MAD2L1

Summary

MAD2L1 (mitotic arrest deficient 2 like 1, HGNC:6763) is a protein-coding gene on chromosome 4q27, encoding Mitotic spindle assembly checkpoint protein MAD2A (Q13257). Component of the spindle-assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate. It is a common-essential gene (DepMap: required in 97.9% of cancer cell lines).

MAD2L1 is a component of the mitotic spindle assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate. MAD2L1 is related to the MAD2L2 gene located on chromosome 1. A MAD2 pseudogene has been mapped to chromosome 14.

Source: NCBI Gene 4085 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 25 total
• Cancer dependency (DepMap): dependent in 97.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_002358

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6763
Approved symbol	MAD2L1
Name	mitotic arrest deficient 2 like 1
Location	4q27
Locus type	gene with protein product
Status	Approved
Aliases	MAD2, HSMAD2
Ensembl gene	ENSG00000164109
Ensembl biotype	protein_coding
OMIM	601467
Entrez	4085

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 3 protein_coding, 2 nonsense_mediated_decay, 2 retained_intron

ENST00000296509, ENST00000333047, ENST00000504707, ENST00000511295, ENST00000512484, ENST00000890762, ENST00000946974

RefSeq mRNA: 1 — MANE Select: NM_002358 NM_002358

CCDS: CCDS3715

Canonical transcript exons

ENST00000296509 — 5 exons

Exon	Start	End
ENSE00001081493	120061975	120062095
ENSE00001081494	120065672	120065818
ENSE00001705676	120066662	120066848
ENSE00001796865	120055623	120060290
ENSE00003529434	120060874	120060977

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 99.79.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.2416 / max 328.5775, expressed in 1616 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53780	20.1475	1612
53779	1.0941	535

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.79	gold quality
oocyte	CL:0000023	99.60	gold quality
ventricular zone	UBERON:0003053	98.02	gold quality
embryo	UBERON:0000922	96.32	gold quality
ganglionic eminence	UBERON:0004023	95.82	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.20	gold quality
epithelium of nasopharynx	UBERON:0001951	90.74	gold quality
nasopharynx	UBERON:0001728	90.73	gold quality
bone marrow	UBERON:0002371	89.44	gold quality
mucosa of transverse colon	UBERON:0004991	87.53	gold quality
amniotic fluid	UBERON:0000173	86.90	gold quality
esophagus squamous epithelium	UBERON:0006920	86.44	gold quality
rectum	UBERON:0001052	86.36	gold quality
vermiform appendix	UBERON:0001154	86.07	gold quality
trabecular bone tissue	UBERON:0002483	85.56	gold quality
oral cavity	UBERON:0000167	85.41	gold quality
mucosa of sigmoid colon	UBERON:0004993	85.19	gold quality
colonic mucosa	UBERON:0000317	84.81	gold quality
epithelium of esophagus	UBERON:0001976	84.37	gold quality
adrenal tissue	UBERON:0018303	84.37	gold quality
stromal cell of endometrium	CL:0002255	84.32	gold quality
bone marrow cell	CL:0002092	83.35	gold quality
right testis	UBERON:0004534	83.35	gold quality
caecum	UBERON:0001153	83.29	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.21	gold quality
thymus	UBERON:0002370	83.10	gold quality
esophagus mucosa	UBERON:0002469	83.05	gold quality
testis	UBERON:0000473	82.81	gold quality
tibia	UBERON:0000979	82.65	gold quality
lymph node	UBERON:0000029	82.49	gold quality

Single-cell (SCXA)

Detected in 22 experiment(s), a significant marker in 21.

Experiment	Marker?	Max mean expression
E-HCAD-56	yes	742.83
E-MTAB-10485	yes	675.39
E-GEOD-114530	yes	491.17
E-HCAD-10	yes	488.17
E-GEOD-124472	yes	470.59
E-MTAB-11121	yes	450.82
E-GEOD-124858	yes	335.04
E-MTAB-10662	yes	298.37
E-MTAB-6108	yes	290.41
E-MTAB-7052	yes	287.82
E-MTAB-10855	yes	212.88
E-GEOD-99795	yes	157.45
E-CURD-112	yes	44.61
E-GEOD-125970	yes	25.43
E-HCAD-13	yes	22.61

