RIOK3

Summary

RIOK3 (RIO kinase 3, HGNC:11451) is a protein-coding gene on chromosome 18q11.2, encoding Serine/threonine-protein kinase RIO3 (O14730). Serine/threonine-protein kinase involved in a ribosome quality control that takes place when ribosomes have stalled, leading to 18S non-functional rRNA decay and degradation of the 40S ribosomal subunit.

This gene was first identified by the similarity of its product to the Aspergillus nidulans SUDD protein. This gene is now recognized as a member of the right open reading frame (RIO) kinase gene family. This gene encodes a serine/threonine kinase that localizes to the cytoplasm and plays a role in the processing of the pre-40 S ribosomal subunit. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 8780 — RefSeq curated summary.

At a glance

• GWAS associations: 20
• Clinical variants (ClinVar): 69 total
• Druggable target: yes — 17 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_003831

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11451
Approved symbol	RIOK3
Name	RIO kinase 3
Location	18q11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000101782
Ensembl biotype	protein_coding
OMIM	603579
Entrez	8780

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 15 protein_coding, 6 retained_intron, 1 nonsense_mediated_decay

ENST00000339486, ENST00000577250, ENST00000577501, ENST00000581220, ENST00000581302, ENST00000581339, ENST00000581585, ENST00000584052, ENST00000584130, ENST00000584960, ENST00000584992, ENST00000871584, ENST00000871585, ENST00000871586, ENST00000871587, ENST00000871588, ENST00000871589, ENST00000928585, ENST00000966655, ENST00000966656, ENST00000966657, ENST00000966658

RefSeq mRNA: 2 — MANE Select: NM_003831 NM_001348193, NM_003831

CCDS: CCDS11877, CCDS86664

Canonical transcript exons

ENST00000339486 — 13 exons

Exon	Start	End
ENSE00001276480	23477179	23477268
ENSE00001866134	23481172	23483140
ENSE00003481453	23467399	23467526
ENSE00003485274	23464206	23464313
ENSE00003542280	23474948	23475107
ENSE00003579909	23473429	23473626
ENSE00003581713	23466133	23466276
ENSE00003604813	23477006	23477086
ENSE00003621281	23453287	23453502
ENSE00003636746	23463967	23464112
ENSE00003652532	23479317	23479424
ENSE00003659071	23464519	23464628
ENSE00003678805	23462964	23463079

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.39.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.9498 / max 1186.5773, expressed in 1815 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
169670	25.6733	1814
169671	0.6321	277
169669	0.5406	214
169667	0.0760	15
169668	0.0209	4
169666	0.0069	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	99.39	gold quality
sperm	CL:0000019	98.89	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.60	gold quality
colonic mucosa	UBERON:0000317	98.32	gold quality
esophagus squamous epithelium	UBERON:0006920	98.27	gold quality
upper leg skin	UBERON:0004262	98.23	gold quality
trabecular bone tissue	UBERON:0002483	98.17	gold quality
secondary oocyte	CL:0000655	98.15	gold quality
lower esophagus mucosa	UBERON:0035834	98.10	gold quality
skin of hip	UBERON:0001554	97.91	gold quality
epithelium of esophagus	UBERON:0001976	97.85	gold quality
bone marrow	UBERON:0002371	97.80	gold quality
oral cavity	UBERON:0000167	97.70	gold quality
male germ cell	CL:0000015	97.45	gold quality
duodenum	UBERON:0002114	97.44	gold quality
jejunum	UBERON:0002115	97.42	gold quality
monocyte	CL:0000576	97.26	gold quality
mononuclear cell	CL:0000842	97.26	gold quality
esophagus mucosa	UBERON:0002469	97.22	gold quality
palpebral conjunctiva	UBERON:0001812	97.11	gold quality
leukocyte	CL:0000738	96.99	gold quality
pharyngeal mucosa	UBERON:0000355	96.65	gold quality
gluteal muscle	UBERON:0002000	96.65	gold quality
rectum	UBERON:0001052	96.63	gold quality
biceps brachii	UBERON:0001507	96.52	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.47	gold quality
gingiva	UBERON:0001828	96.25	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.14	gold quality
penis	UBERON:0000989	95.94	gold quality
squamous epithelium	UBERON:0006914	95.93	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-9221	yes	17.54
E-HCAD-9	yes	5.36
E-MTAB-9467	no	2.01
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

