DSTYK

Summary

DSTYK (dual serine/threonine and tyrosine protein kinase, HGNC:29043) is a protein-coding gene on chromosome 1q32.1, encoding Dual serine/threonine and tyrosine protein kinase (Q6XUX3). Acts as a positive regulator of ERK phosphorylation downstream of fibroblast growth factor-receptor activation.

This gene encodes a dual serine/threonine and tyrosine protein kinase which is expressed in multiple tissues. It is thought to function as a regulator of cell death. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 25778 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital anomalies of kidney and urinary tract 1 (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 35
• Clinical variants (ClinVar): 390 total — 2 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 37
• Druggable target: yes — 15 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_015375

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29043
Approved symbol	DSTYK
Name	dual serine/threonine and tyrosine protein kinase
Location	1q32.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0472, DustyPK, RIP5
Ensembl gene	ENSG00000133059
Ensembl biotype	protein_coding
OMIM	612666
Entrez	25778

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 10 protein_coding

ENST00000367161, ENST00000367162, ENST00000893236, ENST00000893237, ENST00000893238, ENST00000893239, ENST00000893240, ENST00000893241, ENST00000956899, ENST00000956900

RefSeq mRNA: 2 — MANE Select: NM_015375 NM_015375, NM_199462

CCDS: CCDS1451, CCDS1452

Canonical transcript exons

ENST00000367162 — 13 exons

Exon	Start	End
ENSE00000791764	205148205	205148339
ENSE00000791765	205150680	205150794
ENSE00000791767	205159547	205159679
ENSE00000791769	205161258	205161387
ENSE00001177331	205162923	205163006
ENSE00001177356	205162036	205162212
ENSE00001264688	205163723	205163955
ENSE00001334592	205160114	205160270
ENSE00001334600	205169163	205169832
ENSE00001334604	205187418	205187806
ENSE00001341975	205157273	205157386
ENSE00001879279	205142505	205147745
ENSE00003851038	205211271	205211702

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 93.34.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.1494 / max 178.4977, expressed in 1745 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
16962	2.8175	1308
16960	2.6107	1303
16958	0.8906	551
16957	0.8855	591
16961	0.7532	386
16959	0.1919	54

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	93.34	gold quality
medial globus pallidus	UBERON:0002477	92.92	gold quality
superior vestibular nucleus	UBERON:0007227	92.59	gold quality
globus pallidus	UBERON:0001875	92.46	gold quality
inferior vagus X ganglion	UBERON:0005363	92.40	gold quality
ventral tegmental area	UBERON:0002691	91.88	gold quality
pons	UBERON:0000988	91.57	gold quality
substantia nigra pars compacta	UBERON:0001965	91.43	gold quality
cerebellar vermis	UBERON:0004720	91.32	gold quality
substantia nigra pars reticulata	UBERON:0001966	91.31	gold quality
subthalamic nucleus	UBERON:0001906	90.85	gold quality
dorsal plus ventral thalamus	UBERON:0001897	90.79	gold quality
medulla oblongata	UBERON:0001896	90.45	gold quality
renal medulla	UBERON:0000362	90.02	gold quality
parietal lobe	UBERON:0001872	89.69	gold quality
lateral globus pallidus	UBERON:0002476	89.66	gold quality
buccal mucosa cell	CL:0002336	89.27	gold quality
postcentral gyrus	UBERON:0002581	88.83	gold quality
saphenous vein	UBERON:0007318	88.57	gold quality
tendon of biceps brachii	UBERON:0008188	88.26	gold quality
nipple	UBERON:0002030	88.11	gold quality
entorhinal cortex	UBERON:0002728	88.04	gold quality
Brodmann (1909) area 23	UBERON:0013554	87.85	gold quality
trigeminal ganglion	UBERON:0001675	87.77	gold quality
dorsal root ganglion	UBERON:0000044	87.61	gold quality
superior frontal gyrus	UBERON:0002661	87.52	gold quality
endothelial cell	CL:0000115	87.38	gold quality
middle temporal gyrus	UBERON:0002771	87.16	gold quality
urethra	UBERON:0000057	86.82	gold quality
penis	UBERON:0000989	86.44	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	19.70
E-ANND-3	yes	5.13

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

206 targeting DSTYK, 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-8485	100.00	77.57	4731
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548AA	99.96	70.64	3753

Literature-anchored findings (GeneRIF, showing 8)

