NEK8

Summary

NEK8 (NIMA related kinase 8, HGNC:13387) is a protein-coding gene on chromosome 17q11.2, encoding Serine/threonine-protein kinase Nek8 (Q86SG6). Required for renal tubular integrity.

This gene encodes a member of the serine/threionine protein kinase family related to NIMA (never in mitosis, gene A) of Aspergillus nidulans. The encoded protein may play a role in cell cycle progression from G2 to M phase. Mutations in the related mouse gene are associated with a disease phenotype that closely parallels the juvenile autosomal recessive form of polycystic kidney disease in humans.

Source: NCBI Gene 284086 — RefSeq curated summary.

At a glance

• Gene–disease (curated): renal-hepatic-pancreatic dysplasia 2 (Definitive, ClinGen) — +5 more curated relationships
• Clinical variants (ClinVar): 476 total — 16 pathogenic, 20 likely-pathogenic
• Phenotypes (HPO): 89
• Druggable target: yes
• MANE Select transcript: NM_178170

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13387
Approved symbol	NEK8
Name	NIMA related kinase 8
Location	17q11.2
Locus type	gene with protein product
Status	Approved
Aliases	NPHP9
Ensembl gene	ENSG00000160602
Ensembl biotype	protein_coding
OMIM	609799
Entrez	284086

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000268766, ENST00000543014, ENST00000579060, ENST00000579671, ENST00000581000, ENST00000584342, ENST00000592510, ENST00000593261, ENST00000903448, ENST00000969681

RefSeq mRNA: 1 — MANE Select: NM_178170 NM_178170

CCDS: CCDS32597

Canonical transcript exons

ENST00000268766 — 15 exons

Exon	Start	End
ENSE00001053215	28741078	28741236
ENSE00001113927	28740463	28740613
ENSE00001197941	28740822	28740985
ENSE00001252906	28741413	28741571
ENSE00001252942	28741959	28743455
ENSE00001252947	28739084	28739201
ENSE00001503945	28737675	28737736
ENSE00001503946	28737306	28737514
ENSE00002711692	28728788	28728860
ENSE00002769136	28734772	28735004
ENSE00003596510	28738671	28738747
ENSE00003644503	28733983	28734188
ENSE00003676950	28737819	28738000
ENSE00003787730	28738095	28738245
ENSE00003791625	28735240	28735371

Expression profiles

Bgee: expression breadth ubiquitous, 196 present calls, max score 89.63.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 2.1106 / max 28.7448, expressed in 1062 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
160064	1.2213	734
160062	0.7548	336
160061	0.1345	65

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	89.63	gold quality
metanephros cortex	UBERON:0010533	82.03	gold quality
left lobe of thyroid gland	UBERON:0001120	81.12	gold quality
granulocyte	CL:0000094	81.02	gold quality
right lobe of thyroid gland	UBERON:0001119	81.01	gold quality
right uterine tube	UBERON:0001302	80.43	gold quality
thyroid gland	UBERON:0002046	80.36	gold quality
lymph node	UBERON:0000029	77.41	gold quality
right adrenal gland cortex	UBERON:0035827	77.32	gold quality
monocyte	CL:0000576	76.89	gold quality
leukocyte	CL:0000738	76.84	gold quality
visceral pleura	UBERON:0002401	76.41	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.10	gold quality
body of pancreas	UBERON:0001150	76.06	gold quality
spleen	UBERON:0002106	75.98	gold quality
cortex of kidney	UBERON:0001225	75.91	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	75.80	gold quality
right adrenal gland	UBERON:0001233	75.79	gold quality
right lobe of liver	UBERON:0001114	75.41	gold quality
secondary oocyte	CL:0000655	75.38	silver quality
metanephros	UBERON:0000081	75.19	gold quality
islet of Langerhans	UBERON:0000006	75.18	gold quality
pancreas	UBERON:0001264	74.96	gold quality
endothelial cell	CL:0000115	74.71	silver quality
minor salivary gland	UBERON:0001830	74.68	gold quality
pituitary gland	UBERON:0000007	74.61	gold quality
adenohypophysis	UBERON:0002196	74.16	gold quality
vermiform appendix	UBERON:0001154	74.00	gold quality
adrenal cortex	UBERON:0001235	73.98	gold quality
stromal cell of endometrium	CL:0002255	73.79	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.96

