MKI67

Summary

MKI67 (marker of proliferation Ki-67, HGNC:7107) is a protein-coding gene on chromosome 10q26.2, encoding Proliferation marker protein Ki-67 (P46013). Protein that associates with the surface of mitotic chromosomes and acts both as a chromosome repellent during early mitosis and chromosome attractant during late mitosis.

Enables RNA binding activity and molecular condensate scaffold activity. Involved in chromosome segregation and regulation of mitotic nuclear division. Located in chromosome; nucleolus; and nucleoplasm. Is active in condensed chromosome. Implicated in several diseases, including Crohn’s disease; colorectal cancer; endocrine gland cancer (multiple); graft-versus-host disease; and human immunodeficiency virus infectious disease. Biomarker of several diseases, including Barrett’s esophagus; autoimmune disease of musculoskeletal system (multiple); endocrine gland cancer (multiple); gastrointestinal system cancer (multiple); and lung cancer (multiple).

Source: NCBI Gene 4288 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 594 total — 1 pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002417

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7107
Approved symbol	MKI67
Name	marker of proliferation Ki-67
Location	10q26.2
Locus type	gene with protein product
Status	Approved
Aliases	MIB-1, PPP1R105, Ki-67
Ensembl gene	ENSG00000148773
Ensembl biotype	protein_coding
OMIM	176741
Entrez	4288

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 3 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000368653, ENST00000368654, ENST00000464771, ENST00000478293, ENST00000484853, ENST00000935442

RefSeq mRNA: 2 — MANE Select: NM_002417 NM_001145966, NM_002417

CCDS: CCDS53588, CCDS7659

Canonical transcript exons

ENST00000368654 — 15 exons

Exon	Start	End
ENSE00000987369	128123091	128123169
ENSE00000987370	128122881	128122996
ENSE00000987373	128114928	128116007
ENSE00000987374	128113427	128113602
ENSE00000987375	128112133	128112445
ENSE00000987377	128111645	128111816
ENSE00000987378	128110378	128110533
ENSE00001385972	128096659	128099255
ENSE00001387181	128125576	128125756
ENSE00001447684	128126099	128126423
ENSE00002510572	128101258	128101701
ENSE00002712946	128102579	128109423
ENSE00003516917	128116491	128116536
ENSE00003590971	128119253	128119319
ENSE00003593206	128111927	128112045

Expression profiles

Bgee: expression breadth ubiquitous, 195 present calls, max score 98.10.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.9145 / max 275.9711, expressed in 1394 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
112022	6.9853	1241
112023	6.5723	1133
112004	0.7082	394
112021	0.3024	163
112020	0.1445	48
112024	0.1279	40
112025	0.0739	23

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	98.10	gold quality
ganglionic eminence	UBERON:0004023	94.87	gold quality
embryo	UBERON:0000922	93.36	gold quality
bone marrow cell	CL:0002092	90.68	gold quality
endometrium epithelium	UBERON:0004811	89.96	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.35	gold quality
trabecular bone tissue	UBERON:0002483	89.23	gold quality
bone marrow	UBERON:0002371	89.00	gold quality
cervix squamous epithelium	UBERON:0006922	88.91	silver quality
tendon of biceps brachii	UBERON:0008188	86.75	silver quality
thymus	UBERON:0002370	84.35	gold quality
stromal cell of endometrium	CL:0002255	82.88	gold quality
mucosa of transverse colon	UBERON:0004991	82.45	gold quality
tongue squamous epithelium	UBERON:0006919	81.93	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.81	gold quality
ileal mucosa	UBERON:0000331	81.11	gold quality
cervix epithelium	UBERON:0004801	80.22	silver quality
colonic epithelium	UBERON:0000397	80.16	gold quality
esophagus mucosa	UBERON:0002469	80.09	gold quality
lower esophagus mucosa	UBERON:0035834	80.04	gold quality
rectum	UBERON:0001052	79.84	gold quality
adrenal tissue	UBERON:0018303	79.31	gold quality
vermiform appendix	UBERON:0001154	78.66	gold quality
gingival epithelium	UBERON:0001949	78.44	silver quality
cartilage tissue	UBERON:0002418	78.19	gold quality
lymph node	UBERON:0000029	78.13	gold quality
oral cavity	UBERON:0000167	77.65	gold quality
squamous epithelium	UBERON:0006914	77.57	gold quality
gingiva	UBERON:0001828	77.08	gold quality
caecum	UBERON:0001153	77.06	gold quality

Single-cell (SCXA)

Detected in 45 experiment(s), a significant marker in 40.

