RIOK1

Summary

RIOK1 (RIO kinase 1, HGNC:18656) is a protein-coding gene on chromosome 6p24.3, encoding Serine/threonine-protein kinase RIO1 (Q9BRS2). Involved in the final steps of cytoplasmic maturation of the 40S ribosomal subunit. It is a common-essential gene (DepMap: required in 96.7% of cancer cell lines).

The protein encoded by this gene competes with pICln for inclusion in the protein arginine methyltransferase 5 complex. This complex targets substrates for dimethylation. The encoded protein is essential for the last steps in the maturation of 40S subunits.

Source: NCBI Gene 83732 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 104 total
• Druggable target: yes — 19 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 96.7% of screened cell lines (common-essential)
• MANE Select transcript: NM_031480

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18656
Approved symbol	RIOK1
Name	RIO kinase 1
Location	6p24.3
Locus type	gene with protein product
Status	Approved
Aliases	AD034, FLJ30006, bA288G3.1, RRP10
Ensembl gene	ENSG00000124784
Ensembl biotype	protein_coding
OMIM	617753
Entrez	83732

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 8 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000264874, ENST00000379834, ENST00000475351, ENST00000484626, ENST00000493691, ENST00000875536, ENST00000875537, ENST00000911539, ENST00000911540, ENST00000967569, ENST00000967570, ENST00000967571

RefSeq mRNA: 2 — MANE Select: NM_031480 NM_001348194, NM_031480

CCDS: CCDS4500

Canonical transcript exons

ENST00000379834 — 17 exons

Exon	Start	End
ENSE00000847927	7393099	7393303
ENSE00000847928	7395053	7395143
ENSE00000847933	7402817	7402897
ENSE00001909019	7389808	7390073
ENSE00003465710	7396703	7396772
ENSE00003504413	7410386	7410451
ENSE00003525591	7400958	7401050
ENSE00003534695	7404918	7405021
ENSE00003566872	7402603	7402715
ENSE00003568787	7414238	7414390
ENSE00003618580	7403941	7404027
ENSE00003620506	7411332	7411451
ENSE00003627560	7404418	7404555
ENSE00003636350	7405249	7405355
ENSE00003645638	7412889	7412942
ENSE00003677790	7417331	7418037
ENSE00003678208	7398698	7398740

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 94.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.3851 / max 234.7217, expressed in 1786 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
65649	13.1514	1782
65648	0.2338	106

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
epithelial cell of pancreas	CL:0000083	94.71	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.93	gold quality
secondary oocyte	CL:0000655	92.16	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.68	gold quality
oocyte	CL:0000023	89.76	gold quality
cortical plate	UBERON:0005343	88.77	gold quality
tibialis anterior	UBERON:0001385	88.01	gold quality
gingival epithelium	UBERON:0001949	87.59	gold quality
calcaneal tendon	UBERON:0003701	87.39	gold quality
pancreatic ductal cell	CL:0002079	86.59	silver quality
testis	UBERON:0000473	86.56	gold quality
skin of abdomen	UBERON:0001416	86.51	gold quality
omental fat pad	UBERON:0010414	86.51	gold quality
peritoneum	UBERON:0002358	86.48	gold quality
left testis	UBERON:0004533	86.44	gold quality
right testis	UBERON:0004534	86.43	gold quality
gastrocnemius	UBERON:0001388	86.29	gold quality
esophagus mucosa	UBERON:0002469	86.27	gold quality
ectocervix	UBERON:0012249	86.03	gold quality
gingiva	UBERON:0001828	85.99	gold quality
smooth muscle tissue	UBERON:0001135	85.89	gold quality
adipose tissue of abdominal region	UBERON:0007808	85.84	gold quality
body of uterus	UBERON:0009853	85.84	gold quality
ganglionic eminence	UBERON:0004023	85.75	gold quality
muscle of leg	UBERON:0001383	85.72	gold quality
right ovary	UBERON:0002118	85.61	gold quality
skin of leg	UBERON:0001511	85.53	gold quality
body of pancreas	UBERON:0001150	85.49	gold quality
left uterine tube	UBERON:0001303	85.45	gold quality
monocyte	CL:0000576	85.43	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.41

