NEK4

Summary

NEK4 (NIMA related kinase 4, HGNC:11399) is a protein-coding gene on chromosome 3p21.1, encoding Serine/threonine-protein kinase Nek4 (P51957). Protein kinase that seems to act exclusively upon threonine residues.

The protein encoded by this gene is a serine/threonine protein kinase required for normal entry into replicative senescence. The encoded protein also is involved in cell cycle arrest in response to double-stranded DNA damage. Finally, this protein plays a role in maintaining cilium integrity, and defects in this gene have been associated with ciliopathies.

Source: NCBI Gene 6787 — RefSeq curated summary.

At a glance

• GWAS associations: 25
• Clinical variants (ClinVar): 141 total — 1 likely-pathogenic
• Druggable target: yes — 9 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003157

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11399
Approved symbol	NEK4
Name	NIMA related kinase 4
Location	3p21.1
Locus type	gene with protein product
Status	Approved
Aliases	NRK2, pp12301
Ensembl gene	ENSG00000114904
Ensembl biotype	protein_coding
OMIM	601959
Entrez	6787

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 19 protein_coding, 2 nonsense_mediated_decay, 1 retained_intron

ENST00000233027, ENST00000383721, ENST00000461689, ENST00000487068, ENST00000493199, ENST00000496822, ENST00000535191, ENST00000862198, ENST00000862199, ENST00000862200, ENST00000862201, ENST00000862202, ENST00000911340, ENST00000911341, ENST00000911342, ENST00000944571, ENST00000944572, ENST00000944573, ENST00000944574, ENST00000944575, ENST00000944576, ENST00000944577

RefSeq mRNA: 5 — MANE Select: NM_003157 NM_001193533, NM_001348412, NM_001348413, NM_001348414, NM_003157

CCDS: CCDS2863, CCDS54593, CCDS87089

Canonical transcript exons

ENST00000233027 — 16 exons

Exon	Start	End
ENSE00000771354	52739429	52739634
ENSE00000771355	52741411	52741499
ENSE00000771358	52746061	52746210
ENSE00000771360	52749692	52749829
ENSE00000771361	52751932	52752336
ENSE00000771362	52760795	52760936
ENSE00000771363	52763470	52763624
ENSE00000771364	52765887	52765994
ENSE00000771365	52766178	52766375
ENSE00000771366	52768338	52768604
ENSE00001127829	52743352	52743461
ENSE00001127938	52708444	52711869
ENSE00001956216	52770654	52770940
ENSE00003593211	52744239	52744305
ENSE00003689367	52746734	52746904
ENSE00003789347	52737586	52737719

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 92.59.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.3483 / max 157.8797, expressed in 1790 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42469	13.3483	1790

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bronchial epithelial cell	CL:0002328	92.59	gold quality
choroid plexus epithelium	UBERON:0003911	92.18	gold quality
adult organism	UBERON:0007023	91.08	gold quality
ventricular zone	UBERON:0003053	89.70	gold quality
secondary oocyte	CL:0000655	89.62	gold quality
sperm	CL:0000019	87.87	gold quality
monocyte	CL:0000576	87.84	gold quality
testis	UBERON:0000473	87.80	gold quality
left testis	UBERON:0004533	87.63	gold quality
right testis	UBERON:0004534	87.51	gold quality
mucosa of paranasal sinus	UBERON:0005030	87.44	gold quality
mononuclear cell	CL:0000842	87.30	gold quality
endothelial cell	CL:0000115	87.13	gold quality
pigmented layer of retina	UBERON:0001782	87.04	gold quality
leukocyte	CL:0000738	86.79	gold quality
caput epididymis	UBERON:0004358	86.72	gold quality
epithelium of bronchus	UBERON:0002031	86.65	gold quality
germinal epithelium of ovary	UBERON:0001304	86.29	gold quality
male germ cell	CL:0000015	86.24	gold quality
ganglionic eminence	UBERON:0004023	86.20	gold quality
bronchus	UBERON:0002185	86.15	gold quality
eye	UBERON:0000970	85.75	gold quality
corpus epididymis	UBERON:0004359	85.48	gold quality
palpebral conjunctiva	UBERON:0001812	85.40	gold quality
epithelium of nasopharynx	UBERON:0001951	85.28	gold quality
nasopharynx	UBERON:0001728	85.27	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.21	gold quality
cortical plate	UBERON:0005343	85.21	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.68	gold quality
seminal vesicle	UBERON:0000998	84.48	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.76

