KIF4A

Summary

KIF4A (kinesin family member 4A, HGNC:13339) is a protein-coding gene on chromosome Xq13.1, encoding Chromosome-associated kinesin KIF4A (O95239). Iron-sulfur (Fe-S) cluster binding motor protein that has a role in chromosome segregation during mitosis. It is a selective cancer dependency (DepMap: 61.7% of cell lines).

This gene encodes a member of the kinesin 4 subfamily of kinesin related proteins. The encoded protein is an ATP dependent microtubule-based motor protein that is involved in the intracellular transport of membranous organelles. This protein also associates with condensed chromosome arms and may be involved in maintaining chromosome integrity during mitosis. This protein may also be involved in the organization of the central spindle prior to cytokinesis. A pseudogene of this gene is found on chromosome X.

Source: NCBI Gene 24137 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability, X-linked 100 (Strong, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 338 total — 6 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 6
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 61.7% of screened cell lines
• MANE Select transcript: NM_012310

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13339
Approved symbol	KIF4A
Name	kinesin family member 4A
Location	Xq13.1
Locus type	gene with protein product
Status	Approved
Aliases	KIF4-G1, KIF4, HSA271784, FLJ12530, FLJ12655, FLJ14204, FLJ20631, MRX100
Ensembl gene	ENSG00000090889
Ensembl biotype	protein_coding
OMIM	300521
Entrez	24137

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 13 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000374403, ENST00000485406, ENST00000859344, ENST00000859345, ENST00000859346, ENST00000924308, ENST00000924309, ENST00000924310, ENST00000924311, ENST00000924312, ENST00000924313, ENST00000924314, ENST00000924315, ENST00000924316

RefSeq mRNA: 1 — MANE Select: NM_012310 NM_012310

CCDS: CCDS14401

Canonical transcript exons

ENST00000374403 — 31 exons

Exon	Start	End
ENSE00000672202	70419661	70419783
ENSE00000672204	70417888	70418004
ENSE00000672236	70406893	70407075
ENSE00000672237	70406259	70406354
ENSE00000672238	70405828	70405905
ENSE00000672239	70404715	70404822
ENSE00000672240	70403864	70404034
ENSE00000672241	70402566	70402695
ENSE00000672256	70376100	70376210
ENSE00000672258	70375204	70375348
ENSE00000672260	70374151	70374254
ENSE00000672261	70353622	70353807
ENSE00000672262	70352600	70352656
ENSE00000672263	70343877	70343982
ENSE00000672264	70343703	70343761
ENSE00000672265	70341799	70341931
ENSE00000672266	70333628	70333689
ENSE00000672267	70330157	70330332
ENSE00000672275	70329405	70329521
ENSE00000672278	70302304	70302398
ENSE00000672280	70301900	70302066
ENSE00000815653	70395949	70396049
ENSE00000815654	70395671	70395826
ENSE00000815655	70387184	70387297
ENSE00000815656	70386618	70386701
ENSE00000815660	70299113	70299202
ENSE00001421111	70420062	70420886
ENSE00001958990	70290104	70290150
ENSE00003487419	70290438	70290578
ENSE00003504635	70296998	70297188
ENSE00003673760	70290691	70290805

Expression profiles

Bgee: expression breadth ubiquitous, 179 present calls, max score 96.22.

FANTOM5 (CAGE): breadth broad, TPM avg 2.2291 / max 39.0389, expressed in 865 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196621	1.5298	728
196620	0.6993	444

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	96.22	gold quality
secondary oocyte	CL:0000655	96.14	gold quality
ventricular zone	UBERON:0003053	94.34	gold quality
ganglionic eminence	UBERON:0004023	87.16	gold quality
embryo	UBERON:0000922	86.47	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.23	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.57	gold quality
bone marrow	UBERON:0002371	77.98	gold quality
trabecular bone tissue	UBERON:0002483	77.25	gold quality
stromal cell of endometrium	CL:0002255	76.84	gold quality
mucosa of transverse colon	UBERON:0004991	76.20	gold quality
rectum	UBERON:0001052	73.77	gold quality
bone marrow cell	CL:0002092	73.04	gold quality
thymus	UBERON:0002370	71.94	gold quality
vermiform appendix	UBERON:0001154	70.06	gold quality
esophagus mucosa	UBERON:0002469	69.90	gold quality
lower esophagus mucosa	UBERON:0035834	68.02	gold quality
adrenal tissue	UBERON:0018303	67.33	gold quality
caecum	UBERON:0001153	66.82	gold quality
lymph node	UBERON:0000029	66.50	gold quality
esophagus squamous epithelium	UBERON:0006920	66.09	silver quality
amniotic fluid	UBERON:0000173	65.79	gold quality
duodenum	UBERON:0002114	64.77	gold quality
gingival epithelium	UBERON:0001949	64.76	silver quality
placenta	UBERON:0001987	64.27	gold quality
ileal mucosa	UBERON:0000331	64.19	gold quality
squamous epithelium	UBERON:0006914	64.03	silver quality
oviduct epithelium	UBERON:0004804	63.93	gold quality
epithelium of esophagus	UBERON:0001976	63.92	silver quality
endometrium	UBERON:0001295	63.51	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.76
E-GEOD-99795	no	181.94