101 targeting RIOK3, 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-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-6508-5P	99.92	70.67	2465

Literature-anchored findings (GeneRIF, showing 10)

• Like RIOK3, PAK4 promotes pancreas ductal cell motility and invasion in pancreatic cancer (PMID:19050074)
• RioK3 is a novel cytoplasmic component of pre-40S pre-ribosomal particle(s) in human cells, required for normal processing of the 21S pre-rRNA. (PMID:22418843)
• Functionally, RIOK3 acts as a SUFU-dependent positive regulator of Hedgehog signaling. (PMID:24018050)
• Authors found that RIOK3 physically interacts with TBK1 and IRF3 and bridges the functions between TBK1 and IRF3 in the activation of type I interferon pathway. (PMID:24807708)
• These findings demonstrate that RIOK3 is necessary for maintaining actin cytoskeletal organisation required for migration and invasion, biological processes that are necessary for hypoxia-driven metastasis. (PMID:25486436)
• the ectopic expression of RIOK3 or a phosphomimetic MDA5-S828D mutation attenuated MDA5-mediated signaling. (PMID:25865883)
• RIO kinase 3 (RIOK3) positively regulates the activity of the AKT/mTOR pathway in glioma cells. (PMID:29233656)
• The Atypical Kinase RIOK3 Limits RVFV Propagation and Is Regulated by Alternative Splicing. (PMID:33652597)
• RIOK3 promotes mTORC1 activation by facilitating SLC7A2-mediated arginine uptake in pancreatic ductal adenocarcinoma. (PMID:36880835)
• Alternative Splicing of RIOK3 Engages the Noncanonical NFkappaB Pathway during Rift Valley Fever Virus Infection. (PMID:37515252)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	riok3	ENSDARG00000042751
mus_musculus	Riok3	ENSMUSG00000024404
rattus_norvegicus	Riok3	ENSRNOG00000023376
drosophila_melanogaster	CG3008	FBGN0031643
caenorhabditis_elegans		WBGENE00014012

Paralogs (3): RIOK2 (ENSG00000058729), RIOK1 (ENSG00000124784), ATMIN (ENSG00000166454)

Protein

Protein identifiers

Serine/threonine-protein kinase RIO3 — O14730 (reviewed: O14730)

Alternative names: RIO kinase 3, sudD homolog

All UniProt accessions (5): O14730, B0YJ89, B4E1Q4, J3QLP4, J3QQL5

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine-protein kinase involved in a ribosome quality control that takes place when ribosomes have stalled, leading to 18S non-functional rRNA decay and degradation of the 40S ribosomal subunit. Acts downstream of RNF10: specifically recognizes and binds RPS2/us5 and RPS3/us3 monoubiquitinated by RNF10, promoting degradation of the 40S ribosomal subunit in a kinase-dependent manner. The RNF10-RIOK3 ribosome quality control takes place in response to ribosome subunit imbalance or downstream the EIF2AK4/GCN2-mediated integrated stress response (ISR). Also involved in regulation of type I interferon (IFN)-dependent immune response, possibly by acting as an adapter protein essential for the recruitment of TBK1 to IRF3. Phosphorylates IFIH1 on ‘Ser-828’ interfering with IFIH1 filament assembly on long dsRNA and resulting in attenuated IFIH1-signaling. Can inhibit CASP10 isoform 7-mediated activation of the NF-kappa-B signaling pathway.

Subunit / interactions. Interacts with CASP10. Interacts with IRF3; RIOK3 probably mediates the interaction of TBK1 with IRF3. Associated with 40S pre-ribosomal particles.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Widely expressed.

Post-translational modifications. Autophosphorylated (in vitro).

Domain organisation. The ubiquitin interaction motif (UIM) specifically recognizes and binds monoubiquitinated RPS2/us5 and RPS3/us3.

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

Isoforms (2)

UniProt ID	Names	Canonical?
O14730-1	1	yes
O14730-2	2

RefSeq proteins (2): NP_001335122, NP_003822* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000687	RIO_kinase	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017406	Ser/Thr_kinase_Rio3	Family
IPR018934	RIO_dom	Domain
IPR018935	RIO_kinase_CS	Conserved_site
IPR051272	RIO-type_Ser/Thr_kinase	Family

Pfam: PF01163

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 (23 total): modified residue 6, sequence variant 3, mutagenesis site 3, region of interest 3, binding site 2, chain 1, domain 1, splice variant 1, sequence conflict 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8ZDB	ELECTRON MICROSCOPY	3.6
8ZDD	ELECTRON MICROSCOPY	3.7
8ZDC	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14730-F1	74.68	0.30

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): 406 (proton acceptor)

Ligand- & substrate-binding residues (2): 257–265; 290

Post-translational modifications (6): 112, 122, 125, 127, 128, 8

Mutagenesis-validated functional residues (3):

Position	Phenotype
60–95	abolished ability to recognize and bind monoubiquitinated rps2/us5 and rps3/us3.
290	decreases autophosphorylation (in vitro); abolishes inhibition of tnf-induced nf-kappab activation; no effect on interac
406	abolished serine/threonine-protein kinase activity, leading to impaired ribosome quality control in response to ribosome

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6791226	Major pathway of rRNA processing in the nucleolus and cytosol

MSigDB gene sets: 275 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_RIBOSOME_BIOGENESIS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, ACTACCT_MIR196A_MIR196B, GOBP_CELLULAR_RESPONSE_TO_VIRUS, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, GOBP_MATURATION_OF_SSU_RRNA, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, MENSE_HYPOXIA_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, TAL1ALPHAE47_01, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS

GO Biological Process (15): chromosome segregation (GO:0007059), maturation of SSU-rRNA (GO:0030490), negative regulation of protein-containing complex assembly (GO:0031333), positive regulation of interferon-beta production (GO:0032728), negative regulation of MDA-5 signaling pathway (GO:0039534), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), innate immune response (GO:0045087), positive regulation of innate immune response (GO:0045089), defense response to virus (GO:0051607), cellular response to dsRNA (GO:0071359), cellular response to virus (GO:0098586), cellular response to dsDNA (GO:1990786), immune system process (GO:0002376), protein phosphorylation (GO:0006468), ribosome biogenesis (GO:0042254)

GO Molecular Function (10): protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), metal ion binding (GO:0046872), caspase binding (GO:0089720), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (3): cytosol (GO:0005829), preribosome, small subunit precursor (GO:0030688), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
rRNA processing in the nucleus and cytosol	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to virus	2
cellular response to nitrogen compound	2
protein kinase activity	2
cellular anatomical structure	2
cell cycle process	1
rRNA processing	1
ribosomal small subunit biogenesis	1
regulation of protein-containing complex assembly	1
negative regulation of cellular component organization	1
protein-containing complex assembly	1
positive regulation of type I interferon production	1
interferon-beta production	1
regulation of interferon-beta production	1
MDA-5 signaling pathway	1
negative regulation of cytoplasmic pattern recognition receptor signaling pathway	1
regulation of MDA-5 signaling pathway	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
negative regulation of intracellular signal transduction	1
immune response	1
defense response to symbiont	1
positive regulation of response to biotic stimulus	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
innate immune response	1
regulation of innate immune response	1
positive regulation of immune response	1
defense response	1
response to dsRNA	1
response to dsDNA	1
biological_process	1
phosphorylation	1
protein modification process	1
ribonucleoprotein complex biogenesis	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cation binding	1
protease binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1

Protein interactions and networks

STRING

1693 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RIOK3	RIOK2	Q9BVS4	775
RIOK3	LTV1	Q96GA3	533
RIOK3	NOB1	Q9ULX3	514
RIOK3	MXI1	P50539	502
RIOK3	TSR1	Q2NL82	473
RIOK3	CIRBP	Q14011	463
RIOK3	SBK1	Q52WX2	462
RIOK3	BYSL	Q13895	452
RIOK3	KLF3	P57682	440
RIOK3	PRMT5	O14744	425
RIOK3	TANC1	Q9C0D5	419
RIOK3	RBM28	Q9NW13	414
RIOK3	SIL1	Q9H173	413
RIOK3	PAFAH2	Q99487	412
RIOK3	MTUS1	Q9ULD2	409

IntAct

71 interactions, top by confidence:

A	B	Type	Score
RIOK3	CASP10	psi-mi:“MI:0915”(physical association)	0.720
CASP10	RIOK3	psi-mi:“MI:0915”(physical association)	0.720
CASP10	RIOK3	psi-mi:“MI:0403”(colocalization)	0.720
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
RACK1	RIOK3	psi-mi:“MI:0914”(association)	0.640
RIOK3	IRF3	psi-mi:“MI:0915”(physical association)	0.610
RIOK3	IRF3	psi-mi:“MI:0914”(association)	0.610
IRF3	RIOK3	psi-mi:“MI:0914”(association)	0.610
RIOK3	CASP10	psi-mi:“MI:0407”(direct interaction)	0.540
CASP10	RIOK3	psi-mi:“MI:0915”(physical association)	0.540
RIOK3	IFIH1	psi-mi:“MI:0915”(physical association)	0.540
RIOK3	IFIH1	psi-mi:“MI:0403”(colocalization)	0.540
RPS2	MPHOSPH10	psi-mi:“MI:0914”(association)	0.530
KRR1	MPHOSPH10	psi-mi:“MI:0914”(association)	0.530
KCNE3	RIOK3	psi-mi:“MI:0914”(association)	0.530
RIOK3	TBK1	psi-mi:“MI:0915”(physical association)	0.500
RIOK3	CREB3L3	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (104): RIOK3 (Affinity Capture-RNA), RIOK3 (Affinity Capture-MS), RIOK3 (Affinity Capture-MS), SUPT6H (Affinity Capture-MS), RIOK3 (Affinity Capture-MS), RIOK3 (Affinity Capture-MS), RIOK3 (Affinity Capture-MS), RIOK3 (Affinity Capture-MS), ZMAT3 (Affinity Capture-MS), OSBPL5 (Affinity Capture-MS), RIOK3 (Biochemical Activity), RIOK3 (Reconstituted Complex), RUVBL2 (Affinity Capture-MS), SSR4 (Affinity Capture-MS), CALM3 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8G016, A1A5Q0, B3DH20, D3Z8X7, D4A1F2, E1BTG2, F1MF74, F1RA39, O14730, O60308, O88978, O94851, O95801, P51432, P70566, Q1RMR5, Q1RMT7, Q28FY0, Q2YDM7, Q3UHZ5, Q3UM18, Q4KLT3, Q4R3F0, Q4R8L2, Q5BJT6, Q5EA11, Q5ZJD3, Q6AZN0, Q6P5Q4, Q7Z569, Q80V31, Q863A4, Q863A5, Q863A6, Q863A7, Q86X45, Q8BML1, Q8CCP0, Q8R368, Q8R3H9

Diamond homologs: A3CXS0, D4GYY1, G0S3J5, O14730, O27476, O28471, O29592, O30245, O42650, O44959, P34649, Q03021, Q12196, Q1RMT7, Q2FS43, Q54VD8, Q57886, Q8SVI7, Q922Q2, Q95Q34, Q9BRS2, Q9DBU3, Q9P7W5, Q9UYB9, Q2NIA4, Q58473

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RIOK3	“down-regulates activity”	IFIH1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 61 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Eukaryotic Translation Initiation	5	35.1×	1e-05
Cap-dependent Translation Initiation	5	35.1×	1e-05
SARS-CoV-1 modulates host translation machinery	5	35.1×	1e-05
Eukaryotic Translation Elongation	5	31.6×	2e-05
Regulation of activated PAK-2p34 by proteasome mediated degradation	5	31.6×	2e-05
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	5	30.9×	2e-05
SARS-CoV-1-host interactions	7	27.9×	2e-06
Nonsense-Mediated Decay (NMD)	5	26.5×	3e-05

GO biological processes:

GO term	Partners	Fold	FDR
ribosomal small subunit biogenesis	6	25.3×	6e-05
cytoplasmic translation	6	20.6×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	2
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1828 predictions. Top by Δscore:

Variant	Effect	Δscore
18:23462958:TCATA:T	acceptor_loss	1.0000
18:23462959:CATAG:C	acceptor_loss	1.0000
18:23462960:A:AG	acceptor_gain	1.0000
18:23462960:ATAGT:A	acceptor_gain	1.0000
18:23462961:T:G	acceptor_gain	1.0000
18:23462961:TAGT:T	acceptor_loss	1.0000
18:23462962:A:AG	acceptor_gain	1.0000
18:23462962:AG:A	acceptor_loss	1.0000
18:23462962:AGT:A	acceptor_gain	1.0000
18:23462963:G:GG	acceptor_gain	1.0000
18:23462963:GT:G	acceptor_gain	1.0000
18:23462963:GTG:G	acceptor_gain	1.0000
18:23462963:GTGT:G	acceptor_gain	1.0000
18:23462963:GTGTC:G	acceptor_gain	1.0000
18:23463004:T:TA	acceptor_gain	1.0000
18:23463075:GTTGC:G	donor_gain	1.0000
18:23463076:T:G	donor_gain	1.0000
18:23463076:TTGC:T	donor_gain	1.0000
18:23463077:TGC:T	donor_gain	1.0000
18:23463078:GC:G	donor_gain	1.0000
18:23463078:GCG:G	donor_gain	1.0000
18:23463079:CGTA:C	donor_loss	1.0000
18:23463080:GTA:G	donor_loss	1.0000
18:23463080:GTAA:G	donor_gain	1.0000
18:23463083:A:AG	donor_gain	1.0000
18:23463084:G:GG	donor_gain	1.0000
18:23463965:A:AG	acceptor_gain	1.0000
18:23463966:G:GT	acceptor_gain	1.0000
18:23463966:GT:G	acceptor_gain	1.0000
18:23463966:GTGTT:G	acceptor_gain	1.0000

AlphaMissense

3475 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:23464038:T:C	L84P	1.000
18:23467494:G:C	K261N	1.000
18:23467494:G:T	K261N	1.000
18:23467498:T:C	S263P	1.000
18:23467499:C:T	S263F	1.000
18:23473481:A:G	K290E	1.000
18:23473483:G:C	K290N	1.000
18:23473483:G:T	K290N	1.000
18:23473487:T:C	F292L	1.000
18:23473489:T:A	F292L	1.000
18:23473489:T:G	F292L	1.000
18:23473508:T:C	F299L	1.000
18:23473509:T:C	F299S	1.000
18:23473509:T:G	F299C	1.000
18:23473510:T:A	F299L	1.000
18:23473510:T:G	F299L	1.000
18:23473526:T:C	Y305H	1.000
18:23473527:A:G	Y305C	1.000
18:23473544:A:G	R311G	1.000
18:23473545:G:C	R311T	1.000
18:23473545:G:T	R311M	1.000
18:23473546:G:C	R311S	1.000
18:23473546:G:T	R311S	1.000
18:23473547:T:C	F312L	1.000
18:23473549:T:A	F312L	1.000
18:23473549:T:G	F312L	1.000
18:23473595:T:A	W328R	1.000
18:23473595:T:C	W328R	1.000
18:23473597:G:C	W328C	1.000
18:23473597:G:T	W328C	1.000