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BRCA1, CDK5RAP2, E2F4, ETV6, GLI2, MYC, POU2F1, REST, RUNX1

miRNA regulators (miRDB)

43 targeting MAD2L1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-139-5P	99.80	69.50	1399
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-1284	99.67	73.56	1353
HSA-MIR-497-3P	99.61	69.71	1990
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-4427	99.34	70.33	1854
HSA-MIR-499A-3P	99.18	69.20	1392
HSA-MIR-499B-3P	99.18	69.27	1391
HSA-MIR-29A-5P	99.08	68.59	1813
HSA-MIR-670-3P	99.03	68.88	2404

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 97.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• BubR1 and Mad2 act cooperatively to prevent premature separation of sister chromatids by directly inhibiting the anaphase-promoting complex (PMID:11907259)
• The steady-state amount of MAD2 inside cells may represent a molecular switch for mitotic checkpoint control. (PMID:11912137)
• Hec1 was required for the recruitment of Mps1 kinase and Mad1/Mad2 complexes to kinetochores (PMID:12351790)
• Defect of spindle checkpoint gene Mad2 and mutation of p53 gene are involved mainly in colorectal carcinogenesis, and cancer/normal tissue ratio >2 is associated with prognosis of colorectal cancer. (PMID:12970887)
• No apparent selection trend was established with neoplastic progression or aneuploidy for MAD2 in Barrett esophagus. (PMID:15013707)
• The unusual two-state behavior of Mad2 is critical for spindle checkpoint signaling. (PMID:15024386)
• Reduction of MAD2 protein levels results in mitotic failure and extensive cell death. (PMID:15070740)
• p31(comet, formerly known as Cmt2) counteracts the function of Mad2 and is required for the silencing of the spindle checkpoint (PMID:15257285)
• Generation of Rb pathway lesions in normal and transformed cells produces aberrant Mad2 expression and mitotic defects leading to aneuploidy, such that elevated Mad2 contributes directly to these defects (PMID:15306814)
• Defect of spindle checkpoint gene Mad2 and mutation of p27 gene are involved mainly in colorectal carcinogenesis (PMID:15457580)
• Elevation of MAD2 level is present in 74% of gastric cancer patients, and correlates with increased mitotic checkpoint activity but is not associated with patients’ aneuploidy and any of the clinicopathological characteristics (PMID:15484292)
• reconstitution of Mad2 in Brca1(Delta11/Delta11) cells partially restored the spindle checkpoint and attenuated apoptosis (PMID:15563594)
• MAD2 deficiency may cause a mitotic checkpoint defect in hepatoma cells (PMID:15591789)
• Frequent mutations of MAD2 in gastric cancers cause defective mitotic spindle checkpoint. (PMID:16112690)
• Mad2beta is an alternative splicing variant of spindle checkpoint gene mad2, related to drug resistance in gastric cancer cells. (PMID:16214181)
• high levels of FAT10 protein in cells lead to increased mitotic nondisjunction and chromosome instability, which is mediated by an abbreviated mitotic phase and reduction in the kinetochore localization of MAD2 during prometaphase (PMID:16495226)
• Functional analysis suggests that an optimum Mad2 binding efficiency of Cdc20 is required during checkpoint arrest and release (PMID:16497171)
• down regulation of MAD2 could promote the drug resistance of gastric cancer cells and inhibit anticancer drugs induced-apoptosis by upregulating Bcl-2 and interfering the mitochondrion apoptosis pathway (PMID:16714000)
• Kidney papillary carcinoma showed overexpression of MAD2L1. (PMID:17333263)
