RPS2

Summary

RPS2 (ribosomal protein S2, HGNC:10404) is a protein-coding gene on chromosome 16p13.3, encoding Small ribosomal subunit protein uS5 (P15880). Component of the ribosome, a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell. It is a common-essential gene (DepMap: required in 99.7% of cancer cell lines).

Ribosomes, the organelles that catalyze protein synthesis, consist of a small 40S subunit and a large 60S subunit. Together these subunits are composed of 4 RNA species and approximately 80 structurally distinct proteins. This gene encodes a ribosomal protein that is a component of the 40S subunit. The protein belongs to the S5P family of ribosomal proteins. It is located in the cytoplasm. This gene shares sequence similarity with mouse LLRep3. It is co-transcribed with the small nucleolar RNA gene U64, which is located in its third intron. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome.

Source: NCBI Gene 6187 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 38 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 99.7% of screened cell lines (common-essential)
• MANE Select transcript: NM_002952

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10404
Approved symbol	RPS2
Name	ribosomal protein S2
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	LLREP3, S2, uS5
Ensembl gene	ENSG00000140988
Ensembl biotype	protein_coding
OMIM	603624
Entrez	6187

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 23 protein_coding, 8 retained_intron, 1 nonsense_mediated_decay

ENST00000343262, ENST00000526522, ENST00000526586, ENST00000526908, ENST00000527109, ENST00000527302, ENST00000527826, ENST00000527871, ENST00000529806, ENST00000530225, ENST00000531065, ENST00000532746, ENST00000533161, ENST00000533186, ENST00000533872, ENST00000534461, ENST00000563194, ENST00000872227, ENST00000872228, ENST00000872229, ENST00000872230, ENST00000872231, ENST00000872232, ENST00000872233, ENST00000872234, ENST00000929923, ENST00000929924, ENST00000929925, ENST00000929926, ENST00000968780, ENST00000968781, ENST00000968782

RefSeq mRNA: 1 — MANE Select: NM_002952 NM_002952

CCDS: CCDS10452

Canonical transcript exons

ENST00000343262 — 7 exons

Exon	Start	End
ENSE00001411617	1964807	1964826
ENSE00002615156	1962058	1962270
ENSE00003384926	1964449	1964628
ENSE00003476243	1964276	1964365
ENSE00003535003	1963149	1963256
ENSE00003596226	1962736	1962909
ENSE00003624369	1962497	1962656

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 73.0759 / max 475.6973, expressed in 1819 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155890	72.9337	1819
155889	0.1422	49

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	99.89	gold quality
right uterine tube	UBERON:0001302	99.88	gold quality
ovary	UBERON:0000992	99.86	gold quality
body of pancreas	UBERON:0001150	99.86	gold quality
right ovary	UBERON:0002118	99.86	gold quality
left ovary	UBERON:0002119	99.86	gold quality
ventricular zone	UBERON:0003053	99.86	gold quality
cortical plate	UBERON:0005343	99.86	gold quality
granulocyte	CL:0000094	99.85	gold quality
ganglionic eminence	UBERON:0004023	99.85	gold quality
mucosa of transverse colon	UBERON:0004991	99.85	gold quality
zone of skin	UBERON:0000014	99.84	gold quality
skin of abdomen	UBERON:0001416	99.84	gold quality
skin of leg	UBERON:0001511	99.84	gold quality
lymph node	UBERON:0000029	99.83	gold quality
spleen	UBERON:0002106	99.83	gold quality
esophagus mucosa	UBERON:0002469	99.83	gold quality
fallopian tube	UBERON:0003889	99.83	gold quality
endocervix	UBERON:0000458	99.82	gold quality
adenohypophysis	UBERON:0002196	99.82	gold quality
thoracic mammary gland	UBERON:0005200	99.82	gold quality
lower esophagus mucosa	UBERON:0035834	99.82	gold quality
leukocyte	CL:0000738	99.81	gold quality
pituitary gland	UBERON:0000007	99.81	gold quality
left uterine tube	UBERON:0001303	99.81	gold quality
placenta	UBERON:0001987	99.81	gold quality
prostate gland	UBERON:0002367	99.81	gold quality
ectocervix	UBERON:0012249	99.81	gold quality
monocyte	CL:0000576	99.80	gold quality
vagina	UBERON:0000996	99.80	gold quality

Single-cell (SCXA)

Detected in 55 experiment(s), a significant marker in 19.

