UBE3C

Summary

UBE3C (ubiquitin protein ligase E3C, HGNC:16803) is a protein-coding gene on chromosome 7q36.3, encoding Ubiquitin-protein ligase E3C (Q15386). E3 ubiquitin-protein ligase that specifically catalyzes ‘Lys-29’- and ‘Lys-48’-linked polyubiquitin chains.

Enables ubiquitin protein ligase activity. Involved in protein K29-linked ubiquitination; protein K48-linked ubiquitination; and ubiquitin-dependent protein catabolic process. Predicted to be part of proteasome complex.

Source: NCBI Gene 9690 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with absent speech and movement and behavioral abnormalities (Strong, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 159 total
• Phenotypes (HPO): 26
• Druggable target: yes
• MANE Select transcript: NM_014671

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16803
Approved symbol	UBE3C
Name	ubiquitin protein ligase E3C
Location	7q36.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0010, KIAA10
Ensembl gene	ENSG00000009335
Ensembl biotype	protein_coding
OMIM	614454
Entrez	9690

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 19 protein_coding, 5 retained_intron, 1 nonsense_mediated_decay

ENST00000348165, ENST00000389103, ENST00000430750, ENST00000469336, ENST00000470408, ENST00000474153, ENST00000494532, ENST00000497368, ENST00000929825, ENST00000929826, ENST00000929827, ENST00000929828, ENST00000929829, ENST00000929830, ENST00000929831, ENST00000929832, ENST00000945956, ENST00000945957, ENST00000945958, ENST00000945959, ENST00000945960, ENST00000945961, ENST00000945962, ENST00000945963, ENST00000945964

RefSeq mRNA: 1 — MANE Select: NM_014671 NM_014671

CCDS: CCDS34789

Canonical transcript exons

ENST00000348165 — 23 exons

Exon	Start	End
ENSE00000382149	157178690	157178847
ENSE00000382151	157182108	157182328
ENSE00000730718	157163810	157163863
ENSE00000730736	157174919	157175034
ENSE00000730744	157181518	157181671
ENSE00000730750	157183878	157184029
ENSE00000730758	157201721	157201807
ENSE00000730761	157207398	157207555
ENSE00000730765	157216867	157216971
ENSE00000730769	157220689	157220776
ENSE00001086718	157223254	157223351
ENSE00001395532	157267585	157269370
ENSE00001474851	157186834	157187021
ENSE00001887227	157138926	157139338
ENSE00003468771	157231080	157231327
ENSE00003486062	157256914	157257044
ENSE00003490509	157254244	157254310
ENSE00003506964	157169048	157169122
ENSE00003531186	157207703	157207935
ENSE00003552041	157248368	157248580
ENSE00003592345	157170304	157170450
ENSE00003595429	157225407	157225539
ENSE00003634773	157253954	157254142

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 94.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 61.4728 / max 375.8485, expressed in 1827 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
82276	59.1629	1827
82277	2.3099	1294

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	94.83	gold quality
calcaneal tendon	UBERON:0003701	94.68	gold quality
islet of Langerhans	UBERON:0000006	94.44	gold quality
adrenal tissue	UBERON:0018303	93.74	gold quality
colonic epithelium	UBERON:0000397	93.49	gold quality
gastrocnemius	UBERON:0001388	93.45	gold quality
muscle of leg	UBERON:0001383	93.41	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.04	gold quality
stromal cell of endometrium	CL:0002255	93.03	gold quality
gingival epithelium	UBERON:0001949	92.98	gold quality
tendon	UBERON:0000043	92.21	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	92.19	gold quality
rectum	UBERON:0001052	92.12	gold quality
biceps brachii	UBERON:0001507	92.04	gold quality
muscle organ	UBERON:0001630	91.99	gold quality
tonsil	UBERON:0002372	91.78	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.74	gold quality
gingiva	UBERON:0001828	91.53	gold quality
epithelium of nasopharynx	UBERON:0001951	91.45	gold quality
monocyte	CL:0000576	91.30	gold quality
mononuclear cell	CL:0000842	91.19	gold quality
leukocyte	CL:0000738	91.14	gold quality
smooth muscle tissue	UBERON:0001135	91.08	gold quality
endometrium epithelium	UBERON:0004811	90.72	gold quality
esophagus squamous epithelium	UBERON:0006920	90.58	gold quality
bone marrow cell	CL:0002092	90.55	gold quality
pancreas	UBERON:0001264	90.53	gold quality
mucosa of stomach	UBERON:0001199	90.49	gold quality
gall bladder	UBERON:0002110	90.45	gold quality
secondary oocyte	CL:0000655	90.44	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.20