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PARP1

miRNA regulators (miRDB)

44 targeting KIF4A, 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-6873-3P	100.00	71.42	2626
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-510-3P	99.54	70.06	2965
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-3127-3P	98.94	67.34	1055
HSA-MIR-6756-3P	98.94	66.79	1104
HSA-MIR-421	98.90	67.04	1883
HSA-MIR-4451	98.82	68.17	1455
HSA-MIR-767-3P	98.61	67.69	1192
HSA-MIR-1178-3P	98.57	67.09	890

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 61.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Results demonstrating association of KIF4 with BRAF35 through the interaction of their respective alpha-helical coiled-coil domains is unique so far in mammals. (PMID:12809554)
• These results suggest that KIF4 is involved in cytokinesis, although direct evidence was not provided in this study. (PMID:15031677)
• KIF4 and its binding partner protein regulator of cytokinesis 1 play essential roles in the organization of central spindles and midzone formation (PMID:15297875)
• Human KIF4A is an essential chromosome-associated molecular motor involved in faithful chromosome segregation. HKIF4A localizes in the nucleoplasm during interphase and on condensed chromosome arms during mitosis. (PMID:15326200)
• role of PRC1 in midzone formation, indicate that cell cycle-dependent translocation of PRC1 by Kif4 is essential for midzone formation and cytokinesis. (PMID:15625105)
• Zip1 and CR motifs are important for Kif4A chromatin-binding and its mitotic function. (PMID:18502200)
• results suggest a novel role for a chromokinesin family member Kif4 in the DNA damage response by modulating the BRCA2/Rad51 pathway (PMID:18604178)
• These studies identify a novel transit station through which Gag traffics en route to particle assembly and highlight the importance of KIF4 in regulating HIV-1 Gag trafficking and stability. (PMID:18684836)
• Loss of KIF4 expression is associated with gastric carcinoma. (PMID:20711700)
• KIF4 regulates midzone length during cytokinesis. (PMID:21565503)
• Abeta impairs the assembly and maintenance of the mitotic spindle. Mechanistically, these defects result from Abeta’s inhibition of mitotic motor kinesins, including Eg5, KIF4A and MCAK. (PMID:21566458)
• Studies reveal how interactions between the conserved nonmotor MAP, PRC1, and the motor protein, kinesin-4, generate filament length-dependent tags at microtubule plus ends. PRC1 tags ends of microtubules in dividing cells and the size of these tags increases linearly with filament length. (PMID:23870126)
• The KIF4A phosphorylation by Aurora B stimulates the maximal microtubule-dependent ATPase activity of KIF4A and promotes its interaction with PRC1. (PMID:23940115)
• KIF4A might be a key regulator for tumoral progression in OSCCs. (PMID:24386490)
• Genetic association of KIF4A and KIF5C mutations in intellectual disability and synaptic function. (PMID:24812067)
• KIF4A and PP2A-B56G and -B56E create a spatially restricted negative feedback loop counteracting Aurora B in anaphase. (PMID:25512391)
• Hepatitis B virus activates the KIF4A gene promoter and upregulates the mRNA and protein expression of KIF4A. (PMID:25998931)
• Chromokinesin represents a kinesin superfamily regulating cell division through chromosome and spindle. (Review) (PMID:27196062)
• Neither KIF4A nor condensin I alone can sufficiently accumulate on the chromosomal axis and confer physiological properties to chromosomes, thus establishing that the functions of KIF4A and condensin I are inseparable (PMID:27633014)
• High KIF4A expression is associated with lung cancer. (PMID:28160558)
• This work identified KIF4A as a potential predictive and prognostic marker for hepatocellular carcinoma. (PMID:28646197)
• decrease in Aurora B results in diminished binding of the chromokinesin Kif4A to chromosome arms. (PMID:28821562)
• AMPK and Aurora B competitively phosphoregulate KIF4A during mitotic phase due to overlapping recognition motifs, resulting in the elaborate phosphoregulation for KIF4A-dependent central spindle length control. (PMID:28992084)
• KIF4A promotes drug resistance of lung adenocarcinoma cells through transporting LRP-based vaults along microtubules towards the cell membrane (PMID:29204984)
• KIF4A may act as a prognostic biomarker and potential therapeutic target in human Hepatocellular carcinoma. (PMID:29396392)
• these findings not only demonstrate that KIF4A contributes to colorectal carcinoma proliferation via modulation of p21-mediated cell cycle progression but also suggest the potential value of KIF4A as a clinical prognostic marker and target for molecular treatments. (PMID:29706624)
• Phosphorylated Kif4A (Kif4AWT) or Cdk phospho-mimetic Kif4A mutant (Kif4ATE) associated with chromosomes and condensin I (non-SMC subunit CAP-G and core subunit SMC2) to regulate chromosome condensation, spindle morphology, and chromosome congression/alignment in early mitosis. (PMID:29771379)
• Here, the authors show that the collective activity of PRC1 and Kif4A results in relative microtubule sliding and concurrent end-tag formation on antiparallel microtubules. (PMID:30353849)
• The chromokinesin KIF4A as a novel modulator of cisplatin sensitivity. (PMID:30417376)
• our novel results revealed that Cdk1-dependent KIF4A phosphorylation at S1186 is a trigger for chromosomal organization during early mitosis. (PMID:30576375)
• The results revealed that circKIF4A and KIF4A could bind to miR-375 and that circKIF4A regulated the expression of KIF4A via sponging miR-375. (PMID:30744636)
• We found that KIF4A was dominantly regulated by FOXM1c among the four isoforms, and further identified KIF4A as a direct downstream target of FOXM1c. Inhibiting FOXM1 decreased KIF4A expression in hepatocellular carcinoma (HCC) cells, whereas its overexpression had the opposite effect. (PMID:31072351)
• Targeting the KIF4A/AR Axis to Reverse Endocrine Therapy Resistance in Castration-resistant Prostate Cancer. (PMID:31796514)
• Aurora A phosphorylates the condensin I-dependent pool of KIF4A. (PMID:31881080)
• Circular RNA KIF4A promotes cell migration, invasion and inhibits apoptosis through miR-152/ZEB1 axis in breast cancer. (PMID:32408908)
• The kinesin motor protein KIF4A as a potential therapeutic target in renal cell carcinoma. (PMID:32533288)
• KIF4A: A potential biomarker for prediction and prognostic of prostate cancer. (PMID:32971585)
• PRC1 is a critical regulator for anaphase spindle midzone assembly and cytokinesis in mouse oocyte meiosis. (PMID:33206458)
• KIF4A enhanced cell proliferation and migration via Hippo signaling and predicted a poor prognosis in esophageal squamous cell carcinoma. (PMID:33350074)
• Identification of KIF4A and its effect on the progression of lung adenocarcinoma based on the bioinformatics analysis. (PMID:33398330)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	kif4	ENSDARG00000005462
mus_musculus	Kif4	ENSMUSG00000034311
rattus_norvegicus	Kif4a	ENSRNOG00000038035