Experiment	Marker?	Max mean expression
E-GEOD-150728	yes	2478.08
E-CURD-79	yes	1989.27
E-GEOD-75140	yes	1403.28
E-MTAB-8894	yes	1385.87
E-MTAB-11121	yes	1134.82
E-MTAB-8559	yes	1081.00
E-MTAB-10485	yes	907.51
E-MTAB-6911	yes	877.33
E-HCAD-56	yes	860.30
E-HCAD-6	yes	756.54
E-MTAB-9067	yes	744.77
E-HCAD-5	yes	743.38
E-MTAB-6308	yes	740.35
E-MTAB-8410	yes	668.56
E-MTAB-10662	yes	652.99

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F4, GJA1, IMPDH2, IRF1, MITF, PRDM1, SATB1, SOX2, SP1, TP53

miRNA regulators (miRDB)

99 targeting MKI67, 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-4673	100.00	66.64	1490
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488
HSA-MIR-548Y	99.94	71.28	3514
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-515-5P	99.92	69.82	2343

Literature-anchored findings (GeneRIF, showing 40)

• There is no significant correlation between Ki-67 labelling index and tumor size of anterior pituitary adenomas, even if this index can be considered a useful marker in the determination of the infiltrative behavior of these tumors. (PMID:11570981)
• Not significantly correlated with lymph node metastasis of breast invasive ductal carcinoma. (PMID:11744991)
• Use of tissue microarray technique shows immunohistochemical tumor heterogeneity in expression levels of Ki-67 in malignant fibrous histiocytoma cells. (PMID:11759064)
• Ki-67 antigen overexpressioin is an early event in esophageal carcinogenesis and useful biomarkers for early detection. (PMID:11783017)
• patients that progressed to breast cancer showed significantly higher Ki-67 expression in their HUT (hyperplasia of usual type)foci compared with controls (PMID:11839580)
• overexpression may be marker of radioresistance in head and neck cancer (PMID:11857304)
• Results indicate that loss of RAR-beta expression and accumulation of p 53 and Ki67 proteins may serve as biomarkers for early identification of esophageal cancer in the high-risk populations. (PMID:11925591)
• The combined evaluation of p27Kip1 and Ki-67 expression provides independent information on overall survival of ovarian carcinoma patients. (PMID:12051866)
• presence in CNS tumors correlates with histological type and grade (PMID:12125971)
• This marker is masked to MIB-1 staining after expression of its tandem repeats. (PMID:12432453)
• p53 and Ki-67 expression in epithelial gastric dysplasia and in gastric cancer. (PMID:12434121)
• Increase of CD44s, MMP-9, and Ki-67 were involved in the growth and local invasion of osteosarcoma. (PMID:12479099)
• Data suggest that marsupial chmadrin and human Ki-67 induce chromatin compaction across species, possibly via the interaction of its LR domain with heterochromatin protein 1. (PMID:12485163)
• No relationship was observed between Ki-67 staining & the E-cadherin mutation status. The presence of E-cadherin mutations does not correlate with Ki-67 staining. (PMID:12532420)
• increased p53 and Ki-67 expression in varying grades of urothelial dysplasia of bladder (PMID:12607601)
• Ki-67 proved to be a better prognostic marker, as compared to metallothionein, in large intestine adenocarcinomas (PMID:12647790)
• Ki-67 antigen reactivity was significantly higher in the patient with laryngeal carcinoma remission, compared with the control group. (PMID:12649825)