• Confocal imaging of transiently expressed human Dusty-GFP fusion proteins showed a cytoplasmic distribution. (PMID:17123648)
• We detected independent DSTYK mutations in 2.3% of patients with congenital abnormalities of the kidney or urinary tract, a finding that suggests that DSTYK is a major determinant of human urinary tract development, downstream of FGF signaling. (PMID:23862974)
• we identified a complex homozygous 4-kb deletion/20-bp insertion in DSTYK in all four affected family members with Autosomal-Recessive Complicated Spastic Paraparesis, SPG23 (PMID:28157540)
• RIPK3 promotes adenovirus type 5 oncolytic activity. (PMID:29238045)
• DSTYK Enhances Chemoresistance in Triple-Negative Breast Cancer Cells. (PMID:35011659)
• DSTYK inhibition increases the sensitivity of lung cancer cells to T cell-mediated cytotoxicity. (PMID:36169652)
• Aberrations in FGFR1, FGFR2, and RIP5 Expression in Human Congenital Anomalies of the Kidney and Urinary Tract (CAKUT). (PMID:36555181)
• Mouse and human studies support DSTYK loss of function as a low-penetrance and variable expressivity risk factor for congenital urinary tract anomalies. (PMID:37746849)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	dstyk	ENSDARG00000000853
mus_musculus	Dstyk	ENSMUSG00000042046
rattus_norvegicus	Dstyk	ENSRNOG00000021298
drosophila_melanogaster	Madm	FBGN0027497
drosophila_melanogaster	Wnk	FBGN0037098
caenorhabditis_elegans		WBGENE00006941
caenorhabditis_elegans	hpo-11	WBGENE00010427

Paralogs (6): WNK1 (ENSG00000060237), NRBP1 (ENSG00000115216), WNK4 (ENSG00000126562), WNK2 (ENSG00000165238), NRBP2 (ENSG00000185189), WNK3 (ENSG00000196632)

Protein

Protein identifiers

Dual serine/threonine and tyrosine protein kinase — Q6XUX3 (reviewed: Q6XUX3)

Alternative names: Dusty protein kinase, RIP-homologous kinase, Receptor-interacting serine/threonine-protein kinase 5, Sugen kinase 496

All UniProt accessions (1): Q6XUX3

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a positive regulator of ERK phosphorylation downstream of fibroblast growth factor-receptor activation. Involved in the regulation of both caspase-dependent apoptosis and caspase-independent cell death. In the skin, it plays a predominant role in suppressing caspase-dependent apoptosis in response to UV stress in a range of dermal cell types.

Subcellular location. Cytoplasm. Cell membrane. Apical cell membrane. Basolateral cell membrane. Cell junction.

Tissue specificity. Predominantly expressed in skeletal muscle and testis. Expressed in basolateral and apical membranes of all tubular epithelia. Expressed in thin ascending limb of the loop of Henle and the distal convoluted tubule. Expressed in all layers of transitional ureteric epithelium and in the ureteric smooth-muscle cells. Weakly expressed in heart, brain, placenta, kidney, pancreas, spleen, thymus, prostate, uterus, small intestine, white blood cells, stomach, spinal cord and adrenal gland. Is widely distributed in the CNS. Also detected in several tumor cell lines. Expressed in the skin.

Disease relevance. Congenital anomalies of the kidney and urinary tract 1 (CAKUT1) [MIM:610805] A disorder encompassing a broad spectrum of renal and urinary tract malformations that include renal agenesis, kidney hypodysplasia, multicystic kidney dysplasia, duplex collecting system, posterior urethral valves and ureter abnormalities. Congenital anomalies of kidney and urinary tract are the commonest cause of chronic kidney disease in children. Disease susceptibility is associated with variants affecting the gene represented in this entry. Spastic paraplegia 23, autosomal recessive (SPG23) [MIM:270750] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG23 is an autosomal recessive form characterized by childhood-onset of gait difficulties and pigmentary abnormalities, including premature graying of the hair and vitiligo-like or hyperpigmented skin lesions. The disease is caused by variants affecting the gene represented in this entry.

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

Isoforms (4)

UniProt ID	Names	Canonical?
Q6XUX3-1	1	yes
Q6XUX3-2	2
Q6XUX3-3	3
Q6XUX3-4	4

RefSeq proteins (2): NP_056190, NP_955749 (=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
IPR051302	Dual_SerThr-Tyr_Kinase	Family

Pfam: PF00069

Catalyzed reactions (Rhea), 3 shown:

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)
• 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 (22 total): splice variant 5, sequence variant 4, sequence conflict 3, coiled-coil region 2, binding site 2, chain 1, domain 1, mutagenesis site 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-Q6XUX3-F1	81.02	0.41

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): 777 (proton acceptor)

Ligand- & substrate-binding residues (2): 658–666; 681

Mutagenesis-validated functional residues (1):

