KIF21A

Summary

KIF21A (kinesin family member 21A, HGNC:19349) is a protein-coding gene on chromosome 12q12, encoding Kinesin-like protein KIF21A (Q7Z4S6). Processive microtubule plus-end directed motor protein involved in neuronal axon guidance.

This gene encodes a member of the KIF4 subfamily of kinesin-like motor proteins. The encoded protein is characterized by an N-terminal motor domain a coiled-coil stalk domain and a C-terminal WD-40 repeat domain. This protein may be involved in microtubule dependent transport. Mutations in this gene are the cause of congenital fibrosis of extraocular muscles-1. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 55605 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital fibrosis of extraocular muscles (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 414 total — 8 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 66
• Druggable target: yes
• MANE Select transcript: NM_001173464

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19349
Approved symbol	KIF21A
Name	kinesin family member 21A
Location	12q12
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20052
Ensembl gene	ENSG00000139116
Ensembl biotype	protein_coding
OMIM	608283
Entrez	55605

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 14 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000361418, ENST00000361961, ENST00000541463, ENST00000544797, ENST00000546817, ENST00000547108, ENST00000547733, ENST00000550429, ENST00000551066, ENST00000551264, ENST00000552475, ENST00000552908, ENST00000552961, ENST00000636569, ENST00000854162, ENST00000854163, ENST00000919054, ENST00000919055, ENST00000919056

RefSeq mRNA: 7 — MANE Select: NM_001173464 NM_001173463, NM_001173464, NM_001173465, NM_001378439, NM_001378440, NM_001378441, NM_017641

CCDS: CCDS31773, CCDS53774, CCDS53775, CCDS53776

Canonical transcript exons

ENST00000361418 — 38 exons

Exon	Start	End
ENSE00000936431	39322668	39322882
ENSE00000936433	39318073	39318201
ENSE00000936434	39311417	39311553
ENSE00000998398	39332893	39333107
ENSE00000998401	39315932	39315970
ENSE00000998407	39332591	39332744
ENSE00000998409	39332214	39332408
ENSE00000998410	39356832	39356895
ENSE00000998411	39357248	39357437
ENSE00000998413	39351777	39351980
ENSE00001098339	39358178	39358373
ENSE00001098341	39367030	39367164
ENSE00001098342	39367883	39368032
ENSE00001098343	39363098	39363213
ENSE00001098344	39370039	39370261
ENSE00001098346	39369729	39369911
ENSE00001098347	39366350	39366517
ENSE00001098358	39342034	39342124
ENSE00001251468	39337096	39337203
ENSE00001332329	39340165	39340364
ENSE00001332331	39340906	39341094
ENSE00001332333	39341505	39341622
ENSE00001486811	39346466	39346504
ENSE00001486840	39330242	39330262
ENSE00001805807	39315229	39315240
ENSE00002329066	39442927	39443120
ENSE00002356509	39293228	39294517
ENSE00003461145	39326264	39326324
ENSE00003463515	39302965	39303135
ENSE00003485369	39307565	39307729
ENSE00003538115	39330746	39330911
ENSE00003585669	39331690	39331791
ENSE00003592185	39309586	39309766
ENSE00003614556	39319906	39320013
ENSE00003641485	39333212	39333280
ENSE00003673048	39304821	39304938
ENSE00003676539	39325839	39325893
ENSE00003694091	39301480	39301679

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 99.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.2319 / max 1356.8538, expressed in 1499 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
130449	8.9308	1362
130450	1.3941	563
130451	1.0074	431
130439	0.8147	210
130443	0.6090	184
130444	0.3759	118
130452	0.3501	149
130442	0.3378	67
130453	0.2131	115
206670	0.1416	72