• a biological marker in Langerhans cell histiocytosis (PMID:12716386)
• distribution of staining pattern for Ki-67 paralleled the staining pattern of 34-betaE12 (PMID:14582704)
• Detected in nuclei of neoplastic cells and in nuclei of epithelial cells in adjacent colonic mucosa. (PMID:14627346)
• nmr analysis of the solution structure of the FHA domain of human Ki67 and mapping of the binding surface for NIFK binding (PMID:14659764)
• compared the expression of Ki-67 between primary breast tumors and metastasis to regional lymph nodes; estimated the relationships between Ki-67 and the anatomoclinical features of the breast cancer (PMID:14674120)
• The expression of Ki67 and p53 in various forms of leukoplakia point to the increasing instability of the genome in parallel with the severity of leukoplakia. (PMID:14707453)
• Mutations in the cDNA of the proliferation marker Ki-67 protein is associated with cervix, colonic and lung neoplasms (PMID:15104289)
• study expands the immunophenotype of granular cell tumor (S100, CD68, protein gene product 9.5, and inhibin-alpha) regardless of location and supports a neural origin (PMID:15214825)
• Ki-67 may have a role in distant metastasis of radiotherapy-treated prostate neoplasms (PMID:15217948)
• Ki-67 LI (labeling index) is a useful prognosticator for PENs (pancreatic endocrine neoplasms). (PMID:15452376)
• Ki-67 is a factor of poor prognosis for survival in NSCLC. (PMID:15545971)
• ER alpha and Ki67 might be involved in distinct pathological and molecular features during breast cancer development (PMID:15591788)
• Expression correlates with intensity of apoptosis in colorectal adenocarcinoma. (PMID:15638357)
• Expression of Ki-67, PCNA proteins were closely connected with the high grade of stomach tumour malignancy. (PMID:15638377)
• Evaluation of expression of PCNA and Ki-67 may provide an additional information about the progression of uveal melanoma. (PMID:15638382)
• Ki-67 and hTERT have roles in meningioma cell proliferation, but only hTERT has a role in disease recurrence (PMID:15679862)
• a useful msarkser in patients with lung adenocarcinoma. (PMID:15809747)
• Ki-67 by itself is a less reliable marker of dysplasia. (PMID:15871722)
• Altered expression is associated with therapy failure and death in patients with multiple types of cancer. (PMID:15931389)
• Study suggests that the clinical characteristics such as visual field defect and recurrence are correlated with the high Ki-67 labeling index. (PMID:15953875)
• Proliferative activity of 13 biopsy specimens of Kaposi sarcoma was assessed immunohistochemically using the monoclonal antibody to KI-67. (PMID:15964376)
• Aberrant proliferative patterns with Ki67 staining are not useful in differentiating reactive epithelia from low-grade dysplasia, but may prove useful in the diagnosis of high-grade dysplasia. (PMID:16045773)
• p27(kip1) and Ki-67 have roles in post-surgical disease progression of prostate cancer (PMID:16097446)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mki67	ENSDARG00000091150
mus_musculus	Mki67	ENSMUSG00000031004
rattus_norvegicus	Mki67	ENSRNOG00000028137

Paralogs (1): CDCA2 (ENSG00000184661)

Protein

Protein identifiers

Proliferation marker protein Ki-67 — P46013 (reviewed: P46013)

Alternative names: Antigen identified by monoclonal antibody Ki-67

All UniProt accessions (1): P46013

UniProt curated annotations — full annotation on UniProt →

Function. Protein that associates with the surface of mitotic chromosomes and acts both as a chromosome repellent during early mitosis and chromosome attractant during late mitosis. Required to maintain individual mitotic chromosomes dispersed in the cytoplasm following nuclear envelope disassembly. During early mitosis, relocalizes from nucleoli to the chromosome surface where it forms extended brush structures that cover a substantial fraction of the chromosome surface. The MKI67 brush structure prevents chromosomes from collapsing into a single chromatin mass by forming a steric and electrostatic charge barrier: the protein has a high net electrical charge and acts as a surfactant, dispersing chromosomes and enabling independent chromosome motility. During mitotic anaphase, the MKI67 brush structure collapses and MKI67 switches from a chromosome repellent to a chromosome attractant to promote chromosome clustering and facilitate the exclusion of large cytoplasmic particles from the future nuclear space. Mechanistically, dephosphorylation during mitotic exit and simultaneous exposure of a conserved basic patch induce the RNA-dependent formation of a liquid-like condensed phase on the chromosome surface, promoting coalescence of neighboring chromosome surfaces and clustering of chromosomes. Binds premature ribosomal RNAs during anaphase; promoting liquid-liquid phase separation. Binds DNA, with a preference for supercoiled DNA and AT-rich DNA. Does not contribute to the internal structure of mitotic chromosomes. May play a role in chromatin organization; it is however unclear whether it plays a direct role in chromatin organization or whether it is an indirect consequence of its function in mitotic chromosome.

Subunit / interactions. Interacts with KIF15. Interacts (via the FHA domain) with NIFK. Interacts with PPP1CC. Component of a complex at least composed of ZNF335, HCFC1, CCAR2, EMSY, MKI67, RBBP5, ASH2L and WDR5; the complex is formed as a result of interactions between components of a nuclear receptor-mediated transcription complex and a histone methylation complex. Interacts with ZNF335.

Subcellular location. Chromosome. Nucleus. Nucleolus.

Post-translational modifications. Hyperphosphorylated by CDK1 in mitosis; hyperphosphorylatiom prevents undergoing liquid-liquid phase separation. Dephosphorylated by PPP1CC at the onset of anaphase. Dephosphorylated by protein phosphatase 2A (PP2A) at the onset of anaphase. Dephosphorylation by protein phosphatase 2A (PP2A) and simultaneous exposure of the positively charged patch (CP) during mitotic exit induce the RNA-dependent formation of a liquid-like condensed phase on the chromosome surface. Ubiquitinated by the APC/C complex after neuronal progenitors exit mitosis during brain development, leading to clearance from constitutive heterochromatin.

Domain organisation. The positively charged patch (CP) region mediates liquid-liquid phase separation.

Isoforms (2)

UniProt ID	Names	Canonical?
P46013-1	Long	yes
P46013-2	Short

RefSeq proteins (2): NP_001139438, NP_002408* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000253	FHA_dom	Domain
IPR008984	SMAD_FHA_dom_sf	Homologous_superfamily
IPR012568	KI67R	Repeat
IPR029334	PP1-bd	Domain

Pfam: PF00498, PF08065, PF15276

UniProt features (279 total): modified residue 121, compositionally biased region 39, sequence variant 35, region of interest 24, cross-link 22, repeat 16, strand 11, sequence conflict 4, domain 2, mutagenesis site 2, chain 1, splice variant 1, binding site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
5J28	X-RAY DIFFRACTION	2
1R21	SOLUTION NMR
2AFF	SOLUTION NMR

Predicted structure (AlphaFold)

No AlphaFold model available for P46013 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

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

Ligand- & substrate-binding residues (1): 3034–3041

Post-translational modifications (143): 648, 761, 859, 1017, 1071, 1091, 1098, 1111, 1131, 1139, 1142, 1167, 1169, 1176, 1193, 1207, 1233, 1253, 1256, 1261 …

Mutagenesis-validated functional residues (2):

Position	Phenotype
502–678	abolished ability to undergo liquid-liquid phase separation.
506–508	abolihed binding with ppp1cc; induces a slight delay in mki67 enrichment on chromosomes.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 408 (showing top): WU_APOPTOSIS_BY_CDKN1A_VIA_TP53, HORIUCHI_WTAP_TARGETS_DN, MODULE_451, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, KANG_DOXORUBICIN_RESISTANCE_UP, GNF2_CENPF, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_REGULATION_OF_NUCLEAR_DIVISION, PAL_PRMT5_TARGETS_UP, CROONQUIST_NRAS_SIGNALING_DN, MORF_BRCA1, GEORGES_CELL_CYCLE_MIR192_TARGETS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, JOHANSSON_GLIOMAGENESIS_BY_PDGFB_UP, MITSIADES_RESPONSE_TO_APLIDIN_DN

GO Biological Process (4): chromosome segregation (GO:0007059), regulation of mitotic nuclear division (GO:0007088), cell population proliferation (GO:0008283), regulation of chromatin organization (GO:1902275)

GO Molecular Function (6): DNA binding (GO:0003677), RNA binding (GO:0003723), ATP binding (GO:0005524), molecular condensate scaffold activity (GO:0140693), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (6): condensed chromosome (GO:0000793), nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), nucleolus (GO:0005730), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nucleic acid binding	2
nuclear lumen	2
cellular anatomical structure	2
intracellular membraneless organelle	2
cell cycle process	1
regulation of mitotic cell cycle	1
regulation of cell cycle process	1
regulation of nuclear division	1
mitotic nuclear division	1
cellular process	1
chromatin organization	1
regulation of cellular component organization	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein-macromolecule adaptor activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

3748 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MKI67	NIFK	Q9BYG3	856
MKI67	TOP2A	P11388	845
MKI67	GTPBP10	A4D1E9	840
MKI67	RRP1	P56182	763
MKI67	CENPF	P49454	727
MKI67	RRM2	P31350	708
MKI67	AURKA	O14965	700
MKI67	TPX2	Q9ULW0	687
MKI67	BIRC5	O15392	684
MKI67	CCNB2	O95067	679
MKI67	CCND1	P24385	671
MKI67	NUSAP1	Q9BXS6	665
MKI67	BUB1	O43683	653
MKI67	BCL2	P10415	642
MKI67	PGR	P06401	636

IntAct

200 interactions, top by confidence:

A	B	Type	Score
MKI67	NIFK	psi-mi:“MI:0407”(direct interaction)	0.750
MKI67	NIFK	psi-mi:“MI:0915”(physical association)	0.750
PPP1CC	CCDC85C	psi-mi:“MI:0914”(association)	0.740
PPP1CC	CCDC85C	psi-mi:“MI:2364”(proximity)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PPP1CA	CCDC85C	psi-mi:“MI:0914”(association)	0.670
TOP1	HNRNPR	psi-mi:“MI:0914”(association)	0.600
TBK1	TTC4	psi-mi:“MI:0914”(association)	0.540
MKI67	KIF15	psi-mi:“MI:0915”(physical association)	0.530
KIF15	MKI67	psi-mi:“MI:0407”(direct interaction)	0.530
N	RBM47	psi-mi:“MI:0914”(association)	0.530
KSR2	POLR3A	psi-mi:“MI:0914”(association)	0.530
GRK7	HSP90AA1	psi-mi:“MI:0914”(association)	0.530
LTBR	ZNF724	psi-mi:“MI:0914”(association)	0.530
LRRK2	DFFA	psi-mi:“MI:0914”(association)	0.530
MKI67	ZC3H11A	psi-mi:“MI:0914”(association)	0.480
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
ZNF335	MKI67	psi-mi:“MI:0914”(association)	0.460
ESR1		psi-mi:“MI:0914”(association)	0.460
ESR2	FBLL1	psi-mi:“MI:0914”(association)	0.460
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410

BioGRID (765): MKI67 (Affinity Capture-MS), MKI67 (Affinity Capture-MS), MKI67 (Affinity Capture-MS), MKI67 (Affinity Capture-MS), MKI67 (Reconstituted Complex), MKI67 (Affinity Capture-MS), MKI67 (Affinity Capture-MS), MKI67 (Affinity Capture-MS), MKI67 (Affinity Capture-MS), MKI67 (Affinity Capture-MS), PPIB (Co-fractionation), MKI67 (Affinity Capture-MS), Cbx1 (Two-hybrid), Cbx3 (Two-hybrid), Cbx5 (Two-hybrid)

ESM2 similar proteins: A0A087WXM9, A0A2K1JJ00, A0JM83, A4IGL8, E1BC15, E9Q5F9, O14513, O35923, O60673, O88491, P46013, P97929, Q14B71, Q28DZ0, Q29RT4, Q3MHH3, Q3TNU4, Q3ZBP0, Q4QY64, Q4V7J0, Q5DTT3, Q5E9A0, Q5F2C3, Q5RD08, Q5VWN6, Q5VYV7, Q61493, Q69YH5, Q6NS59, Q703I1, Q80U59, Q86XD8, Q8IXS0, Q8IYL3, Q8L7I1, Q8N7Z5, Q8NFU7, Q8TEP8, Q92628, Q96BU1

Diamond homologs: E9PVX6, P46013, Q14B71, Q29RT4, Q69YH5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
IMPDH2	“up-regulates quantity by expression”	MKI67	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 231 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
SARS-CoV-1 modulates host translation machinery	6	11.9×	7e-04
Eukaryotic Translation Initiation	5	10.0×	4e-03
Cap-dependent Translation Initiation	5	10.0×	4e-03
Formation of the ternary complex, and subsequently, the 43S complex	7	9.7×	6e-04
SARS-CoV-1-host interactions	8	9.1×	3e-04
Nonsense-Mediated Decay (NMD)	6	9.0×	2e-03
Eukaryotic Translation Elongation	5	9.0×	5e-03
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	5	8.8×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
activation of innate immune response	6	14.3×	7e-04
ribosomal large subunit biogenesis	5	11.0×	8e-03
positive regulation of protein import into nucleus	5	10.4×	1e-02
mRNA transport	7	9.1×	2e-03
ribosomal small subunit biogenesis	8	9.0×	7e-04
regulation of alternative mRNA splicing, via spliceosome	7	8.5×	3e-03
cytoplasmic translation	9	8.2×	5e-04
rRNA processing	10	7.0×	5e-04

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	481
Likely benign	66
Benign	25

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
59707	GRCh38/hg38 10q24.31-26.3(chr10:100194215-132432797)x3	Pathogenic

SpliceAI

2221 predictions. Top by Δscore:

Variant	Effect	Δscore
10:128110376:A:AC	donor_gain	1.0000
10:128110377:C:CC	donor_gain	1.0000
10:128110386:T:A	donor_gain	1.0000
10:128110412:T:TA	donor_gain	1.0000
10:128110424:T:A	donor_gain	1.0000
10:128110529:TATTC:T	acceptor_gain	1.0000
10:128110531:TTC:T	acceptor_gain	1.0000
10:128110531:TTCC:T	acceptor_loss	1.0000
10:128110532:TC:T	acceptor_gain	1.0000
10:128110533:CC:C	acceptor_gain	1.0000
10:128110533:CCTGT:C	acceptor_loss	1.0000
10:128110534:C:CC	acceptor_gain	1.0000
10:128114926:A:AC	donor_gain	1.0000
10:128114927:C:CC	donor_gain	1.0000
10:128116020:T:C	acceptor_gain	1.0000
10:128116020:T:TC	acceptor_gain	1.0000
10:128116022:A:AC	acceptor_gain	1.0000
10:128116022:A:C	acceptor_gain	1.0000
10:128116483:CTACT:C	donor_loss	1.0000
10:128116487:TCA:T	donor_loss	1.0000
10:128116488:CA:C	donor_loss	1.0000
10:128116489:ACCAG:A	donor_loss	1.0000
10:128116534:CTC:C	acceptor_gain	1.0000
10:128116535:TC:T	acceptor_gain	1.0000
10:128116535:TCC:T	acceptor_loss	1.0000
10:128116536:CC:C	acceptor_gain	1.0000
10:128116536:CCTG:C	acceptor_loss	1.0000
10:128116537:C:CC	acceptor_gain	1.0000
10:128116537:C:CG	acceptor_loss	1.0000
10:128116538:T:A	acceptor_loss	1.0000

AlphaMissense

21302 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:128112034:A:G	W661R	0.998
10:128112034:A:T	W661R	0.998
10:128112032:C:A	W661C	0.997
10:128112032:C:G	W661C	0.997
10:128112138:A:G	L655P	0.997
10:128113559:A:C	F508L	0.997
10:128113559:A:T	F508L	0.997
10:128113561:A:G	F508L	0.997
10:128113532:A:C	F517L	0.995
10:128113532:A:T	F517L	0.995
10:128113534:A:G	F517L	0.995
10:128123115:G:C	C49W	0.995
10:128122884:A:G	F95S	0.994
10:128112045:A:T	V657D	0.993
10:128122883:G:C	F95L	0.993
10:128122883:G:T	F95L	0.993
10:128122885:A:G	F95L	0.993
10:128122890:C:G	R93P	0.993
10:128122905:A:T	I88K	0.993
10:128123117:A:G	C49R	0.993
10:128122989:A:G	L60S	0.992
10:128123159:A:G	C35R	0.992
10:128123140:A:G	L41P	0.991
10:128123149:C:G	R38P	0.990
10:128111755:A:T	I717K	0.989
10:128122905:A:G	I88T	0.989
10:128123116:C:T	C49Y	0.989
10:128112033:C:G	W661S	0.988
10:128112164:T:A	R646S	0.988
10:128112164:T:G	R646S	0.988

dbSNP variants (sampled 300 via entrez): RS1000336206 (10:128120515 A>G), RS1000512453 (10:128114183 C>T), RS1000562547 (10:128117614 G>T), RS1000565458 (10:128113305 G>A), RS1000578125 (10:128099021 C>A), RS1000631876 (10:128099303 A>G), RS1000864770 (10:128102288 T>A,C), RS1000929334 (10:128125908 C>G), RS1000954234 (10:128113157 T>C,G), RS1001130582 (10:128108353 G>A), RS1001384626 (10:128125553 C>A,T), RS1001456012 (10:128121145 A>C), RS1001642472 (10:128100600 A>C,G), RS1001708431 (10:128104371 T>C), RS1001727825 (10:128121545 TTA>T)

Disease associations

OMIM: gene MIM:176741 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): long QT syndrome (MONDO:0002442)

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000083_2	Select biomarker traits	1.000000e-06
GCST002817_24	Alzheimer’s disease in APOE e4- carriers	8.000000e-06
GCST002935_26	Lead levels	9.000000e-06
GCST007630_5	Drug experimentation measurement	2.000000e-06
GCST009615_12	Triglyceride levels x loop diuretics use interaction	5.000000e-07
GCST012279_9	Suicide attempt severity in mood disorders	6.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004618	vitamin K measurement
EFO:0007010	drug use measurement
EFO:0004530	triglyceride measurement
EFO:0006882	suicide behaviour measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066170 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.40	Kd	39.91	nM	CHEMBL5653589
7.40	ED50	39.91	nM	CHEMBL5653589
5.61	IC50	2440	nM	MOLIBRESIB
5.33	Kd	4640	nM	CHEMBL3752910
5.33	ED50	4640	nM	CHEMBL3752910