• BUB1B mRNA levels but not MAD2L1 levels correlate with intrachromosomal insttability in ductal breast carcinomas. (PMID:17498870)
• The evidence presented here provides a link between MAD2 inactivation and malignant transformation of epithelial cells. (PMID:17621272)
• Mad2 is negatively regulated by p31 in heptacellular carcinoma (PMID:17934339)
• PRP4 is a spindle assembly checkpoint protein required for MAD2 localization to the kinetochores. (PMID:17998396)
• Data suggest that the structure of the O-Mad2-C-Mad2 conformational dimer is consistent with a catalytic model in which a C-Mad2 template facilitates the binding of O-Mad2 to Cdc20, the target of Mad2 in the spindle checkpoint. (PMID:18022367)
• Data suggest that p31(comet)(CMT2) exploits the two-state behavior of Mad2 to block its activation by acting as an “anti-Mad2.” (PMID:18022368)
• Existence of a symmetric Mad2 dimer with Mad1-assisted conformational activation in the spindle checkpoint. (PMID:18318601)
• REST is degraded by means of the ubiquitin ligase SCF(beta-TrCP) during the G2 phase of the cell cycle to allow transcriptional derepression of Mad2, an essential component of the spindle assembly checkpoint (PMID:18354482)
• hBUB1, hBUBR1 and hMAD2 expressions in anaplastic thyroid cancer were significantly higher than those in diffuse cancer. hBUBR1 and hMAD2 expressions in advanced DTCs were significantly higher than those in non-advanced DTCs. (PMID:18383837)
• No somatic mutations of the Mad2 gene is associated with tumors. (PMID:18423499)
• Aberrant MAD2 expression is potentially associated with pleomorphic morphology and abnormal mitosis in soft-tissue sarcomas. (PMID:18477210)
• In human cells, Mps1 catalytic activity is required for spindle checkpoint function and recruitment of Mad2. (PMID:18541701)
• suggest a novel function of MAD2 by interfering with DNA repair proteins (PMID:18597777)
• HsMAD2 and BubR1 were significantly higher in cancer tissue than in adjacent normal tissue (P < 0.01). Tumoral hsMAD2 and BubR1 were significantly decreased after radiochemotherapy (PMID:18691855)
• chromosomal binding of the mitotic regulators such as Mad2 is essential for mitotic progression (PMID:18712773)
• MAD2 is overexpressed in hepatocellular carcinoma, including high-grade dysplastic nodules and early-stage small hepatocellular carcinoma, indicating that overexpression of MAD2 plays a role in the development and progression of hepatocellular carcinoma. (PMID:18715617)
• Smurf2 regulates the localization and stability of Mad2. (PMID:18852296)
• Reduced expression of hsMAD2 gene may be one of the mechanisms inducing numerical chromosome aberration, abnormal embryo development and the occurrence of spontaneous abortion. (PMID:18953867)
• Tpr regulates Mad1-Mad2 proteins are regulated during the cell cycle and mitotic spindle checkpoint signaling. (PMID:18981471)
• The degradation of Cdc20 represents a critical control mechanism to ensure inactivation of APC/C(Cdc20) in response to the spindle assembly checkpoint. (PMID:19098431)
• Results support a model in which immobilized Mad1/Mad2 at kinetochores provides a template for initial assembly of Mad2 bound to Cdc20 that is then converted to a final mitotic checkpoint inhibitor with Cdc20 bound to BubR1. (PMID:19154722)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mad2l1	ENSDARG00000004713
mus_musculus	Mad2l1	ENSMUSG00000029910
rattus_norvegicus	Mad2l1	ENSRNOG00000005376
drosophila_melanogaster	mad2	FBGN0035640
caenorhabditis_elegans		WBGENE00003161