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

46 targeting RIOK1, 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-6748-5P	100.00	65.81	1057
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
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-570-3P	99.96	72.41	4910
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
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-3941	99.86	70.54	2735
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-3177-5P	99.65	70.38	1174
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-5683	99.36	68.59	2083
HSA-MIR-148A-5P	99.30	68.27	1141

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 96.7% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 11)

• RioK1, a new interactor of protein arginine methyltransferase 5 (PRMT5), competes with pICln for binding and modulates PRMT5 complex composition and substrate specificity. (PMID:21081503)
• These data reveal a role of hRio1 in the final stages of cytoplasmic pre-40S maturation (PMID:22072790)
• These results imply that, in glioblastoma cells, constitutive Akt signaling drives RIO kinase overexpression, which creates a feedforward loop that promotes and maintains oncogenic Akt activity through stimulation of mTor signaling. (PMID:23459592)
• The RIO kinase fold generates a versatile ATPase enzyme, which in the case of Rio1 is activated following the Rio2 step to regulate one of the final 40S maturation events, at which time the 60S subunit is recruited for final quality control check. (PMID:24948609)
• methionine adenosyltransferase II alpha (MAT2A), and the arginine methyltransferase, PRMT5, as vulnerable enzymes in cells with MTAP deletion. (PMID:27068473)
• Docking studies revealed that TIBI can occupy the ATP-binding site of Rio1 in a manner similar to toyocamycin, and enhances the thermostability of the enzyme. (PMID:27909846)
• we demonstrate that RIOK1 promotes lung colonization in vivo and that RIOK1 is overexpressed in different subtypes of human lung- and breast cancer. (PMID:28499923)
• Elevated Expression of RIOK1 Is Correlated with Breast Cancer Hormone Receptor Status and Promotes Cancer Progression. (PMID:32599985)
• The final step of 40S ribosomal subunit maturation is controlled by a dual key lock. (PMID:33908345)
• RIOK1 mediates p53 degradation and radioresistance in colorectal cancer through phosphorylation of G3BP2. (PMID:35589951)
• The Oncogenic Protein Kinase/ATPase RIOK1 Is Up-Regulated via the c-myc/E2F Transcription Factor Axis in Prostate Cancer. (PMID:37301535)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	riok1	ENSDARG00000016399
mus_musculus	Riok1	ENSMUSG00000021428
rattus_norvegicus	Riok1	ENSRNOG00000014049
drosophila_melanogaster	RIOK1	FBGN0036187
caenorhabditis_elegans	riok-1	WBGENE00019698

Paralogs (3): RIOK2 (ENSG00000058729), RIOK3 (ENSG00000101782), ATMIN (ENSG00000166454)

Protein

Protein identifiers

Serine/threonine-protein kinase RIO1 — Q9BRS2 (reviewed: Q9BRS2)

Alternative names: RIO kinase 1

All UniProt accessions (2): E9PFQ8, Q9BRS2

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the final steps of cytoplasmic maturation of the 40S ribosomal subunit. Involved in processing of 18S-E pre-rRNA to the mature 18S rRNA. Required for the recycling of NOB1 and PNO1 from the late 40S precursor. The association with the very late 40S subunit intermediate may involve a translation-like checkpoint point cycle preceeding the binding to the 60S ribosomal subunit. Despite the protein kinase domain is proposed to act predominantly as an ATPase. The catalytic activity regulates its dynamic association with the 40S subunit. In addition to its role in ribosomal biogenesis acts as an adapter protein by recruiting NCL/nucleolin the to PRMT5 complex for its symmetrical methylation.

Subunit / interactions. Associates with the precursor of the 40S ribosome subunit. Interacts (via its N-terminus) with PRMT5 (via its N-terminus). Interacts with WDR77. Found in a PRMT5 complex composed of PRMT5, WDR77 and RIOK1. Interacts (via its C-terminus) with NCL; this interaction targets NCL for PRTM5 methylation.

Subcellular location. Cytoplasm. Cytosol.

