TP53RK

Summary

TP53RK (TP53 regulating kinase, HGNC:16197) is a protein-coding gene on chromosome 20q13.12, encoding EKC/KEOPS complex subunit TP53RK (Q96S44). Component of the EKC/KEOPS complex that is required for the formation of a threonylcarbamoyl group on adenosine at position 37 (t(6)A37) in tRNAs that read codons beginning with adenine. It is a selective cancer dependency (DepMap: 83.6% of cell lines).

Enables p53 binding activity and protein serine/threonine kinase activity. Involved in protein phosphorylation. Located in cytoplasm and nucleus. Part of EKC/KEOPS complex. Implicated in Galloway-Mowat syndrome 4.

Source: NCBI Gene 112858 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Galloway-Mowat syndrome 4 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 33
• Clinical variants (ClinVar): 166 total — 4 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 50
• Druggable target: yes — 6 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 83.6% of screened cell lines
• MANE Select transcript: NM_033550

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16197
Approved symbol	TP53RK
Name	TP53 regulating kinase
Location	20q13.12
Locus type	gene with protein product
Status	Approved
Aliases	dJ101A2.2, prpk, Nori-2p, BUD32, TPRKB
Ensembl gene	ENSG00000172315
Ensembl biotype	protein_coding
OMIM	608679
Entrez	112858

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000372102, ENST00000372114

RefSeq mRNA: 1 — MANE Select: NM_033550 NM_033550

CCDS: CCDS13401

Canonical transcript exons

ENST00000372114 — 2 exons

Exon	Start	End
ENSE00001456942	46689132	46689444
ENSE00001820707	46684365	46687231

Expression profiles

Bgee: expression breadth ubiquitous, 222 present calls, max score 89.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.3330 / max 127.3112, expressed in 1818 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
187583	18.1221	1758
187587	2.1778	686
187586	1.9089	1111
187584	1.2024	893
187585	0.5190	274
187582	0.3324	147
187581	0.0703	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	89.65	gold quality
ganglionic eminence	UBERON:0004023	89.43	gold quality
cortical plate	UBERON:0005343	87.38	gold quality
adrenal tissue	UBERON:0018303	84.54	gold quality
islet of Langerhans	UBERON:0000006	83.46	gold quality
bronchial epithelial cell	CL:0002328	82.90	gold quality
adult organism	UBERON:0007023	82.75	gold quality
stromal cell of endometrium	CL:0002255	82.41	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.30	gold quality
cartilage tissue	UBERON:0002418	82.25	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	82.03	gold quality
bronchus	UBERON:0002185	82.01	gold quality
right adrenal gland cortex	UBERON:0035827	81.33	gold quality
epithelium of nasopharynx	UBERON:0001951	80.96	gold quality
upper arm skin	UBERON:0004263	80.59	silver quality
gingival epithelium	UBERON:0001949	80.36	gold quality
granulocyte	CL:0000094	80.33	gold quality
gingiva	UBERON:0001828	80.19	gold quality
right adrenal gland	UBERON:0001233	80.06	gold quality
skin of abdomen	UBERON:0001416	79.92	gold quality
left testis	UBERON:0004533	79.68	gold quality
left adrenal gland cortex	UBERON:0035825	79.64	gold quality
right testis	UBERON:0004534	79.57	gold quality
left adrenal gland	UBERON:0001234	79.56	gold quality
esophagus mucosa	UBERON:0002469	79.55	gold quality
testis	UBERON:0000473	79.45	gold quality
lymph node	UBERON:0000029	79.35	gold quality
leukocyte	CL:0000738	79.28	gold quality
adrenal gland	UBERON:0002369	79.21	gold quality
ileal mucosa	UBERON:0000331	79.09	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.78

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

85 targeting TP53RK, 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-4425	100.00	67.59	1049
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-609	99.82	64.26	505
HSA-MIR-489-3P	99.80	66.46	839
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-4690-5P	99.65	66.24	813
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 83.6% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• A Small Ras-like GTPase protein Ray was indicated to modulate p53 transcriptional activity of PRPK. (PMID:16600182)
• activation of PRPK is mediated by another kinase, Akt/PKB, which phosphorylates PRPK at Ser250 (PMID:17712528)
• In a study addressing genetic, social, and environmental contributors of chronic kidney disease with tubulointerstitial damages in Sri Lanka, TP53RK was not confirmed to be genetically significant. (PMID:24351856)
• we show that TP53RK confers poor prognosis in multiple myeloma (PMID:28082445)
• Finding indicate that levels of phosphorylated p53-related protein kinase (p-PRPK) were higher in metastatic versus malignant human colon adenocarcinomas. (PMID:29483219)
• This is only the second report on GAMOS in association with a TP53RK mutation. (PMID:30053862)
• Crystal structure of the human PRPK-TPRKB complex. (PMID:33547416)
• TP53RK Drives the Progression of Chronic Kidney Disease by Phosphorylating Birc5. (PMID:37382161)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	tp53rk	ENSDARG00000112667
mus_musculus	Trp53rka	ENSMUSG00000039725
mus_musculus	Trp53rkb	ENSMUSG00000042854
rattus_norvegicus	Tp53rkb	ENSRNOG00000007285
rattus_norvegicus	Tp53rka	ENSRNOG00000029470
drosophila_melanogaster	Tcs5	FBGN0035590
caenorhabditis_elegans		WBGENE00138717

Protein

Protein identifiers

EKC/KEOPS complex subunit TP53RK — Q96S44 (reviewed: Q96S44)

Alternative names: Atypical serine/threonine protein kinase TP53RK, Nori-2, TP53-regulating kinase, p53-related protein kinase

All UniProt accessions (2): Q96S44, Q5JZ02

UniProt curated annotations — full annotation on UniProt →

Function. Component of the EKC/KEOPS complex that is required for the formation of a threonylcarbamoyl group on adenosine at position 37 (t(6)A37) in tRNAs that read codons beginning with adenine. The complex is probably involved in the transfer of the threonylcarbamoyl moiety of threonylcarbamoyl-AMP (TC-AMP) to the N6 group of A37. TP53RK has ATPase activity in the context of the EKC/KEOPS complex and likely plays a supporting role to the catalytic subunit OSGEP. Atypical protein kinase that phosphorylates ‘Ser-15’ of p53/TP53 protein and may therefore participate in its activation.

Subunit / interactions. Component of the EKC/KEOPS complex composed of at least GON7, TP53RK, TPRKB, OSGEP and LAGE3; the whole complex dimerizes.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Highly expressed in testis. Weakly expressed in heart kidney and spleen.

Disease relevance. Galloway-Mowat syndrome 4 (GAMOS4) [MIM:617730] A form of Galloway-Mowat syndrome, a severe renal-neurological disease characterized by early-onset nephrotic syndrome associated with microcephaly, central nervous system abnormalities, developmental delays, and a propensity for seizures. Brain anomalies include gyration defects ranging from lissencephaly to pachygyria and polymicrogyria, and cerebellar hypoplasia. Most patients show facial dysmorphism characterized by a small, narrow forehead, large/floppy ears, deep-set eyes, hypertelorism and micrognathia. Additional variable features are visual impairment and arachnodactyly. Most patients die in early childhood. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. This protein is considered an atypical serine/threonine kinase, because it lacks the conventional structural elements necessary for the substrate recognition as well as a lysine residue that in all other serine/threonine kinases participates in the catalytic event. TP53RK has protein kinase activity in vitro, but in the context of the EKC/KEOPS complex, the catalytic subunit OSGEP switches the activity of TP53RK from kinase into ATPase.

Similarity. Belongs to the protein kinase superfamily. BUD32 family.

RefSeq proteins (1): NP_291028* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR022495	Bud32	Family

Pfam: PF06293

Enzyme classification (BRENDA):

• EC 2.7.11.1 — non-specific serine/threonine protein kinase (BRENDA: 71 organisms, 682 substrates, 228 inhibitors, 23 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0007–0.64	11
KKRAARATSNVFA	0.013–0.045	3
PAH1 PHOSPHATIDATE PHOSPHATASE	0.0002	2
RRRLSSLRA	0.0036–0.0037	2
GTP	0.46	1
KKRAARASSNVFA	0.02	1
LYS-LYS-PHE-ASN-ARG-THR-LEU-SER-VAL-ALA	0.0093	1
MYELIN BASIC PROTEIN	0.145	1

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 (37 total): helix 9, strand 9, sequence variant 7, sequence conflict 2, binding site 2, modified residue 2, chain 1, domain 1, region of interest 1, turn 1, short sequence motif 1, active site 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
7SZC	X-RAY DIFFRACTION	1.71
7SZA	X-RAY DIFFRACTION	1.9
7SZB	X-RAY DIFFRACTION	2.02
7SZD	X-RAY DIFFRACTION	2.05
6WQX	X-RAY DIFFRACTION	2.53
9FL9	ELECTRON MICROSCOPY	3.74

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96S44-F1	91.58	0.79

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): 162 (proton acceptor)

Ligand- & substrate-binding residues (2): 39–47; 60

Post-translational modifications (2): 34, 135

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6782315	tRNA modification in the nucleus and cytosol
R-HSA-6804756	Regulation of TP53 Activity through Phosphorylation

MSigDB gene sets: 358 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, MODULE_151, GOBP_TRNA_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GOBP_TRANSLATION, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_RNA_MODIFICATION, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, GARCIA_TARGETS_OF_FLI1_AND_DAX1_DN, GOBP_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR, GOBP_REGULATION_OF_SIGNAL_TRANSDUCTION_BY_P53_CLASS_MEDIATOR, BASAKI_YBX1_TARGETS_UP, GOBP_TRNA_THREONYLCARBAMOYLADENOSINE_METABOLIC_PROCESS

GO Biological Process (4): protein phosphorylation (GO:0006468), tRNA processing (GO:0008033), tRNA threonylcarbamoyladenosine metabolic process (GO:0070525), regulation of signal transduction by p53 class mediator (GO:1901796)

GO Molecular Function (11): p53 binding (GO:0002039), protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), hydrolase activity (GO:0016787), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (5): EKC/KEOPS complex (GO:0000408), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
tRNA processing	1
Regulation of TP53 Activity	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
tRNA metabolic process	2
protein kinase activity	2
catalytic activity	2
phosphorylation	1
protein modification process	1
RNA processing	1
signal transduction by p53 class mediator	1
regulation of intracellular signal transduction	1
protein binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	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
transferase complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

1148 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TP53RK	TPRKB	Q9Y3C4	999
TP53RK	OSGEP	Q9NPF4	997
TP53RK	LAGE3	Q14657	997
TP53RK	GON7	Q9BXV9	994
TP53RK	TP53	P04637	870
TP53RK	OSGEPL1	Q9H4B0	842
TP53RK	YRDC	Q86U90	839
TP53RK	WDR73	Q6P4I2	710
TP53RK	ARPC1B	O15143	563
TP53RK	RIOK1	Q9BRS2	546
TP53RK	WDR4	P57081	533
TP53RK	MAP1B	P46821	516
TP53RK	MTERF3	Q96E29	512
TP53RK	NUP107	P57740	479
TP53RK	NUP133	Q8WUM0	460

IntAct

65 interactions, top by confidence:

A	B	Type	Score
UBA5	GABARAPL2	psi-mi:“MI:0914”(association)	0.950
ARPC1A	ARPC2	psi-mi:“MI:0914”(association)	0.900
CPSF6	NUDT21	psi-mi:“MI:0914”(association)	0.890
GON7	LAGE3	psi-mi:“MI:0915”(physical association)	0.880
GON7	LAGE3	psi-mi:“MI:0914”(association)	0.880
TPRKB	TP53RK	psi-mi:“MI:0915”(physical association)	0.850
TP53RK	TPRKB	psi-mi:“MI:0915”(physical association)	0.850
TP53RK	GON7	psi-mi:“MI:0914”(association)	0.820
CALCOCO2	TP53RK	psi-mi:“MI:0915”(physical association)	0.740
TP53RK	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.740
TP53RK	NUP43	psi-mi:“MI:0914”(association)	0.730
PAGR1	KDM6A	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
NUP43	NUP98	psi-mi:“MI:0914”(association)	0.640
TP53RK	MTUS2	psi-mi:“MI:0915”(physical association)	0.560
TP53RK	GORASP2	psi-mi:“MI:0915”(physical association)	0.560
UBA5	GAPDHS	psi-mi:“MI:0914”(association)	0.530
COMMD10	VPS26C	psi-mi:“MI:0914”(association)	0.530
POP7	RPP40	psi-mi:“MI:0914”(association)	0.530
ANO4	ANO6	psi-mi:“MI:0914”(association)	0.530
LAGE3	CTSA	psi-mi:“MI:0914”(association)	0.530

BioGRID (141): TP53RK (Two-hybrid), TP53RK (Two-hybrid), TP53RK (Affinity Capture-MS), TPRKB (Affinity Capture-MS), C14orf142 (Affinity Capture-MS), OSGEP (Affinity Capture-MS), NUP43 (Affinity Capture-MS), TP53RK (Affinity Capture-MS), TP53RK (Affinity Capture-MS), TP53RK (Affinity Capture-MS), TP53RK (Two-hybrid), TP53RK (Affinity Capture-MS), TP53RK (Two-hybrid), ARPP19 (Co-fractionation), PRPS1 (Co-fractionation)

ESM2 similar proteins: A4RPM5, A5WVX1, B2RZ55, B2ZFP3, B4FAT0, B6TNK6, D3ZHP7, E2RDZ6, P25741, P35520, P38935, P40694, P52431, P53323, Q0VCE9, Q1LVN8, Q2H317, Q2HGY8, Q2TBI4, Q3U3Q1, Q4HYC1, Q4V7Q6, Q58H57, Q5BBC5, Q5ZJH6, Q60560, Q6C2A3, Q6CXB9, Q6JQN1, Q6K881, Q6PHR2, Q74Z75, Q75LD5, Q80WS1, Q8BKJ9, Q8C7H1, Q8K370, Q8R216, Q8R4H7, Q91XU0

Diamond homologs: A1CLD2, A2SR70, A3CXS0, A6US28, O27476, P0CP72, P0CP73, P36174, P53323, Q1EBD3, Q2FS43, Q2HGY8, Q2U3T8, Q4HYC1, Q4WYU4, Q54W07, Q5AGC7, Q5BAB7, Q6BHA8, Q6C2A3, Q6CXB9, Q6FTW0, Q74Z75, Q8PZ92, Q8SVD9, Q8TJS2, Q96S44, Q99PW4, Q9P7N1, Q9UYB9, A4FZ86, A5UMH5, A6VJ51, A9A6L6, B7XIB8, O29592, Q2NIA4, Q58530, Q6M056, Q7T6Y1

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
AKT	up-regulates	TP53RK	phosphorylation
TP53RK	up-regulates	TP53	phosphorylation
AKT1	up-regulates	TP53RK	phosphorylation
PBK	“up-regulates activity”	TP53RK	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	5
Uncertain significance	99
Likely benign	28
Benign	14

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
444880	NM_033550.4(TP53RK):c.179del (p.Lys60fs)	Pathogenic
444881	NM_033550.4(TP53RK):c.242C>G (p.Thr81Arg)	Pathogenic
444882	NM_033550.4(TP53RK):c.125G>A (p.Gly42Asp)	Pathogenic
444885	NM_016058.5(TPRKB):c.446A>G (p.Tyr149Cys)	Pathogenic
1210333	NM_033550.4(TP53RK):c.193A>C (p.Lys65Gln)	Likely pathogenic
3065453	NM_016058.5(TPRKB):c.445T>A (p.Tyr149Asn)	Likely pathogenic
3587281	NM_033550.4(TP53RK):c.675C>G (p.Tyr225Ter)	Likely pathogenic
3587283	NM_033550.4(TP53RK):c.602_603del (p.Tyr201fs)	Likely pathogenic
3587287	NM_033550.4(TP53RK):c.520dup (p.Leu174fs)	Likely pathogenic

SpliceAI

690 predictions. Top by Δscore:

Variant	Effect	Δscore
2:73730570:T:TA	donor_gain	1.0000
2:73732161:A:AC	donor_gain	1.0000
2:73732162:C:CC	donor_gain	1.0000
2:73737297:CTCA:C	donor_loss	1.0000
2:73737298:TCA:T	donor_loss	1.0000
2:73737299:CA:C	donor_loss	1.0000
2:73737300:A:AC	donor_gain	1.0000
2:73737300:A:T	donor_loss	1.0000
2:73737300:ACCAT:A	donor_gain	1.0000
2:73737301:C:CC	donor_gain	1.0000
2:73737301:C:CT	donor_loss	1.0000
2:73737301:CCAT:C	donor_gain	1.0000
2:73737301:CCATC:C	donor_gain	1.0000
2:73730737:C:CC	acceptor_gain	0.9900
2:73732162:CA:C	donor_gain	0.9900
2:73734428:CCA:C	donor_gain	0.9900
2:73734587:TTCTA:T	acceptor_gain	0.9900
2:73734589:CTA:C	acceptor_gain	0.9900
2:73734599:C:CT	acceptor_gain	0.9900
2:73737295:AACTC:A	donor_loss	0.9900
2:73737296:ACTCA:A	donor_loss	0.9900
2:73737300:AC:A	donor_gain	0.9900
2:73737301:CC:C	donor_gain	0.9900
2:73737301:CCA:C	donor_gain	0.9900
2:73730737:C:CA	acceptor_loss	0.9800
2:73732216:T:TA	donor_gain	0.9800
2:73732282:CAAT:C	acceptor_gain	0.9800
2:73734428:C:CT	donor_gain	0.9800
2:73734590:TA:T	acceptor_gain	0.9800
2:73734592:C:CC	acceptor_gain	0.9800

AlphaMissense

1623 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:46686966:G:C	D183E	0.999
20:46686966:G:T	D183E	0.999
20:46686954:A:C	S187R	0.998
20:46686954:A:T	S187R	0.998
20:46686956:T:G	S187R	0.998
20:46686967:T:A	D183V	0.998
20:46686967:T:G	D183A	0.998
20:46687030:T:A	D162V	0.998
20:46687030:T:C	D162G	0.998
20:46689235:C:A	K60N	0.998
20:46689235:C:G	K60N	0.998
20:46687029:A:C	D162E	0.997
20:46687029:A:T	D162E	0.997
20:46687030:T:G	D162A	0.997
20:46686774:T:A	R247S	0.996
20:46686774:T:G	R247S	0.996
20:46686775:C:G	R247T	0.996
20:46686925:C:T	G197E	0.996
20:46686967:T:C	D183G	0.996
20:46689237:T:C	K60E	0.996
20:46686771:C:A	K248N	0.995
20:46686771:C:G	K248N	0.995
20:46686920:C:G	D199H	0.995
20:46686926:C:G	G197R	0.995
20:46686926:C:T	G197R	0.995
20:46686958:A:G	L186P	0.995
20:46686961:C:T	G185E	0.995
20:46686968:C:G	D183H	0.995
20:46686781:C:G	R245T	0.994
20:46686888:A:C	S209R	0.994

dbSNP variants (sampled 300 via entrez): RS1000307380 (20:46684247 T>C), RS1000419591 (20:46684416 G>A), RS1000851345 (20:46689544 C>A,G,T), RS1001243221 (20:46684678 A>C,G), RS1001295583 (20:46684918 A>G), RS1001363919 (20:46691113 A>G), RS1001827889 (20:46690832 T>C), RS1002009514 (20:46685118 T>C), RS1002235705 (20:46689845 C>T), RS1002430733 (20:46689647 C>A), RS1002763812 (20:46689869 T>A), RS1002918519 (20:46686353 A>G), RS1002970816 (20:46686513 T>C), RS1003871864 (20:46689893 C>T), RS1003871957 (20:46684590 C>A)

Disease associations

OMIM: gene MIM:608679 | disease phenotypes: MIM:617730, MIM:617731

GenCC curated gene-disease

Disease	Classification	Inheritance
Galloway-Mowat syndrome 4	Strong	Autosomal recessive
Galloway-Mowat syndrome 5	Strong	Autosomal recessive
Galloway-Mowat syndrome	Supportive	Autosomal recessive

Mondo (4): Galloway-Mowat syndrome 4 (MONDO:0033008), Galloway-Mowat syndrome 5 (MONDO:0033009), nephrotic syndrome (MONDO:0005377), Galloway-Mowat syndrome (MONDO:0009627)

Orphanet (0):

HPO phenotypes

50 total (30 of 50 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000097	Focal segmental glomerulosclerosis
HP:0000100	Nephrotic syndrome
HP:0000112	Nephropathy
HP:0000164	Abnormality of the dentition
HP:0000252	Microcephaly
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000400	Macrotia
HP:0000411	Protruding ear
HP:0000505	Visual impairment
HP:0000601	Hypotelorism
HP:0000750	Delayed speech and language development
HP:0001034	Hypermelanotic macule
HP:0001181	Adducted thumb
HP:0001182	Tapered finger
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001302	Pachygyria
HP:0001321	Cerebellar hypoplasia
HP:0001357	Plagiocephaly
HP:0001511	Intrauterine growth retardation
HP:0001622	Premature birth
HP:0001967	Diffuse mesangial sclerosis
HP:0002036	Hiatus hernia

