is required for timely recruitment of the RAP80 and BRCA1 proteins and proper organization of RAP80- and BRCA1-associated protein complexes at DSB sites. (PMID:29499138)
• Biallelic UBE4A loss-of-function variants cause intellectual disability and global developmental delay. (PMID:33420346)
• PTBP3 modulates P53 expression and promotes colorectal cancer cell proliferation by maintaining UBE4A mRNA stability. (PMID:35136024)
• UBE4A catalyzes NRF1 ubiquitination and facilitates DDI2-mediated NRF1 cleavage. (PMID:37084817)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ube4a	ENSDARG00000040571
mus_musculus	Ube4a	ENSMUSG00000059890
rattus_norvegicus	Ube4a	ENSRNOG00000026833
drosophila_melanogaster	Ube4A	FBGN0028467

Paralogs (1): UBE4B (ENSG00000130939)

Protein

Protein identifiers

Ubiquitin conjugation factor E4 A — Q14139 (reviewed: Q14139)

Alternative names: RING-type E3 ubiquitin transferase E4 A

All UniProt accessions (2): Q14139, B7Z7P0

UniProt curated annotations — full annotation on UniProt →

Function. Ubiquitin-protein ligase that probably functions as an E3 ligase in conjunction with specific E1 and E2 ligases. May also function as an E4 ligase mediating the assembly of polyubiquitin chains on substrates ubiquitinated by another E3 ubiquitin ligase. Mediates ‘Lys-48’-linked polyubiquitination of substrates.

Subcellular location. Cytoplasm.

Disease relevance. Neurodevelopmental disorder with hypotonia and gross motor and speech delay (NEDHMS) [MIM:619639] An autosomal recessive disorder characterized by severe global developmental delay apparent from infancy, axial hypotonia, limited or absent ability to walk, impaired intellectual development, and poor or absent speech. Additional features may include seizures, behavioral problems, distal skeletal anomalies, and facial dysmorphism. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The U-box domain is required for the ubiquitin protein ligase activity.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the ubiquitin conjugation factor E4 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14139-1	1	yes
Q14139-2	2

RefSeq proteins (2): NP_001191006, NP_004779 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003613	Ubox_domain	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR019474	Ub_conjug_fac_E4_core	Domain
IPR045132	UBE4	Family

Pfam: PF04564, PF10408

Enzyme classification (BRENDA):

• EC 2.3.2.27 — RING-type E3 ubiquitin transferase (BRENDA: 28 organisms, 138 substrates, 10 inhibitors, 1 Km, 1 kcat entries)
• EC 2.3.2.B12 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[UBE2W]-S-UBIQUITINYL-L-CYSTEINE	0.3014	1

UniProt features (19 total): turn 6, strand 3, helix 2, sequence variant 2, chain 1, domain 1, region of interest 1, modified residue 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1WGM	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14139-F1	87.83	0.65

Functional residue map

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

Post-translational modifications (1): 386

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 198 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MORF_MBD4, MORF_RAB5A, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, HASLINGER_B_CLL_WITH_11Q23_DELETION, GTGCCTT_MIR506, YOKOE_CANCER_TESTIS_ANTIGENS, MORF_SKP1A, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, MODULE_206, SCHAEFFER_PROSTATE_DEVELOPMENT_12HR_UP

GO Biological Process (4): protein polyubiquitination (GO:0000209), ubiquitin-dependent protein catabolic process (GO:0006511), ERAD pathway (GO:0036503), protein ubiquitination (GO:0016567)

GO Molecular Function (5): ubiquitin-ubiquitin ligase activity (GO:0034450), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515), transferase activity (GO:0016740), ubiquitin protein ligase activity (GO:0061630)

GO Cellular Component (3): ubiquitin ligase complex (GO:0000151), nucleus (GO:0005634), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein ubiquitination	2
modification-dependent protein catabolic process	1
proteasomal protein catabolic process	1
response to endoplasmic reticulum stress	1
response to chemical	1
protein modification by small protein conjugation	1
ubiquitin protein ligase activity	1
ubiquitin-like protein transferase activity	1
binding	1
catalytic activity	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
intracellular protein-containing complex	1
transferase complex	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1866 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UBE4A	VCP	P55072	933
UBE4A	STUB1	Q9UNE7	926
UBE4A	UBQLN1	Q9UMX0	869
UBE4A	UBQLN2	Q9UHD9	857
UBE4A	UFD1	Q92890	820
UBE4A	NPLOC4	Q8TAT6	761
UBE4A	RAD23A	P54725	720
UBE4A	ANKZF1	Q9H8Y5	719
UBE4A	PSMD4	P55036	699
UBE4A	PLAA	Q9Y263	695
UBE4A	UNC45B	Q8IWX7	688
UBE4A	UBE2D1	P51668	655
UBE4A	DERL1	Q9BUN8	650
UBE4A	MARCHF6	O60337	639
UBE4A	UBXN6	Q9BZV1	639

IntAct

93 interactions, top by confidence:

A	B	Type	Score
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
VCP	UBXN8	psi-mi:“MI:0914”(association)	0.690
UBE4A	IP6K1	psi-mi:“MI:0915”(physical association)	0.680
UBXN4	UBE4A	psi-mi:“MI:0914”(association)	0.620
UBXN4	UBE4A	psi-mi:“MI:0915”(physical association)	0.620
MAVS	RIPK2	psi-mi:“MI:0914”(association)	0.580
GYPB	TCAF2	psi-mi:“MI:0914”(association)	0.530
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
LRRTM1	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
VSIG1	TNPO2	psi-mi:“MI:0914”(association)	0.530
B4GALT3	ATP5MC1	psi-mi:“MI:0914”(association)	0.530
ANKRD22	ESYT2	psi-mi:“MI:0914”(association)	0.530
ILVBL	SLC33A1	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
MAVS	UBE4A	psi-mi:“MI:0915”(physical association)	0.500
CWC25	UBE4A	psi-mi:“MI:0915”(physical association)	0.400
UBE4A	UBE2D1	psi-mi:“MI:0915”(physical association)	0.370
UBE2D2	UBE4A	psi-mi:“MI:0915”(physical association)	0.370
UBE4A	UBE2D3	psi-mi:“MI:0915”(physical association)	0.370
UBE4A	UBE2D4	psi-mi:“MI:0915”(physical association)	0.370
FOXB1	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXI2	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXL1	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXL2	DDX39A	psi-mi:“MI:0914”(association)	0.350

BioGRID (163): UBE4A (Affinity Capture-MS), UBE4A (Affinity Capture-MS), UBE4A (Affinity Capture-MS), UBE4A (Affinity Capture-MS), UBE4A (Affinity Capture-MS), UBE4A (Affinity Capture-MS), UBE4A (Affinity Capture-MS), UBE4A (Affinity Capture-MS), UBE4A (Affinity Capture-MS), UBE4A (Affinity Capture-MS), UBE4A (Affinity Capture-MS), UBE4A (Affinity Capture-MS), UBE4A (Affinity Capture-MS), UBXN4 (Affinity Capture-MS), UBE4A (Affinity Capture-MS)

ESM2 similar proteins: A5PKG6, B1AY13, B3N449, B4F766, B4IMI7, B4ISV0, B4NP05, E9Q735, O04375, O70481, O95155, P52590, P54860, P55824, P57740, Q14139, Q15172, Q28BM0, Q293C2, Q5R629, Q5R9G3, Q5RAW5, Q5T2E6, Q5ZLW3, Q6DCP6, Q6DCT2, Q6P7A2, Q6PD19, Q6PGW3, Q7KNA0, Q7PLS8, Q7RTS9, Q7SYB2, Q7ZYV9, Q80X82, Q8CHY3, Q8CIM8, Q8IWV7, Q8MSU4, Q8R1F6

Diamond homologs: A5PKG6, A6HD62, E9Q735, Q09349, Q14139, Q5R9G3, Q5ZHY5, Q6P7A2, Q9LF41, Q9UNE7, Q9WUD1, A2ZLU6, A4K2V0, D3ZSP7, D7REX8, E4NKF8, F1RBN2, F8RP11, O13754, O13797, O14217, O16259, O35814, O54981, O80742, O81902, O88196, P0C6E7, P0CT30, P15705, P25638, P31948, P53041, P53042, P53804, Q07617, Q0IMG9, Q0JL44, Q15785, Q32PZ3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	UBE4A	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 115 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
E3 ubiquitin ligases ubiquitinate target proteins	6	16.6×	8e-04

GO biological processes:

GO term	Partners	Fold	FDR
ERAD pathway	7	13.5×	7e-04
ubiquitin-dependent protein catabolic process	9	7.1×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	2
Uncertain significance	90
Likely benign	10
Benign	0

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1326859	NM_001204077.2(UBE4A):c.384G>A (p.Trp128Ter)	Pathogenic
1326860	NM_001204077.2(UBE4A):c.631C>T (p.Arg211Ter)	Pathogenic
1333516	NM_001204077.2(UBE4A):c.992del (p.Gly331fs)	Pathogenic
2412716	NM_001204077.2(UBE4A):c.1214_1215del (p.Asn405fs)	Likely pathogenic
2505262	NM_001204077.2(UBE4A):c.217C>T (p.Arg73Ter)	Likely pathogenic

SpliceAI

2987 predictions. Top by Δscore:

Variant	Effect	Δscore
11:118365039:GC:G	acceptor_gain	1.0000
11:118365039:GCC:G	acceptor_gain	1.0000
11:118365039:GCCT:G	acceptor_gain	1.0000
11:118365039:GCCTC:G	acceptor_gain	1.0000
11:118365197:ATCTG:A	donor_gain	1.0000
11:118365198:TCTG:T	donor_gain	1.0000
11:118365199:CTG:C	donor_gain	1.0000
11:118365200:TG:T	donor_gain	1.0000
11:118365200:TGGT:T	donor_loss	1.0000
11:118365201:GG:G	donor_gain	1.0000
11:118365201:GGT:G	donor_loss	1.0000
11:118365202:G:GG	donor_gain	1.0000
11:118365202:GTAA:G	donor_loss	1.0000
11:118365203:T:G	donor_loss	1.0000
11:118368625:T:TA	acceptor_gain	1.0000
11:118368626:G:A	acceptor_gain	1.0000
11:118368629:A:AG	acceptor_gain	1.0000
11:118368629:AG:A	acceptor_loss	1.0000
11:118368629:AGAT:A	acceptor_gain	1.0000
11:118368630:G:GC	acceptor_gain	1.0000
11:118368630:GA:G	acceptor_gain	1.0000
11:118368630:GAT:G	acceptor_gain	1.0000
11:118368630:GATG:G	acceptor_gain	1.0000
11:118368630:GATGA:G	acceptor_gain	1.0000
11:118368738:G:GT	donor_gain	1.0000
11:118368800:CAACA:C	donor_gain	1.0000
11:118368801:AACA:A	donor_gain	1.0000
11:118368802:ACA:A	donor_gain	1.0000
11:118368803:CA:C	donor_gain	1.0000
11:118368803:CAG:C	donor_loss	1.0000

AlphaMissense

7128 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:118384649:T:C	F738L	1.000
11:118384650:T:G	F738C	1.000
11:118384651:T:A	F738L	1.000
11:118384651:T:G	F738L	1.000
11:118384661:T:C	F742L	1.000
11:118384663:T:A	F742L	1.000
11:118384663:T:G	F742L	1.000
11:118384670:C:A	R745S	1.000
11:118384914:A:C	D794A	1.000
11:118384914:A:G	D794G	1.000
11:118384914:A:T	D794V	1.000
11:118384916:G:C	A795P	1.000
11:118389791:T:C	L885P	1.000
11:118389800:T:C	L888P	1.000
11:118389853:T:C	F906L	1.000
11:118389854:T:C	F906S	1.000
11:118389855:C:A	F906L	1.000
11:118389855:C:G	F906L	1.000
11:118389869:T:C	L911P	1.000
11:118390737:T:A	V950D	1.000
11:118371527:G:C	R141P	0.999
11:118372549:T:C	C202R	0.999
11:118379481:T:C	L536P	0.999
11:118382602:C:G	H675D	0.999
11:118382606:T:C	L676P	0.999
11:118382609:G:T	R677M	0.999
11:118382610:G:C	R677S	0.999
11:118382610:G:T	R677S	0.999
11:118382612:C:A	A678D	0.999
11:118382755:T:C	F726L	0.999

dbSNP variants (sampled 300 via entrez): RS1000258308 (11:118364271 C>A,T), RS1000368140 (11:118357688 A>G), RS1000418227 (11:118359924 G>A,T), RS1000466505 (11:118372823 T>A,C,G), RS1000527310 (11:118378118 G>A), RS1000688732 (11:118385108 A>G), RS1000756679 (11:118392249 G>A), RS1000805949 (11:118365376 G>A), RS1000858523 (11:118362718 T>C), RS1000879597 (11:118365024 C>T), RS1000894846 (11:118359643 T>C,G), RS1001139301 (11:118360745 G>C), RS1001214261 (11:118360370 C>A), RS1001233063 (11:118358700 G>A,T), RS1001349476 (11:118364652 A>G)

Disease associations

OMIM: gene MIM:603753 | disease phenotypes: MIM:619639

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with hypotonia and gross motor and speech delay	Strong	Autosomal recessive
autosomal recessive non-syndromic intellectual disability	Supportive	Autosomal recessive
multiple congenital anomalies/dysmorphic syndrome	Limited	Autosomal recessive

Mondo (4): neurodevelopmental disorder with hypotonia and gross motor and speech delay (MONDO:0859207), neurodevelopmental disorder (MONDO:0700092), multiple congenital anomalies/dysmorphic syndrome (MONDO:0019042), autosomal recessive non-syndromic intellectual disability (MONDO:0019502)

Orphanet (0):

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0001252	Hypotonia
HP:0002061	Lower limb spasticity
HP:0002069	Bilateral tonic-clonic seizure
HP:0002540	Inability to walk
HP:0004322	Short stature
HP:0007018	Attention deficit hyperactivity disorder
HP:0010864	Severe intellectual disability

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001343_6	Fat distribution (HIV)	2.000000e-06
GCST008644_3	Celiac disease and Rheumatoid arthritis	2.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004341	body fat distribution

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067182 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.49	Kd	321.9	nM	CHEMBL5653589
6.42	ED50	376.9	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149715: Binding affinity to human UBE4A incubated for 45 mins by Kinobead based pull down assay	kd	0.3219	uM

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression	2
Valproic Acid	affects expression, increases expression	2
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
terbufos	decreases methylation	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	increases expression	1
jinfukang	decreases expression	1
Resveratrol	increases expression	1
Sunitinib	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Aspirin	increases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Fonofos	decreases methylation	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Parathion	decreases methylation	1
Thiram	increases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	decreases expression	1
Lactic Acid	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652757	Binding	Binding affinity to human UBE4A incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TV98	HAP1 UBE4A (-) 1	Cancer cell line	Male
CVCL_TV99	HAP1 UBE4A (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice