ANAPC4

Summary

ANAPC4 (anaphase promoting complex subunit 4, HGNC:19990) is a protein-coding gene on chromosome 4p15.2, encoding Anaphase-promoting complex subunit 4 (Q9UJX5). Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. It is a common-essential gene (DepMap: required in 96.8% of cancer cell lines).

A large protein complex, termed the anaphase-promoting complex (APC), or the cyclosome, promotes metaphase-anaphase transition by ubiquitinating its specific substrates such as mitotic cyclins and anaphase inhibitor, which are subsequently degraded by the 26S proteasome. Biochemical studies have shown that the vertebrate APC contains eight subunits. The composition of the APC is highly conserved in organisms from yeast to humans. The exact function of this gene product is not known. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 29945 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 119 total — 2 pathogenic, 1 likely-pathogenic
• Cancer dependency (DepMap): dependent in 96.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_013367

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19990
Approved symbol	ANAPC4
Name	anaphase promoting complex subunit 4
Location	4p15.2
Locus type	gene with protein product
Status	Approved
Aliases	APC4
Ensembl gene	ENSG00000053900
Ensembl biotype	protein_coding
OMIM	606947
Entrez	29945

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 26 protein_coding, 7 retained_intron, 1 nonsense_mediated_decay

ENST00000315368, ENST00000503805, ENST00000504256, ENST00000505080, ENST00000505842, ENST00000505991, ENST00000506973, ENST00000507809, ENST00000507925, ENST00000510092, ENST00000515848, ENST00000902885, ENST00000902886, ENST00000902887, ENST00000902888, ENST00000902889, ENST00000902890, ENST00000902891, ENST00000902892, ENST00000902893, ENST00000922643, ENST00000922644, ENST00000922645, ENST00000922646, ENST00000922647, ENST00000971380, ENST00000971381, ENST00000971382, ENST00000971383, ENST00000971384, ENST00000971385, ENST00000971386, ENST00000971387, ENST00000971388

RefSeq mRNA: 2 — MANE Select: NM_013367 NM_001286756, NM_013367

CCDS: CCDS3434, CCDS68684

Canonical transcript exons

ENST00000315368 — 29 exons

Exon	Start	End
ENSE00000479627	25390136	25390220
ENSE00000708068	25390911	25391015
ENSE00000708123	25392338	25392421
ENSE00000708187	25394829	25394905
ENSE00000708288	25413645	25413742
ENSE00000799372	25393805	25393891
ENSE00001008388	25377418	25377556
ENSE00001008394	25380374	25380479
ENSE00001234734	25414324	25414385
ENSE00001390668	25377263	25377344
ENSE00003464024	25409698	25409791
ENSE00003471282	25394671	25394713
ENSE00003483689	25402971	25403026
ENSE00003489388	25388838	25388882
ENSE00003503005	25416425	25416598
ENSE00003513549	25417616	25417739
ENSE00003520635	25414466	25414504
ENSE00003522485	25388500	25388574
ENSE00003527717	25396848	25396899
ENSE00003535957	25407197	25407253
ENSE00003569682	25414599	25414700
ENSE00003571356	25406829	25406885
ENSE00003593640	25394310	25394374
ENSE00003640830	25388717	25388743
ENSE00003648262	25415466	25415540
ENSE00003663500	25396664	25396764
ENSE00003676453	25405573	25405619
ENSE00003681226	25383261	25383393
ENSE00003685209	25418155	25418498

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 99.43.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.6252 / max 139.4870, expressed in 1781 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47131	9.0714	1759
47132	2.5537	1151

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oviduct epithelium	UBERON:0004804	99.43	gold quality
right uterine tube	UBERON:0001302	99.08	gold quality
endometrium	UBERON:0001295	97.60	gold quality
tendon of biceps brachii	UBERON:0008188	97.49	gold quality
germinal epithelium of ovary	UBERON:0001304	97.10	gold quality
bronchial epithelial cell	CL:0002328	96.81	gold quality
bronchus	UBERON:0002185	96.58	gold quality
fallopian tube	UBERON:0003889	96.56	gold quality
parietal pleura	UBERON:0002400	96.52	gold quality
visceral pleura	UBERON:0002401	96.50	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.41	gold quality
thymus	UBERON:0002370	96.17	gold quality
tibia	UBERON:0000979	95.99	gold quality
middle temporal gyrus	UBERON:0002771	95.95	gold quality
epithelial cell of pancreas	CL:0000083	95.93	gold quality
caput epididymis	UBERON:0004358	95.87	gold quality
seminal vesicle	UBERON:0000998	95.71	gold quality
upper arm skin	UBERON:0004263	95.60	gold quality
secondary oocyte	CL:0000655	95.29	gold quality
tendon	UBERON:0000043	94.93	gold quality
endothelial cell	CL:0000115	94.85	gold quality
uterus	UBERON:0000995	94.85	gold quality
layer of synovial tissue	UBERON:0007616	94.25	gold quality
parotid gland	UBERON:0001831	93.81	gold quality
calcaneal tendon	UBERON:0003701	93.77	gold quality
primary visual cortex	UBERON:0002436	93.69	gold quality
right ovary	UBERON:0002118	93.64	gold quality
oocyte	CL:0000023	93.58	gold quality
female reproductive system	UBERON:0000474	93.42	gold quality
epithelium of nasopharynx	UBERON:0001951	93.40	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-10287	yes	47.38
E-GEOD-99795	no	111.96
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): YBX1

miRNA regulators (miRDB)

15 targeting ANAPC4, 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-8485	100.00	77.57	4731
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-323A-5P	98.59	65.13	651
HSA-MIR-603	98.58	68.28	1603
HSA-MIR-3187-3P	97.38	65.80	904
HSA-MIR-4435	95.90	65.47	1201

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 96.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 3)

• Studies indicate that APC/C(Cdh1) is required to maintain genomic stability. (PMID:19826416)
• Inactivation and disassembly of the anaphase-promoting complex during human cytomegalovirus infection is associated with degradation of the APC5 and APC4 subunits and does not require UL97-mediated phosphorylation of Cdh1. (PMID:20686030)
• We have also identified a functionally important SUMO interacting motif in the cullin-homology domain of APC2 located near the APC4 sumoylation sites and APC/C catalytic core. Our findings provide evidence of an important regulatory role for SUMO modification and binding in affecting APC/C activation and mitotic exit. (PMID:29517484)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	anapc4	ENSDARG00000032237
mus_musculus	Anapc4	ENSMUSG00000029176
rattus_norvegicus	Anapc4	ENSRNOG00000004130
drosophila_melanogaster	APC4	FBGN0052707

Protein

Protein identifiers

Anaphase-promoting complex subunit 4 — Q9UJX5 (reviewed: Q9UJX5)

Alternative names: Cyclosome subunit 4

All UniProt accessions (3): D6RAP6, D6RFM7, Q9UJX5

UniProt curated annotations — full annotation on UniProt →

Function. Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of ‘Lys-11’-linked polyubiquitin chains and, to a lower extent, the formation of ‘Lys-48’- and ‘Lys-63’-linked polyubiquitin chains. The APC/C complex catalyzes assembly of branched ‘Lys-11’-/‘Lys-48’-linked branched ubiquitin chains on target proteins.

Subunit / interactions. The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5. In the context of the APC/C complex, directly interacts with UBE2S. Interacts with FBXO43.

Subcellular location. Nucleus.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the APC4 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9UJX5-1	1	yes
Q9UJX5-2	2
Q9UJX5-3	3

RefSeq proteins (2): NP_001273685, NP_037499* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR017169	APC4_metazoa	Family
IPR024789	APC4	Family
IPR024790	APC4_long_dom	Domain
IPR024977	Apc4-like_WD40_dom	Domain
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR056358	APC4_C	Domain

Pfam: PF12894, PF12896, PF23405

UniProt features (90 total): strand 39, helix 21, turn 12, modified residue 5, splice variant 3, sequence variant 3, sequence conflict 3, cross-link 2, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
9GAW	ELECTRON MICROSCOPY	2.9
6Q6G	ELECTRON MICROSCOPY	3.2
6Q6H	ELECTRON MICROSCOPY	3.2
8PKP	ELECTRON MICROSCOPY	3.2
5BPW	X-RAY DIFFRACTION	3.4
5G05	ELECTRON MICROSCOPY	3.4
8TAU	ELECTRON MICROSCOPY	3.5
4UI9	ELECTRON MICROSCOPY	3.6
6TNT	ELECTRON MICROSCOPY	3.78
6TLJ	ELECTRON MICROSCOPY	3.8
5G04	ELECTRON MICROSCOPY	3.9
6TM5	ELECTRON MICROSCOPY	3.9
9N9R	ELECTRON MICROSCOPY	3.9
9N9S	ELECTRON MICROSCOPY	3.9
8TAR	ELECTRON MICROSCOPY	4
5LCW	ELECTRON MICROSCOPY	4.2
5A31	ELECTRON MICROSCOPY	4.3
5KHU	ELECTRON MICROSCOPY	4.8
5KHR	ELECTRON MICROSCOPY	6.1
5L9T	ELECTRON MICROSCOPY	6.4
5L9U	ELECTRON MICROSCOPY	6.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UJX5-F1	81.03	0.43

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 (7): 469, 757, 758, 777, 779, 772, 798

Mutagenesis-validated functional residues (1):

Position	Phenotype
33	impairs ube2s-mediated polyubiquitination, decreasing substrate affinity. does not affect ube2c-mediated multiubiquitina

Function

Pathways and Gene Ontology

Reactome pathways

47 pathways

ID	Pathway
R-HSA-141430	Inactivation of APC/C via direct inhibition of the APC/C complex
R-HSA-174048	APC/C:Cdc20 mediated degradation of Cyclin B
R-HSA-174084	Autodegradation of Cdh1 by Cdh1:APC/C
R-HSA-174154	APC/C:Cdc20 mediated degradation of Securin
R-HSA-174178	APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1
R-HSA-174184	Cdc20:Phospho-APC/C mediated degradation of Cyclin A
R-HSA-176407	Conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase
R-HSA-176408	Regulation of APC/C activators between G1/S and early anaphase
R-HSA-176409	APC/C:Cdc20 mediated degradation of mitotic proteins
R-HSA-176412	Phosphorylation of the APC/C
R-HSA-179409	APC-Cdc20 mediated degradation of Nek2A
R-HSA-2467813	Separation of Sister Chromatids
R-HSA-2559582	Senescence-Associated Secretory Phenotype (SASP)
R-HSA-68867	Assembly of the pre-replicative complex
R-HSA-69017	CDK-mediated phosphorylation and removal of Cdc6
R-HSA-8853884	Transcriptional Regulation by VENTX
R-HSA-9687136	Aberrant regulation of mitotic exit in cancer due to RB1 defects
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280218	Adaptive Immune System
R-HSA-141405	Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint components
R-HSA-1640170	Cell Cycle
R-HSA-1643685	Disease
R-HSA-168256	Immune System
R-HSA-174143	APC/C-mediated degradation of cell cycle proteins
R-HSA-176814	Activation of APC/C and APC/C:Cdc20 mediated degradation of mitotic proteins
R-HSA-179419	APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint
R-HSA-212436	Generic Transcription Pathway
R-HSA-2262752	Cellular responses to stress
R-HSA-2555396	Mitotic Metaphase and Anaphase
R-HSA-2559583	Cellular Senescence

MSigDB gene sets: 162 (showing top): GOBP_CHROMOSOME_ORGANIZATION, REACTOME_DNA_REPLICATION, REACTOME_APC_C_CDH1_MEDIATED_DEGRADATION_OF_CDC20_AND_OTHER_APC_C_CDH1_TARGETED_PROTEINS_IN_LATE_MITOSIS_EARLY_G1, REACTOME_APC_C_CDC20_MEDIATED_DEGRADATION_OF_CYCLIN_B, REACTOME_CONVERSION_FROM_APC_C_CDC20_TO_APC_C_CDH1_IN_LATE_ANAPHASE, REACTOME_PHOSPHORYLATION_OF_THE_APC_C, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_ANAPHASE_PROMOTING_COMPLEX_DEPENDENT_CATABOLIC_PROCESS, REACTOME_APC_CDC20_MEDIATED_DEGRADATION_OF_NEK2A, GOBP_CELL_CYCLE_PHASE_TRANSITION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS

GO Biological Process (9): regulation of mitotic cell cycle (GO:0007346), regulation of mitotic metaphase/anaphase transition (GO:0030071), anaphase-promoting complex-dependent catabolic process (GO:0031145), cell division (GO:0051301), regulation of meiotic cell cycle (GO:0051445), protein K48-linked ubiquitination (GO:0070936), protein K11-linked ubiquitination (GO:0070979), protein branched polyubiquitination (GO:0141198), protein ubiquitination (GO:0016567)

GO Molecular Function (3): ubiquitin-protein transferase activity (GO:0004842), protein phosphatase binding (GO:0019903), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), anaphase-promoting complex (GO:0005680), cytosol (GO:0005829), nuclear periphery (GO:0034399)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
APC/C-mediated degradation of cell cycle proteins	4
APC/C:Cdc20 mediated degradation of mitotic proteins	2
APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint	2
Activation of APC/C and APC/C:Cdc20 mediated degradation of mitotic proteins	2
Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint components	1
Mitotic Anaphase	1
Cellular Senescence	1
DNA Replication Pre-Initiation	1
Switching of origins to a post-replicative state	1
Generic Transcription Pathway	1
Aberrant regulation of mitotic cell cycle due to RB1 defects	1
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Regulation of APC/C activators between G1/S and early anaphase	1
Mitotic Spindle Checkpoint	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein polyubiquitination	3
cellular anatomical structure	3
regulation of cell cycle	2
nuclear lumen	2
mitotic cell cycle	1
metaphase/anaphase transition of mitotic cell cycle	1
regulation of mitotic cell cycle phase transition	1
regulation of metaphase/anaphase transition of cell cycle	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
cellular process	1
meiotic cell cycle	1
regulation of reproductive process	1
protein modification by small protein conjugation	1
ubiquitin-like protein transferase activity	1
phosphatase binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear ubiquitin ligase complex	1
cullin-RING ubiquitin ligase complex	1
cytoplasm	1

Protein interactions and networks

STRING

1986 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANAPC4	CDC16	Q13042	988
ANAPC4	CDC27	P30260	981
ANAPC4	ANAPC5	Q9UJX4	967
ANAPC4	CDC23	Q9UJX2	963
ANAPC4	ANAPC1	Q9H1A4	924
ANAPC4	ANAPC2	Q9UJX6	908
ANAPC4	ANAPC7	Q9UJX3	898
ANAPC4	ANAPC10	Q9UM13	804
ANAPC4	ANAPC11	Q9NYG5	797
ANAPC4	CDC20	Q12834	688
ANAPC4	UBE2C	O00762	596
ANAPC4	CCNB2	O95067	536
ANAPC4	CCNB1	P14635	532
ANAPC4	FZR1	Q9UM11	530
ANAPC4	CCDC149	Q6ZUS6	475

IntAct

142 interactions, top by confidence:

A	B	Type	Score
CDC20	BUB1B	psi-mi:“MI:0914”(association)	0.980
BUB1B	CDC20	psi-mi:“MI:0914”(association)	0.980
CDC16	CDC26	psi-mi:“MI:0914”(association)	0.940
ANAPC2	CDC27	psi-mi:“MI:0915”(physical association)	0.910
BUB1B	CDC27	psi-mi:“MI:0914”(association)	0.900
CDC27	ANAPC4	psi-mi:“MI:0914”(association)	0.860
ANAPC4	CDC27	psi-mi:“MI:0915”(physical association)	0.860
ANAPC4	CDC27	psi-mi:“MI:0914”(association)	0.860
CDC27	CDC16	psi-mi:“MI:0914”(association)	0.860
CDC20	ANAPC4	psi-mi:“MI:0915”(physical association)	0.840
ANAPC4	BUB1B	psi-mi:“MI:0914”(association)	0.820
ANAPC5	CDC27	psi-mi:“MI:0914”(association)	0.810
CDC16	BUB1B	psi-mi:“MI:0914”(association)	0.790
CDC23	BUB1B	psi-mi:“MI:0914”(association)	0.790
ANAPC16	CDC27	psi-mi:“MI:0914”(association)	0.760
ANAPC16	BUB1B	psi-mi:“MI:0914”(association)	0.730

BioGRID (445): ANAPC4 (Reconstituted Complex), ANAPC4 (Affinity Capture-Western), NEK2 (Affinity Capture-MS), KIF18A (Affinity Capture-MS), KIF18A (Affinity Capture-Western), NEK2 (Affinity Capture-Western), ANAPC7 (Affinity Capture-Western), ANAPC4 (Affinity Capture-Western), ANAPC1 (Affinity Capture-Western), CDC27 (Affinity Capture-Western), ANAPC4 (Affinity Capture-Western), BUB1B (Affinity Capture-Western), CDC20 (Affinity Capture-Western), BUB3 (Affinity Capture-Western), ANAPC4 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IES7, A0JN62, A0JNW5, A2AAE1, A2AGL3, A2RSJ4, A2RT67, A2RUS2, A2RV80, B0LPN4, B1H2P5, E7F240, E9Q401, O00507, O94967, P30957, P48553, P51593, Q14161, Q2LD37, Q3TLI0, Q3UHE1, Q3UVG3, Q3UX43, Q5F361, Q5M7Q1, Q5RAQ5, Q5ZJK1, Q658Y4, Q68CL5, Q6BDS2, Q6P6Y1, Q6TEP1, Q6VNB8, Q7TMY8, Q7TSG1, Q7Z6Z7, Q8BHY8, Q8CB44, Q8CGF6

Diamond homologs: Q5RAQ5, Q91W96, Q9UJX5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ANAPC4	“form complex”	APC-c	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 104 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
Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint components	14	132.6×	4e-27
Inactivation of APC/C via direct inhibition of the APC/C complex	14	108.5×	3e-25
APC-Cdc20 mediated degradation of Nek2A	16	101.0×	4e-28
APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint	16	101.0×	4e-28
Activation of APC/C and APC/C:Cdc20 mediated degradation of mitotic proteins	16	97.4×	8e-28
Conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase	12	93.0×	2e-20
APC/C-mediated degradation of cell cycle proteins	18	90.2×	4e-30
Regulation of mitotic cell cycle	18	90.2×	4e-30

GO biological processes:

GO term	Partners	Fold	FDR
regulation of meiotic cell cycle	13	131.0×	3e-23
protein branched polyubiquitination	11	122.0×	2e-19
anaphase-promoting complex-dependent catabolic process	13	120.1×	8e-23
protein K11-linked ubiquitination	12	61.9×	4e-17
regulation of mitotic cell cycle	14	44.4×	8e-18
mitotic spindle assembly checkpoint signaling	6	44.4×	2e-07
protein K48-linked ubiquitination	12	26.6×	2e-12
cell division	23	14.0×	2e-18

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	77
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
146078	GRCh38/hg38 4p15.2(chr4:23862000-27685546)x1	Pathogenic
253450	GRCh37/hg19 4p15.2-15.1(chr4:23458442-29252060)x1	Pathogenic
1527079	GRCh37/hg19 4p15.2-15.1(chr4:23790131-32302608)	Likely pathogenic

SpliceAI

4119 predictions. Top by Δscore:

Variant	Effect	Δscore
4:25377556:GGT:G	donor_loss	1.0000
4:25377557:G:GA	donor_loss	1.0000
4:25377558:T:A	donor_loss	1.0000
4:25380368:TCTTA:T	acceptor_loss	1.0000
4:25380369:CTTA:C	acceptor_loss	1.0000
4:25380370:TTAG:T	acceptor_loss	1.0000
4:25380372:A:C	acceptor_loss	1.0000
4:25380439:A:T	donor_gain	1.0000
4:25380443:G:GT	donor_gain	1.0000
4:25380480:G:GG	donor_gain	1.0000
4:25383259:A:AG	acceptor_gain	1.0000
4:25383260:G:GG	acceptor_gain	1.0000
4:25383260:GTTTT:G	acceptor_gain	1.0000
4:25383374:G:GT	donor_gain	1.0000
4:25383390:GCAG:G	donor_gain	1.0000
4:25383391:CAG:C	donor_loss	1.0000
4:25383392:AG:A	donor_loss	1.0000
4:25383393:GG:G	donor_loss	1.0000
4:25383394:GT:G	donor_loss	1.0000
4:25383395:T:G	donor_loss	1.0000
4:25388497:TA:T	acceptor_loss	1.0000
4:25388498:A:AG	acceptor_gain	1.0000
4:25388498:AG:A	acceptor_loss	1.0000
4:25388498:AGT:A	acceptor_gain	1.0000
4:25388499:G:GT	acceptor_gain	1.0000
4:25388499:GT:G	acceptor_gain	1.0000
4:25388499:GTG:G	acceptor_gain	1.0000
4:25388499:GTGT:G	acceptor_gain	1.0000
4:25388499:GTGTT:G	acceptor_gain	1.0000
4:25388570:AAAAA:A	donor_gain	1.0000