Experiment	Marker?	Max mean expression
E-CURD-98	yes	16529.57
E-MTAB-6308	yes	16268.04
E-CURD-112	yes	9857.34
E-CURD-46	yes	8373.87
E-MTAB-8205	yes	8048.06
E-MTAB-9221	yes	7072.46
E-MTAB-11011	yes	4713.18
E-GEOD-137537	yes	4108.40
E-GEOD-130473	yes	2516.60
E-MTAB-8142	yes	179.08
E-CURD-122	yes	81.53
E-CURD-88	yes	57.62
E-HCAD-9	yes	32.33
E-GEOD-81547	yes	20.32
E-MTAB-7316	yes	17.84

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.7% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 14)

• two genes coding for ribosomal proteins (S2 and L10a) encoded tumor antigens recognized by HLA-A26-restricted CTLs (PMID:12694581)
• rpS2 is methylated by PRMT3 in vitro and is also methylated in cell lines. Deletion analysis of the rpS2 amino acid sequence identified a N-terminal Arg-Gly repeat as the methylation site. (PMID:15473865)
• the nuclear targeting domain shares no significant similarity to already characterized nuclear localization signals in ribosomal proteins or other nuclear proteins (PMID:16061210)
• These findings suggest that the nuclear form of FGF3 inhibits cell proliferation by interfering with ribosomal biogenesis. (PMID:16263090)
• These results suggest that in addition to its catalytic function, PRMT3 may control the level of rpS2 protein in cells by inhibiting ubiquitin-mediated proteolysis of rpS2. (PMID:18573314)
• RPS2 or other aberrantly over-expressed ribosomal proteins might promote cancer and be excellent therapeutic targets for treatment of the disease (PMID:19138403)
• PAD4 citrullinates the Arg-Gly repeat region of RPS2, which is also an established site for Arg methylation by protein arginine methyltransferase 3 (PRMT3). (PMID:21584310)
• Findings uncover the existence of an extra-ribosomal complex consisting of PDCD2L, RPS2, and PRMT3 and support a role for PDCD2L in the late maturation of 40S ribosomal subunits. (PMID:27697862)
• ZNF277 and PRMT3 compete for uS5 binding, because overexpression of PRMT3 inhibited the formation of the ZNF277-uS5 complex, whereas depletion of cellular ZNF277 resulted in increased levels of uS5-PRMT3. (PMID:30530495)
• The RPS2([r78-94]) peptide is further extended from its N- and C-termini until reaching two spatially vicinal residues 74 and 98 in the crystal structure of intact BMP2-receptor complex system, consequently resulting in a longer peptide RPS2([r74-98]), which is then cyclized in a head-to-tail manner to obtain its cyclic counterpart cycRPS2([r74-98]). (PMID:31894111)
• Ribosomal protein S2 interplays with MDM2 to induce p53. (PMID:31928715)
• PDCD2 functions as an evolutionarily conserved chaperone dedicated for the 40S ribosomal protein uS5 (RPS2). (PMID:33245768)
• Silencing of long chain noncoding RNA paternally expressed gene (PEG10) inhibits the progression of neuroblastoma by regulating microRNA-449a (miR-449a)/ribosomal protein S2 (RPS2) axis. (PMID:35212607)
• DNA methylation-mediated epigenetic regulation of oncogenic RPS2 as a novel therapeutic target and biomarker in hepatocellular carcinoma. (PMID:38181486)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rps2	ENSDARG00000077291
mus_musculus	Rps2	ENSMUSG00000044533
drosophila_melanogaster	RpS2	FBGN0004867
caenorhabditis_elegans		WBGENE00004471

Paralogs (1): MRPS5 (ENSG00000144029)

Protein

Protein identifiers

Small ribosomal subunit protein uS5 — P15880 (reviewed: P15880)

Alternative names: 40S ribosomal protein S2, 40S ribosomal protein S4, Protein LLRep3

All UniProt accessions (9): P15880, E9PM36, E9PMM9, E9PPT0, E9PQD7, H0YE27, H0YEN5, H3BNG3, I3L404