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting NEK8, 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-6778-3P	99.96	67.29	2693
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-1179	99.71	68.70	1040
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-3926	98.95	69.26	1438
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-2115-5P	98.66	68.07	1191
HSA-MIR-197-3P	98.09	69.23	1004
HSA-MIR-6783-5P	97.67	67.21	1528
HSA-MIR-665	97.60	65.64	1781

Literature-anchored findings (GeneRIF, showing 15)

• Data demonstrate for the first time that Nek8 is a novel tumor associated gene, and shares considerable sequence homology with the Nek family of protein kinases and may be involved in G(2)/M progression. (PMID:15019993)
• characterization of the proteome in mice that have a double point mutation in the related gene. (PMID:15872312)
• mutations cause nephronophthisis; mutant forms show defects in ciliary localization (PMID:18199800)
• study finds that induction of ciliogenesis upon cell cycle exit is accompanied by both activation and proteasomal degradation of Nek8, and that activation is dependent upon phosphorylation within the catalytic domain (PMID:22106379)
• NPHP9 promotes signalling through the transcriptional co-activator TAZ. (PMID:23026745)
• NEK8 is essential for organ development and that the complete loss of NEK8 perturbs multiple signalling pathways resulting in a severe early embryonic phenotype. (PMID:23418306)
• ANKS6 as a new NPHP family member that assembles a distinct module of nephronophthisis-associated proteins, encompassing NEK8, INVS and NPHP3. (PMID:23793029)
• Mutation in NEK8 is associated with renal ciliopathies (PMID:23973373)
• NEK8 may be a new target gene of HIFs; pVHL can down-regulate NEK8 via HIFs to maintain the primary cilia structure in human renal cancer cells (PMID:25451921)
• The mutations: c.2069_2070insC variant (p.Ter693LeufsTer86), and a c.1043C>T variant (p.Thr348Met) in RCC1 domain of NEK8 in two brothers with cardiac, renal, and hepatic anomalies (PMID:26697755)
• our study demonstrates that NEK8 human mutations cause major organ developmental defects due to altered ciliogenesis and cell differentiation/proliferation through deregulation of the Hippo pathway (PMID:26967905)
• NEK8 plays a critical role in replication fork stability through its regulation of the DNA repair and replication fork protection protein RAD51. (PMID:27892797)
• Homozygous NEK8 Mutations in Siblings With Neonatal Cholestasis Progressing to End-stage Liver, Renal, and Cardiac Disease. (PMID:31633649)
• NEK8 regulates colorectal cancer progression via phosphorylating MYC. (PMID:37596667)
• Certain heterozygous variants in the kinase domain of the serine/threonine kinase NEK8 can cause an autosomal dominant form of polycystic kidney disease. (PMID:37598857)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nek8	ENSDARG00000045626
mus_musculus	Nek8	ENSMUSG00000017405
rattus_norvegicus	Nek8	ENSRNOG00000012866

Paralogs (8): NEK11 (ENSG00000114670), NEK2 (ENSG00000117650), NEK6 (ENSG00000119408), NEK9 (ENSG00000119638), NEK3 (ENSG00000136098), NEK7 (ENSG00000151414), NEK10 (ENSG00000163491), NEK5 (ENSG00000197168)

Protein

Protein identifiers

Serine/threonine-protein kinase Nek8 — Q86SG6 (reviewed: Q86SG6)

Alternative names: Never in mitosis A-related kinase 8, Nima-related protein kinase 12a

All UniProt accessions (5): Q86SG6, K7EL04, K7EMF0, K7END4, K7EPD3

UniProt curated annotations — full annotation on UniProt →

Function. Required for renal tubular integrity. May regulate local cytoskeletal structure in kidney tubule epithelial cells. May regulate ciliary biogenesis through targeting of proteins to the cilia. Plays a role in organogenesis, and is involved in the regulation of the Hippo signaling pathway.

Subunit / interactions. Interacts with PKD2; may regulate PKD2 targeting to the cilium. Interacts with ANKS6. Component of a complex containing at least ANKS6, INVS, NEK8 and NPHP3. ANKS6 may organize complex assembly by linking INVS and NPHP3 to NEK8 and INVS may target the complex to the proximal ciliary axoneme. Interacts with ANKS3.