Paralogs (41): KIF1B (ENSG00000054523), KIF26A (ENSG00000066735), KIF2A (ENSG00000068796), KIF22 (ENSG00000079616), KIF3C (ENSG00000084731), KIF9 (ENSG00000088727), KIF16B (ENSG00000089177), KIF3B (ENSG00000101350), KIF20A (ENSG00000112984), KIF21B (ENSG00000116852), KIF17 (ENSG00000117245), KIF14 (ENSG00000118193), KIF18A (ENSG00000121621), KIF25 (ENSG00000125337), KIF1C (ENSG00000129250), KIF1A (ENSG00000130294), KIF3A (ENSG00000131437), KIF12 (ENSG00000136883), KIF13A (ENSG00000137177), KIF23 (ENSG00000137807), KIF11 (ENSG00000138160), CENPE (ENSG00000138778), KIF21A (ENSG00000139116), KIFC3 (ENSG00000140859), KIF2B (ENSG00000141200), KIF2C (ENSG00000142945), KIF5A (ENSG00000155980), KIF26B (ENSG00000162849), KIF15 (ENSG00000163808), KIF6 (ENSG00000164627), KIF27 (ENSG00000165115), KIF7 (ENSG00000166813), KIFC2 (ENSG00000167702), KIF5C (ENSG00000168280), KIF5B (ENSG00000170759), KIF18B (ENSG00000186185), KIF24 (ENSG00000186638), KIF19 (ENSG00000196169), KIF13B (ENSG00000197892), KIF4B (ENSG00000226650)

Protein

Protein identifiers

Chromosome-associated kinesin KIF4A — O95239 (reviewed: O95239)

Alternative names: Chromokinesin-A

All UniProt accessions (1): O95239

UniProt curated annotations — full annotation on UniProt →

Function. Iron-sulfur (Fe-S) cluster binding motor protein that has a role in chromosome segregation during mitosis. Translocates PRC1 to the plus ends of interdigitating spindle microtubules during the metaphase to anaphase transition, an essential step for the formation of an organized central spindle midzone and midbody and for successful cytokinesis. May play a role in mitotic chromosomal positioning and bipolar spindle stabilization.

Subunit / interactions. Interacts with the cytosolic iron-sulfur protein assembly (CIA) complex components CIAO2B and MMS19; the interactions facilitate the transfer of Fe-S clusters to KIF4A to ensure proper localization of KIF4A to mitotic machinery components. Interacts (via C-terminus) with unphosphorylated PRC1 (via N-terminus); the interaction is required for the progression of mitosis.

Subcellular location. Nucleus matrix. Cytoplasm. Cytoskeleton. Spindle. Midbody. Chromosome.

Tissue specificity. Highly expressed in hematopoietic tissues, fetal liver, spleen, thymus and adult thymus and bone marrow. Lower levels are found in heart, testis, kidney, colon and lung.