UniProt curated annotations — full annotation on UniProt →

Function. Component of the ribosome, a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell. The small ribosomal subunit (SSU) binds messenger RNAs (mRNAs) and translates the encoded message by selecting cognate aminoacyl-transfer RNA (tRNA) molecules. The large subunit (LSU) contains the ribosomal catalytic site termed the peptidyl transferase center (PTC), which catalyzes the formation of peptide bonds, thereby polymerizing the amino acids delivered by tRNAs into a polypeptide chain. The nascent polypeptides leave the ribosome through a tunnel in the LSU and interact with protein factors that function in enzymatic processing, targeting, and the membrane insertion of nascent chains at the exit of the ribosomal tunnel. Plays a role in the assembly and function of the 40S ribosomal subunit. Mutations in this protein affects the control of translational fidelity. Involved in nucleolar processing of pre-18S ribosomal RNA and ribosome assembly.

Subunit / interactions. Component of the small ribosomal subunit. Interacts with zinc finger protein ZNF277 (via zinc-finger domains); the interaction is direct; the interaction is extra-ribosomal. Interaction with ZNF277 competes with the binding of RPS2 to protein arginine methyltransferase PRMT3. Interacts with PRMT3. Interacts with PDCD2; the interaction is direct, occurs cotranslationally, and serves to chaperone uS5 to assembly sites in the nucleus. Interacts with PDCD2L; for chaperone function of PDC2L. Interacts (when monoubiquitinated at Lys-54 and Lys-58) with RIOK3.

Subcellular location. Cytoplasm. Nucleus. Nucleolus.

Post-translational modifications. Citrullinated by PADI4 in the Arg/Gly-rich region. Asymmetric arginine dimethylation by PRMT3 occurs at multiple sites in the Arg/Gly-rich region. Monoubiquitinated at Lys-54 and Lys-58 by RNF10 when a ribosome has stalled during translation, leading to its degradation by the proteasome. Monoubiquitination at Lys-54 and Lys-58 promotes interaction with RIOK3. Deubiquitinated at Lys-54 and Lys-58 by USP10, preventing degradation by the proteasome and promoting 40S ribosome subunit recycling following ribosome dissociation.

Similarity. Belongs to the universal ribosomal protein uS5 family.

RefSeq proteins (1): NP_002943* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000851	Ribosomal_uS5	Family
IPR005324	Ribosomal_uS5_C	Domain
IPR005711	Ribosomal_uS5_euk_arc	Family
IPR013810	Ribosomal_uS5_N	Domain
IPR014721	Ribsml_uS5_D2-typ_fold_subgr	Homologous_superfamily
IPR018192	Ribosomal_uS5_N_CS	Conserved_site
IPR020568	Ribosomal_Su5_D2-typ_SF	Homologous_superfamily

Pfam: PF00333, PF03719

UniProt features (42 total): helix 10, strand 9, modified residue 7, cross-link 5, mutagenesis site 3, turn 2, compositionally biased region 2, initiator methionine 1, chain 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

209 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
8GLP	ELECTRON MICROSCOPY	1.67
8QOI	ELECTRON MICROSCOPY	1.9
9O3W	ELECTRON MICROSCOPY	1.9
8YOO	ELECTRON MICROSCOPY	2
9C3H	ELECTRON MICROSCOPY	2
7R4X	ELECTRON MICROSCOPY	2.15
9I2D	ELECTRON MICROSCOPY	2.19
9PBE	ELECTRON MICROSCOPY	2.19
8YOP	ELECTRON MICROSCOPY	2.2
9O3V	ELECTRON MICROSCOPY	2.2
9O3Y	ELECTRON MICROSCOPY	2.2
8JDK	ELECTRON MICROSCOPY	2.26
8G5Y	ELECTRON MICROSCOPY	2.29
9S3D	ELECTRON MICROSCOPY	2.32
9RPV	ELECTRON MICROSCOPY	2.35
9S3B	ELECTRON MICROSCOPY	2.38
8K2C	ELECTRON MICROSCOPY	2.4
8XSX	ELECTRON MICROSCOPY	2.4
9SPF	ELECTRON MICROSCOPY	2.4
9SPI	ELECTRON MICROSCOPY	2.4
8JDL	ELECTRON MICROSCOPY	2.42
9S3C	ELECTRON MICROSCOPY	2.42
9QLO	ELECTRON MICROSCOPY	2.47
9P8B	ELECTRON MICROSCOPY	2.48
7XNY	ELECTRON MICROSCOPY	2.5
8JDJ	ELECTRON MICROSCOPY	2.5
9RUC	ELECTRON MICROSCOPY	2.5
8G60	ELECTRON MICROSCOPY	2.54
8IFE	ELECTRON MICROSCOPY	2.57
9P7D	ELECTRON MICROSCOPY	2.57