Subcellular location. Cytoplasm. Cytoskeleton. Cell projection. Cilium. Microtubule organizing center. Centrosome. Cilium axoneme.

Tissue specificity. Highest expression in thyroid, adrenal gland and skin. Low levels in spleen, colon and uterus. Overexpressed in breast tumors, with highest expression in infiltrating ductal carcinomas and moderate levels in mucinous adenocarcinoma.

Disease relevance. Nephronophthisis 9 (NPHP9) [MIM:613824] An autosomal recessive disorder resulting in end-stage renal disease. It is a progressive tubulo-interstitial kidney disorder histologically characterized by modifications of the tubules with thickening of the basement membrane, interstitial fibrosis and, in the advanced stages, medullary cysts. The disease is caused by variants affecting the gene represented in this entry. Renal-hepatic-pancreatic dysplasia 2 (RHPD2) [MIM:615415] A form of renal-hepatic-pancreatic dysplasia, a disease characterized by cystic malformations of the kidneys, liver, and pancreas. The pathological findings consist of multicystic dysplastic kidneys, dilated and dysgenetic bile ducts, a dysplastic pancreas with dilated ducts, cysts, fibrosis and inflammatory infiltrates. The disease is caused by variants affecting the gene represented in this entry. Polycystic kidney disease 8 (PKD8) [MIM:620903] A form of polycystic kidney disease, a disorder characterized by progressive formation and enlargement of cysts in both kidneys, typically leading to end-stage renal disease in adult life. Cysts may also occur in other organs, particularly the liver. PKD8 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

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

RefSeq proteins (1): NP_835464* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000408	Reg_chr_condens	Repeat
IPR000719	Prot_kinase_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR009091	RCC1/BLIP-II	Homologous_superfamily
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR044120	STKc_Nek8	Domain
IPR051997	STK_NEK	Family
IPR058923	RCC1-like_dom	Domain

Pfam: PF00069, PF25390

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 (25 total): sequence variant 12, repeat 5, binding site 2, chain 1, domain 1, modified residue 1, region of interest 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86SG6-F1	85.23	0.64

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): 128 (proton acceptor)

Ligand- & substrate-binding residues (2): 10–18; 33

Post-translational modifications (1): 162

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 293 (showing top): GOBP_HIPPO_SIGNALING, chr17q11, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_SPECIFICATION_OF_SYMMETRY, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOCC_CENTROSOME, TGANTCA_AP1_C, FUJII_YBX1_TARGETS_DN, GOBP_CIRCULATORY_SYSTEM_DEVELOPMENT, GOCC_CYTOPLASMIC_REGION, YGCGYRCGC_UNKNOWN, AHR_Q5, GOCC_CILIARY_BASE, GOCC_CILIUM, BOCHKIS_FOXA2_TARGETS

GO Biological Process (6): determination of left/right symmetry (GO:0007368), heart development (GO:0007507), animal organ morphogenesis (GO:0009887), regulation of hippo signaling (GO:0035330), protein phosphorylation (GO:0006468), animal organ development (GO:0048513)

GO Molecular Function (9): protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), metal ion binding (GO:0046872), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (8): centrosome (GO:0005813), cilium (GO:0005929), axoneme (GO:0005930), ciliary inversin compartment (GO:0097543), ciliary base (GO:0097546), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
animal organ development	2
protein kinase activity	2
cilium	2
determination of bilateral symmetry	1
left/right pattern formation	1
circulatory system development	1
anatomical structure morphogenesis	1
hippo signaling	1
regulation of intracellular signal transduction	1
phosphorylation	1
protein modification process	1
anatomical structure development	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cation 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
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
centriole	1
microtubule organizing center	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1
cytoskeleton	1
microtubule	1
ciliary plasm	1
ciliary transition zone	1
ciliary transition fiber	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