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

RefSeq proteins (2): NP_001335123, NP_113668* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000687	RIO_kinase	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017407	Ser/Thr_kinase_Rio1	Family
IPR018934	RIO_dom	Domain
IPR018935	RIO_kinase_CS	Conserved_site
IPR051272	RIO-type_Ser/Thr_kinase	Family

Pfam: PF01163

Catalyzed reactions (Rhea), 3 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)
• 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 (53 total): strand 15, helix 15, compositionally biased region 6, binding site 5, region of interest 3, active site 2, modified residue 2, chain 1, domain 1, sequence variant 1, mutagenesis site 1, turn 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
6V0N	X-RAY DIFFRACTION	2.11
7BOC	X-RAY DIFFRACTION	2.55
6ZXG	ELECTRON MICROSCOPY	2.6
4OTP	X-RAY DIFFRACTION	2.7
6ZXH	ELECTRON MICROSCOPY	2.7
6ZV6	ELECTRON MICROSCOPY	2.9
6ZXE	ELECTRON MICROSCOPY	3
6ZXD	ELECTRON MICROSCOPY	3.2
6G5I	ELECTRON MICROSCOPY	3.5
6ZXF	ELECTRON MICROSCOPY	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BRS2-F1	69.10	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 (2): 324 (proton acceptor); 341 (4-aspartylphosphate intermediate)

Ligand- & substrate-binding residues (5): 208; 278; 280; 329; 341

Post-translational modifications (2): 21, 22

Mutagenesis-validated functional residues (1):

Position	Phenotype
324	abolishes autophosphorylation activity; enhances association with pre-40s ribosomal subunits; inhibits processing of 18s

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: 124 (showing top): GOBP_RIBOSOME_BIOGENESIS, MIDORIKAWA_AMPLIFIED_IN_LIVER_CANCER, chr6p24, GOBP_MATURATION_OF_SSU_RRNA, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_RIBOSOMAL_SMALL_SUBUNIT_BIOGENESIS, GROSS_HYPOXIA_VIA_ELK3_DN, CTTTGTA_MIR524, GOBP_RIBONUCLEOPROTEIN_COMPLEX_BIOGENESIS, MILI_PSEUDOPODIA_CHEMOTAXIS_DN, REACTOME_METABOLISM_OF_RNA, GOCC_TRANSFERASE_COMPLEX, GOCC_PRERIBOSOME, GOCC_METHYLTRANSFERASE_COMPLEX, MARSON_BOUND_BY_FOXP3_UNSTIMULATED

GO Biological Process (4): maturation of SSU-rRNA (GO:0030490), ribosomal small subunit biogenesis (GO:0042274), positive regulation of rRNA processing (GO:2000234), ribosome biogenesis (GO:0042254)

GO Molecular Function (11): protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), metal ion binding (GO:0046872), 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), hydrolase activity (GO:0016787)

GO Cellular Component (5): nucleoplasm (GO:0005654), cytosol (GO:0005829), preribosome, small subunit precursor (GO:0030688), methyltransferase complex (GO:0034708), 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
cellular anatomical structure	3
rRNA processing	2
ribonucleoprotein complex biogenesis	2
protein kinase activity	2
catalytic activity	2
intracellular anatomical structure	2
ribosomal small subunit biogenesis	1
ribosome biogenesis	1
positive regulation of RNA metabolic process	1
regulation of rRNA processing	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
nuclear lumen	1
cytoplasm	1
preribosome	1
transferase complex	1

Protein interactions and networks

STRING

2138 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RIOK1	NUCLEOLIN	P19338	890
RIOK1	NOB1	Q9ULX3	875
RIOK1	BYSL	Q13895	841
RIOK1	PNO1	Q9NRX1	832
RIOK1	RIOX1	Q9H6W3	806
RIOK1	TSR1	Q2NL82	805
RIOK1	PRMT5	O14744	796
RIOK1	RASGEF1A	Q8N9B8	796
RIOK1	SBNO1	A3KN83	795
RIOK1	WDR77	Q9BQA1	793
RIOK1	LTV1	Q96GA3	776
RIOK1	TGFBRAP1	Q8WUH2	776
RIOK1	RIOK2	Q9BVS4	725
RIOK1	CLNS1A	P54105	668
RIOK1	MTAP	Q13126	665