Disease relevance. Intellectual developmental disorder, X-linked 100 (XLID100) [MIM:300923] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked forms, while syndromic forms present with associated physical, neurological and/or psychiatric manifestations. XLID100 clinical features include intellectual disability, epilepsy, microcephaly and cortical malformations. The disease may be caused by variants affecting the gene represented in this entry. Taurodontism, microdontia, and dens invaginatus (TMDI) [MIM:313490] An X-linked recessive disorder characterized by the triad of taurodontism, microdontia, and dens invaginatus. Taurodontism is a rare developmental dental condition that largely affects the molar teeth and may be associated with hypodontia. In taurodontism, the crown of the molar tooth and pulp chamber are disproportionately longer than the roots. Microdontia, a mild form of hypodontia, is defined as smaller than normal teeth with shortened crowns (vertically or mesio-distally) and loss of contact areas between the teeth. Dens invaginatus or dens invagination is a tooth developmental anomaly that results from either the dental papilla folding into the developing tooth or the entire enamel organ folding into the dental papilla. In both instances, this leads to the formation of a tooth within a tooth. The disease may be caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 [4Fe-4S] cluster. In the presence of oxygen, the [4Fe-4S] cluster may be converted to [2Fe-2S].

Similarity. Belongs to the TRAFAC class myosin-kinesin ATPase superfamily. Kinesin family. Chromokinesin subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
O95239-1	1	yes
O95239-2	2

RefSeq proteins (1): NP_036442* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001752	Kinesin_motor_dom	Domain
IPR019821	Kinesin_motor_CS	Conserved_site
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR027640	Kinesin-like_fam	Family
IPR036961	Kinesin_motor_dom_sf	Homologous_superfamily

Pfam: PF00225, PF25764

UniProt features (54 total): modified residue 15, sequence conflict 15, region of interest 5, sequence variant 5, mutagenesis site 4, compositionally biased region 2, splice variant 2, chain 1, domain 1, binding site 1, cross-link 1, coiled-coil region 1, short sequence motif 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6OYL	X-RAY DIFFRACTION	3.15

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95239-F1	71.70	0.21

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): 88–95

Post-translational modifications (16): 394, 799, 801, 810, 815, 951, 995, 1001, 1013, 1017, 1028, 1126, 1181, 1186, 1225, 1194

Mutagenesis-validated functional residues (4):

Position	Phenotype
1086–1144	diffuse localization and does not localize to the spindle midzone or midbody during anaphase and telophase. does not aff
1106	abolishes chromatin localization; in association with a-1110 and a-1112.
1110	abolishes chromatin localization; in association with a-1106 and a-1112.
1112	abolishes chromatin localization; in association with a-1106 and a-1110.

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-2132295	MHC class II antigen presentation
R-HSA-437239	Recycling pathway of L1
R-HSA-6811434	COPI-dependent Golgi-to-ER retrograde traffic
R-HSA-983189	Kinesins
R-HSA-109582	Hemostasis
R-HSA-1266738	Developmental Biology
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-199991	Membrane Trafficking
R-HSA-373760	L1CAM interactions
R-HSA-422475	Axon guidance
R-HSA-5653656	Vesicle-mediated transport
R-HSA-6811442	Intra-Golgi and retrograde Golgi-to-ER traffic
R-HSA-8856688	Golgi-to-ER retrograde transport
R-HSA-9675108	Nervous system development
R-HSA-983231	Factors involved in megakaryocyte development and platelet production

MSigDB gene sets: 314 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GSE45365_NK_CELL_VS_CD8_TCELL_DN, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, GOBP_MITOTIC_CYTOKINESIS, GOBP_CHROMOSOME_ORGANIZATION, HORIUCHI_WTAP_TARGETS_DN, KANG_DOXORUBICIN_RESISTANCE_UP, GOBP_AXO_DENDRITIC_TRANSPORT, GNF2_CENPF, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, MITSIADES_RESPONSE_TO_APLIDIN_DN, REACTOME_MEMBRANE_TRAFFICKING, CAGCTG_AP4_Q5

GO Biological Process (7): mitotic cytokinesis (GO:0000281), organelle organization (GO:0006996), mitotic spindle organization (GO:0007052), anterograde axonal transport (GO:0008089), spindle elongation (GO:0051231), mitotic spindle midzone assembly (GO:0051256), microtubule-based movement (GO:0007018)

GO Molecular Function (8): DNA binding (GO:0003677), microtubule motor activity (GO:0003777), ATP binding (GO:0005524), microtubule binding (GO:0008017), metal ion binding (GO:0046872), iron-sulfur cluster binding (GO:0051536), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (13): chromosome (GO:0005694), cytoplasm (GO:0005737), cytosol (GO:0005829), microtubule associated complex (GO:0005875), spindle microtubule (GO:0005876), membrane (GO:0016020), nuclear matrix (GO:0016363), midbody (GO:0030496), axon cytoplasm (GO:1904115), nucleus (GO:0005634), spindle (GO:0005819), cytoskeleton (GO:0005856), microtubule (GO:0005874)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Adaptive Immune System	1
L1CAM interactions	1
Golgi-to-ER retrograde transport	1
Factors involved in megakaryocyte development and platelet production	1
Immune System	1
Vesicle-mediated transport	1
Axon guidance	1
Nervous system development	1
Membrane Trafficking	1
Intra-Golgi and retrograde Golgi-to-ER traffic	1
Developmental Biology	1
Hemostasis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
intracellular membraneless organelle	3
microtubule cytoskeleton	3
mitotic cell cycle	2
mitotic cell cycle process	2
spindle organization	2
microtubule-based process	2
cytoskeleton-dependent cytokinesis	1
cellular component organization	1
microtubule cytoskeleton organization involved in mitosis	1
axonal transport	1
axon cytoplasm	1
cell cycle process	1
nuclear chromosome segregation	1
mitotic spindle elongation	1
spindle midzone assembly	1
mitotic spindle assembly	1
mitotic nuclear division	1
nucleic acid binding	1
cytoskeletal motor activity	1
polypeptide conformation or assembly isomerase activity	1
ATP-dependent activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
tubulin binding	1
cation binding	1
metal cluster binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
protein-containing complex	1
spindle	1
microtubule	1
nuclear lumen	1
axon	1
neuron projection cytoplasm	1
intracellular membrane-bounded organelle	1
polymeric cytoskeletal fiber	1