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

54 targeting NEK4, 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-3163	100.00	77.23	8605
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-200A-5P	99.76	69.10	949
HSA-MIR-200B-5P	99.76	69.05	948
HSA-MIR-12129	99.72	67.45	1311
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-545-5P	99.66	70.18	2308
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-549A-3P	99.54	68.17	825
HSA-MIR-154-3P	99.50	70.05	831
HSA-MIR-487A-3P	99.50	69.95	840
HSA-MIR-3128	99.50	67.85	1258
HSA-MIR-3123	99.47	67.15	2693

Literature-anchored findings (GeneRIF, showing 7)

• Data show that after Taxol treatment, Nek4 promoted microtubule outgrowth, whereas Nek4 deficiency impaired G(2)-M arrest and decreased formation of mitotic-like asters. (PMID:20103636)
• Nek4 interaction with both RPGRIP1 and the RPGRIP1L is involved in cilium assembly. (PMID:21685204)
• Nek4 as a novel regulator of replicative senescence and the response to double-stranded DNA damage. (PMID:22851694)
• High NEK4 expression is associated with lung cancer and colorectal cancer. (PMID:27602754)
• this study demonstrates NEK4 as a novel kinase involved in regulation of Epithelial-to-mesenchymal transition. (PMID:30247800)
• NRK-2 deficiency promotes post-MI scar expansion, rapid LV chamber dilatation, cardiac dysfunction and fibrosis possibly due to increased p38alpha activation. (PMID:31743747)
• Unraveling NEK4 as a Potential Drug Target in Schizophrenia and Bipolar I Disorder: A Proteomic and Genomic Approach. (PMID:38869147)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nek4	ENSDARG00000040152
mus_musculus	Nek4	ENSMUSG00000021918
rattus_norvegicus	Nek4	ENSRNOG00000017997

Paralogs (35): MAP3K14 (ENSG00000006062), MAP4K3 (ENSG00000011566), MAP4K5 (ENSG00000012983), MAP2K3 (ENSG00000034152), SLK (ENSG00000065613), MAP4K4 (ENSG00000071054), STK10 (ENSG00000072786), PAK3 (ENSG00000077264), STRADB (ENSG00000082146), MAP3K1 (ENSG00000095015), STK4 (ENSG00000101109), PAK5 (ENSG00000101349), STK24 (ENSG00000102572), STK3 (ENSG00000104375), MAP4K1 (ENSG00000104814), MAP3K8 (ENSG00000107968), MAP2K6 (ENSG00000108984), STK25 (ENSG00000115694), NRK (ENSG00000123572), PAK4 (ENSG00000130669), STK26 (ENSG00000134602), TAOK3 (ENSG00000135090), PAK6 (ENSG00000137843), MINK1 (ENSG00000141503), PAK1 (ENSG00000149269), TAOK2 (ENSG00000149930), TNIK (ENSG00000154310), TAOK1 (ENSG00000160551), MAP4K2 (ENSG00000168067), OXSR1 (ENSG00000172939), MAP3K19 (ENSG00000176601), PAK2 (ENSG00000180370), SBK2 (ENSG00000187550), STK39 (ENSG00000198648), STRADA (ENSG00000266173)

Protein

Protein identifiers

Serine/threonine-protein kinase Nek4 — P51957 (reviewed: P51957)

Alternative names: Never in mitosis A-related kinase 4, Serine/threonine-protein kinase 2, Serine/threonine-protein kinase NRK2

All UniProt accessions (4): P51957, E7EX48, F8WAX1, H7C5M0

UniProt curated annotations — full annotation on UniProt →

Function. Protein kinase that seems to act exclusively upon threonine residues. Required for normal entry into proliferative arrest after a limited number of cell divisions, also called replicative senescence. Required for normal cell cycle arrest in response to double-stranded DNA damage.

Subunit / interactions. Interacts with RPGRIP1 and RPGRIP1L.

Subcellular location. Cell projection. Cilium. Cytoplasm.

Tissue specificity. Highest expression in adult heart, followed by pancreas, skeletal muscle, brain, testis, retina, liver, kidney, lung and placenta. Present in most primary carcinomas.

Similarity. Belongs to the protein kinase superfamily. NEK Ser/Thr protein kinase family. NIMA subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P51957-1	1	yes
P51957-2	2
P51957-3	3

RefSeq proteins (5): NP_001180462, NP_001335341, NP_001335342, NP_001335343, NP_003148* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR051131	NEK_Ser/Thr_kinase_NIMA	Family

Pfam: PF00069

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (30 total): modified residue 7, sequence variant 7, compositionally biased region 4, splice variant 3, sequence conflict 3, binding site 2, chain 1, domain 1, region of interest 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51957-F1	58.95	0.25

Functional residue map

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

Catalytic / active sites (1): 131 (proton acceptor)

Ligand- & substrate-binding residues (2): 12–20; 35

Post-translational modifications (7): 165, 340, 343, 461, 563, 622, 723

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 0 (showing top):

GO Biological Process (6): mitotic cell cycle (GO:0000278), protein phosphorylation (GO:0006468), DNA damage response (GO:0006974), positive regulation of DNA-templated transcription (GO:0045893), cell division (GO:0051301), regulation of cellular senescence (GO:2000772)

GO Molecular Function (9): protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), manganese ion binding (GO:0030145), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (8): cytoplasm (GO:0005737), cytosol (GO:0005829), ciliary rootlet (GO:0035253), ciliary transition zone (GO:0035869), ciliary basal body (GO:0036064), ciliary plasm (GO:0097014), cilium (GO:0005929), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cilium	4
protein kinase activity	2
cytoplasm	2
cell cycle	1
mitotic nuclear division	1
phosphorylation	1
protein modification process	1
cellular response to stress	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
cellular process	1
regulation of cellular process	1
cellular senescence	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transition metal ion binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
cytoskeleton	1
microtubule organizing center	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

2064 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NEK4	RPGRIP1L	Q68CZ1	736
NEK4	RCC1L	Q96I51	618
NEK4	ITIH3	Q06033	612
NEK4	GLT8D1	Q68CQ7	612
NEK4	RPGRIP1	Q96KN7	596
NEK4	TSKS	Q9UJT2	585
NEK4	MKNK2	Q9HBH9	535
NEK4	NEK6	Q9HC98	529
NEK4	SPAG17	Q6Q759	499
NEK4	D6RI10	D6RI10	495
NEK4	ITIH1	P19827	481
NEK4	GNL3	Q9BVP2	479
NEK4	RCC1	P18754	465
NEK4	SDCCAG8	Q86SQ7	459
NEK4	BICD2	Q8TD16	436

IntAct

60 interactions, top by confidence:

A	B	Type	Score
PRKAB1	PRKAB2	psi-mi:“MI:0914”(association)	0.740
RPGRIP1	NEK4	psi-mi:“MI:0914”(association)	0.620
CD79A	METTL15	psi-mi:“MI:0914”(association)	0.530
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
ISLR	BCKDK	psi-mi:“MI:0914”(association)	0.530
PLAUR	XRCC3	psi-mi:“MI:0914”(association)	0.530
SDF4	GTPBP6	psi-mi:“MI:0914”(association)	0.530
NEK4	SLC25A4	psi-mi:“MI:0914”(association)	0.510
RPGRIP1L	KIF2A	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
RPGRIP1L	NPHP1	psi-mi:“MI:0914”(association)	0.350
NEK4	QSOX1	psi-mi:“MI:0914”(association)	0.350
NEK4	PGRMC1	psi-mi:“MI:0914”(association)	0.350
FKBP5	IFT56	psi-mi:“MI:0914”(association)	0.350
PTGES3	KIFBP	psi-mi:“MI:0914”(association)	0.350
SPACA1	ESYT2	psi-mi:“MI:0914”(association)	0.350
HLA-DRA	TMEM223	psi-mi:“MI:0914”(association)	0.350
PDGFRA	GXYLT2	psi-mi:“MI:0914”(association)	0.350
RAMP2	GXYLT2	psi-mi:“MI:0914”(association)	0.350
PIPSL	C1orf226	psi-mi:“MI:0914”(association)	0.350
FTL	SH3PXD2B	psi-mi:“MI:0914”(association)	0.350
PTGES3	SBNO1	psi-mi:“MI:0914”(association)	0.350
PCDHA12	KLRG2	psi-mi:“MI:0914”(association)	0.350
TMEM74	KLRG2	psi-mi:“MI:0914”(association)	0.350
DNAJA2	DENND11	psi-mi:“MI:0914”(association)	0.350
GLMP	RTL8C	psi-mi:“MI:0914”(association)	0.350
SKAP1	MYO9A	psi-mi:“MI:0914”(association)	0.350
SLC18A1	UBXN8	psi-mi:“MI:0914”(association)	0.350

BioGRID (630): NEK4 (Affinity Capture-MS), NEK4 (Affinity Capture-MS), NEK4 (Affinity Capture-MS), NEK4 (Affinity Capture-MS), NEK4 (Affinity Capture-MS), NEK4 (Affinity Capture-MS), NEK4 (Affinity Capture-MS), NEK4 (Affinity Capture-MS), NEK4 (Affinity Capture-MS), NEK4 (Affinity Capture-MS), NEK4 (Affinity Capture-MS), NEK4 (Affinity Capture-MS), NEK4 (Affinity Capture-MS), NEK4 (Affinity Capture-MS), NEK4 (Affinity Capture-MS)

ESM2 similar proteins: A0AUV4, A0JM98, A1A5Q6, A2KF29, B1WAS2, C0HKC8, C0HKC9, O60285, O70551, O88866, P51957, P57058, P57059, Q2T9U5, Q4R9F7, Q5R7G9, Q5RD27, Q5REX1, Q5XHI9, Q60670, Q641K5, Q66HE5, Q68UT7, Q6IFT4, Q6P3R8, Q6REY9, Q6VZ17, Q80VH0, Q8BI55, Q8BLD6, Q8BZN4, Q8C0N0, Q8C0V7, Q8C0X8, Q8CFH6, Q8NE63, Q8TF76, Q96SB4, Q9H093, Q9H0K1

Diamond homologs: A0A096LPI5, A6NIU2, A6NJG6, F2Z398, P0DTE4, P51957, Q09FC8, Q5H9K5, Q5T7P6, Q68CZ1, Q6B4Z3, Q6UX73, Q86U02, Q8IV13, Q8N7M2, Q8N9N2, Q8NDZ0, Q8NEM8, Q8TDM0, Q92918, Q96J02, Q96MD7, Q9BUA6, Q9NXG0, A0A7J6K7I9, A0A7J6K7Y0, A0A7J6KD88, A2QHV0, A8XJQ6, C4YRB7, O13839, O14047, O34507, O75011, O80888, O88664, P0CY23, P0CY24, P16912, P27636