IntAct

103 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
LSM6	LSM1	psi-mi:“MI:0914”(association)	0.840
PRPF6	SNRNP200	psi-mi:“MI:0914”(association)	0.770
COPRS	PRMT5	psi-mi:“MI:0914”(association)	0.770
RIOK1	PRMT5	psi-mi:“MI:0914”(association)	0.710
PRMT5	RIOK1	psi-mi:“MI:0915”(physical association)	0.710
RIOK1	PRMT5	psi-mi:“MI:0915”(physical association)	0.710
SNRPB	PRMT5	psi-mi:“MI:0914”(association)	0.670
SNRPB	SART1	psi-mi:“MI:0914”(association)	0.640
LACTB	CCDC102A	psi-mi:“MI:0914”(association)	0.560
RPS2	MPHOSPH10	psi-mi:“MI:0914”(association)	0.530
LSM6	PRMT5	psi-mi:“MI:0914”(association)	0.530
SNRPN	PRMT5	psi-mi:“MI:0914”(association)	0.530
CIRBP	PRMT5	psi-mi:“MI:0914”(association)	0.530
FAM177A1	SLC27A2	psi-mi:“MI:0914”(association)	0.530
EPB41L3	AP3B1	psi-mi:“MI:0914”(association)	0.530
GAR1	PRMT5	psi-mi:“MI:0914”(association)	0.530
LSM4	PRMT5	psi-mi:“MI:0914”(association)	0.530

BioGRID (694): PRMT5 (Affinity Capture-MS), WDR77 (Affinity Capture-MS), RIOK1 (Affinity Capture-MS), RIOK1 (Affinity Capture-MS), RIOK1 (Affinity Capture-MS), RIOK1 (Affinity Capture-MS), RIOK1 (Affinity Capture-MS), RIOK1 (Affinity Capture-MS), RIOK1 (Affinity Capture-MS), RIOK1 (Affinity Capture-MS), RIOK1 (Affinity Capture-MS), RIOK1 (Affinity Capture-MS), RIOK1 (Affinity Capture-MS), RIOK1 (Proximity Label-MS), RIOK1 (Affinity Capture-MS)

ESM2 similar proteins: A9JRL3, E1C3P4, E9Q4Z2, E9Q5G3, F1M5F3, F1N2W9, F1ND48, F1QDI9, F6RIX4, I0IUP4, O00763, O88974, O94851, P51004, P55265, P55266, Q08J23, Q149N8, Q15047, Q2KHI9, Q4KWZ7, Q5R4N7, Q5R6Z9, Q5RGE5, Q5XIX3, Q5ZKK7, Q641K1, Q69ZT9, Q6NRM6, Q76CY8, Q7TPQ3, Q7TQE7, Q7ZU92, Q8BND4, Q8H2D5, Q8IU60, Q8K2I9, Q8K4J0, Q8K4S7, Q8NFZ0

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

4 interactions.

A	Effect	B	Mechanism
CSNK2A1	“up-regulates quantity by stabilization”	RIOK1	phosphorylation
SPC25	“up-regulates activity”	RIOK1	binding
RIOK1	“up-regulates activity”	MYH9	phosphorylation
RIOK1	“up-regulates activity”	NfKb-p65/p50

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 111 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
mRNA Splicing - Minor Pathway	7	19.6×	3e-06
SARS-CoV-2 modulates host translation machinery	7	19.6×	3e-06
Eukaryotic Translation Initiation	5	19.3×	1e-04
Cap-dependent Translation Initiation	5	19.3×	1e-04
SARS-CoV-1 modulates host translation machinery	5	19.3×	1e-04
Eukaryotic Translation Elongation	5	17.4×	1e-04
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	5	17.0×	2e-04
Formation of the ternary complex, and subsequently, the 43S complex	6	16.2×	5e-05

GO biological processes:

GO term	Partners	Fold	FDR
RNA splicing, via transesterification reactions	6	37.1×	2e-06
spliceosomal snRNP assembly	6	34.5×	3e-06
positive regulation of transcription elongation by RNA polymerase II	5	14.9×	2e-03
cytoplasmic translation	8	14.7×	9e-06
ribosomal small subunit biogenesis	6	13.5×	6e-04
RNA polymerase II preinitiation complex assembly	5	13.5×	2e-03
positive regulation of transcription initiation by RNA polymerase II	5	13.5×	2e-03
mRNA splicing, via spliceosome	14	12.7×	3e-09

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	80
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2461 predictions. Top by Δscore:

Variant	Effect	Δscore
6:7390070:ACAG:A	donor_loss	1.0000
6:7390072:AG:A	donor_loss	1.0000
6:7390073:GG:G	donor_loss	1.0000
6:7393097:A:AG	acceptor_gain	1.0000
6:7393097:AGT:A	acceptor_gain	1.0000
6:7393098:G:GT	acceptor_gain	1.0000
6:7393098:GT:G	acceptor_gain	1.0000
6:7393098:GTG:G	acceptor_gain	1.0000
6:7393098:GTGA:G	acceptor_gain	1.0000
6:7393098:GTGAA:G	acceptor_gain	1.0000
6:7393271:GGT:G	donor_gain	1.0000
6:7393290:G:GT	donor_gain	1.0000
6:7396701:A:AG	acceptor_gain	1.0000
6:7396702:G:GG	acceptor_gain	1.0000
6:7396702:GATAA:G	acceptor_gain	1.0000
6:7396762:G:GT	donor_gain	1.0000
6:7396768:GATAT:G	donor_gain	1.0000
6:7396769:A:G	donor_gain	1.0000
6:7396769:ATAT:A	donor_gain	1.0000
6:7396770:TAT:T	donor_gain	1.0000
6:7396770:TATGT:T	donor_loss	1.0000
6:7396771:ATGT:A	donor_loss	1.0000
6:7396772:TGTAA:T	donor_loss	1.0000
6:7396773:G:GG	donor_gain	1.0000
6:7396773:G:T	donor_loss	1.0000
6:7396774:T:TG	donor_loss	1.0000
6:7396775:AA:A	donor_loss	1.0000
6:7396776:AGTAA:A	donor_loss	1.0000
6:7401048:G:GT	donor_gain	1.0000
6:7401048:GAA:G	donor_gain	1.0000

AlphaMissense

3846 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:7401043:G:A	G189E	1.000
6:7401046:A:T	K190I	1.000
6:7401047:A:C	K190N	1.000
6:7401047:A:T	K190N	1.000
6:7402603:G:C	A192P	1.000
6:7402651:A:G	K208E	1.000
6:7402653:A:C	K208N	1.000
6:7402653:A:T	K208N	1.000
6:7402678:T:C	F217L	1.000
6:7402679:T:C	F217S	1.000
6:7402680:C:A	F217L	1.000
6:7402680:C:G	F217L	1.000
6:7402711:T:C	F228L	1.000
6:7402713:C:A	F228L	1.000
6:7402713:C:G	F228L	1.000
6:7402818:T:C	F230L	1.000
6:7402820:T:A	F230L	1.000
6:7402820:T:G	F230L	1.000
6:7402866:T:A	W246R	1.000
6:7402866:T:C	W246R	1.000
6:7402868:G:C	W246C	1.000
6:7402868:G:T	W246C	1.000
6:7402875:A:C	K249Q	1.000
6:7402876:A:T	K249I	1.000
6:7402877:A:C	K249N	1.000
6:7402877:A:T	K249N	1.000
6:7403994:T:A	V274D	1.000
6:7398726:G:C	A156P	0.999
6:7400974:C:G	T166R	0.999
6:7401042:G:A	G189R	0.999

dbSNP variants (sampled 300 via entrez): RS1000001721 (6:7393229 G>A,C), RS1000039236 (6:7394531 A>G), RS1000110048 (6:7401148 A>G), RS1000132764 (6:7399380 G>A), RS1000194608 (6:7409267 G>T), RS1000208181 (6:7399716 A>G), RS1000496235 (6:7398946 C>T), RS1000607510 (6:7413436 G>A), RS1000615475 (6:7405879 G>A), RS1000617358 (6:7412997 A>C), RS1000667260 (6:7418485 G>A), RS1001041874 (6:7394397 G>A,T), RS1001166370 (6:7392672 G>A,C), RS1001317964 (6:7393520 A>G,T), RS1001358852 (6:7398883 C>T)