Protein interactions and networks

STRING

1780 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KIF4A	PRC1	O43663	908
KIF4A	KIF20A	O95235	854
KIF4A	PDZD11	Q5EBL8	806
KIF4A	TPX2	Q9ULW0	765
KIF4A	AURKB	Q96GD4	757
KIF4A	MELK	Q14680	750
KIF4A	CEP55	Q53EZ4	748
KIF4A	CIT	O14578	747
KIF4A	DLGAP5	Q15398	742
KIF4A	BUB1	O43683	733
KIF4A	NUF2	Q9BZD4	721
KIF4A	BUB1B	O60566	696
KIF4A	SACK1D	Q9H4H8	676
KIF4A	CDCA2	Q69YH5	664
KIF4A	RAD51	Q06609	654

IntAct

70 interactions, top by confidence:

A	B	Type	Score
CDK8	MED19	psi-mi:“MI:2364”(proximity)	0.850
FAM9C	NDC80	psi-mi:“MI:0914”(association)	0.670
PHF14	KIF4A	psi-mi:“MI:0915”(physical association)	0.590
KIF4A	PHF14	psi-mi:“MI:0915”(physical association)	0.590
PICK1	ILVBL	psi-mi:“MI:0914”(association)	0.530
PHF14	KIF4A	psi-mi:“MI:0915”(physical association)	0.460
KIF4A	PHF14	psi-mi:“MI:0915”(physical association)	0.460
KIF4A	PHF14	psi-mi:“MI:0403”(colocalization)	0.460
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410
EAF2	KIF4A	psi-mi:“MI:0915”(physical association)	0.400
Kif4		psi-mi:“MI:0915”(physical association)	0.400
KIF4A	TBC1D23	psi-mi:“MI:0915”(physical association)	0.400
KIF4B	KIF4A	psi-mi:“MI:0915”(physical association)	0.400
SVIL	KIF4A	psi-mi:“MI:0915”(physical association)	0.370
NFATC1	SMARCA5	psi-mi:“MI:0914”(association)	0.350
TUBA1A	CAPZB	psi-mi:“MI:0914”(association)	0.350
TUBA1A	KIF2A	psi-mi:“MI:0914”(association)	0.350
CCND1	PHF14	psi-mi:“MI:0914”(association)	0.350
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
SPATA6L	KIF4A	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
RHOG	COPE	psi-mi:“MI:0914”(association)	0.350

BioGRID (132): KIF4A (Affinity Capture-RNA), KIF4A (Affinity Capture-RNA), KIF4A (Affinity Capture-MS), KIF4A (Affinity Capture-MS), KIF4A (Affinity Capture-MS), ACTR6 (Co-fractionation), GBF1 (Co-fractionation), ZPR1 (Co-fractionation), KIF4A (Affinity Capture-MS), KIF4A (Proximity Label-MS), KIF4A (Affinity Capture-MS), KIF4A (Affinity Capture-MS), KIF4A (Affinity Capture-MS), KIF4A (Affinity Capture-MS), KIF4A (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2JDV3, A0MWD1, A2EI35, A3KMI0, A4UUI3, A6ZP10, A8N5E5, B0BNF1, B0KWP7, B1AVY7, B3LJJ8, B5FW69, B5VS52, B6K0N7, C5DEL5, C5DTA7, O95239, P32455, P32456, P33174, Q01514, Q0JLS6, Q0VCP4, Q14141, Q1MT80, Q5D1D6, Q5I2P5, Q5PQK1, Q5R9T9, Q5RBE1, Q5REG8, Q5XUN4, Q61107, Q63663, Q6ZN66, Q8C650, Q8CFB4, Q8CHH9, Q8N8V2, Q90640

Diamond homologs: A0A068FIK2, A0JN40, A1ZAJ2, A8BB91, A8BKD1, B1AVY7, B7EJ91, B7ZNG0, B9F2Y7, B9GE13, F1M4A4, F1M5N7, F1QN54, F4IIS5, F4J1U4, F4K0J3, G5EGS3, O14343, O14782, O15066, O23826, O35066, O35071, O35787, O43896, O45935, O55165, O60282, O60333, O75037, O88658, O95239, P17210, P21613, P23678, P28738, P28741, P33173, P33174, P33175