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 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
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	6	23.7×	6e-05
Translocation of SLC2A4 (GLUT4) to the plasma membrane	5	15.8×	2e-03
MHC class II antigen presentation	5	9.1×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	102
Likely benign	13
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
266082	NM_003157.6(NEK4):c.2017dup (p.Ile673fs)	Likely pathogenic

SpliceAI

2435 predictions. Top by Δscore:

Variant	Effect	Δscore
3:52737581:CTCA:C	donor_loss	1.0000
3:52737582:TCACC:T	donor_loss	1.0000
3:52737583:CACCT:C	donor_loss	1.0000
3:52737584:A:AC	donor_gain	1.0000
3:52737584:A:C	donor_loss	1.0000
3:52737585:C:CC	donor_gain	1.0000
3:52737585:C:CT	donor_loss	1.0000
3:52737585:CCT:C	donor_gain	1.0000
3:52737585:CCTCT:C	donor_gain	1.0000
3:52737715:AATAG:A	acceptor_gain	1.0000
3:52737716:ATAG:A	acceptor_gain	1.0000
3:52737717:TAG:T	acceptor_gain	1.0000
3:52737718:AG:A	acceptor_gain	1.0000
3:52737720:C:CC	acceptor_gain	1.0000
3:52737720:CTAAA:C	acceptor_loss	1.0000
3:52737721:T:G	acceptor_loss	1.0000
3:52739424:ATCAC:A	donor_loss	1.0000
3:52739426:CACC:C	donor_loss	1.0000
3:52739427:A:C	donor_loss	1.0000
3:52739428:CCTG:C	donor_loss	1.0000
3:52739455:T:A	donor_gain	1.0000
3:52739630:CTTTC:C	acceptor_gain	1.0000
3:52739633:TC:T	acceptor_gain	1.0000
3:52739634:CC:C	acceptor_gain	1.0000
3:52739635:C:CC	acceptor_gain	1.0000
3:52744233:CTTTA:C	donor_loss	1.0000
3:52744234:TTTA:T	donor_loss	1.0000
3:52744236:TAC:T	donor_loss	1.0000
3:52744238:C:CT	donor_loss	1.0000
3:52744304:TCC:T	acceptor_loss	1.0000

AlphaMissense

5485 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:52763544:C:A	R249S	1.000
3:52763544:C:G	R249S	1.000
3:52763545:C:A	R249M	1.000
3:52763566:A:G	L242P	1.000
3:52765935:G:C	F206L	1.000
3:52765935:G:T	F206L	1.000
3:52765936:A:G	F206S	1.000
3:52765937:A:G	F206L	1.000
3:52765937:A:T	F206I	1.000
3:52765939:G:T	A205D	1.000
3:52765960:T:A	E198V	1.000
3:52765971:G:C	C194W	1.000
3:52765973:A:G	C194R	1.000
3:52765975:C:T	G193E	1.000
3:52765976:C:G	G193R	1.000
3:52765976:C:T	G193R	1.000
3:52765978:A:G	L192P	1.000
3:52765983:C:A	W190C	1.000
3:52765983:C:G	W190C	1.000
3:52765984:C:G	W190S	1.000
3:52765985:A:G	W190R	1.000
3:52765985:A:T	W190R	1.000
3:52765990:T:A	D188V	1.000
3:52765990:T:C	D188G	1.000
3:52765990:T:G	D188A	1.000
3:52765991:C:A	D188Y	1.000
3:52765991:C:G	D188H	1.000
3:52766214:G:C	S174R	1.000
3:52766214:G:T	S174R	1.000
3:52766216:T:G	S174R	1.000

dbSNP variants (sampled 300 via entrez): RS1000011731 (3:52715492 T>C), RS1000040160 (3:52722395 C>A), RS1000054705 (3:52758402 C>T), RS1000120225 (3:52716899 C>G,T), RS1000132726 (3:52747858 T>C), RS1000133128 (3:52760962 T>C), RS1000205673 (3:52715155 G>A), RS1000221164 (3:52770934 C>G,T), RS1000240287 (3:52716540 A>G), RS1000248099 (3:52764446 A>G), RS1000279896 (3:52722159 A>C), RS1000296187 (3:52710439 C>CAAAG), RS1000304952 (3:52734873 T>A), RS1000369428 (3:52752074 T>A,G), RS1000436433 (3:52753884 T>C)