Disease associations

OMIM: gene MIM:617753 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003488_12	Response to fenofibrate (triglyceride levels)	3.000000e-06
GCST012207_5	Shigella-associated diarrhea	7.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007681	triglyceride change measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL5483002 (PROTEIN-PROTEIN INTERACTION), CHEMBL5975 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

19 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 173,656 (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
CHEMBL31965	CANERTINIB	3	8,083
CHEMBL522892	DOVITINIB	3	4,944
CHEMBL603469	LESTAURTINIB	3
CHEMBL91829	RUBOXISTAURIN	3	77
CHEMBL1721885	SU-014813	2	363
CHEMBL230011	TG100-115	2	1,504
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 — RIO1 subfamily

Binding affinities (BindingDB)

8 measured of 8 human assays (8 total across all organisms); most potent 8 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
(18S)-18-[(dimethylamino)methyl]-17-oxa-4,14,21-triazahexacyclo[19.6.1.1^{7,14}.0^{2,6}.0^{8,13}.0^{22,27}]nonacosa-1(28),2(6),7(29),8(13),9,11,22(27),23,25-nonaene-3,5-dione	KD	700 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

41 potent at pChembl≥5 of 44 total, top 29 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.05	Kd	9	nM	LESTAURTINIB
7.64	Kd	23	nM	NINTEDANIB
7.46	Kd	35	nM	SUNITINIB
7.33	Kd	47	nM	KW-2449
7.14	Kd	72	nM	CHEMBL4452939
7.00	Kd	100	nM	FEDRATINIB
6.89	Kd	130	nM	STAUROSPORINE
6.47	Kd	340	nM	R-406
6.44	Kd	360	nM	TOZASERTIB
6.38	Kd	420	nM	DOVITINIB
6.33	Kd	470	nM	PHA-665752
6.23	Kd	590	nM	SU-014813
6.21	Kd	620	nM	CHEMBL379218
6.09	Kd	810	nM	RUBOXISTAURIN
5.96	Kd	1100	nM	JNJ-7706621
5.92	Kd	1200	nM	CHEMBL4744041
5.92	Kd	1200	nM	MIDOSTAURIN
5.92	Kd	1200	nM	CGP-52421
5.92	Kd	1200	nM	AXITINIB
5.66	Kd	2200	nM	BI-2536
5.66	Kd	2200	nM	BOSUTINIB
5.64	Kd	2300	nM	CHEMBL1908395
5.60	Kd	2500	nM	RUXOLITINIB
5.54	Kd	2900	nM	CHEMBL4564337
5.47	Kd	3400	nM	GSK-461364
5.24	Kd	5800	nM	TG100-115
5.21	Kd	6100	nM	CRIZOTINIB
5.12	IC50	7500	nM	CHEMBL4859105
5.08	Kd	8400	nM	CANERTINIB