Position	Phenotype
681	no change.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 346 (showing top): GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, OSWALD_HEMATOPOIETIC_STEM_CELL_IN_COLLAGEN_GEL_UP, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, MARTINEZ_RB1_TARGETS_DN, GOBP_POSITIVE_REGULATION_OF_PHOSPHORUS_METABOLIC_PROCESS, GOBP_RESPONSE_TO_FIBROBLAST_GROWTH_FACTOR, GOBP_REGULATION_OF_FIBROBLAST_GROWTH_FACTOR_RECEPTOR_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOCC_APICAL_PLASMA_MEMBRANE, GOBP_RESPONSE_TO_GROWTH_FACTOR, AFFAR_YY1_TARGETS_UP

GO Biological Process (6): positive regulation of kinase activity (GO:0033674), negative regulation of apoptotic process (GO:0043066), cellular response to fibroblast growth factor stimulus (GO:0044344), positive regulation of fibroblast growth factor receptor signaling pathway (GO:0045743), positive regulation of ERK1 and ERK2 cascade (GO:0070374), protein phosphorylation (GO:0006468)

GO Molecular Function (10): protein serine/threonine kinase activity (GO:0004674), protein serine/threonine/tyrosine kinase activity (GO:0004712), protein tyrosine kinase activity (GO:0004713), ATP binding (GO:0005524), 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 (6): cytoplasm (GO:0005737), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), anchoring junction (GO:0070161), plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein kinase activity	4
kinase activity	2
cellular anatomical structure	2
plasma membrane region	2
positive regulation of phosphorylation	1
positive regulation of catalytic activity	1
regulation of kinase activity	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
cellular response to growth factor stimulus	1
response to fibroblast growth factor	1
fibroblast growth factor receptor signaling pathway	1
positive regulation of signal transduction	1
regulation of fibroblast growth factor receptor signaling pathway	1
positive regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
phosphorylation	1
protein modification process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	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
intracellular anatomical structure	1
basal plasma membrane	1
apical part of cell	1
cell junction	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1336 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DSTYK	SPINK14	Q6IE38	524
DSTYK	FAXC	Q5TGI0	509
DSTYK	TMEM81	Q6P7N7	506
DSTYK	ATP11A	P98196	490
DSTYK	REEP1	Q9H902	480
DSTYK	MSANTD2	Q6P1R3	474
DSTYK	TMCC2	O75069	472
DSTYK	SPG11	Q96JI7	460
DSTYK	QSER1	Q2KHR3	460
DSTYK	RBBP5	Q15291	444
DSTYK	TMTC2	Q8N394	443
DSTYK	NUFIP2	Q7Z417	428
DSTYK	USP49	Q70CQ1	417
DSTYK	NECAP2	Q9NVZ3	417
DSTYK	BYSL	Q13895	409

IntAct

65 interactions, top by confidence:

A	B	Type	Score
CDK13	CCNK	psi-mi:“MI:0914”(association)	0.830
MS4A10	NEDD4	psi-mi:“MI:0914”(association)	0.590
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
CXCR4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
FRMD1	A2ML1	psi-mi:“MI:0914”(association)	0.530
CD226	MEN1	psi-mi:“MI:0914”(association)	0.530
CTDSP1	CTDSP2	psi-mi:“MI:0914”(association)	0.530
CDH13	INSIG1	psi-mi:“MI:0914”(association)	0.530
CCL22	PLXNA2	psi-mi:“MI:0914”(association)	0.530
IL1R2	EXOC5	psi-mi:“MI:0914”(association)	0.530
DSTYK	YWHAE	psi-mi:“MI:0915”(physical association)	0.400
SFN	DSTYK	psi-mi:“MI:0915”(physical association)	0.400
PB2	SEC15L3	psi-mi:“MI:0914”(association)	0.350
ARHGAP25	UBA6	psi-mi:“MI:0914”(association)	0.350
IGHM	ESYT2	psi-mi:“MI:0914”(association)	0.350
GPR17	TMEM120B	psi-mi:“MI:0914”(association)	0.350
HCST	TMEM120B	psi-mi:“MI:0914”(association)	0.350
LRCH1	TMEM131L	psi-mi:“MI:0914”(association)	0.350
TUBB4B	POTEF	psi-mi:“MI:0914”(association)	0.350
BSG	METTL15	psi-mi:“MI:0914”(association)	0.350
DGCR2	CCDC85C	psi-mi:“MI:0914”(association)	0.350
NPTN	RTL8C	psi-mi:“MI:0914”(association)	0.350
GRPR	GPR89A	psi-mi:“MI:0914”(association)	0.350
TFPI2	AP3B1	psi-mi:“MI:0914”(association)	0.350
IL1R2	QSOX1	psi-mi:“MI:0914”(association)	0.350
CD79B	GOLIM4	psi-mi:“MI:0914”(association)	0.350
TACR3	TCAF2	psi-mi:“MI:0914”(association)	0.350