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
dorsal root ganglion	UBERON:0000044	99.64	gold quality
substantia nigra pars compacta	UBERON:0001965	99.51	gold quality
pons	UBERON:0000988	99.41	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.32	gold quality
superior vestibular nucleus	UBERON:0007227	99.32	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.27	gold quality
bronchial epithelial cell	CL:0002328	99.07	gold quality
medulla oblongata	UBERON:0001896	98.97	gold quality
palpebral conjunctiva	UBERON:0001812	98.92	gold quality
bronchus	UBERON:0002185	98.83	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.77	gold quality
ventral tegmental area	UBERON:0002691	98.29	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.19	gold quality
dorsal plus ventral thalamus	UBERON:0001897	98.13	gold quality
oviduct epithelium	UBERON:0004804	97.93	gold quality
medial globus pallidus	UBERON:0002477	97.92	gold quality
lateral globus pallidus	UBERON:0002476	97.87	gold quality
globus pallidus	UBERON:0001875	97.86	gold quality
nasal cavity epithelium	UBERON:0005384	97.85	gold quality
pigmented layer of retina	UBERON:0001782	97.71	gold quality
endothelial cell	CL:0000115	97.57	gold quality
trigeminal ganglion	UBERON:0001675	97.53	gold quality
parietal lobe	UBERON:0001872	97.47	gold quality
subthalamic nucleus	UBERON:0001906	97.41	gold quality
inferior vagus X ganglion	UBERON:0005363	97.32	gold quality
postcentral gyrus	UBERON:0002581	97.22	gold quality
corpus callosum	UBERON:0002336	97.19	gold quality
superior frontal gyrus	UBERON:0002661	97.19	gold quality
ventricular zone	UBERON:0003053	97.07	gold quality
occipital lobe	UBERON:0002021	96.93	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	22.53
E-GEOD-135922	yes	8.50
E-HCAD-10	yes	5.36
E-ENAD-17	no	861.65
E-MTAB-8060	no	687.37
E-MTAB-11268	no	600.87
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

104 targeting KIF21A, 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-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-1305	99.91	71.43	3443

Literature-anchored findings (GeneRIF, showing 40)