PubChem BioAssay actives

39 with measured affinity, of 207 total; 29 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	508062: Binding affinity to RIOK1	kd	0.0090	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	625141: Binding constant for RIOK1 kinase domain	kd	0.0230	uM
Sunitinib	435324: Binding constant for full-length RIOK1	kd	0.0350	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	625141: Binding constant for RIOK1 kinase domain	kd	0.0470	uM
N-[6-[3-(diethylsulfamoylamino)phenyl]-1H-indazol-3-yl]cyclopropanecarboxamide	1547810: Binding affinity to wild type human full length RIOK1 (M1 to K568 residues) expressed in bacterial expression system by Kinomescan method	kd	0.0720	uM
Fedratinib	625141: Binding constant for RIOK1 kinase domain	kd	0.1000	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	435324: Binding constant for full-length RIOK1	kd	0.1300	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	625141: Binding constant for RIOK1 kinase domain	kd	0.3400	uM
N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide	435324: Binding constant for full-length RIOK1	kd	0.3600	uM
4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one	435324: Binding constant for full-length RIOK1	kd	0.4200	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	625141: Binding constant for RIOK1 kinase domain	kd	0.4700	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	435324: Binding constant for full-length RIOK1	kd	0.5900	uM
(2S)-1-[[5-(3-methyl-2H-indazol-5-yl)-3-pyridinyl]oxy]-3-phenylpropan-2-amine	625141: Binding constant for RIOK1 kinase domain	kd	0.6200	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	435324: Binding constant for full-length RIOK1	kd	0.8100	uM
4-[[5-amino-1-(2,6-difluorobenzoyl)-1,2,4-triazol-3-yl]amino]benzenesulfonamide	435324: Binding constant for full-length RIOK1	kd	1.1000	uM
N-[[2-methyl-4-[2-[(1-methylpyrazol-4-yl)amino]pyrimidin-4-yl]phenyl]methyl]-3-propan-2-yloxyazetidine-1-carboxamide	1696277: Binding affinity to wild-type human full length RIOK1 (M1 to K568 residues) expressed in bacterial expression system by Kinomescan method	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	508062: Binding affinity to RIOK1	kd	1.2000	uM
Axitinib	625141: Binding constant for RIOK1 kinase domain	kd	1.2000	uM
Midostaurin	435324: Binding constant for full-length RIOK1	kd	1.2000	uM
4-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide	625141: Binding constant for RIOK1 kinase domain	kd	2.2000	uM
Bosutinib	625141: Binding constant for RIOK1 kinase domain	kd	2.2000	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	625141: Binding constant for RIOK1 kinase domain	kd	2.3000	uM
Ruxolitinib	625141: Binding constant for RIOK1 kinase domain	kd	2.5000	uM
5-(6-bromo-5-methoxy-1H-indol-3-yl)-2-(1H-pyrrol-2-yl)-1,3-oxazole	1541251: Binding affinity to wild-type human full length RIOK1 (M1 to K568 residues) expressed in bacterial expression system by active-site directed competition binding assay based Kinomescan method	kd	2.9000	uM
5-[6-[(4-methylpiperazin-1-yl)methyl]benzimidazol-1-yl]-3-[(1R)-1-[2-(trifluoromethyl)phenyl]ethoxy]thiophene-2-carboxamide	625141: Binding constant for RIOK1 kinase domain	kd	3.4000	uM
3-[2,4-diamino-7-(3-hydroxyphenyl)pteridin-6-yl]phenol	625141: Binding constant for RIOK1 kinase domain	kd	5.8000	uM
Crizotinib	625141: Binding constant for RIOK1 kinase domain	kd	6.1000	uM
(2S)-2-(4-chloro-6-oxopyridazin-1-yl)-N-[4-methyl-3-(2-pyridin-2-ylethylsulfamoyl)phenyl]propanamide	1980376: Inhibition of PRMT5 (unknown origin)/Riok1 (unknown origin) interaction in permeabilised cells	ic50	7.5000	uM
N-[4-(3-chloro-4-fluoroanilino)-7-(3-morpholin-4-ylpropoxy)quinazolin-6-yl]prop-2-enamide	625141: Binding constant for RIOK1 kinase domain	kd	8.4000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, affects expression, decreases expression	3
Ozone	increases oxidation, increases abundance, affects expression, affects cotreatment	2
Tetrachlorodibenzodioxin	decreases expression	2
Valproic Acid	increases expression	2
Cyclosporine	increases expression	2
Aflatoxin B1	increases expression, increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
quercitrin	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	increases expression	1
corosolic acid	increases expression	1
K 7174	increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Temozolomide	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Estradiol	increases expression	1
Formaldehyde	decreases expression	1
Manganese	increases abundance, increases expression, affects cotreatment	1
Ribonucleotides	affects binding	1
Dronabinol	decreases expression	1

ChEMBL screening assays

104 unique, capped per target: 104 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5333062	Binding	Inhibition of Riok1 (unknown origin)/recombinant PRMT5 (unknown origin) interaction at 20 uM by FP assay	Discovery of cysteine-targeting covalent histone methyltransferase inhibitors. — Eur J Med Chem

Clinical trials (associated diseases)

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