GWAS associations

33 associations (top):

Study	Trait	p-value
GCST000651_1	Creatinine levels	1.000000e-15
GCST001220_3	Metabolite levels	1.000000e-11
GCST005758_5	Dimensional psychopathology (Arousal)	1.000000e-06
GCST005956_29	Waist-to-hip ratio adjusted for BMI	4.000000e-10
GCST005957_10	Waist-to-hip ratio adjusted for BMI (age <50)	5.000000e-06
GCST005958_17	Waist-to-hip ratio adjusted for BMI (age >50)	3.000000e-06
GCST005962_25	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	1.000000e-09
GCST006249_13	Serum metabolite levels	1.000000e-77
GCST006249_52	Serum metabolite levels	5.000000e-11
GCST006249_62	Serum metabolite levels	7.000000e-24
GCST006249_77	Serum metabolite levels	7.000000e-33
GCST006879_11	Blood metabolite levels	1.000000e-12
GCST006879_6	Blood metabolite levels	5.000000e-14
GCST006879_7	Blood metabolite levels	2.000000e-15
GCST006879_9	Blood metabolite levels	2.000000e-14
GCST008746_1	Estimated glomerular filtration rate in diabetes	4.000000e-08
GCST012020_270	Serum metabolite levels	8.000000e-103
GCST012020_271	Serum metabolite levels	4.000000e-120
GCST012020_594	Serum metabolite levels	1.000000e-25
GCST012020_595	Serum metabolite levels	3.000000e-123
GCST012021_42	Serum metabolite levels	1.000000e-25
GCST012021_43	Serum metabolite levels	3.000000e-123
GCST012353_13	Serum metabolite concentrations in chronic kidney disease	1.000000e-41
GCST012353_14	Serum metabolite concentrations in chronic kidney disease	6.000000e-13
GCST012353_15	Serum metabolite concentrations in chronic kidney disease	5.000000e-23
GCST012353_16	Serum metabolite concentrations in chronic kidney disease	2.000000e-11
GCST012353_17	Serum metabolite concentrations in chronic kidney disease	3.000000e-31
GCST012353_18	Serum metabolite concentrations in chronic kidney disease	7.000000e-37
GCST012353_19	Serum metabolite concentrations in chronic kidney disease	7.000000e-29
GCST012353_20	Serum metabolite concentrations in chronic kidney disease	7.000000e-37

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004725	metabolite measurement
EFO:0009099	arousal domain measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D009404	Nephrotic Syndrome	C12.050.351.968.419.630.643; C12.200.777.419.630.643; C12.950.419.630.643
C537548	Galloway Mowat syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1938223 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

6 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 9,763 (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
CHEMBL3301622	GILTERITINIB	4	2,395
CHEMBL1230165	SILMITASERTIB	2	593
CHEMBL3039513	DECERNOTINIB	2	1,418
CHEMBL3218578	BGT-226 FREE BASE	2	2,878
CHEMBL3544966	GSK-1059615	1	1,928
CHEMBL3545083	RGB-286638	1	551

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Bud32 family

ChEMBL bioactivities

12 potent at pChembl≥5 of 12 total, top 12 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.24	Kd	58	nM	GSK-1059615
6.51	Kd	311	nM	CHEMBL3688339
6.32	Kd	484.6	nM	CHEMBL5653589
6.32	ED50	484.6	nM	CHEMBL5653589
6.00	Kd	1009	nM	BGT-226 FREE BASE
5.91	Kd	1241	nM	SILMITASERTIB
5.76	Kd	1716	nM	RGB-286638
5.57	Kd	2716	nM	GILTERITINIB
5.55	Kd	2830	nM	DECERNOTINIB
5.46	Kd	3471	nM	CHEMBL3752910
5.46	ED50	3471	nM	CHEMBL3752910
5.42	Kd	3840	nM	K-252A