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

144 targeting UBE3C, 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-9-5P	100.00	72.28	2361
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-4775	99.98	75.00	6394

Literature-anchored findings (GeneRIF, showing 21)

• TIP120B is a specific substrate of KIAA10; both are highly expressed in human skeletal muscle, suggesting that KIAA10 may regulate TIP120B homeostasis specifically in this tissue. (PMID:12692129)
• gene polymorphism is associated with the risk of Aspirin-intolerant asthma (PMID:20934631)
• negatively regulates type I interferon through ubiquitination of the transcription factors (PMID:21167755)
• Our findings provide evidence that variations in UBE3C are potent genetic markers of nasal polyps development in Korean asthmatics. (PMID:21881582)
• knockdown renders cells more susceptible to the Hsp90 inhibitor 17-AAG, suggesting that UBE3C protects against the harmful accumulation of protein fragments arising from incompletely degraded proteasome substrates. (PMID:24158444)
• UBE3C is a mutant candidate oncogene involved in tumor development and progression of hepatocellular carcinoma. (PMID:24425307)
• these observations suggest that UBE3C plays an important role in RCC development and progression, and UBE3C may be a novel target for prevention and treatment of ccRCC. (PMID:25658088)
• data reveal that high UBE3C expression contributes to glioma progression by ubiquitination and degradation of ANXA7, and thus presents a novel and promising target for glioma therapy. (PMID:26067607)
• UBE3C promotes melanoma progression, possibly by inducing epithelial-mesenchymal transition in melanoma cells (PMID:26894856)
• Findings indicate that miR-30a-5p inhibits ubiquitin Protein ligase E3C (UBE3C) expression by directly targeting its 3’ untranslated regions (3’-UTR). (PMID:27003255)
• 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)
• Usp14 and Ube3c cycle together on and off proteasomes, and the presence of ubiquitinated substrates promotes their association. This mechanism enables proteasome activity to adapt to the supply of substrates. (PMID:28396413)
• miR-542-3p functioned as a tumor suppressor gene in regulating the epithelial-mesenchymal transition and metastasis of hepatocellular carcinoma via targeting UBE3C. (PMID:28666208)
• Data suggest UBE3C-mediated AHNAK ubiquitination and degradation accompanied by subsequent blockage of p53 inhibition of stemness-related-gene transcription as a new posttranslational regulatory model describing maintenance of non-small-cell lung cancer (NSCLC) cell stemness. UBE3C knockdown increased p53 binding to the promoter regions inhibiting their transcription and preventing NSCLC tumorigenesis. (PMID:30503554)
• Crystal structure of HECT domain of UBE3C E3 ligase and its ubiquitination activity. (PMID:32039437)
• UBE3C promotes proliferation and inhibits apoptosis by activating the beta-catenin signaling via degradation of AXIN1 in gastric cancer. (PMID:32930707)
• VPS34 K29/K48 branched ubiquitination governed by UBE3C and TRABID regulates autophagy, proteostasis and liver metabolism. (PMID:33637724)
• Circular RNA circPOLR2A promotes clear cell renal cell carcinoma progression by facilitating the UBE3C-induced ubiquitination of PEBP1 and, thereby, activating the ERK signaling pathway. (PMID:35840930)
• Novel gene-intergenic fusion involving ubiquitin E3 ligase UBE3C causes distal hereditary motor neuropathy. (PMID:36380488)
• Biallelic variants in HECT E3 paralogs, HECTD4 and UBE3C, encoding ubiquitin ligases cause neurodevelopmental disorders that overlap with Angelman syndrome. (PMID:36401616)
• UBE3C restricts EV-A71 replication by ubiquitination-dependent degradation of 2C. (PMID:39212385)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ube3c	ENSDARG00000035978
mus_musculus	Ube3c	ENSMUSG00000039000
rattus_norvegicus	Ube3c	ENSRNOG00000010702
drosophila_melanogaster	CG3356	FBGN0034989
caenorhabditis_elegans		WBGENE00008429