AlphaMissense

5318 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:25377509:T:A	W28R	1.000
4:25377509:T:C	W28R	1.000
4:25377524:G:C	D33H	1.000
4:25377525:A:C	D33A	1.000
4:25377525:A:G	D33G	1.000
4:25377525:A:T	D33V	1.000
4:25377528:T:C	L34P	1.000
4:25377534:C:A	A36D	1.000
4:25380381:T:C	L46P	1.000
4:25380461:T:A	W73R	1.000
4:25380461:T:C	W73R	1.000
4:25380463:G:C	W73C	1.000
4:25380463:G:T	W73C	1.000
4:25383368:T:A	W115R	1.000
4:25383368:T:C	W115R	1.000
4:25393841:T:A	W276R	1.000
4:25393841:T:C	W276R	1.000
4:25393875:T:C	L287P	1.000
4:25394356:T:C	L308P	1.000
4:25394364:G:T	G311W	1.000
4:25394691:T:C	L321S	1.000
4:25396893:T:C	L403P	1.000
4:25403014:T:A	W420R	1.000
4:25403014:T:C	W420R	1.000
4:25403018:T:C	L421P	1.000
4:25406854:T:A	V448D	1.000
4:25406856:G:C	A449P	1.000
4:25406862:T:C	F451L	1.000
4:25406863:T:C	F451S	1.000
4:25406864:T:A	F451L	1.000

dbSNP variants (sampled 300 via entrez): RS1000030943 (4:25407387 T>A,G), RS1000086215 (4:25399297 A>G), RS10001307 (4:25390361 C>A,T), RS10001352 (4:25411352 T>C,G), RS1000175425 (4:25375875 T>C), RS1000227893 (4:25375411 A>G), RS1000258328 (4:25378718 T>C), RS1000312206 (4:25405880 A>C), RS1000438947 (4:25412396 G>A), RS10004635 (4:25384328 A>G), RS1000475454 (4:25391096 G>A,T), RS1000541097 (4:25416209 T>G), RS10005501 (4:25409367 A>G,T), RS1000550539 (4:25417313 G>A), RS1000556806 (4:25411364 C>T)

Disease associations

OMIM: gene MIM:606947 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST000837_5	Weight	1.000000e-06
GCST005316_148	Intelligence (MTAG)	2.000000e-10
GCST006269_802	General cognitive ability	7.000000e-09
GCST006979_427	Heel bone mineral density	3.000000e-09
GCST007005_2	Logical memory (immediate recall) in normal cognition	1.000000e-07
GCST008129_14	Body mass index	3.000000e-30
GCST008512_9	Multisite chronic pain	3.000000e-11
GCST010988_227	Adult body size	2.000000e-24
GCST010989_237	Body size at age 10	8.000000e-10
GCST012226_214	Waist circumference adjusted for body mass index	1.000000e-09
GCST90000047_62	Age at first sexual intercourse	1.000000e-10

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004338	body weight
EFO:0004337	intelligence
EFO:0009270	heel bone mineral density
EFO:0004874	memory performance
EFO:0004340	body mass index
EFO:0010100	multisite chronic pain
EFO:0009819	comparative body size at age 10, self-reported
EFO:0007789	BMI-adjusted waist circumference
EFO:0009749	age at first sexual intercourse measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
arsenite	decreases methylation	1
sodium arsenite	decreases expression	1
tetrabromobisphenol A	increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	increases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	increases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Chelating Agents	affects binding, decreases expression	1
Copper	affects binding, decreases expression	1
Quercetin	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin M1	decreases expression	1

Clinical trials (associated diseases)

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