• Surgery is effective at improving ptosis in the majority of patients with classic CFEOM (congenital fibiosis of the extraocular muscles). (PMID:12702216)
• Heterozygous mutations of the kinesin KIF21A is associated with congenital fibrosis of the extraocular muscles type 1 (PMID:14595441)
• The results demonstrate that KIF21A mutations are a rare cause of CFEOM3 (congenital fibrosis of the extraocular muscles) (PMID:15223798)
• Mutation in KIF21A is associated with congenital fibrosis of the extraocular muscles patients (PMID:15621876)
• Mutation in cpg island of KIF21A is associated with congenital fibrosis of the extraocular muscles patients (PMID:15621877)
• Orbital imaging in CFEOM1 due to various amino acid substitutions in the kinesin KIF21A demonstrates consistent abnormalities of motor and sensory innervation in the orbit. (PMID:15671279)
• CFEOM (congenital fibrosis of the extraocular muscles) is present in Chinese populations. Both CFEOM1 and CFEOM3 can be caused by the same mutation at the KIF21A gene. (PMID:15827546)
• This report introduces a new CFEOM1 (congenital fibrosis of the extraocular muscles) KIF21A mutation and is, to our knowledge, the first report of a genetic defect associated with Marcus Gunn jaw-winking. (PMID:16157808)
• Mutations of the KIF21A gene contribute to the development of CFEOM1 regardless of ethnicity. (PMID:16365788)
• mutation p.Arg954Trp of the KIF21A is the genetic basis of the congenital fibrosis of the extraocular muscles type 1 (PMID:16939002)
• All three new mutations alter amino acids in heptad repeats within the third coiled-coil region of the KIF21A stalk, highlighting the importance of alterations in this domain in the etiology of Congenital fibrosis of the extraocular muscles types 1 and 3. (PMID:17511870)
• No KIF21A nucleotide change was found in any patients with congenital superior oblique muscle palsy (PMID:18323871)
• The novel KIF21A mutation 84C>G demonstrated in a CFEOM1 family affects the kinesin motor domain, supporting that mutations may also occur outside the commonly involved coiled-coil domain. (PMID:18332320)
• The finding of R954W mutation in the historically isolated population of the Arabian Peninsula confirms that R954 is a “hotspot” for KIF21A mutation. (PMID:18363169)
• Overexpression of full-length KIF21A and BIG1 and their fragments in HEK293 cells followed by reciprocal IP revealed that the C-terminal tail of KIF21A, with seven WD-40 repeats, may interact with structure in the C-terminal region of BIG1. (PMID:19020088)
• Using shotgun mass spectrometry, we found this protein differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19165527)
• The patients had marked restriction of movement bilaterally with nearly complete loss of vertical ocular motility, graded reduction of horizontal motility, ptosis, and compensatory chin elevation. (PMID:19551685)
• These results suggest that KIF21A regulates the distribution of Kank1 and that KIF21A mutations associated with congenital fibrosis of the extraocular muscles type 1 enhanced the accumulation of Kank1 in the membrane fraction. (PMID:19559006)
• Our 16-patient sample suggests that KIF21A and PHOX2A sequence variation does not have a role in common forms of congenital incomitant vertical strabismus. (PMID:19852579)
• Parental germline mosaicism can mimic recessive inheritance in congenital fibrosis of the extraocular muscles (CFEOM) and likely is underrecognized. (PMID:19896199)
• The observation of these two KIF21A mutations in a Chinese pedigree underscores the homogeneity of these mutations as a cause of congenital fibrosis of the extraocular muscles CFEOM1 and CFEOM3 across ethnic divisions. (PMID:21042561)
• patients with congenital fibrosis of the extraocular muscles type I patients from consanguineous Saudi Arabian families do not have KIF21A mutations (PMID:21264235)
• KIF21A novel deletion and recurrent mutation have been fonund in Chinese patients with congenital fibrosis of the extraocular muscles-1. (PMID:21805025)
• This Chinese family with congenital fibrosis of the extraocular muscles type I(CFEOM1) may be caused by a c.2860C to T mutation in the KIF21A gene. (PMID:21983718)
• This study indicated that KIF21A-mediated axonal transport and selective somatodendritic endocytosis underlie the axonal polarized surface expression of NCKX2. (PMID:22442075)
• The diffuse and widespread expression of KIF21A in the developing human and mouse central and peripheral nervous system as well as in extraocular muscle does not account for the restricted ocular phenotype observed in Congenital fibrosis of the extraocular muscles type 1. (PMID:22465342)
• Expression of RRP1B, PCNT, KIF21A and ADRB2 in leucocytes of Down’s syndrome subjects, was analyzed. (PMID:22552340)
• The data of this study suggested that KIF21A gene expression could have a role on the axonal transport and the development of the nervous system with implications on the resulting phenotype of subjects with Down syndrome. (PMID:22968744)
• Congenital fibrosis of extraocular muscle assciated with KIF21A mutation. (PMID:23535681)
• CFEOM1-associated mutations relieve autoinhibition of the KIF21A motor, and this results in enhanced KIF21A accumulation in axonal growth cones, aberrant axon morphology, and reduced responsiveness to inhibitory cues. (PMID:24120883)
• Germline mosaicism of KIF21A c.2860C>T is likely to cause the high occurrence of this mutation in the population. (PMID:24426772)
• This study demonistrated that the interaction between Kif21a and Map1b is likely to play a critical role in the pathogenesis of CFEOM1 and highlights a selective vulnerability of the developing oculomotor nerve to perturbations of the axon cytoskeleton. (PMID:24656932)
• We explain the phenotypic findings associated with mutations in KIF21A (PMID:26190014)
• A heterozygous mutation, c.2860C>T (p.R954W), in KIF21A was identified in two families with congenital fibrosis of the extraocular muscles type 1 and 3, and this was cosegregated with the presence of the diseases in the two families, however, it was absent in the 200 normal control subjects. (PMID:27513105)
• We describe a recurrent (c.2860C>T) missense KIF21A mutation identified in a Chinese family with CFEOM1 (congenital fibrosis of the extraocular muscles type 1) phenotypes. (PMID:28930843)
• Several key residues (i.e. Thr-1147, Leu-1152, Leu-1153, and Tyr-1154) at the C-terminal half of the KIF21A KBD peptide contact with the hydrophobic patch formed by Tyr-1176, Met-1209, Leu-1210, Leu-1213, and Leu-1248 from KANK1. (PMID:29158259)
• Prognostic value of Kinesin-4 family genes mRNA expression in early-stage pancreatic ductal adenocarcinoma patients after pancreaticoduodenectomy. (PMID:31489986)
• Outcomes of strabismus surgery in genetically confirmed congenital fibrosis of the extraocular muscles. (PMID:31541710)
• KIF21A pathogenic variants cause congenital fibrosis of extraocular muscles type 3. (PMID:33251926)
• Nephrotic-syndrome-associated mutation of KANK2 induces pathologic binding competition with physiological interactor KIF21A. (PMID:34274317)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	kif21a	ENSDARG00000061131
danio_rerio	si:cabz01066312.1	ENSDARG00000100624
mus_musculus	Kif21a	ENSMUSG00000022629
rattus_norvegicus	Kif21a	ENSRNOG00000014844

Paralogs (41): KIF1B (ENSG00000054523), KIF26A (ENSG00000066735), KIF2A (ENSG00000068796), KIF22 (ENSG00000079616), KIF3C (ENSG00000084731), KIF9 (ENSG00000088727), KIF16B (ENSG00000089177), KIF4A (ENSG00000090889), 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), 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

Kinesin-like protein KIF21A — Q7Z4S6 (reviewed: Q7Z4S6)

Alternative names: Kinesin-like protein KIF2, Renal carcinoma antigen NY-REN-62

All UniProt accessions (7): Q7Z4S6, A0A1B0GV47, H0YHG9, H0YHT2, H0YI78, H0YIM6, H0YIM7

UniProt curated annotations — full annotation on UniProt →

Function. Processive microtubule plus-end directed motor protein involved in neuronal axon guidance. Is recruited by KANK1 to cortical microtubule stabilizing complexes (CMSCs) at focal adhesions (FAs) rims where it promotes microtubule capture and stability. Controls microtubule polymerization rate at axonal growth cones and suppresses microtubule growth without inducing microtubule disassembly once it reaches the cell cortex.