Paralogs (24): HECW1 (ENSG00000002746), NEDD4L (ENSG00000049759), NEDD4 (ENSG00000069869), ITCH (ENSG00000078747), HACE1 (ENSG00000085382), HUWE1 (ENSG00000086758), HECTD1 (ENSG00000092148), UBR5 (ENSG00000104517), SMURF2 (ENSG00000108854), UBE3A (ENSG00000114062), AREL1 (ENSG00000119682), WWP1 (ENSG00000123124), HERC2 (ENSG00000128731), HECW2 (ENSG00000138411), HERC3 (ENSG00000138641), HERC6 (ENSG00000138642), HERC5 (ENSG00000138646), HERC4 (ENSG00000148634), UBE3B (ENSG00000151148), TRIP12 (ENSG00000153827), HECTD2 (ENSG00000165338), HECTD4 (ENSG00000173064), WWP2 (ENSG00000198373), SMURF1 (ENSG00000198742)

Protein

Protein identifiers

Ubiquitin-protein ligase E3C — Q15386 (reviewed: Q15386)

Alternative names: HECT-type ubiquitin transferase E3C, Homologous to E6AP carboxyl terminus homologous protein 2, RTA-associated ubiquitin ligase

All UniProt accessions (2): Q15386, H7C0Y1

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that specifically catalyzes ‘Lys-29’- and ‘Lys-48’-linked polyubiquitin chains. Accepts ubiquitin from the E2 ubiquitin-conjugating enzyme UBE2D1 in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Associates with the proteasome and promotes elongation of ubiquitin chains on substrates bound to the 26S proteasome. Also catalyzes ‘Lys-29’- and ‘Lys-48’-linked ubiquitination of 26S proteasome subunit ADRM1/RPN13 in response to proteotoxic stress, impairing the ability of the proteasome to bind and degrade ubiquitin-conjugated proteins. Acts as a negative regulator of autophagy by mediating ‘Lys-29’- and ‘Lys-48’-linked ubiquitination of PIK3C3/VPS34, promoting its degradation. Can assemble unanchored poly-ubiquitin chains in either ‘Lys-29’- or ‘Lys-48’-linked polyubiquitin chains; with some preference for ‘Lys-48’ linkages. Acts as a negative regulator of type I interferon by mediating ‘Lys-48’-linked ubiquitination of IRF3 and IRF7, leading to their degradation by the proteasome. Catalyzes ubiquitination and degradation of CAND2.

Subunit / interactions. Interacts with 26S proteasomes. Interacts (via the HECT domain) with UBE2D1 and, less efficiently, with UBE2L3.

Tissue specificity. Highly expressed in skeletal muscle. Detected at much lower levels in kidney and pancreas.

Post-translational modifications. Autoubiquitinated; promoting its own degradation.