dbSNP variants (sampled 300 via entrez): RS1000133621 (18:23482032 T>C), RS1000138880 (18:23469019 C>T), RS1000187522 (18:23480567 A>G), RS1000237685 (18:23462106 T>A,G), RS1000418817 (18:23472791 A>G), RS1000463258 (18:23481817 A>G), RS1000617898 (18:23475081 A>C,G), RS1000636624 (18:23481897 A>G), RS1000706604 (18:23480352 C>G,T), RS1000732319 (18:23473206 T>A,C), RS1000848789 (18:23468188 A>G), RS1000877308 (18:23460587 A>G), RS1000924441 (18:23482227 G>A), RS1001075698 (18:23483391 A>T), RS1001115590 (18:23460811 G>A)

Disease associations

OMIM: gene MIM:603579 | disease phenotypes: MIM:617145

GenCC curated gene-disease

Mondo (1): neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset (MONDO:0014940)

Orphanet (0):

HPO phenotypes

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

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST004611_137	High light scatter reticulocyte count	1.000000e-12
GCST004612_86	High light scatter reticulocyte percentage of red cells	3.000000e-13
GCST004619_73	Reticulocyte fraction of red cells	8.000000e-14
GCST004622_64	Reticulocyte count	6.000000e-13
GCST004628_27	Immature fraction of reticulocytes	2.000000e-10
GCST007485_11	Anthropometric traits	1.000000e-13
GCST007490_1	Anthropometric traits (multi-trait analysis)	3.000000e-21
GCST008181_19	Spontaneous preterm birth without premature rupture of membranes	1.000000e-06
GCST010139_1	Poultry consumption	1.000000e-09
GCST90002385_333	High light scatter reticulocyte count	8.000000e-35
GCST90002385_334	High light scatter reticulocyte count	2.000000e-50
GCST90002386_82	High light scatter reticulocyte percentage of red cells	2.000000e-35
GCST90002386_83	High light scatter reticulocyte percentage of red cells	9.000000e-51
GCST90002387_208	Immature fraction of reticulocytes	5.000000e-32
GCST90002387_209	Immature fraction of reticulocytes	2.000000e-28
GCST90002405_563	Reticulocyte count	4.000000e-22
GCST90002405_564	Reticulocyte count	4.000000e-40
GCST90002406_510	Reticulocyte fraction of red cells	7.000000e-23
GCST90002406_511	Reticulocyte fraction of red cells	2.000000e-41
GCST90020029_9	Waist circumference adjusted for body mass index	4.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007986	reticulocyte count
EFO:0004324	body weights and measures
EFO:0006917	spontaneous preterm birth
EFO:0008111	diet measurement
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5659 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

17 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 164,069 (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
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL608533	MIDOSTAURIN	4	7,259
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL1721885	SU-014813	2	363
CHEMBL475251	R-406	2	762
CHEMBL513909	BI-2536	2	895
CHEMBL572878	TOZASERTIB	2	2,998
CHEMBL1908394	GSK-461364	1	1,093
CHEMBL1908397	KW-2449	1	622

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — RIO3 subfamily

Binding affinities (BindingDB)

7 measured of 7 human assays (7 total across all organisms); most potent 7 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
Staurosporine	KD	1.7 nM
PKC-412	KD	190 nM
(3Z)-4-amino-5-fluoro-3-[5-(4-methylpiperazino)-1,3-dihydrobenzimidazol-2-ylidene]carbostyril	KD	520 nM
N-[4-({4-[(3-methyl-1H-pyrazol-5-yl)amino]-6-(4-methylpiperazin-1-yl)pyrimidin-2-yl}sulfanyl)phenyl]cyclopropanecarboxamide	KD	1100 nM
5-[(Z)-(5-fluoranyl-2-oxidanylidene-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[(2S)-3-morpholin-4-yl-2-oxidanyl-propyl]-1H-pyrrole-3-carboxamide	KD	2600 nM
1-Acyl-1H-[1,2,4]triazole-3,5-diamine Analogue 3b	KD	3100 nM
N-[2-(diethylamino)ethyl]-5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	KD	3500 nM

ChEMBL bioactivities

67 potent at pChembl≥5 of 67 total, top 42 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.11	Kd	7.7	nM	LESTAURTINIB
8.10	Kd	7.943	nM	LESTAURTINIB
7.44	Kd	36	nM	NINTEDANIB
7.21	Kd	61	nM	KW-2449
7.20	Kd	63.1	nM	KW-2449
7.12	Kd	76	nM	STAUROSPORINE
7.10	Kd	79.43	nM	STAUROSPORINE
7.04	Kd	91	nM	FEDRATINIB
7.00	Kd	100	nM	FEDRATINIB
6.70	Kd	199.5	nM	R-406
6.68	Kd	210	nM	R-406
6.54	Kd	290	nM	CHEMBL4452939
6.41	Kd	390	nM	PHA-665752
6.40	Kd	398.1	nM	MIDOSTAURIN
6.40	Kd	398.1	nM	PHA-665752
6.38	Kd	420	nM	MIDOSTAURIN
6.22	Kd	600	nM	TOZASERTIB
6.20	Kd	631	nM	RUBOXISTAURIN
6.20	Kd	631	nM	CHEMBL379218
6.20	Kd	631	nM	DOVITINIB
6.20	Kd	631	nM	TOZASERTIB
6.19	Kd	650	nM	RUBOXISTAURIN
6.16	Kd	690	nM	CHEMBL379218
6.16	Kd	690	nM	DOVITINIB
6.00	Kd	1000	nM	AXITINIB
5.92	Kd	1200	nM	JNJ-7706621
5.89	Kd	1300	nM	CGP-52421
5.80	Kd	1585	nM	CHEMBL4762015
5.80	Kd	1600	nM	CHEMBL4762015
5.80	Kd	1600	nM	BOSUTINIB
5.70	Kd	1995	nM	RUXOLITINIB
5.70	Kd	1995	nM	CHEMBL1908842
5.70	Kd	2000	nM	RUXOLITINIB
5.70	Kd	2000	nM	CHEMBL1908842
5.70	Kd	2000	nM	CHEMBL1908395
5.64	Kd	2300	nM	GSK-461364
5.60	Kd	2512	nM	GSK-461364
5.46	Kd	3500	nM	TAE-684
5.42	Kd	3800	nM	SUNITINIB
5.40	Kd	4000	nM	CRIZOTINIB
5.36	Kd	4400	nM	BI-2536
5.01	Kd	9700	nM	SU-014813