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
KIF4A	up-regulates	Spindle_assembly
KIF4A	“up-regulates activity”	PRC1	binding
CDK1	“up-regulates activity”	KIF4A	phosphorylation
PLK1	“down-regulates activity”	KIF4A	phosphorylation
PRKAA1	“up-regulates activity”	KIF4A	phosphorylation
AURKB	“up-regulates activity”	KIF4A	phosphorylation
AURKA	“up-regulates activity”	KIF4A	phosphorylation
CyclinB/CDK1	“up-regulates activity”	KIF4A	phosphorylation
APC-c	“down-regulates quantity by destabilization”	KIF4A	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 85 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
Recycling pathway of L1	5	19.6×	4e-04
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	5	17.0×	6e-04
Kinesins	5	15.7×	6e-04
Golgi-to-ER retrograde transport	6	14.0×	4e-04
mRNA Splicing	7	13.5×	8e-05
Processing of Capped Intron-Containing Pre-mRNA	9	13.0×	4e-06
COPI-dependent Golgi-to-ER retrograde traffic	6	11.7×	6e-04
ER to Golgi Anterograde Transport	5	11.7×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
chromatin remodeling	9	8.8×	5e-04
mRNA splicing, via spliceosome	7	8.6×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	2
Uncertain significance	185
Likely benign	26
Benign	14

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
140729	NM_012310.5(KIF4A):c.1489-8_1490delinsATAATGAAAG	Pathogenic
2575210	NM_012310.5(KIF4A):c.1674+1G>A	Pathogenic
2575211	NM_012310.5(KIF4A):c.1616T>C (p.Leu539Pro)	Pathogenic
2575212	NM_012310.5(KIF4A):c.763G>A (p.Asp255Asn)	Pathogenic
2580118	NM_012310.5(KIF4A):c.2312G>A (p.Arg771Lys)	Pathogenic
2580119	NM_012310.5(KIF4A):c.949G>C (p.Asp317His)	Pathogenic
3770236	NM_012310.5(KIF4A):c.1778+21T>C	Likely pathogenic
632604	NM_012310.5(KIF4A):c.794G>T (p.Arg265Leu)	Likely pathogenic

SpliceAI

3624 predictions. Top by Δscore:

Variant	Effect	Δscore
X:70290689:AGGT:A	acceptor_gain	1.0000
X:70290690:GGTG:G	acceptor_gain	1.0000
X:70290802:AAAG:A	donor_loss	1.0000
X:70290803:AAGGT:A	donor_loss	1.0000
X:70290804:AGGTA:A	donor_loss	1.0000
X:70290805:GGTAA:G	donor_loss	1.0000
X:70290806:G:A	donor_loss	1.0000
X:70290807:T:A	donor_loss	1.0000
X:70299096:A:AG	acceptor_gain	1.0000
X:70299097:T:G	acceptor_gain	1.0000
X:70299102:A:AG	acceptor_gain	1.0000
X:70299103:A:G	acceptor_gain	1.0000
X:70299105:A:AG	acceptor_gain	1.0000
X:70299106:A:G	acceptor_gain	1.0000
X:70299191:G:GT	donor_gain	1.0000
X:70299192:A:T	donor_gain	1.0000
X:70301899:GATT:G	acceptor_gain	1.0000
X:70302067:G:GG	donor_gain	1.0000
X:70302294:A:AG	acceptor_gain	1.0000
X:70302295:T:G	acceptor_gain	1.0000
X:70302297:A:AG	acceptor_gain	1.0000
X:70302300:ACAG:A	acceptor_gain	1.0000
X:70302302:A:AG	acceptor_gain	1.0000
X:70302302:A:C	acceptor_loss	1.0000
X:70302302:AG:A	acceptor_gain	1.0000
X:70302303:G:GG	acceptor_gain	1.0000
X:70302303:GG:G	acceptor_gain	1.0000
X:70302303:GGA:G	acceptor_gain	1.0000
X:70302303:GGAAT:G	acceptor_gain	1.0000
X:70302394:AGAGG:A	donor_gain	1.0000

AlphaMissense

8157 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:70297024:G:A	G88R	1.000
X:70297024:G:C	G88R	1.000
X:70297024:G:T	G88W	1.000
X:70297025:G:A	G88E	1.000
X:70297043:A:T	K94I	1.000
X:70302342:T:A	L241H	1.000
X:70302342:T:C	L241P	1.000
X:70302345:C:A	A242D	1.000
X:70302347:G:A	G243R	1.000
X:70302347:G:C	G243R	1.000
X:70302348:G:A	G243E	1.000
X:70302398:G:C	G260R	1.000
X:70329416:A:G	N264D	1.000
X:70329418:C:A	N264K	1.000
X:70329418:C:G	N264K	1.000
X:70329426:T:A	L267H	1.000
X:70329426:T:C	L267P	1.000
X:70329429:T:C	L268P	1.000
X:70329437:G:A	G271R	1.000
X:70329437:G:C	G271R	1.000
X:70329438:G:A	G271E	1.000
X:70329447:T:A	I274N	1.000
X:70330246:T:C	Y329H	1.000
X:70330250:C:A	A330D	1.000
X:70297019:C:A	A86D	0.999
X:70297021:T:C	Y87H	0.999
X:70297025:G:T	G88V	0.999
X:70297031:C:T	T90I	0.999
X:70297040:G:A	G93E	0.999
X:70297040:G:T	G93V	0.999