Disease relevance. Neurodevelopmental disorder with absent speech and movement and behavioral abnormalities (NEDSMB) [MIM:620270] An autosomal recessive disorder characterized by global developmental delay apparent in infancy, severely impaired intellectual development, absent speech, and aggressive behavior. The disease may be caused by variants affecting the gene represented in this entry.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the UBE3C family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q15386-1	1	yes
Q15386-2	2
Q15386-3	3

RefSeq proteins (1): NP_055486* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000048	IQ_motif_EF-hand-BS	Binding_site
IPR000569	HECT_dom	Domain
IPR035983	Hect_E3_ubiquitin_ligase	Homologous_superfamily
IPR044611	E3A/B/C-like	Family

Pfam: PF00632

Enzyme classification (BRENDA):

• EC 2.3.2.26 — HECT-type E3 ubiquitin transferase (BRENDA: 14 organisms, 64 substrates, 19 inhibitors, 5 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
[UBC5B]-L-LYSINE	0.0046–0.037	5

UniProt features (50 total): helix 17, strand 9, splice variant 5, mutagenesis site 5, region of interest 3, compositionally biased region 3, domain 2, turn 2, chain 1, cross-link 1, sequence conflict 1, active site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6K2C	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15386-F1	81.82	0.34

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): 1051 (glycyl thioester intermediate)

Post-translational modifications (1): 903

Mutagenesis-validated functional residues (5):

Position	Phenotype
758–762	abolished e3 ubiquitin-protein ligase activity.
961	reduced e3 ubiquitin-protein ligase activity.
1013	increased e3 ubiquitin-protein ligase activity.
1049	reduced e3 ubiquitin-protein ligase activity.
1051	abolishes e3 ubiquitin-protein ligase activity. no stimulation of in vitro cand2 ubiquitination.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 229 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, KAAB_FAILED_HEART_ATRIUM_DN, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, TTTGTAG_MIR520D, AAGCCAT_MIR135A_MIR135B, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MODULE_206, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEIN_POLYUBIQUITINATION, DODD_NASOPHARYNGEAL_CARCINOMA_UP, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P, ACTTTAT_MIR1425P, MODULE_278

GO Biological Process (7): protein polyubiquitination (GO:0000209), ubiquitin-dependent protein catabolic process (GO:0006511), protein K29-linked ubiquitination (GO:0035519), protein K48-linked ubiquitination (GO:0070936), autophagosome assembly (GO:0000045), protein ubiquitination (GO:0016567), phosphatidylinositol phosphate biosynthetic process (GO:0046854)

GO Molecular Function (4): ubiquitin protein ligase activity (GO:0061630), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515), transferase activity (GO:0016740)

GO Cellular Component (1): proteasome complex (GO:0000502)

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
protein polyubiquitination	2
modification-dependent protein catabolic process	1
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1
autophagosome organization	1
protein modification by small protein conjugation	1
glycerophospholipid biosynthetic process	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
ubiquitin-like protein transferase activity	1
binding	1
catalytic activity	1
intracellular protein-containing complex	1
endopeptidase complex	1

Protein interactions and networks

STRING

1482 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UBE3C	ADRM1	Q16186	623
UBE3C	UBR4	Q5T4S7	610
UBE3C	USP14	P54578	591
UBE3C	NOM1	Q5C9Z4	575
UBE3C	RNF32	Q9H0A6	551
UBE3C	PSMD4	P55036	541
UBE3C	RPL11	P25121	513
UBE3C	RNF181	Q9P0P0	509
UBE3C	HUWE1	Q7Z6Z7	508
UBE3C	A0A087WY85	A0A087WY85	487
UBE3C	MARCHF6	O60337	481
UBE3C	OTUD3	Q5T2D3	473
UBE3C	UBR1	Q8IWV7	463
UBE3C	UCHL5	Q9Y5K5	457
UBE3C	TRIP12	Q14669	450

IntAct

153 interactions, top by confidence:

A	B	Type	Score
VAPB	FAM83G	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
SCN2B	EXOC5	psi-mi:“MI:0914”(association)	0.640
GYPA	TCAF2	psi-mi:“MI:0914”(association)	0.640
FAM234B	ABCD4	psi-mi:“MI:0914”(association)	0.620
GOLGA2	UBE3C	psi-mi:“MI:0915”(physical association)	0.560
UBE3C	GOLGA2	psi-mi:“MI:0915”(physical association)	0.560
ARRDC4	WWP2	psi-mi:“MI:0914”(association)	0.530
EPHA1	EXOC5	psi-mi:“MI:0914”(association)	0.530
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
STK16	UNC119B	psi-mi:“MI:0914”(association)	0.530
CD70	METTL15	psi-mi:“MI:0914”(association)	0.530
TNFSF8	LGALS8	psi-mi:“MI:0914”(association)	0.530
IL1R2	EXOC5	psi-mi:“MI:0914”(association)	0.530
SEM1	PSMC2	psi-mi:“MI:0914”(association)	0.530
NTRK3	FAM171A2	psi-mi:“MI:0914”(association)	0.480
	TK2	psi-mi:“MI:0915”(physical association)	0.400
UBE3C	MTA2	psi-mi:“MI:0915”(physical association)	0.370
TLK1	UBE3C	psi-mi:“MI:0915”(physical association)	0.370
MYC	ILVBL	psi-mi:“MI:0914”(association)	0.350

BioGRID (288): UBE3C (Two-hybrid), UBE2D1 (Reconstituted Complex), UBE3C (Biochemical Activity), UBE3C (Affinity Capture-MS), UBE3C (Affinity Capture-Western), UBE2D2 (Reconstituted Complex), UBC (Biochemical Activity), UBE3C (Affinity Capture-MS), UBE3C (Affinity Capture-MS), UBE3C (Affinity Capture-MS), UBE3C (Affinity Capture-MS), ANXA7 (Affinity Capture-Western), UBE3C (Affinity Capture-Western), UBC (Biochemical Activity), UBE2L3 (Reconstituted Complex)

ESM2 similar proteins: A0A8M3B525, A2AHJ4, A5PJP6, B0KWU8, B2RYM5, B5X8M4, E1C3P4, E9Q4Z2, O00763, O42611, O94967, O95630, P46736, P46737, P48553, Q15386, Q15542, Q3TLI0, Q4VA72, Q5KSL6, Q5R558, Q5R9L6, Q5RAQ5, Q5VVJ2, Q641K1, Q66GV6, Q66H62, Q69Z66, Q6RI45, Q6WKZ8, Q76N33, Q7M757, Q80U95, Q8BPM2, Q8CGF6, Q8IVH8, Q8QFR2, Q8TAT6, Q8VDD9, Q8W206

Diamond homologs: A0A8C0NGY6, A1CQG2, A1D3C5, A2A5Z6, A2QQ28, A9JRZ0, B0XQ72, B8N7E5, D3ZBM7, D6C652, E1B7Q7, E1C656, F1LP64, F1N6G5, F8W2M1, G0S9J5, G5E870, H2LBU8, O00308, O08759, O13834, O14326, O15033, P39940, P40985, P46934, P46935, P46937, P46938, P51593, P53119, Q03280, Q05086, Q08CZ0, Q09291, Q0CCL1, Q14669, Q15034, Q15386, Q1K9C4

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	UBE3C	ubiquitination
UBE3C	“down-regulates quantity by destabilization”	CAND2	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 187 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
Regulation of activated PAK-2p34 by proteasome mediated degradation	21	47.2×	7e-29
Regulation of ornithine decarboxylase (ODC)	21	46.0×	7e-29
Vpu mediated degradation of CD4	21	45.0×	7e-29
Autodegradation of the E3 ubiquitin ligase COP1	21	45.0×	7e-29
Ubiquitin-dependent degradation of Cyclin D	21	45.0×	7e-29
Cross-presentation of soluble exogenous antigens (endosomes)	21	43.0×	2e-28
Vif-mediated degradation of APOBEC3G	21	43.0×	2e-28
AUF1 (hnRNP D0) binds and destabilizes mRNA	21	42.0×	2e-28

