ANAPC2

Summary

ANAPC2 (anaphase promoting complex subunit 2, HGNC:19989) is a protein-coding gene on chromosome 9q34.3, encoding Anaphase-promoting complex subunit 2 (Q9UJX6). Together with the RING-H2 protein ANAPC11, constitutes the catalytic 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 99.5% 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 product of this gene is a component of the complex and shares sequence similarity with a recently identified family of proteins called cullins, which may also be involved in ubiquitin-mediated degradation.

Source: NCBI Gene 29882 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 103 total — 7 pathogenic, 4 likely-pathogenic
• Cancer dependency (DepMap): dependent in 99.5% of screened cell lines (common-essential)
• MANE Select transcript: NM_013366

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19989
Approved symbol	ANAPC2
Name	anaphase promoting complex subunit 2
Location	9q34.3
Locus type	gene with protein product
Status	Approved
Aliases	APC2, KIAA1406
Ensembl gene	ENSG00000176248
Ensembl biotype	protein_coding
OMIM	606946
Entrez	29882

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 11 protein_coding, 5 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000323927, ENST00000471131, ENST00000483432, ENST00000485970, ENST00000487917, ENST00000493730, ENST00000495611, ENST00000618649, ENST00000900362, ENST00000900363, ENST00000900364, ENST00000900365, ENST00000900366, ENST00000900367, ENST00000900368, ENST00000928744, ENST00000950370, ENST00000950371

RefSeq mRNA: 1 — MANE Select: NM_013366 NM_013366

CCDS: CCDS7033

Canonical transcript exons

ENST00000323927 — 13 exons

Exon	Start	End
ENSE00001265581	137180452	137180527
ENSE00001265589	137180788	137180929
ENSE00001265602	137181681	137181862
ENSE00001265621	137186224	137186356
ENSE00001265624	137187481	137188103
ENSE00001817849	137188416	137188560
ENSE00003490907	137175708	137175837
ENSE00003531581	137183125	137183242
ENSE00003559067	137180181	137180384
ENSE00003616712	137183672	137183791
ENSE00003660195	137174784	137175154
ENSE00003663990	137184913	137185087
ENSE00003686520	137175237	137175472

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 96.19.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.2903 / max 312.3710, expressed in 1797 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
103326	12.9061	1796
103327	0.3842	183

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	96.19	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.12	gold quality
left testis	UBERON:0004533	95.97	gold quality
right testis	UBERON:0004534	95.94	gold quality
granulocyte	CL:0000094	95.93	gold quality
cerebellar hemisphere	UBERON:0002245	95.63	gold quality
cerebellar cortex	UBERON:0002129	95.45	gold quality
left ovary	UBERON:0002119	95.43	gold quality
right ovary	UBERON:0002118	95.36	gold quality
skin of leg	UBERON:0001511	95.33	gold quality
tibial nerve	UBERON:0001323	95.30	gold quality
skin of abdomen	UBERON:0001416	95.24	gold quality
metanephros cortex	UBERON:0010533	95.03	gold quality
minor salivary gland	UBERON:0001830	95.01	gold quality
body of pancreas	UBERON:0001150	94.87	gold quality
body of stomach	UBERON:0001161	94.84	gold quality
left uterine tube	UBERON:0001303	94.80	gold quality
right lobe of thyroid gland	UBERON:0001119	94.78	gold quality
apex of heart	UBERON:0002098	94.77	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.70	gold quality
body of uterus	UBERON:0009853	94.56	gold quality
mucosa of stomach	UBERON:0001199	94.52	gold quality
left lobe of thyroid gland	UBERON:0001120	94.33	gold quality
lower esophagus mucosa	UBERON:0035834	94.16	gold quality
endocervix	UBERON:0000458	94.09	gold quality
transverse colon	UBERON:0001157	94.04	gold quality
cerebellum	UBERON:0002037	93.95	gold quality
ectocervix	UBERON:0012249	93.83	gold quality
spleen	UBERON:0002106	93.75	gold quality
adenohypophysis	UBERON:0002196	93.75	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.66

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

2 targeting ANAPC2, 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-4268	94.45	64.09	819
HSA-MIR-4767	86.06	61.02	43

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.5% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 8)

• APC2 Cullin protein and APC11 RING protein comprise the minimal ubiquitin ligase module of the anaphase-promoting complex. (PMID:11739784)
• Results describe the locations of Cdh1 and Apc2 in the anaphase-promoting complex/cyclosome of human and Xenopus laevis. (PMID:16364912)
• The authors showed, in vitro, a direct interaction between Orf virus anaphase promoting complex regulator and APC2 and its interference with interactions between APC11 and APC2. (PMID:20826619)
• It proposes a role for APC/C(Cdh1) in modulating the status of PCNA monoubiquitination and UV DNA repair before S phase entry. (PMID:21768287)
• anaphase-promoting complex (APC)-2-cell cycle and apoptosis regulatory protein (CARP)-1 interaction antagonists are novel regulators of cell growth and apoptosis (PMID:21903591)
• The regulation of Mdm2 by the E3 ubiquitin ligase APC/C is shown. It has important therapeutic implications for tumors with Mdm2 overexpression. (PMID:24804778)
• A transcriptome-wide analysis revealed that SNW1 or PRPF8 depletion affects the splicing of specific introns in a subset of pre-mRNAs, including pre-mRNAs encoding the cohesion protein sororin and the APC/C subunit APC2. (PMID:25257309)
• The results showed that APC2 and APC7 subunits were both over expressed in cancer cell lines (PMID:26046517)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	anapc2	ENSDARG00000105035
mus_musculus	Anapc2	ENSMUSG00000026965
rattus_norvegicus	Anapc2	ENSRNOG00000011295
drosophila_melanogaster	mr	FBGN0002791
caenorhabditis_elegans		WBGENE00000143

Paralogs (7): CUL3 (ENSG00000036257), CUL1 (ENSG00000055130), CUL2 (ENSG00000108094), CUL4A (ENSG00000139842), CACUL1 (ENSG00000151893), CUL4B (ENSG00000158290), CUL5 (ENSG00000166266)

Protein

Protein identifiers

Anaphase-promoting complex subunit 2 — Q9UJX6 (reviewed: Q9UJX6)

Alternative names: Cyclosome subunit 2

All UniProt accessions (1): Q9UJX6

UniProt curated annotations — full annotation on UniProt →

Function. Together with the RING-H2 protein ANAPC11, constitutes the catalytic 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. The CDC20-APC/C complex positively regulates the formation of synaptic vesicle clustering at active zone to the presynaptic membrane in postmitotic neurons. CDC20-APC/C-induced degradation of NEUROD2 drives presynaptic differentiation.

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 UBE2C and UBE2S. Interacts (via cullin domain) with ANAPC11 and with UBCH10. Interacts with NEUROD2. Interacts with FBXO43; the interaction is direct.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the cullin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UJX6-1	1	yes
Q9UJX6-2	2

RefSeq proteins (1): NP_037498* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR014786	ANAPC2_C	Domain
IPR016158	Cullin_homology	Domain
IPR036317	Cullin_homology_sf	Homologous_superfamily
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR044554	ANAPC2	Family
IPR057975	TPR_ANAPC2	Domain
IPR059120	Cullin-like_AB	Domain

Pfam: PF08672, PF25773, PF26557

UniProt features (82 total): helix 37, strand 25, turn 7, modified residue 6, region of interest 2, mutagenesis site 2, chain 1, splice variant 1, compositionally biased region 1

Structure

Experimental structures (PDB)

23 structures.

PDB	Method	Resolution (Å)
4YII	X-RAY DIFFRACTION	1.8
6NXK	X-RAY DIFFRACTION	2.2
9GAW	ELECTRON MICROSCOPY	2.9
6Q6G	ELECTRON MICROSCOPY	3.2
6Q6H	ELECTRON MICROSCOPY	3.2
8PKP	ELECTRON MICROSCOPY	3.2
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
6OB1	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UJX6-F1	79.44	0.15

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 (6): 218, 314, 470, 534, 697, 810

Mutagenesis-validated functional residues (2):

Position	Phenotype
350	impairs ube2s-mediated polyubiquitination, decreasing substrate affinity, does not affect ube2c-mediated multiubiquitina
353	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: 723 (showing top): GOBP_DENDRITE_DEVELOPMENT, GOBP_CHROMOSOME_ORGANIZATION, REACTOME_DNA_REPLICATION, GCM_MAP4K4, 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, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, REACTOME_PHOSPHORYLATION_OF_THE_APC_C, GOBP_NEURON_PROJECTION_EXTENSION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH

GO Biological Process (18): metaphase/anaphase transition of mitotic cell cycle (GO:0007091), regulation of mitotic cell cycle (GO:0007346), nervous system development (GO:0007399), negative regulation of gene expression (GO:0010629), cell differentiation (GO:0030154), anaphase-promoting complex-dependent catabolic process (GO:0031145), positive regulation of synaptic plasticity (GO:0031915), positive regulation of axon extension (GO:0045773), positive regulation of dendrite morphogenesis (GO:0050775), cell division (GO:0051301), regulation of meiotic cell cycle (GO:0051445), protein K48-linked ubiquitination (GO:0070936), protein K11-linked ubiquitination (GO:0070979), positive regulation of synapse maturation (GO:0090129), protein branched polyubiquitination (GO:0141198), ubiquitin-dependent protein catabolic process (GO:0006511), proteasomal protein catabolic process (GO:0010498), protein ubiquitination (GO:0016567)

GO Molecular Function (2): ubiquitin protein ligase binding (GO:0031625), protein binding (GO:0005515)

GO Cellular Component (4): nucleoplasm (GO:0005654), anaphase-promoting complex (GO:0005680), cytosol (GO:0005829), cullin-RING ubiquitin ligase complex (GO:0031461)

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
mitotic cell cycle	2
regulation of cell cycle	2
cellular anatomical structure	2
mitotic cell cycle phase transition	1
metaphase/anaphase transition of cell cycle	1
system development	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
cellular developmental process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
regulation of synaptic plasticity	1
positive regulation of cell growth	1
regulation of axon extension	1
positive regulation of developmental growth	1
axon extension	1
positive regulation of axonogenesis	1
positive regulation of cell morphogenesis	1
positive regulation of cell projection organization	1
dendrite morphogenesis	1
regulation of dendrite morphogenesis	1
positive regulation of neurogenesis	1
cellular process	1
meiotic cell cycle	1
regulation of reproductive process	1
positive regulation of developmental process	1
positive regulation of cellular component organization	1
synapse maturation	1
regulation of synapse maturation	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
protein catabolic process	1
protein modification by small protein conjugation	1
ubiquitin-like protein ligase binding	1
binding	1
nuclear lumen	1
nuclear ubiquitin ligase complex	1
cullin-RING ubiquitin ligase complex	1
cytoplasm	1

Protein interactions and networks

STRING

1753 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANAPC2	FZR1	Q9UM11	967
ANAPC2	CDC27	P30260	955
ANAPC2	ANAPC5	Q9UJX4	931
ANAPC2	CDC16	Q13042	925
ANAPC2	CDC23	Q9UJX2	911
ANAPC2	ANAPC11	Q9NYG5	910
ANAPC2	ANAPC4	Q9UJX5	908
ANAPC2	ANAPC1	Q9H1A4	872
ANAPC2	CDC20	Q12834	818
ANAPC2	ANAPC10	Q9UM13	808
ANAPC2	ANAPC7	Q9UJX3	784
ANAPC2	INVS	Q9Y283	698
ANAPC2	BUB1B	O60566	550
ANAPC2	CDC34	P49427	512
ANAPC2	DIRC1	Q969H9	507

IntAct

119 interactions, top by confidence:

A	B	Type	Score
CDC20	BUB1B	psi-mi:“MI:0914”(association)	0.980
CDC27	CDC20	psi-mi:“MI:0914”(association)	0.950
ANAPC2	CDC27	psi-mi:“MI:0915”(physical association)	0.910
BUB1B	CDC27	psi-mi:“MI:0914”(association)	0.900
ANAPC4	CDC27	psi-mi:“MI:0914”(association)	0.860
CDC27	CDC16	psi-mi:“MI:0914”(association)	0.860
GRAP2	STAMBP	psi-mi:“MI:0914”(association)	0.810
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
CDC27	ANAPC16	psi-mi:“MI:0914”(association)	0.760
MED19	MED19	psi-mi:“MI:0914”(association)	0.730
ANAPC16	BUB1B	psi-mi:“MI:0914”(association)	0.730
ANAPC2	BUB1B	psi-mi:“MI:0914”(association)	0.730
CDC20	BUB1	psi-mi:“MI:0914”(association)	0.730
FBXO5	ANAPC2	psi-mi:“MI:0407”(direct interaction)	0.720
CDC26	BUB1B	psi-mi:“MI:0914”(association)	0.640
ANAPC13	CDC27	psi-mi:“MI:0914”(association)	0.640
TTLL1	CDC27	psi-mi:“MI:0914”(association)	0.640
C16orf87	CDC27	psi-mi:“MI:0914”(association)	0.640

BioGRID (416): ANAPC2 (Reconstituted Complex), ANAPC1 (Affinity Capture-Western), CDC27 (Affinity Capture-Western), ANAPC4 (Affinity Capture-Western), ANAPC5 (Affinity Capture-Western), CDC16 (Affinity Capture-Western), CDC23 (Affinity Capture-Western), CDC26 (Affinity Capture-Western), ANAPC7 (Affinity Capture-Western), ANAPC2 (Reconstituted Complex), CDC27 (Affinity Capture-Western), FZR1 (Affinity Capture-Western), ANAPC2 (Affinity Capture-MS), ANAPC2 (Affinity Capture-Western), ANAPC2 (Reconstituted Complex)

ESM2 similar proteins: A1A4I4, A2SXS5, A6QQ47, B2DCZ9, O00255, O08908, O55166, O75146, O88559, P70268, Q0P5I0, Q0VCR8, Q155U0, Q16512, Q29RB1, Q2KJ58, Q3MHG0, Q3MII6, Q3SZI7, Q3UVL4, Q4V9Y0, Q505L3, Q5R7R6, Q5TJF0, Q5ZJ25, Q63433, Q63788, Q68FF6, Q68FP9, Q69Z89, Q6PB44, Q6ZT62, Q865S3, Q8BI71, Q8BZQ7, Q8C190, Q8C754, Q8N1B4, Q8R1U1, Q8R3I3

Diamond homologs: Q8BZQ7, Q8H1U5, Q9UJX6, Q551S9, Q874R3

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
ANAPC2	down-regulates	DVL1	binding
NAE	“up-regulates activity”	ANAPC2	neddylation
ANAPC2	“form complex”	APC-c	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 89 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	13	126.9×	8e-25
Inactivation of APC/C via direct inhibition of the APC/C complex	14	111.8×	1e-25
APC-Cdc20 mediated degradation of Nek2A	15	97.6×	5e-26
APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint	15	97.6×	5e-26
Conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase	12	95.8×	1e-20
Activation of APC/C and APC/C:Cdc20 mediated degradation of mitotic proteins	15	94.1×	9e-26
Phosphorylation of the APC/C	11	92.0×	1e-18
APC/C:Cdc20 mediated degradation of mitotic proteins	16	87.8×	2e-26

GO biological processes:

GO term	Partners	Fold	FDR
regulation of meiotic cell cycle	12	124.2×	3e-21
anaphase-promoting complex-dependent catabolic process	13	123.3×	9e-23
protein branched polyubiquitination	10	113.9×	3e-17
protein K11-linked ubiquitination	12	63.5×	3e-17
regulation of mitotic cell cycle	14	45.5×	7e-18
mitotic spindle assembly checkpoint signaling	6	45.5×	2e-07
protein K48-linked ubiquitination	11	25.1×	4e-11
cell division	21	13.1×	3e-16

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	4
Uncertain significance	76
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
145579	GRCh38/hg38 9q33.2-34.3(chr9:121073102-138179445)x3	Pathogenic
3238688	GRCh38/hg38 9q34.3(chr9:137106653-138394717)	Pathogenic
3238695	GRCh38/hg38 9q34.3(chr9:137059436-137902321)	Pathogenic
3238717	GRCh38/hg38 9q34.3(chr9:137170000-138360000)	Pathogenic
3390990	GRCh37/hg19 9q34.3(chr9:139674181-141018648)x1	Pathogenic
3390992	GRCh37/hg19 9q34.3(chr9:140033837-141111544)x1	Pathogenic
3391000	GRCh37/hg19 9q34.3(chr9:139937332-141111829)x1	Pathogenic
2576628	GRCh37/hg19 9q34.3(chr9:139942000-141074000)x3	Likely pathogenic
2576631	GRCh37/hg19 9q34.3(chr9:139972953-140954193)x3	Likely pathogenic
2576632	GRCh37/hg19 9q34.3(chr9:140014769-140930811)x3	Likely pathogenic
523294	GRCh37/hg19 9q21.11-34.3(chr9:71069743-140999928)	Likely pathogenic

SpliceAI

3231 predictions. Top by Δscore:

Variant	Effect	Δscore
9:137175247:T:TA	donor_gain	1.0000
9:137175250:T:TA	donor_gain	1.0000
9:137180176:GGTAC:G	donor_loss	1.0000
9:137180177:GTAC:G	donor_loss	1.0000
9:137180178:TA:T	donor_loss	1.0000
9:137180179:A:AT	donor_loss	1.0000
9:137180180:C:CG	donor_loss	1.0000
9:137180195:A:AC	donor_gain	1.0000
9:137180196:C:CC	donor_gain	1.0000
9:137180196:CTT:C	donor_gain	1.0000
9:137180198:T:TA	donor_gain	1.0000
9:137180784:TCAC:T	donor_loss	1.0000
9:137180786:A:AC	donor_gain	1.0000
9:137180787:C:CC	donor_gain	1.0000
9:137180787:CCG:C	donor_gain	1.0000
9:137180787:CCGCT:C	donor_gain	1.0000
9:137180807:A:C	donor_gain	1.0000
9:137180847:A:AC	donor_gain	1.0000
9:137180925:CTTCC:C	acceptor_gain	1.0000
9:137180926:TTCC:T	acceptor_gain	1.0000
9:137180927:TCC:T	acceptor_gain	1.0000
9:137180927:TCCCT:T	acceptor_loss	1.0000
9:137180928:CC:C	acceptor_gain	1.0000
9:137180928:CCC:C	acceptor_gain	1.0000
9:137180929:CC:C	acceptor_gain	1.0000
9:137180929:CCT:C	acceptor_loss	1.0000
9:137180930:C:CA	acceptor_loss	1.0000
9:137180930:C:CC	acceptor_gain	1.0000
9:137180931:T:G	acceptor_loss	1.0000
9:137180934:CATGG:C	acceptor_gain	1.0000

AlphaMissense

5345 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:137174968:A:C	Y815D	1.000
9:137174988:A:T	L808H	1.000
9:137175015:A:G	L799P	1.000
9:137175081:A:G	L777P	1.000
9:137175126:A:G	L762P	1.000
9:137180268:C:A	W601C	1.000
9:137180268:C:G	W601C	1.000
9:137180270:A:G	W601R	1.000
9:137180270:A:T	W601R	1.000
9:137180271:G:C	F600L	1.000
9:137180271:G:T	F600L	1.000
9:137180273:A:G	F600L	1.000
9:137180372:A:G	S567P	1.000
9:137180383:T:A	D563V	1.000
9:137180383:T:G	D563A	1.000
9:137180384:C:G	D563H	1.000
9:137180456:A:G	L561P	1.000
9:137180459:A:G	M560T	1.000
9:137180504:A:G	L545P	1.000
9:137180507:A:G	L544P	1.000
9:137180830:A:G	L523P	1.000
9:137183128:A:G	L428P	1.000
9:137183758:A:G	L361P	1.000
9:137174988:A:G	L808P	0.999
9:137175398:A:G	W699R	0.999
9:137175398:A:T	W699R	0.999
9:137175770:C:G	R653P	0.999
9:137175803:C:T	G642D	0.999
9:137175804:C:G	G642R	0.999
9:137175819:A:G	W637R	0.999

dbSNP variants (sampled 300 via entrez): RS1000143800 (9:137182079 C>T), RS1000219495 (9:137185489 C>T), RS1000250402 (9:137185697 T>A,C), RS1000254588 (9:137175320 C>T), RS1000352600 (9:137183401 C>G,T), RS1000411549 (9:137190156 G>A), RS1000559970 (9:137184519 G>C), RS1000628225 (9:137179908 A>T), RS1000709495 (9:137175103 G>C), RS1001240000 (9:137185369 C>T), RS1001271058 (9:137176567 A>G), RS1001917553 (9:137183906 G>A,C), RS1001970198 (9:137189410 C>A,G), RS1002077314 (9:137182190 G>A), RS1002272841 (9:137188340 C>A,G,T)

Disease associations

OMIM: gene MIM:606946 | disease phenotypes: MIM:614254, MIM:610253

GenCC curated gene-disease

Mondo (2): neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal dominant (MONDO:0013655), Kleefstra syndrome 1 (MONDO:0027407)

Orphanet (1): Kleefstra syndrome (Orphanet:261494)

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002382_283	Eosinophil percentage of white cells	2.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007991	eosinophil percentage of leukocytes

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C563043	Kleefstra Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, increases methylation	1
echimidine	decreases expression, increases metabolic processing	1
lasiocarpine	increases metabolic processing, decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	affects methylation	1
coumarin	increases phosphorylation	1
1-(2-chlorobenzyl)-5’-phenyl-3’H-spiro(indoline-3,2’-(1,3,4)thiadiazol)-2-one	affects binding, decreases reaction	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acrolein	decreases expression	1
Caffeine	affects phosphorylation	1
Chelating Agents	decreases expression, affects binding	1
Copper	affects binding, decreases expression	1
Doxorubicin	affects binding, increases reaction	1
Ivermectin	decreases expression	1
Lead	decreases expression	1
Methapyrilene	increases methylation	1
Selenium	increases expression	1
Smoke	decreases expression	1
Valproic Acid	increases methylation	1
Nocodazole	affects binding, increases reaction	1
Aflatoxin B1	increases methylation	1
Monocrotaline	increases metabolic processing, decreases expression	1
Gold Compounds	increases expression	1

Clinical trials (associated diseases)

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