dbSNP variants (sampled 300 via entrez): RS1000004398 (X:70352816 C>T), RS1000019156 (X:70312785 T>C), RS1000040910 (X:70393730 G>T), RS1000042871 (X:70383221 A>G), RS1000106914 (X:70295954 A>G), RS1000115316 (X:70343124 C>T), RS1000141090 (X:70353477 T>G), RS1000185881 (X:70363167 G>T), RS1000230831 (X:70348803 T>TC), RS1000240297 (X:70310309 G>A), RS1000297121 (X:70335266 T>G), RS1000413572 (X:70399013 T>A), RS1000465759 (X:70411366 C>T), RS1000562498 (X:70383947 A>G), RS1000569886 (X:70395233 G>A)

Disease associations

OMIM: gene MIM:300521 | disease phenotypes: MIM:300923, MIM:313490, MIM:213000, MIM:217990

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, X-linked 100	Strong	X-linked
taurodontism, microdontia, and dens invaginatus	Strong	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
complex neurodevelopmental disorder with or without congenital anomalies	Limited	XL

Mondo (9): intellectual disability, X-linked 100 (MONDO:0010488), taurodontism, microdontia, and dens invaginatus (MONDO:0010740), gynecomastia disorder (MONDO:0001571), flatfoot (MONDO:0005293), obesity disorder (MONDO:0011122), hydrocephalus (MONDO:0001150), isolated cerebellar hypoplasia/agenesis (MONDO:0008939), corpus callosum, agenesis of (MONDO:0009022), multicystic dysplastic kidney (MONDO:0015988)

Orphanet (6): Obesity due to melanocortin 4 receptor deficiency (Orphanet:71529), Isolated cerebellar agenesis (Orphanet:1398), Multicystic dysplastic kidney (Orphanet:1851), Isolated corpus callosum agenesis (Orphanet:200), Cerebellar hypoplasia-tapetoretinal degeneration syndrome (Orphanet:2246), NON RARE IN EUROPE: Non rare obesity (Orphanet:521399)

HPO phenotypes

6 total (8 of 6 shown, HPO-id order):

HPO	Term
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001419	X-linked recessive inheritance
HP:0001999	Abnormal facial shape
HP:0002069	Bilateral tonic-clonic seizure
HP:0002121	Generalized non-motor (absence) seizure
HP:0000771	Gynecomastia
HP:0001513	Obesity

GWAS associations

0 associations (top):

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D061085	Agenesis of Corpus Callosum	C10.500.034; C16.131.666.034; C23.300.008
D005413	Flatfoot	C05.330.488.655.250; C05.330.495.681.250; C05.660.585.512.380.813.250; C16.131.621.585.512.500.681.250
D006177	Gynecomastia	C17.800.090.875
D006849	Hydrocephalus	C10.228.140.602
D021782	Multicystic Dysplastic Kidney	C12.050.351.875.558; C12.050.351.968.419.403.750; C12.200.706.629; C12.200.777.419.403.750; C12.800.629; C12.950.419.403.750; C16.131.939.629
C562568	Cerebellar Hypoplasia (supp.)
C536947	Taurodontism, microdontia, and dens invaginatus (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6163 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression, affects cotreatment, increases methylation	4
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
Cyclosporine	decreases expression	3
sodium arsenite	decreases expression, increases expression	2
cobaltous chloride	decreases expression	2
Acetaminophen	decreases expression, increases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Cadmium	decreases expression	2
Doxorubicin	decreases expression, affects response to substance	2
Progesterone	decreases expression, increases expression	2
Tobacco Smoke Pollution	decreases expression	2
Valproic Acid	decreases expression, decreases methylation	2
Particulate Matter	increases abundance, decreases expression	2
TAK-243	decreases sumoylation	1
propionaldehyde	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
arsenite	affects binding, decreases reaction	1
methylparaben	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
coumarin	decreases phosphorylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
diallyl trisulfide	decreases expression	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
chromium hexavalent ion	decreases expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
corosolic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1