PubChem BioAssay actives

10 with measured affinity, of 295 total; 10 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
(5Z)-5-[(4-pyridin-4-ylquinolin-6-yl)methylidene]-1,3-thiazolidine-2,4-dione	1425204: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.0580	uM
1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-[[4-[(dimethylamino)methyl]cyclohexyl]amino]-1,5-naphthyridin-3-yl]ethanone	1425204: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.3110	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149640: Binding affinity to human TP53RK incubated for 45 mins by Kinobead based pull down assay	kd	0.4846	uM
8-(6-methoxy-3-pyridinyl)-3-methyl-1-[4-piperazin-1-yl-3-(trifluoromethyl)phenyl]imidazo[4,5-c]quinolin-2-one	1425204: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	1.0090	uM
5-(3-chloroanilino)benzo[c][2,6]naphthyridine-8-carboxylic acid	1425204: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	1.2410	uM
1-[3-[4-[[4-(2-methoxyethyl)piperazin-1-yl]methyl]phenyl]-4-oxo-1H-indeno[2,1-d]pyrazol-5-yl]-3-morpholin-4-ylurea	1425204: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	1.7160	uM
Gilteritinib	1425204: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	2.7160	uM
(2R)-2-methyl-2-[[2-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]-N-(2,2,2-trifluoroethyl)butanamide	1425204: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	2.8300	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149640: Binding affinity to human TP53RK incubated for 45 mins by Kinobead based pull down assay	kd	3.4715	uM
methyl (15S,16R,18R)-16-hydroxy-15-methyl-3-oxo-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-nonaene-16-carboxylate	1425204: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	3.8400	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
afimoxifene	decreases response to substance	1
sodium arsenite	decreases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	increases expression	1
bisphenol B	increases expression	1
abrine	increases expression	1
jinfukang	decreases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, affects expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	affects phosphorylation	1
Estradiol	increases expression	1
Formaldehyde	increases expression	1
Methyl Methanesulfonate	increases expression	1
Nickel	increases expression	1
Ozone	affects expression, increases abundance	1
Quercetin	decreases expression	1
Rotenone	decreases expression	1
Silver	decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Urethane	decreases expression	1
Cyclosporine	increases expression	1