Subunit / interactions. Part of a cortical microtubule stabilization complex (CMSC) composed of KANK1, PPFIA1, PPFIBP1, ERC1/ELKS, PHLDB2/LL5beta, CLASPs, KIF21A and possibly additional interactors; within CMSCs KANK1 and PHLDB2/LL5beta seem to be the core components for recruiting microtubule-binding proteins KIF21A and CLASPs, whereas PPFIA1, PPFIBP1 and ERC1/ELKS serve as scaffolds for protein clustering. Interacts (via residues 1146-1167) with KANK1 (via ankyrin repeats 1-5) and KANK2 (via ankyrin repeats 1-5).

Subcellular location. Cytoplasm. Cytoskeleton. Cell cortex. Cell projection. Axon. Dendrite. Growth cone.

Disease relevance. Fibrosis of extraocular muscles, congenital, 1 (CFEOM1) [MIM:135700] A congenital ocular motility disorder marked by restrictive ophthalmoplegia affecting extraocular muscles innervated by the oculomotor and/or trochlear nerves. It is clinically characterized by anchoring of the eyes in downward gaze, ptosis, and backward tilt of the head. Patients affected by congenital fibrosis of extraocular muscles type 1 show an absence of the superior division of the oculomotor nerve (cranial nerve III) and corresponding oculomotor subnuclei. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The coiled coil region interacts with the kinesin motor domain leading to autoinhibition of the motor.

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

Isoforms (6)

UniProt ID	Names	Canonical?
Q7Z4S6-1	1	yes
Q7Z4S6-2	2
Q7Z4S6-3	3
Q7Z4S6-4	4
Q7Z4S6-5	5
Q7Z4S6-6	6

RefSeq proteins (7): NP_001166934, NP_001166935, NP_001166936, NP_001365368, NP_001365369, NP_001365370, NP_060111 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR001752	Kinesin_motor_dom	Domain
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR019775	WD40_repeat_CS	Conserved_site
IPR019821	Kinesin_motor_CS	Conserved_site
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR027640	Kinesin-like_fam	Family
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR036961	Kinesin_motor_dom_sf	Homologous_superfamily
IPR056532	KIF21A/B_hel_2	Domain
IPR056533	KIF21A/B_hel_1	Domain

Pfam: PF00225, PF00400, PF23203, PF23204, PF25764

UniProt features (117 total): strand 32, sequence conflict 20, sequence variant 12, modified residue 9, compositionally biased region 8, repeat 7, region of interest 6, splice variant 6, turn 5, helix 4, coiled-coil region 3, mutagenesis site 2, chain 1, domain 1, binding site 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
7KLJ	X-RAY DIFFRACTION	1.52
5YBU	X-RAY DIFFRACTION	1.89
5YBV	X-RAY DIFFRACTION	2.12
5NFD	X-RAY DIFFRACTION	2.18
5D3A	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z4S6-F1	71.16	0.28

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 (9): 1, 524, 1212, 1225, 1229, 1239, 1662, 1664, 1673

Mutagenesis-validated functional residues (2):

Position	Phenotype
1154	very weak binding affinity for kank1 and kank2.
1164	does not bind to kank1 or kank2.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-6811434	COPI-dependent Golgi-to-ER retrograde traffic
R-HSA-983189	Kinesins
R-HSA-109582	Hemostasis
R-HSA-199991	Membrane Trafficking
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-983231	Factors involved in megakaryocyte development and platelet production

MSigDB gene sets: 407 (showing top): GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_CYTOPLASMIC_MICROTUBULE_ORGANIZATION, GOBP_AXO_DENDRITIC_TRANSPORT, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOCC_KINESIN_COMPLEX, chr12q12, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_AXON_GUIDANCE, REACTOME_MEMBRANE_TRAFFICKING, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLUE_UP, BONCI_TARGETS_OF_MIR15A_AND_MIR16_1, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, MARTORIATI_MDM4_TARGETS_NEUROEPITHELIUM_DN

GO Biological Process (6): microtubule-based movement (GO:0007018), anterograde axonal transport (GO:0008089), regulation of microtubule polymerization (GO:0031113), regulation of microtubule depolymerization (GO:0031114), cortical microtubule organization (GO:0043622), regulation of axon guidance (GO:1902667)