BioGRID (86): DSTYK (Affinity Capture-MS), DSTYK (Affinity Capture-MS), DSTYK (Affinity Capture-MS), DSTYK (Affinity Capture-MS), DSTYK (Affinity Capture-MS), DSTYK (Affinity Capture-MS), DSTYK (Affinity Capture-MS), DSTYK (Affinity Capture-MS), DSTYK (Affinity Capture-MS), DSTYK (Affinity Capture-MS), DSTYK (Affinity Capture-MS), DSTYK (Affinity Capture-MS), DSTYK (Affinity Capture-MS), DSTYK (Affinity Capture-MS), DSTYK (Affinity Capture-MS)

ESM2 similar proteins: A0A386CAB9, A0A7H0DNF0, A2CI98, A6QR20, C6FG12, F1M649, F1MHT9, F6R2G2, O15050, O70167, O70173, P59045, Q13075, Q20CR4, Q2LKV2, Q3UIR3, Q3UP24, Q4TVR5, Q4VSN3, Q4VSN4, Q4VSN5, Q5EB20, Q5H9U9, Q5RBY8, Q5U228, Q66X01, Q66X03, Q66X05, Q66X22, Q6NU22, Q6NU51, Q6XUX0, Q6XUX1, Q6XUX2, Q6XUX3, Q6ZN28, Q7Z2W4, Q80VH0, Q8CCN1, Q8QMP8

Diamond homologs: A0A509AKL0, A1Z9X0, A2CI34, A2CI35, A5K0N4, O73792, P00537, P00538, P00540, P04409, P05128, P05129, P05696, P06245, P09215, P0CD62, P10102, P16879, P17252, P20444, P28582, P28867, P32593, P43298, P63318, P63319, P83099, P83741, P93050, P93759, Q02111, Q04759, Q05655, Q12469, Q1L6Q1, Q20CR4, Q2MHE4, Q38868, Q38872, Q38873

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	4
Uncertain significance	225
Likely benign	84
Benign	27

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
417786	NM_015375.3(DSTYK):c.2467+930_*1895delinsTGTAGTCCTGCTCCTTGAGG	Pathogenic
60685	NM_015375.3(DSTYK):c.24G>A (p.Trp8Ter)	Pathogenic
1333318	NM_015375.3(DSTYK):c.1053dup (p.Gln352fs)	Likely pathogenic
3065572	NM_015375.3(DSTYK):c.1477G>T (p.Gly493Ter)	Likely pathogenic
3235733	NM_015375.3(DSTYK):c.1394A>G (p.Gln465Arg)	Likely pathogenic
3899994	NM_015375.3(DSTYK):c.889del (p.Glu297fs)	Likely pathogenic

SpliceAI

1979 predictions. Top by Δscore:

Variant	Effect	Δscore
1:205147558:T:A	donor_gain	1.0000
1:205147576:T:TA	donor_gain	1.0000
1:205157267:ACTT:A	donor_loss	1.0000
1:205157268:CTT:C	donor_loss	1.0000
1:205157269:TTACC:T	donor_loss	1.0000
1:205157270:TA:T	donor_loss	1.0000
1:205157271:A:AC	donor_gain	1.0000
1:205157271:A:C	donor_loss	1.0000
1:205157272:C:CC	donor_gain	1.0000
1:205157272:CCAG:C	donor_gain	1.0000
1:205157388:T:C	acceptor_gain	1.0000
1:205158201:AACT:A	donor_gain	1.0000
1:205159545:A:AC	donor_gain	1.0000
1:205159545:A:AT	donor_loss	1.0000
1:205159546:C:CA	donor_loss	1.0000
1:205159546:C:CC	donor_gain	1.0000
1:205159546:CCTT:C	donor_gain	1.0000
1:205159675:GAGAC:G	acceptor_gain	1.0000
1:205159676:AGAC:A	acceptor_gain	1.0000
1:205159677:GAC:G	acceptor_gain	1.0000
1:205159678:AC:A	acceptor_gain	1.0000
1:205159678:ACCTG:A	acceptor_loss	1.0000
1:205159679:CC:C	acceptor_gain	1.0000
1:205159679:CCTG:C	acceptor_loss	1.0000
1:205159680:C:CC	acceptor_gain	1.0000
1:205159680:CTGGA:C	acceptor_loss	1.0000
1:205161256:A:AC	donor_gain	1.0000
1:205161257:C:CC	donor_gain	1.0000
1:205161257:CGATG:C	donor_gain	1.0000
1:205161272:T:TA	donor_gain	1.0000