Disease associations

OMIM: gene MIM:601959 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): ciliopathy (MONDO:0005308)

Orphanet (1): Ciliopathy (Orphanet:363250)

HPO phenotypes

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

GWAS associations

25 associations (top):

Study	Trait	p-value
GCST000387_7	Bipolar disorder	2.000000e-07
GCST001241_15	Bipolar disorder	2.000000e-06
GCST002149_14	Schizophrenia	1.000000e-08
GCST002539_48	Schizophrenia	4.000000e-11
GCST004521_123	Autism spectrum disorder or schizophrenia	3.000000e-12
GCST004521_201	Autism spectrum disorder or schizophrenia	4.000000e-08
GCST004521_259	Autism spectrum disorder or schizophrenia	6.000000e-09
GCST004611_51	High light scatter reticulocyte count	4.000000e-13
GCST004904_66	Body mass index	4.000000e-11
GCST004946_141	Schizophrenia	5.000000e-13
GCST005316_398	Intelligence (MTAG)	2.000000e-08
GCST006803_55	Schizophrenia	1.000000e-11
GCST006948_17	Feeling nervous	2.000000e-09
GCST008103_3	Bipolar disorder	7.000000e-11
GCST008839_79	Height	8.000000e-14
GCST010698_14	Subcortical volume (min-P)	8.000000e-09
GCST010699_73	Brain morphology (min-P)	1.000000e-18
GCST010701_137	Cortical surface area (MOSTest)	8.000000e-10
GCST010702_70	Subcortical volume (MOSTest)	2.000000e-11
GCST010703_327	Brain morphology (MOSTest)	1.000000e-10
GCST012226_615	Waist circumference adjusted for body mass index	8.000000e-11
GCST012226_618	Waist circumference adjusted for body mass index	6.000000e-12
GCST012228_62	Waist-hip index	3.000000e-15
GCST012230_263	Waist-to-hip ratio adjusted for BMI	2.000000e-14
GCST012231_186	A body shape index	2.000000e-11

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count
EFO:0004340	body mass index
EFO:0004337	intelligence
EFO:0009597	feeling nervous measurement
EFO:0004346	neuroimaging measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL4524130 (PROTEIN FAMILY), CHEMBL5819 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

9 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 12,259 (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
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL1967878	CENISERTIB	2	358
CHEMBL1980297	ILORASERTIB	2	581
CHEMBL475251	R-406	2	762
CHEMBL1908397	KW-2449	1	622
CHEMBL482767	SNS-314	1	336
CHEMBL482967	CYC-116	1	651
CHEMBL574738	AST-487	1	451

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs112242273	NEK4	3	0.00	1	cyclophosphamide;epirubicin;fluorouracil

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — NIMA (never in mitosis gene a)- related kinase (NEK) family