Paralogs (1): MAD2L2 (ENSG00000116670)

Protein

Protein identifiers

Mitotic spindle assembly checkpoint protein MAD2A — Q13257 (reviewed: Q13257)

Alternative names: Mitotic arrest deficient 2-like protein 1

All UniProt accessions (2): D6RJE3, Q13257

UniProt curated annotations — full annotation on UniProt →

Function. Component of the spindle-assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate. In the closed conformation (C-MAD2) forms a heterotetrameric complex with MAD1L1 at unattached kinetochores during prometaphase, the complex recruits open conformation molecules of MAD2L1 (O-MAD2) and then promotes the conversion of O-MAD2 to C-MAD2. Required for the execution of the mitotic checkpoint which monitors the process of kinetochore-spindle attachment and inhibits the activity of the anaphase promoting complex by sequestering CDC20 until all chromosomes are aligned at the metaphase plate.

Subunit / interactions. Monomer and homodimer. Heterodimerizes with MAD2L1 in order to form a tetrameric MAD1L1-MAD2L1 core complex. In the closed and open conformation, interacts with MAD1L1. Formation of a heterotetrameric core complex containing two molecules each of MAD1L1 and of MAD2L1 promotes binding of another molecule of MAD2L1 to each MAD2L1, resulting in a heterohexamer. Interacts with MAD2L1BP. Interacts with ADAM17/TACE. Interacts with CDC20. Dimeric MAD2L1 in the closed conformation interacts with CDC20. Monomeric MAD2L1 in the open conformation does not interact with CDC20. CDC20 competes with MAD1L1 for MAD2L1 binding. In the closed conformation, interacts with BUB1B. Interacts with TTK. Interacts with TPR. Binds to UBD (via ubiquitin-like 1 domain) during mitosis. Interacts with isoform 1 and isoform 2 of NEK2. Interacts with HSF1; this interaction occurs in mitosis. Interacts with isoform 3 of MAD1L1; this interaction leads to the cytoplasmic sequestration of MAD2L1.

Subcellular location. Nucleus. Chromosome. Centromere. Kinetochore. Cytoplasm. Cytoskeleton. Spindle pole.

Post-translational modifications. Phosphorylated on multiple serine residues. The level of phosphorylation varies during the cell cycle and is highest during mitosis. Phosphorylation abolishes interaction with MAD1L1 and reduces interaction with CDC20. Phosphorylated by NEK2.

Domain organisation. The protein has two highly different native conformations, an inactive open conformation that cannot bind CDC20 and that predominates in cytosolic monomers, and an active closed conformation. The protein in the closed conformation preferentially dimerizes with another molecule in the open conformation, but can also form a dimer with a molecule in the closed conformation. Formation of a heterotetrameric core complex containing two molecules of MAD1L1 and of MAD2L1 in the closed conformation promotes binding of another molecule of MAD2L1 in the open conformation and the conversion of the open to the closed form, and thereby promotes interaction with CDC20.

Similarity. Belongs to the MAD2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13257-1	1	yes
Q13257-2	2

RefSeq proteins (1): NP_002349* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003511	HORMA_dom	Domain
IPR036570	HORMA_dom_sf	Homologous_superfamily
IPR045091	Mad2-like	Family

Pfam: PF02301

UniProt features (51 total): mutagenesis site 16, strand 13, modified residue 7, helix 6, splice variant 2, sequence conflict 2, initiator methionine 1, chain 1, domain 1, region of interest 1, turn 1

Structure

Experimental structures (PDB)

12 structures.

PDB	Method	Resolution (Å)
2VFX	X-RAY DIFFRACTION	1.95
1GO4	X-RAY DIFFRACTION	2.05
2QYF	X-RAY DIFFRACTION	2.3
2V64	X-RAY DIFFRACTION	2.9
6TLJ	ELECTRON MICROSCOPY	3.8
3GMH	X-RAY DIFFRACTION	3.95
5LCW	ELECTRON MICROSCOPY	4.2
6F0X	ELECTRON MICROSCOPY	4.6
5KHU	ELECTRON MICROSCOPY	4.8
1DUJ	SOLUTION NMR
1KLQ	SOLUTION NMR
1S2H	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13257-F1	93.91	0.91

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): 195, 2, 6, 130, 170, 178, 185

Mutagenesis-validated functional residues (16):

Position	Phenotype
13	leads to formation the closed conformation and homodimerization. reduces binding to mad1l1.
75	prevents interaction with cdc20 and leads to formation of the closed conformation; when associated with a-133.
133	prevents aggregation and promotes formation of monomeric protein that slowly interconverts between the open and closed c
153	leads to formation of the closed conformation; when associated with a-133.
156	leads to formation of the closed conformation; when associated with a-133.
170	reduces phosphorylation on serine residues; when associated with a-178. abolishes phosphorylation on serine residues; wh
170	abolishes interaction with mad1l1 and reduces interaction with cdc20; when associated with d-178 and d-195.
178	reduces phosphorylation on serine residues; when associated with a-170. abolishes phosphorylation on serine residues; wh
178	abolishes interaction with mad1l1 and reduces interaction with cdc20; when associated with d-170 and d-195.
186	prevents formation of the closed conformation and interaction with cdc20; when associated with a-133.
188	prevents formation of the closed conformation and interaction with cdc20; when associated with a-133.
191	prevents formation of the closed conformation and interaction with cdc20; when associated with a-133.
195	abolishes phosphorylation on serine residues; when associated with a-170 and a-178.
195	binds to the n and c-terminus of mad1l1. abolishes interaction with mad1l1 and reduces interaction with cdc20; when asso
197	prevents formation of the closed conformation and interaction with cdc20; when associated with a-133.
199	prevents formation of the closed conformation and interaction with cdc20; when associated with a-133.