GO biological processes:

GO term	Partners	Fold	FDR
substantia nigra development	5	11.2×	9e-03
proteasome-mediated ubiquitin-dependent protein catabolic process	27	8.6×	9e-15
positive regulation of cell migration	11	4.1×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	108
Likely benign	11
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

4798 predictions. Top by Δscore:

Variant	Effect	Δscore
7:157139335:G:GT	donor_gain	1.0000
7:157139336:A:T	donor_gain	1.0000
7:157163801:T:TA	acceptor_gain	1.0000
7:157163802:G:A	acceptor_gain	1.0000
7:157163859:GAGAG:G	donor_gain	1.0000
7:157169119:GCAA:G	donor_gain	1.0000
7:157169123:G:GG	donor_gain	1.0000
7:157170302:A:AG	acceptor_gain	1.0000
7:157170303:G:GG	acceptor_gain	1.0000
7:157170303:GT:G	acceptor_gain	1.0000
7:157170303:GTATT:G	acceptor_gain	1.0000
7:157183874:AAAG:A	acceptor_gain	1.0000
7:157183874:AAAGG:A	acceptor_gain	1.0000
7:157184025:GCCCG:G	donor_gain	1.0000
7:157184027:CCGG:C	donor_loss	1.0000
7:157184028:CGG:C	donor_loss	1.0000
7:157184030:G:GA	donor_loss	1.0000
7:157184030:G:GG	donor_gain	1.0000
7:157184031:T:A	donor_loss	1.0000
7:157186832:AGGAG:A	acceptor_gain	1.0000
7:157186833:GGAGG:G	acceptor_gain	1.0000
7:157216963:GCAGA:G	donor_gain	1.0000
7:157223252:A:AG	acceptor_gain	1.0000
7:157223252:AGT:A	acceptor_gain	1.0000
7:157223252:AGTG:A	acceptor_gain	1.0000
7:157223252:AGTGG:A	acceptor_gain	1.0000
7:157223253:G:GT	acceptor_gain	1.0000
7:157223253:GT:G	acceptor_gain	1.0000
7:157223253:GTG:G	acceptor_gain	1.0000
7:157223253:GTGG:G	acceptor_gain	1.0000

AlphaMissense

7124 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:157216936:T:A	W627R	1.000
7:157216936:T:C	W627R	1.000
7:157216938:G:C	W627C	1.000
7:157216938:G:T	W627C	1.000
7:157223329:T:A	V693D	1.000
7:157223344:G:C	R698P	1.000
7:157225486:T:A	I727K	1.000
7:157225492:G:C	R729T	1.000
7:157225492:G:T	R729I	1.000
7:157225493:A:C	R729S	1.000
7:157225493:A:T	R729S	1.000
7:157225512:G:C	A736P	1.000
7:157225513:C:A	A736D	1.000
7:157225525:T:C	L740P	1.000
7:157231138:A:C	E764D	1.000
7:157231138:A:T	E764D	1.000
7:157231142:G:C	G766R	1.000
7:157231143:G:A	G766D	1.000
7:157231148:G:C	D768H	1.000
7:157231149:A:C	D768A	1.000
7:157231149:A:T	D768V	1.000
7:157231150:T:A	D768E	1.000
7:157231150:T:G	D768E	1.000
7:157231152:G:A	G769D	1.000
7:157231157:G:C	G771R	1.000
7:157231157:G:T	G771C	1.000
7:157231158:G:A	G771D	1.000
7:157231167:G:C	R774T	1.000
7:157231167:G:T	R774I	1.000
7:157231168:A:C	R774S	1.000