AlphaMissense

6086 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:205150709:G:T	P813Q	1.000
1:205150715:C:T	G811E	1.000
1:205150716:C:A	G811W	1.000
1:205150716:C:G	G811R	1.000
1:205150716:C:T	G811R	1.000
1:205157288:T:A	K779N	1.000
1:205157288:T:G	K779N	1.000
1:205157294:A:C	D777E	1.000
1:205157294:A:T	D777E	1.000
1:205157295:T:A	D777V	1.000
1:205157295:T:G	D777A	1.000
1:205160176:T:A	K681N	1.000
1:205160176:T:G	K681N	1.000
1:205162054:A:C	F600L	1.000
1:205162054:A:T	F600L	1.000
1:205162056:A:G	F600L	1.000
1:205162076:A:G	L593P	1.000
1:205162164:A:G	W564R	1.000
1:205162164:A:T	W564R	1.000
1:205162993:G:T	A524D	1.000
1:205163730:A:G	L517P	1.000
1:205163784:A:G	L499P	1.000
1:205163796:A:G	L495P	1.000
1:205163841:A:G	L480P	1.000
1:205163865:A:G	L472P	1.000
1:205147660:C:A	R896S	0.999
1:205147660:C:G	R896S	0.999
1:205147661:C:A	R896M	0.999
1:205147661:C:G	R896T	0.999
1:205147683:A:G	W889R	0.999

dbSNP variants (sampled 300 via entrez): RS1000009250 (1:205183160 A>T), RS1000060031 (1:205177224 T>A,C), RS1000194864 (1:205202641 T>G), RS1000247310 (1:205202453 G>A,C), RS1000271337 (1:205190636 A>AAC), RS1000274850 (1:205211263 C>A,T), RS1000280806 (1:205156761 G>A), RS1000388770 (1:205211161 C>A,T), RS1000443378 (1:205163487 G>C), RS1000471624 (1:205157849 C>A,T), RS1000639847 (1:205163594 A>C), RS1000653457 (1:205157986 C>A), RS1000712884 (1:205149720 C>T), RS1000715836 (1:205156509 G>C), RS1000719753 (1:205164975 C>T)

Disease associations

OMIM: gene MIM:612666 | disease phenotypes: MIM:270750, MIM:610805

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital anomalies of kidney and urinary tract 1	Definitive	Autosomal dominant
hereditary spastic paraplegia 23	Strong	Autosomal recessive
renal agenesis, unilateral	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex hereditary spastic paraplegia	Moderate	AR

Mondo (5): hereditary spastic paraplegia 23 (MONDO:0010046), congenital anomalies of kidney and urinary tract 1 (MONDO:0012561), complex hereditary spastic paraplegia (MONDO:0015150), chronic kidney disease (MONDO:0005300), renal agenesis, unilateral (MONDO:0019636)

Orphanet (2): Autosomal recessive spastic paraplegia type 23 (Orphanet:101003), Complex hereditary spastic paraplegia (Orphanet:102013)

HPO phenotypes

37 total (30 of 37 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000074	Ureteropelvic junction obstruction
HP:0000076	Vesicoureteral reflux
HP:0000085	Horseshoe kidney
HP:0000089	Renal hypoplasia
HP:0000122	Unilateral renal agenesis
HP:0000252	Microcephaly
HP:0000275	Narrow face
HP:0000278	Retrognathia
HP:0000347	Micrognathia
HP:0001003	Multiple lentigines
HP:0001045	Vitiligo
HP:0001250	Seizure
HP:0001256	Mild intellectual disability
HP:0001258	Spastic paraplegia
HP:0001347	Hyperreflexia
HP:0002064	Spastic gait
HP:0002218	Silver-gray hair
HP:0002505	Loss of ambulation
HP:0002515	Waddling gait
HP:0002607	Bowel incontinence
HP:0002650	Scoliosis
HP:0002751	Kyphoscoliosis
HP:0002827	Hip dislocation
HP:0003487	Babinski sign
HP:0003577	Congenital onset
HP:0003691	Scapular winging
HP:0003774	Stage 5 chronic kidney disease
HP:0003829	Typified by incomplete penetrance

GWAS associations

35 associations (top):

Study	Trait	p-value
GCST001762_18	Obesity-related traits	5.000000e-06
GCST002184_3	Mean platelet volume	3.000000e-13
GCST003252_3	Systemic lupus erythematosus	2.000000e-06
GCST004618_25	White blood cell count (basophil)	1.000000e-14
GCST004621_42	Red cell distribution width	2.000000e-12
GCST004622_141	Reticulocyte count	3.000000e-13
GCST004631_45	Basophil percentage of white cells	2.000000e-15
GCST006075_2	Hair color	6.000000e-61
GCST006613_71	Triglycerides	4.000000e-09
GCST006988_209	Blond vs. brown/black hair color	2.000000e-54
GCST007325_135	General risk tolerance (MTAG)	9.000000e-11
GCST007455_6	Eye color (brightness)	2.000000e-08
GCST007457_1	Eye color (saturation)	4.000000e-09
GCST007500_31	Waist-to-hip ratio adjusted for BMI (additive genetic model)	4.000000e-11
GCST007502_42	Waist-to-hip ratio adjusted for BMI (additive genetic model)	4.000000e-11
GCST009379_2	Type 2 diabetes	4.000000e-09
GCST010143_34	Meat-related diet	1.000000e-08
GCST010143_9	Meat-related diet	4.000000e-11
GCST010302_33	Cutaneous melanoma or hair colour	2.000000e-82
GCST010303_34	Nevus count or cutaneous melanoma	1.000000e-08
GCST010304_34	Cutaneous malignant melanoma	1.000000e-08
GCST010697_12	Cortical surface area (min-P)	6.000000e-10
GCST010698_16	Subcortical volume (min-P)	8.000000e-09
GCST010699_52	Brain morphology (min-P)	5.000000e-08
GCST010700_66	Cortical thickness (MOSTest)	3.000000e-09
GCST010701_17	Cortical surface area (MOSTest)	5.000000e-08
GCST010702_2	Subcortical volume (MOSTest)	3.000000e-08
GCST010703_27	Brain morphology (MOSTest)	5.000000e-09
GCST90002379_16	Basophil count	3.000000e-42
GCST90002380_119	Basophil percentage of white cells	1.000000e-33

EFO canonical traits (15, from GWAS)

EFO ID	Trait name
EFO:0005090	basophil count
EFO:0009188	Red cell distribution width
EFO:0007986	reticulocyte count
EFO:0007992	basophil percentage of leukocytes
EFO:0004530	triglyceride measurement
EFO:0003924	hair color
EFO:0008579	risk-taking behaviour
EFO:0009764	eye colour measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008111	diet measurement
EFO:0004632	nevus count
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0004527	mean corpuscular hemoglobin
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D007676	Kidney Failure, Chronic	C12.050.351.968.419.780.750.500; C12.200.777.419.780.750.500; C12.950.419.780.750.500; C23.550.291.500.906.500
C563661	Renal Hypodysplasia, Nonsyndromic, 1 (supp.)
C536859	Spastic paraplegia 23 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1908386 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

15 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 171,103 (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
CHEMBL180022	NERATINIB	4	9,404
CHEMBL2028663	DABRAFENIB	4	12,430
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL535	SUNITINIB	4	79,020
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL428690	ALVOCIDIB	3	27,781
CHEMBL603469	LESTAURTINIB	3
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL1721885	SU-014813	2	363
CHEMBL215152	DEFOSBARASERTIB	2	372
CHEMBL384304	RG-547	2	93
CHEMBL1908397	KW-2449	1	622
CHEMBL574738	AST-487	1	451

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Other-unique family

ChEMBL bioactivities

24 potent at pChembl≥5 of 25 total, top 24 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.28	Kd	5.3	nM	LESTAURTINIB
7.96	Kd	11	nM	STAUROSPORINE
7.50	IC50	31.3	nM	STAUROSPORINE
7.24	Kd	57	nM	TAE-684
7.19	IC50	65.2	nM	STAUROSPORINE
7.19	IC50	64.1	nM	STAUROSPORINE
7.16	IC50	69	nM	STAUROSPORINE
6.44	Kd	360	nM	AST-487
6.42	Kd	380	nM	BOSUTINIB
6.35	Kd	450	nM	CRIZOTINIB
6.29	Kd	510	nM	FORETINIB
6.29	Kd	510	nM	CHEMBL1241674
6.18	Kd	660	nM	KW-2449
6.17	Kd	670	nM	CHEMBL5177284
6.13	Kd	740	nM	CHEMBL1908395
6.11	Kd	780	nM	RG-547
6.03	Kd	930	nM	SU-014813
5.89	Kd	1300	nM	SUNITINIB
5.77	Kd	1700	nM	FEDRATINIB
5.52	Kd	3000	nM	DEFOSBARASERTIB
5.38	Kd	4200	nM	ALVOCIDIB
5.37	Kd	4300	nM	CHEMBL464552
5.33	Kd	4700	nM	MIDOSTAURIN
5.19	Kd	6400	nM	NERATINIB