PubChem BioAssay actives

3 with measured affinity, of 10 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148752: Binding affinity to human MKI67 incubated for 45 mins by Kinobead based pull down assay	kd	0.0399	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178533: Inhibition of MKI67 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	2.4400	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148752: Binding affinity to human MKI67 incubated for 45 mins by Kinobead based pull down assay	kd	4.6404	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects cotreatment, decreases expression, increases expression, affects localization, affects reaction	9
palbociclib	affects reaction, decreases expression, increases reaction	7
sodium arsenite	affects expression, decreases expression, affects cotreatment, increases abundance, increases expression	6
Fluorouracil	decreases expression, affects response to substance	6
Tobacco Smoke Pollution	increases methylation, affects expression, decreases expression, increases expression	6
Doxorubicin	decreases expression, increases reaction, affects cotreatment	5
Estradiol	affects cotreatment, increases expression, decreases reaction	5
Tamoxifen	affects cotreatment, decreases expression, increases expression	5
Cyclosporine	decreases expression	5
Cadmium Chloride	increases expression, decreases expression, affects expression, increases abundance	5
Copper	affects cotreatment, increases abundance, increases expression, decreases expression, increases reaction (+1 more)	4
methylmercuric chloride	increases expression, affects cotreatment	3
bisphenol A	decreases reaction, affects expression, decreases expression	3
cobaltous chloride	affects cotreatment, increases expression, decreases expression, decreases reaction	3
perfluorooctanoic acid	affects cotreatment, increases expression, decreases expression	3
perfluorooctane sulfonic acid	affects cotreatment, increases expression, decreases expression	3
Arsenic Trioxide	decreases expression, decreases reaction, increases reaction	3
Arsenic	affects cotreatment, increases expression, increases abundance, decreases expression	3
Cadmium	affects expression, increases abundance, decreases expression	3
Cisplatin	affects cotreatment, decreases expression, increases reaction	3
Curcumin	decreases expression	3
Quercetin	affects cotreatment, decreases expression, affects phosphorylation, increases expression	3
Tretinoin	decreases expression	3
Aflatoxin B1	affects expression, decreases expression, increases expression	3
Particulate Matter	increases abundance, increases expression, decreases expression, decreases reaction	3
lasiocarpine	affects cotreatment, decreases expression, increases expression	2
1,12-benzoperylene	decreases expression, increases expression, decreases reaction	2
deoxynivalenol	increases expression	2
titanium dioxide	decreases expression, increases expression, affects binding	2
trichostatin A	affects expression, decreases expression	2

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651794	Binding	Binding affinity to human MKI67 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

10 cell lines: 10 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1X5	Abcam HeLa MKI67 KO	Cancer cell line	Female
CVCL_B8KJ	Abcam HCT 116 MKI67 KO	Cancer cell line	Male
CVCL_B9MT	Abcam A-549 MKI67 KO	Cancer cell line	Male
CVCL_D2GF	Abcam MCF-7 MKI67 KO	Cancer cell line	Female
CVCL_E0I3	Ubigene HeLa MKI67 KO	Cancer cell line	Female
CVCL_E2CH	HAP1 MKI67 (-) 5	Cancer cell line	Male
CVCL_SY43	HAP1 MKI67 (-) 1	Cancer cell line	Male
CVCL_SY44	HAP1 MKI67 (-) 2	Cancer cell line	Male
CVCL_SY45	HAP1 MKI67 (-) 3	Cancer cell line	Male
CVCL_SY46	HAP1 MKI67 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02425189	Not specified	COMPLETED	The Canadian National Long QT Syndrome Registry
NCT02439645	Not specified	TERMINATED	A Registry to Determine the Clinical and Genetic Risk Factors for Torsade De Pointes
NCT02439658	Not specified	UNKNOWN	Genetics of QT Prolongation With Antiarrhythmics
NCT02549664	Not specified	COMPLETED	Exercise in Genetic Cardiovascular Conditions
NCT02581241	Not specified	COMPLETED	Abnormal QT-Response to the Sudden Tachycardia Provoked by Standing in Individuals With Drug-induced Long QT Syndrome
NCT02680080	Not specified	COMPLETED	Effect of Grapefruit on QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome
NCT02775513	Not specified	UNKNOWN	Metabolism of Patients With Genetically Caused Cardiac Arrhythmia
NCT02814981	Not specified	UNKNOWN	Hydroxyzine and Risk of Prolongation of QT Interval
NCT02876380	Not specified	COMPLETED	Prospective Identification of Long QT Syndrome in Fetal Life
NCT03182777	Not specified	COMPLETED	Safety of Local Dental Anesthesia in Patients With Cardiac Channelopathies
NCT03544918	Not specified	COMPLETED	Prevalence of Congenital Long QT Syndrome and Acquired QT Prolongation in a Hospital Cohort
NCT03642405	Not specified	UNKNOWN	Drug-induced Repolarization ECG Changes
NCT03678311	Not specified	COMPLETED	Long QT Syndrome and Sleep Apnea