806 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NEK8	NPHP3	Q7Z494	992
NEK8	ANKS6	Q68DC2	984
NEK8	INVS	Q9Y283	946
NEK8	PIK3C2A	O00443	796
NEK8	ANKS3	Q6ZW76	793
NEK8	NPHP4	O75161	778
NEK8	PKD1	P98161	758
NEK8	PKD2	Q13563	749
NEK8	SRI	P30626	727
NEK8	NPHP1	O15259	706
NEK8	CEP290	O15078	696
NEK8	TMEM67	Q5HYA8	649
NEK8	PKHD1	P08F94	638
NEK8	IQCB1	Q15051	638
NEK8	RPGRIP1L	Q68CZ1	637

IntAct

46 interactions, top by confidence:

A	B	Type	Score
NEK8	ANKS6	psi-mi:“MI:0914”(association)	0.710
NEK8	NUDCD2	psi-mi:“MI:0915”(physical association)	0.650
TCF4	NEK8	psi-mi:“MI:0915”(physical association)	0.560
NEK8	TRIM69	psi-mi:“MI:0915”(physical association)	0.560
TRIM69	NEK8	psi-mi:“MI:0915”(physical association)	0.560
NEK8	TCF4	psi-mi:“MI:0915”(physical association)	0.560
ADAMTSL4	NEK8	psi-mi:“MI:0915”(physical association)	0.560
RGS20	NEK8	psi-mi:“MI:0915”(physical association)	0.560
NEK8	OXER1	psi-mi:“MI:0915”(physical association)	0.560
NEK8	TRIM42	psi-mi:“MI:0915”(physical association)	0.560
KRTAP13-2	NEK8	psi-mi:“MI:0915”(physical association)	0.560
HTT	NEK8	psi-mi:“MI:0915”(physical association)	0.560
ATXN1	NEK8	psi-mi:“MI:0915”(physical association)	0.560
HSP90AB1	NEK8	psi-mi:“MI:0915”(physical association)	0.560
NEK8	ABL1	psi-mi:“MI:0915”(physical association)	0.400
FYN	NEK8	psi-mi:“MI:0915”(physical association)	0.400
GRB2	NEK8	psi-mi:“MI:0915”(physical association)	0.400
NEK8	NCK1	psi-mi:“MI:0915”(physical association)	0.400
NEK8	TGM5	psi-mi:“MI:0914”(association)	0.350
NEK7	SUPT5H	psi-mi:“MI:0914”(association)	0.350
ANKS3	TNKS	psi-mi:“MI:0914”(association)	0.350
NEK8	AIP	psi-mi:“MI:2364”(proximity)	0.270
NEK8	TTC4	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (74): NEK8 (Two-hybrid), NEK8 (Two-hybrid), NEK8 (Biochemical Activity), AIP (Proximity Label-MS), ANKS6 (Proximity Label-MS), CACYBP (Proximity Label-MS), CDC37 (Proximity Label-MS), CDKAL1 (Proximity Label-MS), FKBP4 (Proximity Label-MS), HSPA1B (Proximity Label-MS), HSPA1L (Proximity Label-MS), HSPA6 (Proximity Label-MS), MTR (Proximity Label-MS), NUDC (Proximity Label-MS), NUDCD2 (Proximity Label-MS)

ESM2 similar proteins: A0A0U1RPR8, A0A7N9VSG0, D3ZGQ5, D3ZHP7, O08644, O09127, O15197, O43542, O73875, O73878, O75676, P0C0K6, P0C0K7, P21709, P23800, P29317, P29322, P41243, P51839, P51840, P52785, P54753, P54754, P54760, P54761, P55203, P57078, P97343, Q1KL86, Q3U3Q1, Q4V7Q6, Q5RCY1, Q5ZJH6, Q60750, Q62270, Q63285, Q6PHR2, Q7ZZC8, Q80YD6, Q86SG6

Diamond homologs: A0A078CGE6, A2BD05, A2QHV0, A2ZMH2, A7SNN5, D3ZBE5, D3ZGQ5, E9Q3S4, G5EFM9, H2L099, O01775, O13839, O14047, O22040, O22042, O35942, O61122, P11837, P22209, P41892, P48479, P48963, P51954, P51955, P51956, P51957, P59895, P84199, Q03428, Q08942, Q0CL79, Q0KHQ5, Q0WPH8, Q10GB1, Q2QAV0, Q2QMH1, Q3SWY6, Q3UGM2, Q40541, Q4FZD7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NEK8	“up-regulates activity”	NEK8	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	20
Uncertain significance	279
Likely benign	110
Benign	13