GO Molecular Function (9): microtubule motor activity (GO:0003777), ATP binding (GO:0005524), microtubule binding (GO:0008017), plus-end-directed microtubule motor activity (GO:0008574), ATP hydrolysis activity (GO:0016887), ankyrin repeat binding (GO:0071532), nucleotide binding (GO:0000166), cytoskeletal motor activity (GO:0003774), protein binding (GO:0005515)

GO Cellular Component (13): cytoplasm (GO:0005737), cytosol (GO:0005829), kinesin complex (GO:0005871), microtubule (GO:0005874), cell cortex (GO:0005938), dendrite (GO:0030425), axonal growth cone (GO:0044295), presynapse (GO:0098793), axon cytoplasm (GO:1904115), cytoskeleton (GO:0005856), axon (GO:0030424), growth cone (GO:0030426), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Golgi-to-ER retrograde transport	1
Factors involved in megakaryocyte development and platelet production	1
Vesicle-mediated transport	1
Membrane Trafficking	1
Intra-Golgi and retrograde Golgi-to-ER traffic	1
Hemostasis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
regulation of microtubule polymerization or depolymerization	2
regulation of supramolecular fiber organization	2
ATP-dependent activity	2
cytoplasm	2
neuron projection	2
microtubule-based process	1
axonal transport	1
axon cytoplasm	1
regulation of protein polymerization	1
microtubule polymerization	1
microtubule depolymerization	1
regulation of protein depolymerization	1
cortical cytoskeleton organization	1
cytoplasmic microtubule organization	1
axon guidance	1
regulation of neuron projection development	1
regulation of chemotaxis	1
cytoskeletal motor activity	1
polypeptide conformation or assembly isomerase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
tubulin binding	1
microtubule motor activity	1
ribonucleoside triphosphate phosphatase activity	1
protein domain specific binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
binding	1
intracellular anatomical structure	1
microtubule associated complex	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
cell periphery	1
dendritic tree	1
growth cone	1
synapse	1
axon	1
neuron projection cytoplasm	1

Protein interactions and networks

STRING

1382 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KIF21A	PHOX2A	O14813	960
KIF21A	TUBB3	Q13509	941
KIF21A	KANK1	Q14678	835
KIF21A	PHLDB2	Q86SQ0	659
KIF21A	PPFIA1	Q13136	583
KIF21A	CHN1	P15882	546
KIF21A	PTHLH	P12272	512
KIF21A	KLC3	Q6P597	480
KIF21A	PPFIBP1	Q86W92	466
KIF21A	TUBB2B	Q9BVA1	458
KIF21A	ROBO3	Q96MS0	445
KIF21A	DYNC1LI2	O43237	440
KIF21A	ARL14EP	Q8N8R7	434
KIF21A	SALL4	Q9UJQ4	425
KIF21A	CLASP1	Q7Z460	425

IntAct

44 interactions, top by confidence:

A	B	Type	Score
KANK1	KIF21A	psi-mi:“MI:0914”(association)	0.750
KIF21A	KANK1	psi-mi:“MI:0914”(association)	0.750
KIF21A	KANK1	psi-mi:“MI:0915”(physical association)	0.750
KANK1	KIF21A	psi-mi:“MI:0915”(physical association)	0.750
DYNLL1	BLTP3B	psi-mi:“MI:0914”(association)	0.730
ARFGEF1	KIF21A	psi-mi:“MI:0915”(physical association)	0.710
KIF21A	ARFGEF1	psi-mi:“MI:0915”(physical association)	0.710
ARFGEF1	KIF21A	psi-mi:“MI:0403”(colocalization)	0.710
KIF21A	ARFGEF1	psi-mi:“MI:0403”(colocalization)	0.710
P4HA3	FAM171A2	psi-mi:“MI:0914”(association)	0.640
ARFGEF1	KANK1	psi-mi:“MI:0914”(association)	0.630
KIF21A	H2BC13	psi-mi:“MI:0915”(physical association)	0.400
KIF21A	H3-4	psi-mi:“MI:0915”(physical association)	0.400
KANK1	KIF21A	psi-mi:“MI:0915”(physical association)	0.400
KIF21A	KANK1	psi-mi:“MI:0915”(physical association)	0.400
KIF21A	KIF21A	psi-mi:“MI:0915”(physical association)	0.400
Kif21b	TCP1	psi-mi:“MI:0914”(association)	0.350
KIF21A	NCOA4	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
ZDHHC5	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
DCAF4	IGLL5	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
TLK2	IGKV1D-13	psi-mi:“MI:0914”(association)	0.350
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350