dbSNP variants (sampled 300 via entrez): RS1000009085 (7:157259767 A>G), RS1000039360 (7:157137685 C>T), RS1000086424 (7:157203825 G>T), RS1000104078 (7:157224167 C>T), RS1000117839 (7:157158158 A>G,T), RS1000180055 (7:157239255 A>C), RS1000183548 (7:157232789 A>G), RS1000192073 (7:157157981 T>C,G), RS1000208140 (7:157206967 C>T), RS1000214105 (7:157166168 T>C), RS1000299069 (7:157160932 C>G), RS1000300313 (7:157243955 G>A), RS1000316194 (7:157211531 G>A), RS1000356954 (7:157249435 C>T), RS1000370080 (7:157211861 A>G,T)

Disease associations

OMIM: gene MIM:614454 | disease phenotypes: MIM:620270

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with absent speech and movement and behavioral abnormalities	Strong	Autosomal recessive

Mondo (1): neurodevelopmental disorder with absent speech and movement and behavioral abnormalities (MONDO:0859519)

Orphanet (0):

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000668	Hypodontia
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000752	Hyperactivity
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001321	Cerebellar hypoplasia
HP:0001337	Tremor
HP:0001511	Intrauterine growth retardation
HP:0001513	Obesity
HP:0001639	Hypertrophic cardiomyopathy
HP:0002254	Intermittent diarrhea
HP:0002300	Mutism
HP:0002360	Sleep disturbance
HP:0002451	Limb dystonia
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0005616	Accelerated skeletal maturation
HP:0010665	Bilateral coxa valga
HP:0010864	Severe intellectual disability
HP:0011968	Feeding difficulties
HP:0033725	Thin corpus callosum

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000337_25	Quantitative traits	3.000000e-06
GCST000509_2	Response to citalopram treatment	5.000000e-07
GCST000509_6	Response to citalopram treatment	4.000000e-07
GCST002783_575	Body mass index	8.000000e-06
GCST006152_1	Language impairment in frontotemporal lobe dementia	4.000000e-06
GCST006867_63	Type 2 diabetes	1.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0004340	body mass index

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067433 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.94	Kd	11.59	nM	CHEMBL3752910
7.93	ED50	11.74	nM	CHEMBL3752910
7.08	Kd	82.53	nM	CHEMBL5653589
7.08	ED50	83.64	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 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-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149714: Binding affinity to human UBE3C incubated for 45 mins by Kinobead based pull down assay	kd	0.0116	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149714: Binding affinity to human UBE3C incubated for 45 mins by Kinobead based pull down assay	kd	0.0825	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression, increases expression	2
Valproic Acid	increases expression	2
FR900359	decreases phosphorylation	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
decabromobiphenyl ether	decreases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	affects expression	1
sodium arsenite	decreases expression	1
tetrabromobisphenol A	decreases expression	1
beta-methylcholine	affects expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	decreases methylation	1
Sunitinib	increases expression	1
Arsenic	affects methylation	1
Arsenicals	increases methylation	1
Aspirin	affects response to substance	1
Atrazine	decreases expression	1
Enzyme Inhibitors	increases O-linked glycosylation, decreases activity	1
Estradiol	increases expression	1
Ivermectin	decreases expression	1
Methotrexate	increases expression	1
Methyl Methanesulfonate	decreases expression	1
Nickel	increases expression	1
Silicon Dioxide	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652756	Binding	Binding affinity to human UBE3C 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

5 cell lines: 3 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E0SI	Ubigene HeLa UBE3C KO	Cancer cell line	Female
CVCL_E2N2	HAP1 UBE3C (-) 1	Cancer cell line	Male
CVCL_E2N3	HAP1 UBE3C (-) 2	Cancer cell line	Male
CVCL_E3BJ	HEK293T UBE3C-/-	Transformed cell line	Female
CVCL_E3BK	HEK293T UBE3C-/- agDD-GFP	Transformed cell line	Female

Clinical trials (associated diseases)

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