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1177403	NM_178170.3(NEK8):c.515dup (p.Pro172_Glu173insTer)	Pathogenic
1413416	NM_178170.3(NEK8):c.1997dup (p.Tyr666Ter)	Pathogenic
1426313	NM_178170.3(NEK8):c.882_885del (p.Cys295fs)	Pathogenic
1488	NM_178170.3(NEK8):c.1273C>T (p.His425Tyr)	Pathogenic
2053489	NM_178170.3(NEK8):c.1924C>T (p.Arg642Ter)	Pathogenic
3256606	NEK8, ARG45TRP	Pathogenic
3256607	K157Q	Pathogenic
3878766	NM_178170.3(NEK8):c.67C>T (p.Arg23Ter)	Pathogenic
4717277	NM_178170.3(NEK8):c.1395del (p.Phe465fs)	Pathogenic
471779	NM_178170.3(NEK8):c.743del (p.Pro248fs)	Pathogenic
490179	NM_178170.3(NEK8):c.259A>G (p.Thr87Ala)	Pathogenic
490181	NM_178170.3(NEK8):c.1738G>A (p.Gly580Ser)	Pathogenic
490182	NM_178170.3(NEK8):c.47+1G>A	Pathogenic
490183	NM_178170.3(NEK8):c.379C>T (p.Arg127Ter)	Pathogenic
490184	NM_178170.3(NEK8):c.1384C>T (p.Arg462Ter)	Pathogenic
503832	NM_178170.3(NEK8):c.238del (p.Met80fs)	Pathogenic
1324797	NM_178170.3(NEK8):c.1072-2A>G	Likely pathogenic
2631301	NM_178170.3(NEK8):c.1568+2T>C	Likely pathogenic
2854673	NM_178170.3(NEK8):c.1418-2A>C	Likely pathogenic
3344433	NM_178170.3(NEK8):c.1114del (p.Ala372fs)	Likely pathogenic
3349857	NM_178170.3(NEK8):c.1071+1G>A	Likely pathogenic
3365399	NM_178170.3(NEK8):c.211del (p.Leu71fs)	Likely pathogenic
3581756	NM_178170.3(NEK8):c.763C>T (p.Gln255Ter)	Likely pathogenic
3581765	NM_178170.3(NEK8):c.995_996del (p.Thr332fs)	Likely pathogenic
3581767	NM_178170.3(NEK8):c.1068G>A (p.Trp356Ter)	Likely pathogenic
3581772	NM_178170.3(NEK8):c.1224_1227del	Likely pathogenic
3581797	NM_178170.3(NEK8):c.1910G>A (p.Trp637Ter)	Likely pathogenic
3780014	NM_178170.3(NEK8):c.1417+1G>C	Likely pathogenic
4082470	NM_178170.3(NEK8):c.1189dup (p.Ala397fs)	Likely pathogenic
4845749	NM_178170.3(NEK8):c.877_878dup (p.Arg294fs)	Likely pathogenic

SpliceAI

2366 predictions. Top by Δscore:

Variant	Effect	Δscore
17:28733975:A:AG	acceptor_gain	1.0000
17:28733976:T:G	acceptor_gain	1.0000
17:28733981:A:AG	acceptor_gain	1.0000
17:28733981:A:T	acceptor_loss	1.0000
17:28733981:AG:A	acceptor_gain	1.0000
17:28733982:G:GG	acceptor_gain	1.0000
17:28733982:GG:G	acceptor_gain	1.0000
17:28733982:GGA:G	acceptor_gain	1.0000
17:28733982:GGAT:G	acceptor_gain	1.0000
17:28733982:GGATT:G	acceptor_gain	1.0000
17:28734126:T:TG	donor_gain	1.0000
17:28734149:G:GT	donor_gain	1.0000
17:28734184:ACCAG:A	donor_loss	1.0000
17:28734185:CCAG:C	donor_loss	1.0000
17:28734186:CAGGT:C	donor_loss	1.0000
17:28734187:AG:A	donor_loss	1.0000
17:28734188:GGT:G	donor_loss	1.0000
17:28734189:G:GC	donor_loss	1.0000
17:28734190:T:A	donor_loss	1.0000
17:28734951:A:G	donor_gain	1.0000
17:28735018:G:GT	donor_gain	1.0000
17:28735023:G:T	donor_gain	1.0000
17:28735372:G:GG	donor_gain	1.0000
17:28737489:G:GT	donor_gain	1.0000
17:28737496:G:GT	donor_gain	1.0000
17:28737496:G:T	donor_gain	1.0000
17:28737499:GT:G	donor_gain	1.0000
17:28737512:G:GT	donor_gain	1.0000
17:28737526:G:T	donor_gain	1.0000
17:28737577:G:GT	donor_gain	1.0000

AlphaMissense

4473 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:28728844:G:A	G11R	1.000
17:28728844:G:C	G11R	1.000
17:28728845:G:A	G11E	1.000
17:28728850:G:C	G13R	1.000
17:28728850:G:T	G13C	1.000
17:28728856:T:A	F15I	1.000
17:28728856:T:C	F15L	1.000
17:28728858:C:A	F15L	1.000
17:28728858:C:G	F15L	1.000
17:28728859:G:A	G16R	1.000
17:28728859:G:C	G16R	1.000
17:28728859:G:T	G16W	1.000
17:28728860:G:A	G16E	1.000
17:28728860:G:T	G16V	1.000
17:28733994:T:C	L20P	1.000
17:28734032:A:G	K33E	1.000
17:28734033:A:T	K33M	1.000
17:28734034:G:C	K33N	1.000
17:28734034:G:T	K33N	1.000
17:28734078:C:A	A48D	1.000
17:28734099:T:C	L55P	1.000
17:28734162:T:C	L76P	1.000
17:28734168:T:A	I78N	1.000
17:28734168:T:G	I78S	1.000
17:28734892:T:C	L125P	1.000
17:28734895:A:G	H126R	1.000
17:28734898:G:C	R127P	1.000
17:28734900:G:C	D128H	1.000
17:28734901:A:C	D128A	1.000
17:28734901:A:G	D128G	1.000

dbSNP variants (sampled 300 via entrez): RS1000435081 (17:28730253 G>A), RS1000523947 (17:28735529 A>C), RS1000606727 (17:28739001 C>G,T), RS1000635095 (17:28743262 G>A), RS1000673362 (17:28743273 C>G), RS1001086505 (17:28742904 C>G), RS1001389577 (17:28729145 G>A,T), RS1001487032 (17:28730981 G>A), RS1001662315 (17:28739336 C>A,G), RS1001713071 (17:28739551 C>T), RS1001815625 (17:28732597 G>A,T), RS1001876402 (17:28729320 G>A,C,T), RS1001876571 (17:28737207 T>C), RS1001934495 (17:28732969 G>A), RS1002536707 (17:28732012 G>T)

Disease associations

OMIM: gene MIM:609799 | disease phenotypes: MIM:613824, MIM:615415, MIM:620903

GenCC curated gene-disease

Disease	Classification	Inheritance
renal-hepatic-pancreatic dysplasia 2	Definitive	Autosomal recessive
nephronophthisis 9	Strong	Autosomal recessive
polycystic kidney disease 8	Moderate	Autosomal dominant
renal-hepatic-pancreatic dysplasia	Supportive	Autosomal recessive
nephronophthisis 2	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
autosomal dominant polycystic kidney disease	Strong	AD
renal-hepatic-pancreatic dysplasia 2	Definitive	AR

Mondo (9): nephronophthisis 9 (MONDO:0013444), renal-hepatic-pancreatic dysplasia 2 (MONDO:0014174), polycystic kidney disease 8 (MONDO:0971178), kidney disorder (MONDO:0005240), kidney failure (MONDO:0001106), familial cystic renal disease (MONDO:0019741), premature menopause (MONDO:0001119), renal-hepatic-pancreatic dysplasia (MONDO:0017417), nephronophthisis 2 (MONDO:0011190)

Orphanet (2): Nephronophthisis (Orphanet:655), Genetic cystic renal disease (Orphanet:93587)