PubChem BioAssay actives

34 with measured affinity, of 186 total; 25 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	508064: Binding affinity to RIOK3	kd	0.0077	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	624926: Binding constant for RIOK3 kinase domain	kd	0.0360	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	624926: Binding constant for RIOK3 kinase domain	kd	0.0610	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	435191: Binding constant for full-length RIOK3	kd	0.0760	uM
Fedratinib	624926: Binding constant for RIOK3 kinase domain	kd	0.0910	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	624926: Binding constant for RIOK3 kinase domain	kd	0.2100	uM
N-[6-[3-(diethylsulfamoylamino)phenyl]-1H-indazol-3-yl]cyclopropanecarboxamide	1547811: Binding affinity to wild type human full length RIOK3 (M1 to E519 residues) expressed in bacterial expression system by Kinomescan method	kd	0.2900	uM
(3Z)-5-[(2,6-dichlorophenyl)methylsulfonyl]-3-[[3,5-dimethyl-4-[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carbonyl]-1H-pyrrol-2-yl]methylidene]-1H-indol-2-one	624926: Binding constant for RIOK3 kinase domain	kd	0.3900	uM
Midostaurin	435191: Binding constant for full-length RIOK3	kd	0.4200	uM
N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide	435191: Binding constant for full-length RIOK3	kd	0.6000	uM
(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.17,14.02,6.08,13.022,27]nonacosa-1(28),2(6),7(29),8,10,12,22,24,26-nonaene-3,5-dione	624926: Binding constant for RIOK3 kinase domain	kd	0.6500	uM
(2S)-1-[[5-(3-methyl-2H-indazol-5-yl)-3-pyridinyl]oxy]-3-phenylpropan-2-amine	624926: Binding constant for RIOK3 kinase domain	kd	0.6900	uM
4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one	435191: Binding constant for full-length RIOK3	kd	0.6900	uM
Axitinib	624926: Binding constant for RIOK3 kinase domain	kd	1.0000	uM
4-[[5-amino-1-(2,6-difluorobenzoyl)-1,2,4-triazol-3-yl]amino]benzenesulfonamide	435191: Binding constant for full-length RIOK3	kd	1.2000	uM
N-[(2S,3R,4R,6R,18S)-18-hydroxy-3-methoxy-2-methyl-16-oxo-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-4-yl]-N-methylbenzamide	508064: Binding affinity to RIOK3	kd	1.3000	uM
Bosutinib	624926: Binding constant for RIOK3 kinase domain	kd	1.6000	uM
Ruxolitinib	624926: Binding constant for RIOK3 kinase domain	kd	2.0000	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	624926: Binding constant for RIOK3 kinase domain	kd	2.0000	uM
5-[6-[(4-methylpiperazin-1-yl)methyl]benzimidazol-1-yl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]thiophene-2-carboxamide	624926: Binding constant for RIOK3 kinase domain	kd	2.3000	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	624926: Binding constant for RIOK3 kinase domain	kd	3.5000	uM
Sunitinib	435191: Binding constant for full-length RIOK3	kd	3.8000	uM
Crizotinib	624926: Binding constant for RIOK3 kinase domain	kd	4.0000	uM
4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide	624926: Binding constant for RIOK3 kinase domain	kd	4.4000	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	435191: Binding constant for full-length RIOK3	kd	9.7000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
cobaltous chloride	increases expression, decreases reaction	3
Hydrogen Peroxide	affects expression, decreases expression, increases expression	3
Valproic Acid	affects expression, increases expression	3
Cadmium Chloride	increases abundance, increases expression	3
bisphenol A	decreases expression, increases methylation	2
monomethylarsonous acid	increases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Tobacco Smoke Pollution	increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	affects expression	1
zinc chloride	decreases reaction, increases expression	1
butyraldehyde	increases expression	1
potassium chromate(VI)	increases expression, affects cotreatment	1
cupric oxide	increases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
JP8 aviation fuel	decreases expression	1
corosolic acid	increases expression	1
K 7174	increases expression	1
dimethylarsinous acid	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
abrine	increases expression	1
jinfukang	decreases expression	1
PCI 5002	increases expression, affects cotreatment	1
Resveratrol	decreases expression	1
Sunitinib	increases expression	1
Leflunomide	increases expression	1

ChEMBL screening assays

84 unique, capped per target: 84 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1017915	Binding	Inhibition of RIOK3 assessed as enzyme activity relative to control	Examining the chirality, conformation and selective kinase inhibition of 3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (CP-690,550). — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2DT	Abcam HeLa RIOK3 KO	Cancer cell line	Female
CVCL_D7ZE	Ubigene A-549 RIOK3 KO	Cancer cell line	Male
CVCL_TJ09	HAP1 RIOK3 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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