Function

Pathways and Gene Ontology

Reactome pathways

28 pathways

ID	Pathway
R-HSA-141405	Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint components
R-HSA-141430	Inactivation of APC/C via direct inhibition of the APC/C complex
R-HSA-141444	Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal
R-HSA-174184	Cdc20:Phospho-APC/C mediated degradation of Cyclin A
R-HSA-176409	APC/C:Cdc20 mediated degradation of mitotic proteins
R-HSA-179409	APC-Cdc20 mediated degradation of Nek2A
R-HSA-2467813	Separation of Sister Chromatids
R-HSA-2500257	Resolution of Sister Chromatid Cohesion
R-HSA-5663220	RHO GTPases Activate Formins
R-HSA-68877	Mitotic Prometaphase
R-HSA-9648025	EML4 and NUDC in mitotic spindle formation
R-HSA-141424	Amplification of signal from the kinetochores
R-HSA-162582	Signal Transduction
R-HSA-1640170	Cell Cycle
R-HSA-174143	APC/C-mediated degradation of cell cycle proteins
R-HSA-176408	Regulation of APC/C activators between G1/S and early anaphase
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-194315	Signaling by Rho GTPases
R-HSA-195258	RHO GTPase Effectors
R-HSA-2555396	Mitotic Metaphase and Anaphase
R-HSA-453276	Regulation of mitotic cell cycle
R-HSA-68882	Mitotic Anaphase
R-HSA-68886	M Phase
R-HSA-69278	Cell Cycle, Mitotic
R-HSA-69618	Mitotic Spindle Checkpoint
R-HSA-69620	Cell Cycle Checkpoints
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 444 (showing top): GOBP_CHROMOSOME_ORGANIZATION, MODULE_416, MODULE_52, GOBP_REGULATION_OF_CELL_CYCLE_CHECKPOINT, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, HORIUCHI_WTAP_TARGETS_DN, KANG_DOXORUBICIN_RESISTANCE_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_REGULATION_OF_NUCLEAR_DIVISION, BASSO_B_LYMPHOCYTE_NETWORK, REACTOME_APC_CDC20_MEDIATED_DEGRADATION_OF_NEK2A, MORF_BRCA1, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GOBP_CELL_CYCLE_PHASE_TRANSITION

GO Biological Process (11): mitotic sister chromatid segregation (GO:0000070), mitotic spindle assembly checkpoint signaling (GO:0007094), negative regulation of protein catabolic process (GO:0042177), negative regulation of mitotic cell cycle (GO:0045930), cell division (GO:0051301), positive regulation of mitotic cell cycle spindle assembly checkpoint (GO:0090267), negative regulation of ubiquitin protein ligase activity (GO:1904667), establishment of mitotic spindle orientation (GO:0000132), establishment of centrosome localization (GO:0051660), regulation of nuclear division (GO:0051783), negative regulation of mitotic cell cycle phase transition (GO:1901991)

GO Molecular Function (3): identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (14): kinetochore (GO:0000776), spindle pole (GO:0000922), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), mitotic checkpoint complex (GO:0033597), nuclear pore nuclear basket (GO:0044615), perinuclear region of cytoplasm (GO:0048471), mitotic spindle (GO:0072686), mitotic spindle assembly checkpoint MAD1-MAD2 complex (GO:1990728), chromosome, centromeric region (GO:0000775), chromosome (GO:0005694), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Mitotic Spindle Checkpoint	2
APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint	2
Mitotic Prometaphase	2
APC/C-mediated degradation of cell cycle proteins	2
Regulation of APC/C activators between G1/S and early anaphase	1
Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint components	1
Amplification of signal from the kinetochores	1
Activation of APC/C and APC/C:Cdc20 mediated degradation of mitotic proteins	1
Mitotic Anaphase	1
RHO GTPase Effectors	1
M Phase	1
Regulation of mitotic cell cycle	1
APC/C:Cdc20 mediated degradation of mitotic proteins	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signaling by Rho GTPases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
mitotic cell cycle	3
intracellular membraneless organelle	3
cytoplasm	3
spindle	2
nuclear protein-containing complex	2
sister chromatid segregation	1
mitotic nuclear division	1
mitotic cell cycle process	1
negative regulation of mitotic metaphase/anaphase transition	1
spindle assembly checkpoint signaling	1
mitotic spindle checkpoint signaling	1
negative regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
negative regulation of protein metabolic process	1
regulation of mitotic cell cycle	1
negative regulation of cell cycle	1
cellular process	1
mitotic spindle assembly checkpoint signaling	1
positive regulation of cell cycle process	1
positive regulation of spindle checkpoint	1
regulation of mitotic cell cycle spindle assembly checkpoint	1
negative regulation of ubiquitin-protein transferase activity	1
ubiquitin protein ligase activity	1
regulation of ubiquitin protein ligase activity	1
establishment of mitotic spindle localization	1
establishment of spindle orientation	1
centrosome localization	1
establishment of localization in cell	1
establishment of organelle localization	1
nuclear division	1
regulation of organelle organization	1
mitotic cell cycle phase transition	1
negative regulation of mitotic cell cycle	1
negative regulation of cell cycle phase transition	1
regulation of mitotic cell cycle phase transition	1
protein binding	1
identical protein binding	1
protein dimerization activity	1

Protein interactions and networks

STRING

4212 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAD2L1	BUB1B	O60566	988
MAD2L1	MAD1L1	Q9Y6D9	987
MAD2L1	CDC20	Q12834	981
MAD2L1	BUB3	O43684	967
MAD2L1	BUB1	O43683	940
MAD2L1	TTK	P33981	911
MAD2L1	CCNB1	P14635	900
MAD2L1	CDK1	P06493	897
MAD2L1	CCNA2	P20248	854
MAD2L1	ESPL1	Q14674	843
MAD2L1	CCNB2	O95067	836
MAD2L1	AURKA	O14965	796
MAD2L1	KIF11	P52732	775
MAD2L1	PTTG1	O95997	774
MAD2L1	ERCC6L	Q2NKX8	774

IntAct

261 interactions, top by confidence:

A	B	Type	Score
MAD2L1	CDC20	psi-mi:“MI:0915”(physical association)	0.980
CDC20	MAD2L1	psi-mi:“MI:0915”(physical association)	0.980
CDC20	MAD2L1	psi-mi:“MI:0407”(direct interaction)	0.980
MAD1L1	MAD2L1	psi-mi:“MI:0407”(direct interaction)	0.980
MAD2L1	CDC20	psi-mi:“MI:0407”(direct interaction)	0.980
CDC20	BUB1B	psi-mi:“MI:0914”(association)	0.980
MAD2L1	CDC20	psi-mi:“MI:0914”(association)	0.980
MAD2L1	MAD1L1	psi-mi:“MI:0407”(direct interaction)	0.980
BUB1B	CDC20	psi-mi:“MI:0915”(physical association)	0.980
BUB1B	CDC20	psi-mi:“MI:0914”(association)	0.980
MAD1L1	MAD2L1	psi-mi:“MI:0914”(association)	0.980
MAD1L1	MAD2L1	psi-mi:“MI:0915”(physical association)	0.980

BioGRID (556): MAD2L1 (Reconstituted Complex), SDCBP (Two-hybrid), MAD2L1BP (Two-hybrid), KEAP1 (Two-hybrid), TSC22D4 (Two-hybrid), MAD2L1 (Affinity Capture-Western), MAD2L1 (Affinity Capture-MS), CDC27 (Affinity Capture-Western), CDC20 (Affinity Capture-Western), MAD2L1 (Affinity Capture-Western), MAD2L1 (Affinity Capture-MS), MAD2L1 (Affinity Capture-MS), TSC22D4 (Two-hybrid), MAD1L1 (Two-hybrid), MAD2L1 (Protein-peptide)

ESM2 similar proteins: A0A571BF63, A2BF66, A6QQY4, B0BN28, D3ZWE7, E2QXH7, F6RRD7, O02799, O60566, O70481, O95905, P52630, Q05B18, Q0V7M7, Q13257, Q28IH8, Q2KIY6, Q2TB18, Q3B7T8, Q3U1T9, Q3UB74, Q4R8B9, Q5JTW2, Q5M7C8, Q5PQQ9, Q5RA37, Q5RCY5, Q5SQP1, Q5XGL1, Q5XIZ9, Q6IQY5, Q7T0S7, Q86VD1, Q86VS3, Q86X24, Q8C5W4, Q8CDK3, Q8IWV7, Q8IXW5, Q8N7B1