ChEMBL bioactivities

209 potent at pChembl≥5 of 209 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.30	Ki	5.012	nM	CHEMBL1997129
8.20	Ki	6.31	nM	CHEMBL1241473
8.00	Ki	10	nM	CHEMBL1987034
7.90	Ki	12.59	nM	CHEMBL244378
7.90	Ki	12.59	nM	CHEMBL396523
7.80	Ki	15.85	nM	CHEMBL1993661
7.60	Ki	25.12	nM	CHEMBL1190711
7.40	Ki	39.81	nM	CHEMBL243088
7.32	IC50	48	nM	CHEMBL4568087
7.31	IC50	49.3	nM	STAUROSPORINE
7.30	IC50	50	nM	CHEMBL497151
7.30	Ki	50.12	nM	CHEMBL1965660
7.30	Ki	50.12	nM	CHEMBL497151
7.20	Ki	63.1	nM	CHEMBL1988163
7.13	IC50	74.2	nM	STAUROSPORINE
7.10	IC50	80	nM	CHEMBL5278787
7.10	IC50	79.43	nM	CHEMBL5278787
7.10	Ki	79.43	nM	CHEMBL1990254
7.02	IC50	96	nM	STAUROSPORINE
7.00	Ki	100	nM	CHEMBL1976240
6.90	Ki	125.9	nM	CHEMBL2000345
6.90	Ki	125.9	nM	CHEMBL1991063
6.80	IC50	160	nM	CHEMBL4569508
6.80	Ki	158.5	nM	CHEMBL1981079
6.80	Ki	158.5	nM	CHEMBL1999931
6.70	IC50	200	nM	ILORASERTIB
6.70	Ki	199.5	nM	CHEMBL1983111
6.70	Ki	199.5	nM	CHEMBL592030
6.70	Ki	199.5	nM	R-406
6.70	Ki	199.5	nM	ILORASERTIB
6.62	IC50	240	nM	CHEMBL4550702
6.60	Ki	251.2	nM	SNS-314
6.60	Ki	251.2	nM	CHEMBL1965836
6.60	Ki	251.2	nM	CHEMBL1978448
6.60	Ki	251.2	nM	CHEMBL1994241
6.60	Ki	251.2	nM	CHEMBL1988838
6.60	Ki	251.2	nM	CHEMBL1974870
6.60	Ki	251.2	nM	CHEMBL1990254
6.50	IC50	316	nM	CHEMBL1994830
6.50	Ki	316.2	nM	CHEMBL1998159
6.50	Ki	316.2	nM	CHEMBL1988387
6.50	Ki	316.2	nM	CHEMBL458997
6.50	Ki	316.2	nM	CHEMBL1981410
6.50	Ki	316.2	nM	CHEMBL1969523
6.50	Ki	316.2	nM	CHEMBL1994830
6.40	Ki	398.1	nM	CHEMBL1986263
6.40	Ki	398.1	nM	CYC-116
6.40	Ki	398.1	nM	CENISERTIB
6.34	Kd	460	nM	AST-487
6.32	IC50	480	nM	CHEMBL4552628