PubChem BioAssay actives

25 with measured affinity, of 146 total; 21 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
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	624758: Binding constant for RIPK5 kinase domain	kd	0.0053	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	624758: Binding constant for RIPK5 kinase domain	kd	0.0110	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	624758: Binding constant for RIPK5 kinase domain	kd	0.0570	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	624758: Binding constant for RIPK5 kinase domain	kd	0.3600	uM
Bosutinib	624758: Binding constant for RIPK5 kinase domain	kd	0.3800	uM
Crizotinib	624758: Binding constant for RIPK5 kinase domain	kd	0.4500	uM
2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol	624758: Binding constant for RIPK5 kinase domain	kd	0.5100	uM
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	624758: Binding constant for RIPK5 kinase domain	kd	0.5100	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	624758: Binding constant for RIPK5 kinase domain	kd	0.6600	uM
7-(4-aminocyclohexyl)-5-(2-fluoro-4-methylphenyl)pyrrolo[2,3-d]pyrimidin-4-amine	1880922: Binding affinity to human RIPK5	kd	0.6700	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	624758: Binding constant for RIPK5 kinase domain	kd	0.7400	uM
[4-amino-2-[(1-methylsulfonylpiperidin-4-yl)amino]pyrimidin-5-yl]-(2,3-difluoro-6-methoxyphenyl)methanone	624758: Binding constant for RIPK5 kinase domain	kd	0.7800	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	624758: Binding constant for RIPK5 kinase domain	kd	0.9300	uM
Sunitinib	624758: Binding constant for RIPK5 kinase domain	kd	1.3000	uM
Fedratinib	624758: Binding constant for RIPK5 kinase domain	kd	1.7000	uM
2-[3-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]quinazolin-4-yl]amino]-1H-pyrazol-5-yl]-N-(3-fluorophenyl)acetamide	624758: Binding constant for RIPK5 kinase domain	kd	3.0000	uM
2-(2-chlorophenyl)-5,7-dihydroxy-8-[(3S,4R)-3-hydroxy-1-methylpiperidin-4-yl]chromen-4-one	624758: Binding constant for RIPK5 kinase domain	kd	4.2000	uM
2-[[2-[[1-[2-(dimethylamino)acetyl]-5-methoxy-2,3-dihydroindol-6-yl]amino]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-N-methylbenzamide	624758: Binding constant for RIPK5 kinase domain	kd	4.3000	uM
Midostaurin	624758: Binding constant for RIPK5 kinase domain	kd	4.7000	uM
3-[(3S)-3-aminopyrrolidine-1-carbonyl]-5,10-dihydroxy-2-methylnaphtho[2,3-f][1]benzofuran-4,11-dione;methanesulfonic acid	1284064: Inhibition of human RIPK5 by flashplate based radiometric 33pan-quinase assay	ic50	5.0000	uM
Neratinib	624758: Binding constant for RIPK5 kinase domain	kd	6.4000	uM

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, affects cotreatment, decreases expression	7
bisphenol A	increases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
methylmercuric chloride	decreases expression	1
uranyl acetate	affects expression	1
arsenite	decreases reaction, affects binding	1
sodium arsenite	increases expression	1
manganese chloride	decreases expression, increases abundance	1
benzo(e)pyrene	decreases methylation	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, decreases expression	1
Leflunomide	decreases expression	1
Benzene	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	increases abundance, increases expression	1
Manganese	decreases expression, increases abundance	1
Methapyrilene	decreases methylation	1
Methyl Methanesulfonate	increases expression	1
Uranium	affects expression	1
Urethane	increases expression	1
Cadmium Chloride	increases abundance, increases expression	1