Diamond homologs: O14417, P40958, Q13257, Q556Y9, Q59VQ3, Q9LU93, Q9XFH3, Q9Z1B5, Q0E7J8, Q28H85, Q8QFR4

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
TPR	up-regulates	MAD2L1	binding
RPS6KA3	“up-regulates activity”	MAD2L1
EIF3E	“down-regulates quantity”	MAD2L1	“translation regulation”
CDK5RAP2	“up-regulates quantity by expression”	MAD2L1	“transcriptional regulation”
MAD2L1	“form complex”	MCC	binding
NEK2	“down-regulates activity”	MAD2L1	phosphorylation
CENPE	“up-regulates activity”	MAD2L1
BUB1	“up-regulates activity”	MAD2L1	relocalization
TTK	“up-regulates activity”	MAD2L1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 96 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	8	84.6×	1e-12
Inactivation of APC/C via direct inhibition of the APC/C complex	8	69.2×	4e-12
APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpoint	9	63.4×	7e-13
Activation of APC/C and APC/C:Cdc20 mediated degradation of mitotic proteins	9	61.2×	8e-13
APC-Cdc20 mediated degradation of Nek2A	8	56.4×	2e-11
Phosphorylation of the APC/C	6	54.4×	2e-08
APC/C:Cdc20 mediated degradation of mitotic proteins	9	53.5×	2e-12
APC/C:Cdc20 mediated degradation of Cyclin B	7	53.3×	9e-10

GO biological processes:

GO term	Partners	Fold	FDR
anaphase-promoting complex-dependent catabolic process	7	62.2×	3e-09
regulation of meiotic cell cycle	6	58.2×	1e-07
mitotic spindle assembly checkpoint signaling	8	56.9×	3e-10
protein branched polyubiquitination	5	53.3×	3e-06
protein K11-linked ubiquitination	5	24.8×	1e-04
regulation of mitotic cell cycle	8	24.4×	2e-07
protein K48-linked ubiquitination	6	12.8×	5e-04
cell division	19	11.1×	3e-12

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	14
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

563 predictions. Top by Δscore:

Variant	Effect	Δscore
4:120060197:T:TA	donor_gain	1.0000
4:120060868:A:AC	donor_gain	1.0000
4:120060869:C:CC	donor_gain	1.0000
4:120060870:TTA:T	donor_loss	1.0000
4:120060871:TACAA:T	donor_loss	1.0000
4:120060872:A:AC	donor_gain	1.0000
4:120060872:A:T	donor_loss	1.0000
4:120060873:C:CA	donor_gain	1.0000
4:120060873:CA:C	donor_gain	1.0000
4:120060873:CAA:C	donor_gain	1.0000
4:120060873:CAAG:C	donor_gain	1.0000
4:120060873:CAAGA:C	donor_gain	1.0000
4:120060882:T:TA	donor_gain	1.0000
4:120060973:GTGCA:G	acceptor_gain	1.0000
4:120060974:TGCA:T	acceptor_gain	1.0000
4:120060975:GCA:G	acceptor_gain	1.0000
4:120060976:CA:C	acceptor_gain	1.0000
4:120060976:CAC:C	acceptor_gain	1.0000
4:120060977:AC:A	acceptor_loss	1.0000
4:120060978:C:A	acceptor_loss	1.0000
4:120060978:C:CC	acceptor_gain	1.0000
4:120060982:C:CT	acceptor_gain	1.0000
4:120060983:A:T	acceptor_gain	1.0000
4:120065817:TG:T	acceptor_gain	1.0000
4:120065819:C:CC	acceptor_gain	1.0000
4:120066660:A:AC	donor_gain	1.0000
4:120066661:C:CC	donor_gain	1.0000
4:120060100:ATTTT:A	donor_gain	0.9900
4:120060104:T:A	donor_gain	0.9900
4:120060158:A:AC	donor_gain	0.9900