PubChem BioAssay actives

25 with measured affinity, of 896 total; 18 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
N-[(1R,2S)-2-aminocyclohexyl]-4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]thiophene-2-carboxamide	1637112: Inhibition of full-length recombinant human GST-tagged NEK4 expressed in baculovirus expression system by Z’-LYTE assay	ic50	0.0480	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	2198343: Inhibition of human NEK4 using myelin basic protein as substrate preincubated for 20 mins followed by [gamma-33P]-ATP addition and measured after 120 mins by radiometric Hot-SpotSM Kinase assay	ic50	0.0493	uM
3-[4-(4-iodophenoxy)thieno[2,3-c]pyridin-2-yl]-4H-1,2,4-oxadiazol-5-one	1948852: Inhibition of NEK4 (unknown origin)	ic50	0.0500	uM
N-[(1S)-2-amino-1-phenylethyl]-4-pyridin-4-ylbenzamide	1948852: Inhibition of NEK4 (unknown origin)	ic50	0.0794	uM
4-[6-[4-(2-piperidin-1-ylethoxy)phenyl]pyrazolo[1,5-a]pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide	1637112: Inhibition of full-length recombinant human GST-tagged NEK4 expressed in baculovirus expression system by Z’-LYTE assay	ic50	0.1600	uM
1-[4-[4-amino-7-[1-(2-hydroxyethyl)pyrazol-4-yl]thieno[3,2-c]pyridin-3-yl]phenyl]-3-(3-fluorophenyl)urea	1948852: Inhibition of NEK4 (unknown origin)	ic50	0.2000	uM
4-[6-(1-methylpyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl]-N-(2,2,2-trifluoroethyl)thiophene-2-carboxamide	1637112: Inhibition of full-length recombinant human GST-tagged NEK4 expressed in baculovirus expression system by Z’-LYTE assay	ic50	0.2400	uM
5-[4-(4-chlorophenoxy)thieno[2,3-c]pyridin-2-yl]-1,3,4-oxadiazol-2-amine	1948852: Inhibition of NEK4 (unknown origin)	ic50	0.3160	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	1948825: Inhibition of NEK4 (unknown origin) assessed as dissociation constant	kd	0.4600	uM
N-[(1R,6R)-6-amino-2,2-difluorocyclohexyl]-4-(6-chloropyrazolo[1,5-a]pyrimidin-3-yl)-5-methylthiophene-2-carboxamide	1637112: Inhibition of full-length recombinant human GST-tagged NEK4 expressed in baculovirus expression system by Z’-LYTE assay	ic50	0.4800	uM
3-(2-methyl-1H-indol-5-yl)-7-(3-methylsulfonylphenyl)thieno[3,2-c]pyridin-4-amine	1948852: Inhibition of NEK4 (unknown origin)	ic50	1.0000	uM
2-methyl-5-[4-[4-(trifluoromethyl)phenoxy]thieno[2,3-c]pyridin-2-yl]-1,3,4-oxadiazole	1948852: Inhibition of NEK4 (unknown origin)	ic50	1.0000	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	1948825: Inhibition of NEK4 (unknown origin) assessed as dissociation constant	kd	1.1000	uM
1-[5-(4-amino-7-methylpyrrolo[2,3-d]pyrimidin-5-yl)-2,3-dihydroindol-1-yl]-2-[3-(trifluoromethyl)phenyl]ethanone	702092: Inhibition of NEK4	ic50	1.4020	uM
Fedratinib	1948825: Inhibition of NEK4 (unknown origin) assessed as dissociation constant	kd	1.6000	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	1948825: Inhibition of NEK4 (unknown origin) assessed as dissociation constant	kd	1.8000	uM
4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one	624904: Binding constant for NEK4 kinase domain	kd	2.7000	uM
2-anilino-7-[(1S)-4-hydroxy-2,3-dihydro-1H-inden-1-yl]-5,5-dimethylpyrrolo[2,3-d]pyrimidin-6-one	1336100: Inhibition of human recombinant full length GST-tagged NEK4 expressed in baculovirus expression system	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects expression, increases abundance, decreases expression	2
Arsenic	increases abundance, increases expression, affects methylation, affects cotreatment	2
Tetrachlorodibenzodioxin	decreases expression	2
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
butyraldehyde	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
2,3-dimethoxy-1,4-naphthoquinone	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Caffeine	affects phosphorylation	1
Estradiol	affects expression	1
Fluorouracil	decreases expression	1
Formaldehyde	decreases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Methyl Methanesulfonate	increases expression	1
Nickel	decreases expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	increases expression, affects cotreatment	1
Quercetin	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Valproic Acid	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	1
Cyclosporine	increases expression	1
Gold Compounds	decreases expression	1
Copper Sulfate	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

171 unique, capped per target: 170 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4887137	Binding	NEK Invitrogen kinase activity assay	Data for DCP probe PF-04554878
CHEMBL1963796	Functional	PUBCHEM_BIOASSAY: Navigating the Kinome. (Class of assay: other) Panel member name: NEK4	PubChem BioAssay data set

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TA40	HAP1 NEK4 (-) 1	Cancer cell line	Male
CVCL_TA41	HAP1 NEK4 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00068224	Not specified	COMPLETED	Clinical and Molecular Investigations Into Ciliopathies
NCT04874909	Not specified	COMPLETED	Classification, Functional Stratification and Biomarkers in Ciliopathy (CILLICORIRCM)