ChEMBL screening assays

20 unique, capped per target: 20 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1026543	Binding	Inhibition of ATPase activity of KIF4 by luminescent kinase assay	Bis(hetero)aryl derivatives as unique kinesin spindle protein inhibitors. — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_SU82	HAP1 KIF4A (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02414087	PHASE4	UNKNOWN	Therapeutic Effects of Customized Insoles on Children With Flat Foot
NCT04564430	PHASE4	UNKNOWN	Clonidine for Tourniquet-related Pain in Children
NCT06211504	PHASE4	RECRUITING	Sinus Tarsi Implant as an Adjuvant Procedure to Medial Displacement Calcaneal Osteotomy in the Treatment of Mobile Adult Acquired Flatfoot Deformity
NCT00076362	PHASE4	COMPLETED	Pediatric Hypothalamic Obesity
NCT00079547	PHASE4	COMPLETED	The Safety and Effectiveness of Low and High Carbohydrate Diets
NCT00115063	PHASE4	TERMINATED	LOSS- Louisiana Obese Subjects Study
NCT00134303	PHASE4	COMPLETED	Trial Comparing Metformin Versus Placebo in Non Alcoholic Steatohepatitis (NASH) Patients Receiving Bariatric Surgery for Obesity
NCT00143936	PHASE4	COMPLETED	The Safety and Efficacy of Low and High Carbohydrate Diets
NCT00143962	PHASE4	COMPLETED	Comparison of Two Approaches to Weight Loss Follow-Up Study
NCT00152360	PHASE4	COMPLETED	The Effect of Xenical on Weight and Risk Factors
NCT00176306	PHASE4	COMPLETED	Levofloxacin Pharmacokinetics (PK) in the Severely Obese
NCT00203450	PHASE4	COMPLETED	Zonegran for the Treatment of Weight Gain Associated With Psychotropic Medication Use: A Placebo-Controlled Trial
NCT00205504	PHASE4	COMPLETED	Oral Contraceptives in the Metabolic Syndrome
NCT00229229	PHASE4	TERMINATED	Comparison of 4 Diets in the Management of Overweight Patients With Vascular Disease
NCT00234988	PHASE4	COMPLETED	A Phase IV, Multi-Center, Open-Label Trial of Sibutramine in Combination With a Hypocaloric Diet in Obese and Overweight Thai Subjects.
NCT00264589	PHASE4	COMPLETED	Exercise Training and Cardiovascular Function in Obesity and in Type 2 Diabetes
NCT00288873	PHASE4	COMPLETED	Characterization of Hyperparathyroidism and Vitamin D Deficiency in Obesity
NCT00298857	PHASE4	TERMINATED	A Pharmacokinetic Study to Compare the Dosing of Valproic Acid in Subjects With Different Body Weights
NCT00315146	PHASE4	COMPLETED	Optimizing Body Composition for Function in Older Adults
NCT00319202	PHASE4	TERMINATED	Clinical Trial to Assess the Effects of Candesartan on the Carbohydrate Metabolism of Obese Subjects
NCT00327912	PHASE4	UNKNOWN	Laparoscopic Roux-en-Y Gastric Bypass Versus Laparoscopic Biliopancreatic Diversion (BPD)- Duodenal Switch for Superobesity
NCT00352287	PHASE4	COMPLETED	Study to Determine the Effects of Human Growth Hormone and Pioglitazone in Overweight, Prediabetic Adults
NCT00353054	PHASE4	COMPLETED	Effect of Calcium/Vitamin D Supplementation on Body Weight and Fat Loss.
NCT00390637	PHASE4	COMPLETED	Diet, Obesity and Genes (DiOGenes)
NCT00415688	PHASE4	COMPLETED	Lifestyle Modification for Obesity-Related Type 2 Diabetes
NCT00433641	PHASE4	COMPLETED	Weight Loss in Response to Sibutramine (MERIDIA) is Influenced by the Inherited Genes
NCT00440375	PHASE4	COMPLETED	Effects of Rosiglitazone on Bone in Postmenopausal Diabetic Women
NCT00453557	PHASE4	COMPLETED	Mechanism of Growth Hormone Effects on Adipose Tissue
NCT00456885	PHASE4	COMPLETED	The Effect of Exenatide on Weight and Hunger in Obese, Healthy Women
NCT00463112	PHASE4	COMPLETED	Effect of Diet Plus Sibutramine on Hormonal and Metabolic Features in Overweight and Obese Women With PCOS
NCT00512187	PHASE4	COMPLETED	Moderate Weight Loss Makes Obese Patients With Severe Chronic Plaque Psoriasis Responsive to Sub-Optimal Dose of Cyclosporine: an Investigator Blinded, Controlled, Randomized Clinical Trial
NCT00516919	PHASE4	COMPLETED	Study of Behavioral Weight Loss Therapy for Obesity and Binge Eating in Monolingual Hispanic Persons
NCT00522470	PHASE4	COMPLETED	Effects of Rosiglitazone on Serum Ghrelin and Peptide YY Levels
NCT00537810	PHASE4	COMPLETED	Treatment of Binge Eating in Obese Patients in Primary Care
NCT00538486	PHASE4	COMPLETED	A Randomized, Double-Blind, Active Control Trial Comparing Effects of Telmisartan, Candesartan and Amlodipine, Alone or Plus Metformin, on Non-Diabetic, Obese Hypertensive Patients
NCT00584389	PHASE4	TERMINATED	The Effect of Rimonabant on Energy Expenditure, Fat Metabolism and Body Composition
NCT00585182	PHASE4	COMPLETED	Study to Evaluate Weight-based Enoxaparin Dosing in Obese Medical Patients at Risk for DVT
NCT00632840	PHASE4	COMPLETED	Pharmacological Regulation of Fat Transport in Metabolic Syndrome
NCT00636142	PHASE4	COMPLETED	Effects of Infliximab on Insulin Sensitivity and Beta Cell Function in Insulin Resistant Human Obesity
NCT00675987	PHASE4	COMPLETED	A Randomized Clinical Trial To Study Losartan On Endothelial Dysfunction and Insulin Resistance In Obese Patients