ChEMBL screening assays

90 unique, capped per target: 90 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1175318	Binding	Inhibition of RIPK5 at 10 uM	Broad spectrum alkynyl inhibitors of T315I Bcr-Abl. — 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_B1QF	Abcam HeLa DSTYK KO	Cancer cell line	Female
CVCL_D8K9	Ubigene HCT 116 DSTYK KO	Cancer cell line	Male
CVCL_SL19	HAP1 DSTYK (-) 1	Cancer cell line	Male
CVCL_SL20	HAP1 DSTYK (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00073710	PHASE4	COMPLETED	Study to Evaluate the Effects of Zemplar Injection and Calcijex on Intestinal Absorption of Calcium
NCT00125593	PHASE4	COMPLETED	Study of Heart and Renal Protection
NCT00132431	PHASE4	COMPLETED	START: Sensipar Treatment Algorithm to Reach K/DOQI Targets in Chronic Kidney Disease Subjects With Secondary Hyperparathyroidism
NCT00155246	PHASE4	COMPLETED	Efficacy of Pentoxifylline on Chronic Kidney Disease
NCT00175149	PHASE4	TERMINATED	Active Vitamin D Effect on Left Ventricular Hypertrophy
NCT00184769	PHASE4	COMPLETED	Growth Hormone Treatment in Infants Aged 1 to 2 Years With Chronic Renal Insufficiency (CRI) and Growth Retardation.
NCT00190580	PHASE4	COMPLETED	Kanagawa Valsartan Trial (KVT): Effects of Valsartan on Renal and Cardiovascular Disease
NCT00194961	PHASE4	TERMINATED	Effect of Growth Hormone on Leptin, Cytokines and Body Composition of Children With Growth Failure Due to Chronic Kidney Disease
NCT00239642	PHASE4	COMPLETED	Safety and Efficacy of Iron Sucrose in Children
NCT00324571	PHASE4	COMPLETED	Dialysis Clinical Outcomes Revisited (DCOR) Trial
NCT00364884	PHASE4	UNKNOWN	Keto-/Amino Acid Supplemented Low Protein Diet in Patients With Chronic Kidney Disease
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
NCT00384618	PHASE4	TERMINATED	Anti-Oxidant Therapy In Chronic Renal Insufficiency (ATIC) Study
NCT00478543	PHASE4	COMPLETED	Loop Diuretics in Chronic Kidney Disease
NCT00632125	PHASE4	COMPLETED	Post-authorization Safety Study in CKD Subjects Receiving HX575 i.v.
NCT00644046	PHASE4	COMPLETED	Chronic Kidney Disease Prevention of An-Lo District, Keelung
NCT00719316	PHASE4	UNKNOWN	Aliskiren and Muscle Sympathetic Nerve Activity
NCT00725517	PHASE4	COMPLETED	Efficacy and Safety of a 7.5% Icodextrin Peritoneal Dialysis Solution in Once-Daily Long Dwell Exchange
NCT00741585	PHASE4	COMPLETED	Prognostic Value of the Circadian Pattern of Ambulatory Blood Pressure for Multiple Risk Assessment
NCT00749736	PHASE4	COMPLETED	The Role of Vitamin D in Immune Function in Patients With Chronic Kidney Disease (CKD) Stages 3 and 4.
NCT00752102	PHASE4	COMPLETED	Vitamin D and Coronary Calcification Study
NCT00756145	PHASE4	COMPLETED	The Use of Low Molecular Weight Heparin in Hemodiafiltration
NCT00768638	PHASE4	COMPLETED	Study of Atorvastatin Dose Dependent Reduction of Proteinuria
NCT00786136	PHASE4	COMPLETED	Rosuvastatin Prevent Contrast Induced Acute Kidney Injury in Patients With Diabetes
NCT00803712	PHASE4	COMPLETED	20070360 Incident Dialysis
NCT00812123	PHASE4	COMPLETED	Calcineurin Free Immunosuppression in Renal Transplant Recipients
NCT00823303	PHASE4	COMPLETED	Paricalcitol Versus Calcitriol for Efficacy and Safety in Stage 3/4 Chronic Kidney Disease (CKD) With Secondary Hyperparathyroidism (SHPT)
NCT00830037	PHASE4	TERMINATED	A Clinical Trial of Oral Versus IV Iron in Patients With Chronic Kidney Disease
NCT00852969	PHASE4	COMPLETED	Niacin and Endothelial Function in Early CKD
NCT00858299	PHASE4	UNKNOWN	The Change of Urinary Angiotensinogen Excretion After Valsartan Treatment in Patients With Persistent Proteinuria
NCT00860431	PHASE4	COMPLETED	Kremezin Study Against Renal Disease Progression in Korea
NCT00882401	PHASE4	COMPLETED	Vitamin D, Chronic Kidney Disease (CKD) and the Microcirculation
NCT00889629	PHASE4	COMPLETED	Pilot Study Evaluating Doxercalciferol Replacement Therapy in Kidney Transplant Recipients
NCT00892892	PHASE4	WITHDRAWN	Sympathetic Nerve Activity in Renal Failure
NCT00893425	PHASE4	COMPLETED	Effect of Renin Angiotensin System Blockade on the Fas Antigen (CD95) and Asymmetric Dimethylarginine (ADMA) Levels in Type-2 Diabetic Patients With Proteinuria
NCT00908310	PHASE4	COMPLETED	Post-marketing Safety Study in Patients With Moderate Renal Insufficiency Who Receive Omniscan for Contrast-enhanced Magnetic Resonance Imaging (MRI)
NCT00958451	PHASE4	COMPLETED	Vitamin D Deficiency in Chronic Kidney Disease (CKD) Patients