BioGRID (138): KIF21A (Affinity Capture-RNA), KIF21A (Affinity Capture-RNA), KIF21A (Affinity Capture-RNA), KIF21A (Affinity Capture-MS), CCT6A (Affinity Capture-MS), MAP3K4 (Affinity Capture-MS), NVL (Affinity Capture-MS), PFDN1 (Affinity Capture-MS), PFDN2 (Affinity Capture-MS), RAD51 (Affinity Capture-MS), RBM4 (Affinity Capture-MS), TBX3 (Affinity Capture-MS), TCP1 (Affinity Capture-MS), CCT3 (Affinity Capture-MS), NCOA4 (Affinity Capture-MS)

ESM2 similar proteins: A0A068FIK2, B3H6Z8, B9F2Y7, B9F7C8, B9FAF3, B9FL70, B9FS33, B9FTR1, B9G8P1, B9GE13, F1M5N7, F4HZF0, F4IAR2, F4IBQ9, F4IGL2, F4IL57, F4J1U4, F4J2M6, F4JUI9, F4JX00, F4K0J3, O75037, O81635, Q0E2L3, Q0IMS9, Q27IK6, Q2QM62, Q58G59, Q5JKW1, Q6H638, Q6YUL8, Q75LL2, Q7M6Z4, Q7XKR9, Q7Z4S6, Q86VH2, Q8GS71, Q8LNZ2, Q8S905, Q8S949

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

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	7
Uncertain significance	257
Likely benign	31
Benign	53

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
2436	NM_001173464.2(KIF21A):c.2860C>T (p.Arg954Trp)	Pathogenic
2437	NM_001173464.2(KIF21A):c.2861G>A (p.Arg954Gln)	Pathogenic
2438	NM_001173464.2(KIF21A):c.3029T>C (p.Ile1010Thr)	Pathogenic
2439	NM_001173464.2(KIF21A):c.1067T>C (p.Met356Thr)	Pathogenic
2440	NM_001173464.2(KIF21A):c.2839A>G (p.Met947Val)	Pathogenic
2441	NM_001173464.2(KIF21A):c.2840T>G (p.Met947Arg)	Pathogenic
2442	NM_001173464.2(KIF21A):c.2841G>A (p.Met947Ile)	Pathogenic
3234052	NM_001173464.2(KIF21A):c.2371del (p.Arg791fs)	Pathogenic
2570656	NM_001173464.2(KIF21A):c.706C>T (p.Gln236Ter)	Likely pathogenic
2630313	NM_001173464.2(KIF21A):c.2840T>C (p.Met947Thr)	Likely pathogenic
2920716	NM_001173464.2(KIF21A):c.2515C>T (p.Pro839Ser)	Likely pathogenic
3775454	NM_001173464.2(KIF21A):c.2861G>T (p.Arg954Leu)	Likely pathogenic
4085289	NM_001173464.2(KIF21A):c.4952G>A (p.Trp1651Ter)	Likely pathogenic
4085290	NM_001173464.2(KIF21A):c.2418+1G>A	Likely pathogenic
432077	NM_001173464.2(KIF21A):c.1991T>C (p.Leu664Pro)	Likely pathogenic

SpliceAI

5408 predictions. Top by Δscore:

Variant	Effect	Δscore
12:39303133:CAT:C	acceptor_gain	1.0000
12:39304816:CATA:C	donor_gain	1.0000
12:39304818:TA:T	donor_loss	1.0000
12:39304819:A:AC	donor_gain	1.0000
12:39304819:ACTTT:A	donor_loss	1.0000
12:39304820:C:CA	donor_gain	1.0000
12:39304820:CT:C	donor_gain	1.0000
12:39304820:CTT:C	donor_gain	1.0000
12:39304820:CTTT:C	donor_gain	1.0000
12:39304820:CTTTG:C	donor_gain	1.0000
12:39304937:AC:A	acceptor_gain	1.0000
12:39304938:CCT:C	acceptor_gain	1.0000
12:39304939:C:CC	acceptor_gain	1.0000
12:39304940:T:C	acceptor_gain	1.0000
12:39304940:T:TC	acceptor_gain	1.0000
12:39304941:T:C	acceptor_gain	1.0000
12:39304941:T:TC	acceptor_gain	1.0000
12:39304947:A:AC	acceptor_gain	1.0000
12:39304947:A:C	acceptor_gain	1.0000
12:39307581:T:TA	donor_gain	1.0000
12:39307729:CCT:C	acceptor_gain	1.0000
12:39307730:C:CC	acceptor_gain	1.0000
12:39307730:C:T	acceptor_gain	1.0000
12:39307731:T:C	acceptor_gain	1.0000
12:39307731:T:TC	acceptor_gain	1.0000
12:39309584:A:AC	donor_gain	1.0000
12:39309585:C:CC	donor_gain	1.0000
12:39318071:A:AC	donor_gain	1.0000
12:39318072:C:CT	donor_gain	1.0000
12:39318072:CTTAT:C	donor_gain	1.0000