HPO phenotypes

89 total (30 of 89 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000083	Renal insufficiency
HP:0000090	Nephronophthisis
HP:0000097	Focal segmental glomerulosclerosis
HP:0000103	Polyuria
HP:0000104	Renal agenesis
HP:0000105	Enlarged kidney
HP:0000107	Renal cyst
HP:0000110	Renal dysplasia
HP:0000546	Retinal degeneration
HP:0000790	Hematuria
HP:0000791	Uric acid nephrolithiasis
HP:0000800	Cystic renal dysplasia
HP:0000822	Hypertension
HP:0000952	Jaundice
HP:0001394	Cirrhosis
HP:0001395	Hepatic fibrosis
HP:0001396	Cholestasis
HP:0001407	Hepatic cysts
HP:0001562	Oligohydramnios
HP:0001634	Mitral valve prolapse
HP:0001639	Hypertrophic cardiomyopathy
HP:0001642	Pulmonic stenosis
HP:0001643	Patent ductus arteriosus
HP:0001650	Aortic valve stenosis
HP:0001660	Truncus arteriosus
HP:0001696	Situs inversus totalis
HP:0001712	Left ventricular hypertrophy

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D007674	Kidney Diseases	C12.050.351.968.419; C12.200.777.419; C12.950.419
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500
D051437	Renal Insufficiency	C12.050.351.968.419.780; C12.200.777.419.780; C12.950.419.780
C566582	Nephronophthisis 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2417353 (SINGLE PROTEIN), CHEMBL4524130 (PROTEIN FAMILY)

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

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

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

pChembl	Type	Value	Unit	Molecule
7.76	IC50	17.5	nM	STAUROSPORINE
7.51	IC50	30.8	nM	STAUROSPORINE
7.46	IC50	35.1	nM	STAUROSPORINE
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2

PubChem BioAssay actives

3 with measured affinity, of 45 total; 1 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
(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	1531805: Inhibition of human NEK8 using casein as substrate by [gamma-33P]-ATP assay	ic50	0.0175	uM

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
methylmercuric chloride	increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
cobaltous chloride	increases expression	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	increases expression	1
Sunitinib	increases expression	1
Amiodarone	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Oxygen	decreases reaction, increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1

ChEMBL screening assays

37 unique, capped per target: 37 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2424428	Binding	Inhibition of NEK8 in human PC3 cell lysates at 10 uM using desthiobiotin-tagged ATP probe AX9989 followed by trypsinization by LC/MS analysis	Hit-to-lead optimization and kinase selectivity of imidazo[1,2-a]quinoxalin-4-amine derived JNK1 inhibitors. — Bioorg Med Chem Lett