ChEMBL screening assays

40 unique, capped per target: 40 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1942759	Binding	Inhibition of human PRPK in HL-60 cells lysate assessed as reduction of labeling of acyl-phosphate ATP probe at 100 nM	6-Position optimization of tricyclic 4-quinolone-based inhibitors of glycogen synthase kinase-3β: discovery of nitrile derivatives with picomolar potency. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00308321	PHASE4	UNKNOWN	Long Term Tapering or Standard Steroids for Nephrotic Syndrome
NCT01021540	PHASE4	COMPLETED	Prospective Study Evaluating the Effect of Repository Corticotropin in the Treatment of Various Nephrotic Syndromes
NCT01028287	PHASE4	COMPLETED	Adrenocorticotropic Hormone (ACTH) Treatment of Nephrotic Range Proteinuria in Diabetic Nephropathy (NRDN)
NCT01162005	PHASE4	COMPLETED	Therapeutic Effect of Tacrolimus on Primary Nephrotic Syndrome in Children
NCT01895894	PHASE4	COMPLETED	Mycophenolate Mofetil in Pediatric Steroid Dependent Nephrotic Syndrome
NCT02238418	PHASE4	COMPLETED	Efficacy of Usual Vitamin D Supplementation and Its Impact on Children and Adolescents Calciuria.
NCT02382575	PHASE4	UNKNOWN	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Resistant Nephrotic Syndrome
NCT02427880	PHASE4	COMPLETED	Role of Acetazolamide and Hydrochlorothiazide Followed by Furosemide in Treating Nephrotic Edema
NCT03210688	PHASE4	COMPLETED	Active Vitamin D And Reduced Dose Prednisolone for Treatment in Minimal Change Nephropathy
NCT03347357	PHASE4	COMPLETED	Pharmacokinetics of Tacrolimus in Children
NCT05696977	PHASE4	UNKNOWN	Effect of Obesity on Cyclosporine Blood Trough Level in Nephrotic Syndrome Patients
NCT05966818	PHASE4	UNKNOWN	Effect of Dapagliflozin in Non-Diabetic Patients With Nephrotic Syndrome.
NCT06026787	PHASE4	COMPLETED	Clinical Value of Adding Dapagliflozin in Patients With Nephrotic Syndrome
NCT00354731	PHASE3	COMPLETED	Efficacy of Pentoxifylline on Primary Nephrotic Syndrome
NCT00615667	PHASE3	COMPLETED	Prospective, Multicenter Study of the Efficacy and Tolerance of Tacrolimus on Refractory Nephrotic Syndrome (RNS)
NCT00981838	PHASE3	COMPLETED	Rituximab in Multirelapsing Minimal Change Disease (MCD) or Focal Segmental Glomerulosclerosis (FSGS)
NCT01197040	PHASE3	COMPLETED	Evaluation of Low Dose Corticosteroids Efficiency, Associated With Myfortic ® in the Treatment of Nephrotic Syndrome
NCT01309477	PHASE3	COMPLETED	The Efficacy and Tolerance of Tacrolimus Sustained-release Capsules on Refractory Nephrotic Syndrome (RNS)
NCT02132195	PHASE3	COMPLETED	Adrenocorticotropic Hormone (ACTH) for Frequently Relapsing and Steroid Dependent Nephrotic Syndrome
NCT02257697	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Mizoribine in the Treatment of Refractory Nephrotic Syndrome
NCT02438982	PHASE3	COMPLETED	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Dependent Nephrotic Syndrome
NCT03141970	PHASE3	COMPLETED	Prednisolone Trial in Children Younger Than 4 Years
NCT03501459	PHASE3	UNKNOWN	Lymphocyte Markers As Predictors Of Responsiveness To Rituximab Among Patients With Idiopathic Nephrotic Syndrome
NCT05079789	PHASE3	TERMINATED	Amiloride in Nephrotic Syndrome
NCT05716880	PHASE3	RECRUITING	Ketoanalogues for Muscle Mass Loss in Nephrotic Syndrome
NCT06635720	PHASE3	ACTIVE_NOT_RECRUITING	REduced-dose Steroid PrOtocol for Childhood Nephrotic SyndromE (RESPONSE)
NCT00001212	PHASE2	COMPLETED	Drug Therapy in Lupus Nephropathy
NCT00001959	PHASE2	COMPLETED	Pirfenidone to Treat Kidney Disease (Focal Segmental Glomerulosclerosis)
NCT00004466	PHASE2	TERMINATED	Pilot Study of Atorvastatin in Children With Chronic Hyperlipidemia Secondary to Nephrotic Syndrome
NCT00004990	PHASE2	COMPLETED	Once-A-Month Steroid Treatment for Patients With Focal Segmental Glomerulosclerosis
NCT00977977	PHASE2	RECRUITING	Rituximab Plus Cyclosporine in Idiopathic Membranous Nephropathy
NCT02394106	PHASE2	TERMINATED	Ofatumumab in Children With Drug Resistant Idiopathic Nephrotic Syndrome
NCT02394119	PHASE2	COMPLETED	Ofatumumab Versus Rituximab in Children With Steroid and Calcineurin Inhibitor Dependent Idiopathic Nephrotic Syndrome
NCT02592798	PHASE2	COMPLETED	Pilot Study to Evaluate the Safety and Efficacy of Abatacept in Adults and Children 6 Years and Older With Excessive Loss of Protein in the Urine Due to Either Focal Segmental Glomerulosclerosis (FSGS) or Minimal Change Disease (MCD)
NCT02966717	PHASE2	UNKNOWN	Rituximab Combined With MSCs in the Treatment of PNS (3-4 Stage of CKD)
NCT03004001	PHASE2	TERMINATED	Effect of PCSK9-Antibody (Alirocumab) on Dyslipidemia Secondary to Nephrotic Syndrome
NCT03949855	PHASE2	RECRUITING	Belimumab With Rituximab for Primary Membranous Nephropathy
NCT05599815	PHASE2	WITHDRAWN	Part 1 - A Clinical Trial in Patients With Frequently Relapsing and Steroid-Dependent Nephrotic Syndrome
NCT05704400	PHASE2	UNKNOWN	Efficacy of Anti-CD20 Ab Associated With Anti-CD38 in the Childhood Multidrug Dependent and Resistant Nephrotic Syndrome
NCT06983028	PHASE2	RECRUITING	Atacicept in Multiple Glomerular Diseases