AlphaMissense

11077 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:39301608:A:C	S1601R	1.000
12:39301608:A:T	S1601R	1.000
12:39301610:T:G	S1601R	1.000
12:39302992:C:A	W1568C	1.000
12:39302992:C:G	W1568C	1.000
12:39302994:A:G	W1568R	1.000
12:39302994:A:T	W1568R	1.000
12:39303011:T:A	D1562V	1.000
12:39303012:C:G	D1562H	1.000
12:39303022:A:C	S1558R	1.000
12:39303022:A:T	S1558R	1.000
12:39303024:T:G	S1558R	1.000
12:39307578:A:G	W1477R	1.000
12:39307578:A:T	W1477R	1.000
12:39309626:A:G	W1413R	1.000
12:39309626:A:T	W1413R	1.000
12:39309747:C:A	W1372C	1.000
12:39309747:C:G	W1372C	1.000
12:39309749:A:G	W1372R	1.000
12:39309749:A:T	W1372R	1.000
12:39311434:A:G	L1360P	1.000
12:39311437:A:G	L1359P	1.000
12:39311485:G:T	A1343D	1.000
12:39332404:C:G	R954P	1.000
12:39337196:A:G	L773P	1.000
12:39341025:A:G	L664P	1.000
12:39341037:A:G	L660P	1.000
12:39356835:A:G	L489P	1.000
12:39357349:A:G	L435P	1.000
12:39357370:A:G	L428P	1.000

dbSNP variants (sampled 300 via entrez): RS1000082874 (12:39306245 A>G), RS1000085340 (12:39376070 C>T), RS1000101583 (12:39353394 T>G), RS1000122009 (12:39419884 G>A,T), RS1000127525 (12:39317284 T>A), RS1000138765 (12:39323742 C>T), RS1000155486 (12:39327209 A>G), RS1000191710 (12:39420131 A>G), RS1000196441 (12:39335723 T>C), RS1000213267 (12:39380769 T>G), RS1000244506 (12:39380448 T>C,G), RS1000247553 (12:39426783 C>G), RS1000280961 (12:39360072 T>C), RS1000292223 (12:39381835 G>T), RS1000316589 (12:39335409 TCAAAAAAAAAAAAAAA>T)

Disease associations

OMIM: gene MIM:608283 | disease phenotypes: MIM:135700

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital fibrosis of extraocular muscles	Definitive	Autosomal dominant
congenital fibrosis of extraocular muscles type 1	Definitive	Autosomal dominant
arthrogryposis multiplex congenita	Moderate	Autosomal recessive
fibrosis of extraocular muscles, congenital, 3b	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital fibrosis of extraocular muscles	Definitive	AD

Mondo (5): congenital fibrosis of extraocular muscles type 1 (MONDO:0021083), aniridia (MONDO:0019172), fibrosis of extraocular muscles, congenital, 3b (MONDO:0800209), congenital fibrosis of extraocular muscles (MONDO:0007614), arthrogryposis multiplex congenita (MONDO:0015168)

Orphanet (2): Congenital fibrosis of extraocular muscles (Orphanet:45358), OBSOLETE: Aniridia (Orphanet:77)

HPO phenotypes

66 total (30 of 66 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000175	Cleft palate
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000473	Torticollis
HP:0000476	Cystic hygroma
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000512	Abnormal electroretinogram
HP:0000518	Cataract
HP:0000539	Abnormality of refraction
HP:0000542	Impaired ocular adduction
HP:0000565	Esotropia
HP:0000577	Exotropia
HP:0000609	Optic nerve hypoplasia
HP:0000616	Miosis
HP:0000646	Amblyopia
HP:0001059	Pterygium
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001262	Excessive daytime somnolence
HP:0001305	Dandy-Walker malformation
HP:0001357	Plagiocephaly
HP:0001477	Compensatory chin elevation
HP:0001488	Bilateral ptosis
HP:0001491	Congenital fibrosis of extraocular muscles
HP:0001511	Intrauterine growth retardation

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST007565_196	Morning person	6.000000e-29
GCST007565_63	Morning person	1.000000e-17