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TA45	HAP1 NEK8 (-) 1	Cancer cell line	Male
CVCL_TA46	HAP1 NEK8 (-) 2	Cancer cell line	Male
CVCL_TA47	HAP1 NEK8 (-) 3	Cancer cell line	Male
CVCL_TA48	HAP1 NEK8 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00067990	PHASE4	COMPLETED	Angiotensin II Blockade for Chronic Allograft Nephropathy
NCT00117078	PHASE4	COMPLETED	Aranesp® Monthly Preference Study - 2
NCT00117130	PHASE4	COMPLETED	Study to Evaluate Effectiveness of Aranesp®
NCT00132431	PHASE4	COMPLETED	START: Sensipar Treatment Algorithm to Reach K/DOQI Targets in Chronic Kidney Disease Subjects With Secondary Hyperparathyroidism
NCT00140985	PHASE4	COMPLETED	Antiproteinuric Efficacy of Losartan Potassium in Patients With Non-Diabetic Proteinuric Renal Diseases (0954-213)
NCT00246129	PHASE4	COMPLETED	CamTac Trial:Campath-Tacrolimus vs IL2R MoAb/Tacrolimus/MMF in Renal Transplantation
NCT00275535	PHASE4	COMPLETED	The Comparison of Tacrolimus and Sirolimus Immunosuppression Based Drug Regimens in Kidney Transplant Recipients
NCT00282217	PHASE4	COMPLETED	Study Evaluating Sirolimus in the Treatment of Kidney Transplant
NCT00289614	PHASE4	COMPLETED	Patients With Renal Impairment and Diabetes Undergoing Computed Tomography (CT)
NCT00290069	PHASE4	UNKNOWN	Renal Function Optimization With Mycophenolate Mofetil (MMF) Immunosuppressor Regimes (ALHAMBRA)
NCT00338468	PHASE4	TERMINATED	A Study to Assess Disability in Anemic Elderly Patients With Kidney Disease Receiving PROCRIT (Epoetin Alfa)
NCT00368901	PHASE4	COMPLETED	STAAR-2 Clinical Study
NCT00369733	PHASE4	COMPLETED	STAAR-3 Clinical Study
NCT00369772	PHASE4	COMPLETED	STAAR-1 Clinical Study
NCT00379899	PHASE4	COMPLETED	ADVANCE: Study to Evaluate Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Hemodialysis
NCT00443508	PHASE4	UNKNOWN	Reduction or Discontinuation of CNI’s With Conversion to Everolimus-Based Immunosuppresion
NCT00452478	PHASE4	TERMINATED	Conversion From Standard Phosphate Binder Therapy to Fosrenol® (Lanthanum Carbonate) in Chronic Kidney Disease Stage 5
NCT00492518	PHASE4	COMPLETED	Acetylcysteine, Theophylline, and a Combination of Both in the Prophylaxis of Contrast-Induced Nephropathy
NCT00505102	PHASE4	UNKNOWN	Safe Renal Function In Long Term Heart Transplanted Patients
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00688480	PHASE4	COMPLETED	Do Xanthine Oxidase Inhibitors Reduce Both Left Ventricular Hypertrophy and Endothelial Dysfunction in Cardiovascular Patients With Renal Dysfunction?
NCT00863707	PHASE4	COMPLETED	A Study of the Safety and Tolerance of Regadenoson in Subjects With Renal Impairment
NCT01101698	PHASE4	UNKNOWN	Vitamin K2 and Vessel Calcification in Chronic Kidney Disease Patients
NCT01150201	PHASE4	COMPLETED	Aliskiren Combined With Losartan in Proteinuric, Non-diabetic Chronic Kidney Disease
NCT01155141	PHASE4	COMPLETED	Idiopathic Focal Segmental Glomerulosclerosis (FSGS) and Treatment With ACTH
NCT01228279	PHASE4	COMPLETED	Sympathetic Activity in Patients With End-stage Renal Disease on Peritoneal Dialysis
NCT01334333	PHASE4	COMPLETED	Comparison of Medication Adherence Between Once and Twice Daily Tacrolimus in Stable Renal Transplant Recipients
NCT01437943	PHASE4	TERMINATED	Effect of Short Term Aliskiren Treatment in Kidney Transplant Patients
NCT01545479	PHASE4	COMPLETED	Increased Renal Oxygenation and Angiotensin Converting Enzyme Inhibition
NCT01614431	PHASE4	COMPLETED	N Acetyl Cysteine for Cystinosis Patients
NCT01631149	PHASE4	COMPLETED	Effect of Deep BLock on Intraoperative Surgical Conditions
NCT01722513	PHASE4	UNKNOWN	Efficacy and Safety of Alprostadil Prevent Contrast Induced Nephropathy
NCT01985360	PHASE4	COMPLETED	ISCHEMIA-Chronic Kidney Disease Trial
NCT02311010	PHASE4	UNKNOWN	Practical Use of Advagraf de Novo After Kidney Transplantation According to Recipient Genetic Polymorphism
NCT02413073	PHASE4	COMPLETED	Whole Body Vibration in Kidney Disease
NCT02444013	PHASE4	UNKNOWN	Folic Acid for Prevention of Contrast Induced Nephropathy
NCT02663713	PHASE4	COMPLETED	A Randomized, Pharmacodynamic Comparison of Low Dose Ticagrelor to Clopidogrel in Patients With Prior Myocardial Infarction
NCT02707809	PHASE4	COMPLETED	Effects of Dexmedetomidine on Microcirculation of Kidney Transplant Recipient
NCT02761577	PHASE4	COMPLETED	A Prospective Study on Incidence and Prevention of Contrast-induced Nephropathy in Croatia
NCT03029351	PHASE4	TERMINATED	GLP-1 Receptor Agonist Therapy and Albuminuria in Patients With Type 2 Diabetes