AlphaMissense

1327 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:120060237:A:G	W167R	1.000
4:120060237:A:T	W167R	1.000
4:120060909:G:T	A137D	1.000
4:120062016:C:A	W100C	1.000
4:120062016:C:G	W100C	1.000
4:120062018:A:G	W100R	1.000
4:120062018:A:T	W100R	1.000
4:120065789:G:T	R35S	1.000
4:120060144:C:G	A198P	0.999
4:120060173:G:A	T188I	0.999
4:120060188:A:G	L183P	0.999
4:120060235:C:A	W167C	0.999
4:120060235:C:G	W167C	0.999
4:120060275:A:G	L154P	0.999
4:120060894:A:G	L142P	0.999
4:120060894:A:T	L142Q	0.999
4:120060896:A:C	F141L	0.999
4:120060896:A:T	F141L	0.999
4:120060898:A:G	F141L	0.999
4:120060910:C:G	A137P	0.999
4:120060917:C:A	Q134H	0.999
4:120060917:C:G	Q134H	0.999
4:120060920:T:A	R133S	0.999
4:120060920:T:G	R133S	0.999
4:120062010:A:C	F102L	0.999
4:120062010:A:T	F102L	0.999
4:120062011:A:G	F102S	0.999
4:120062012:A:G	F102L	0.999
4:120062017:C:G	W100S	0.999
4:120062074:A:T	V81D	0.999

dbSNP variants (sampled 300 via entrez): RS1000452513 (4:120065360 A>G), RS1000725629 (4:120060677 G>A), RS1000733427 (4:120066869 G>A), RS1000765150 (4:120066980 C>T), RS1000803668 (4:120065917 A>G), RS1001401500 (4:120067022 G>A), RS1001624468 (4:120066536 T>C), RS1001826778 (4:120059989 G>A,T), RS1002055463 (4:120066800 G>A,T), RS1002210171 (4:120059920 C>A,G,T), RS1003091962 (4:120056583 A>G), RS1003188676 (4:120062172 C>G), RS1003289160 (4:120061574 G>A,T), RS1003621917 (4:120064992 G>A), RS1003957995 (4:120064823 CAAT>C)

Disease associations

OMIM: gene MIM:601467 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000982_6	F-cell distribution in sickle cell anaemia	7.000000e-06
GCST001352_13	HIV-1 viral setpoint	6.000000e-06
GCST003773_4	Loneliness (multivariate analysis)	4.000000e-06
GCST004787_33	Coronary artery disease (myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, angina or chromic ischemic heart disease)	1.000000e-08
GCST007990_10	Coronary artery disease	3.000000e-08
GCST010002_14	Refractive error	5.000000e-18
GCST010479_69	Coronary artery disease	2.000000e-08
GCST010866_24	Coronary artery disease	1.000000e-14
GCST011365_91	Myocardial infarction	2.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004576	fetal hemoglobin measurement
EFO:0006319	HIV viral set point measurement
EFO:0007865	loneliness measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, affects localization, decreases expression	5
sodium arsenite	decreases expression, increases expression	4
Cyclosporine	decreases expression	3
Resveratrol	affects cotreatment, increases expression, decreases expression	2
Benzo(a)pyrene	decreases expression	2
Doxorubicin	affects response to substance, decreases expression	2
Fluorouracil	affects expression, decreases expression	2
Tretinoin	decreases expression	2
Cadmium Chloride	affects binding, decreases reaction, increases reaction, decreases expression	2
Particulate Matter	decreases expression, increases abundance	2
afuresertib	decreases expression	1
dicrotophos	decreases expression	1
propionaldehyde	decreases expression	1
geraniol	decreases expression	1
trichostatin A	decreases expression	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
perfluorooctanoic acid	decreases expression	1
sulindac sulfide	decreases expression	1
cadmium acetate	decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
diallyl trisulfide	decreases expression	1
bicalutamide	decreases expression	1
2,3-dimethoxy-1,4-naphthoquinone	increases expression	1
16-hydroxycleroda-3,13(14)-dien-15,16-olide	decreases expression	1
4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole	affects binding, decreases reaction, increases reaction	1
2-palmitoylglycerol	increases expression	1
SC 560	decreases expression	1
K 7174	decreases expression	1
GW 4064	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SW20	HAP1 MAD2L1 (-) 1	Cancer cell line	Male
CVCL_XQ26	HAP1 MAD2L1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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