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D015783	Aniridia	C11.250.060; C11.270.060; C11.941.375.060; C16.131.384.079; C16.320.290.078
C580012	congenital fibrosis of the extraocular muscles (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5169171 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment, increases expression	2
Estradiol	affects expression, increases reaction, increases expression	2
Cyclosporine	increases expression	2
Aflatoxin B1	increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
sodium arsenate	decreases expression	1
methylparaben	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	increases expression	1
coumarin	affects phosphorylation	1
perfluorooctane sulfonic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
K 7174	increases expression	1
2,2’,4,4’,5-brominated diphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
(+)-JQ1 compound	increases expression	1
Aspirin	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	increases expression	1
Doxorubicin	decreases expression	1

ChEMBL screening assays

4 unique, capped per target: 3 binding, 1 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5117279	Binding	Inhibition of Kir2.1 (unknown origin)	Discovery and preclinical evaluations of JBD0131, a novel nitrodihydro-imidazooxazole anti-tuberculosis agent. — Bioorg Med Chem Lett
CHEMBL5258219	Toxicity	Inhibition of Kir2.1 (unknown origin) at 10 uM	Discovery of VU2957 (Valiglurax): An mGlu4 Positive Allosteric Modulator Evaluated as a Preclinical Candidate for the Treatment of Parkinson’s Disease. — ACS Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02647359	PHASE2	COMPLETED	Study of Ataluren in Participants With Nonsense Mutation Aniridia
NCT04117880	PHASE2	WITHDRAWN	A Phase 2 Open Label Extension Study in Participants With Nonsense Mutation Aniridia
NCT05909735	PHASE1	COMPLETED	Treatment of LSCD With DM
NCT05393375	Not specified	COMPLETED	Arthrogryposis Multiplex Congenita in Pediatric Age: Correlation Between MUScular MRI and Functional Evaluation
NCT05673265	Not specified	UNKNOWN	Pediatric and Adult Registry for Patients With ARThrogryposis
NCT06130592	Not specified	UNKNOWN	Technical Feasibility Study of Ultrasound Muscle Imaging in Antenatal Ultrasound
NCT07360574	Not specified	NOT_YET_RECRUITING	Piezo2-related Arthrogryposis & physiopathOLOgy 3
NCT03059420	Not specified	RECRUITING	Genetic Studies of Strabismus, Congenital Cranial Dysinnervation Disorders (CCDDs), and Their Associated Anomalies
NCT05044598	PHASE1/PHASE2	COMPLETED	RAFT - Clinical Trial of RAFT for Aniridia Related Keratopathy
NCT00001161	Not specified	COMPLETED	Abnormalities of the Eye’s Anterior Chamber, Iris, Cornea and Lens
NCT00265590	Not specified	COMPLETED	Correlation of Gene Abnormalities and Clinical Manifestations of Aniridia
NCT00503893	Not specified	UNKNOWN	Genetics of Wilms’ Tumor and/or the Associated Conditions of Aniridia, Hemihypertrophy, and Genitourinary Anomalies
NCT00758108	Not specified	COMPLETED	Characterization of WAGR Syndrome and Other Chromosome 11 Gene Deletions
NCT00812708	Not specified	COMPLETED	Clinical Evaluation of Morcher Artificial Iris Diaphragms
NCT01644552	Not specified	COMPLETED	Positive Angle Kappa
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02945176	Not specified	COMPLETED	Safety and Performance Study of the ARGOS-IO System in Patients Undergoing Boston Keratoprosthesis Implantation
NCT03461978	Not specified	COMPLETED	Ultrahigh-resolution Optical Coherence Tomography Imaging of the Anterior Eye Segment Structures
NCT03581864	Not specified	COMPLETED	Clinical Outcomes of Implantationof Black Diaphragm Intraocular Lens in Complete Aniridia and Aphakia Due to Posttraumatic Eye Rupture
NCT05390801	Not specified	RECRUITING	Congenital Aniridia Patient Questionnaire
NCT05400590	Not specified	RECRUITING	Comparison of the Healing Properties on Corneal Cells of Groth Factor-enriched Plasma and Autologous Serum From Aniridia Patients
NCT05562115	Not specified	COMPLETED	Proteomic Study of Tears From Patients With a PAX6 Mutation
NCT05954403	Not specified	RECRUITING	National Cohort on Congenital Defects of the Eye
NCT06412718	Not specified	UNKNOWN	Validation of Human Drugs Target of Repurposed Drugs and Novel Therapies
NCT06491615	Not specified	RECRUITING	National Ophthalmic Genotyping and Phenotyping Network (eyeGENE (Registered Trademark)), Stage 3 - Expansion of DNA and Data Repositories for Rare Inherited Ophthalmic Diseases