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P15880-F1	82.10	0.63

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (12): 270, 275, 281, 54, 58, 275, 275, 275, 2, 252, 263, 264

Mutagenesis-validated functional residues (3):

Position	Phenotype
54–58	abolished ubiquitination and degradation by rnf10.
58	does not affect readthrough on the poly(a)-stall sequences; when associated with r-275.
275	does not affect readthrough on the poly(a)-stall sequences; when associated with r-58.

Function

Pathways and Gene Ontology

Reactome pathways

57 pathways

ID	Pathway
R-HSA-156827	L13a-mediated translational silencing of Ceruloplasmin expression
R-HSA-156902	Peptide chain elongation
R-HSA-1799339	SRP-dependent cotranslational protein targeting to membrane
R-HSA-192823	Viral mRNA Translation
R-HSA-2408557	Selenocysteine synthesis
R-HSA-3214858	RMTs methylate histone arginines
R-HSA-6790901	rRNA modification in the nucleus and cytosol
R-HSA-6791226	Major pathway of rRNA processing in the nucleolus and cytosol
R-HSA-72649	Translation initiation complex formation
R-HSA-72689	Formation of a pool of free 40S subunits
R-HSA-72695	Formation of the ternary complex, and subsequently, the 43S complex
R-HSA-72702	Ribosomal scanning and start codon recognition
R-HSA-72706	GTP hydrolysis and joining of the 60S ribosomal subunit
R-HSA-72764	Eukaryotic Translation Termination
R-HSA-8876725	Protein methylation
R-HSA-9010553	Regulation of expression of SLITs and ROBOs
R-HSA-9633012	Response of EIF2AK4 (GCN2) to amino acid deficiency
R-HSA-9735869	SARS-CoV-1 modulates host translation machinery
R-HSA-9754678	SARS-CoV-2 modulates host translation machinery
R-HSA-975956	Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)
R-HSA-975957	Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)
R-HSA-9954714	PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA
R-HSA-9954716	ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA
R-HSA-1266738	Developmental Biology
R-HSA-1430728	Metabolism
R-HSA-156842	Eukaryotic Translation Elongation
R-HSA-1643685	Disease
R-HSA-168255	Influenza Infection
R-HSA-168273	Influenza Viral RNA Transcription and Replication
R-HSA-2262752	Cellular responses to stress

MSigDB gene sets: 251 (showing top): GOBP_CYTOPLASMIC_TRANSLATION, LU_IL4_SIGNALING, SWEET_KRAS_ONCOGENIC_SIGNATURE, MODULE_151, GNF2_TPT1, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, GCM_NPM1, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, HSIAO_HOUSEKEEPING_GENES, CAFFAREL_RESPONSE_TO_THC_UP, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOBP_TRANSLATION, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, DOANE_RESPONSE_TO_ANDROGEN_DN

GO Biological Process (3): cytoplasmic translation (GO:0002181), translation (GO:0006412), positive regulation of ubiquitin-protein transferase activity (GO:0051443)

GO Molecular Function (7): RNA binding (GO:0003723), mRNA binding (GO:0003729), structural constituent of ribosome (GO:0003735), fibroblast growth factor binding (GO:0017134), enzyme binding (GO:0019899), cadherin binding (GO:0045296), protein binding (GO:0005515)

GO Cellular Component (12): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), focal adhesion (GO:0005925), membrane (GO:0016020), cytosolic ribosome (GO:0022626), cytosolic small ribosomal subunit (GO:0022627), extracellular exosome (GO:0070062), ribosome (GO:0005840), small ribosomal subunit (GO:0015935), ribonucleoprotein complex (GO:1990904)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Cap-dependent Translation Initiation	4
Translation	2
rRNA processing in the nucleus and cytosol	2
Eukaryotic Translation Initiation	1
Eukaryotic Translation Elongation	1
Influenza Viral RNA Transcription and Replication	1
Selenoamino acid metabolism	1
Chromatin modifying enzymes	1
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	1
Post-translational protein modification	1
Signaling by ROBO receptors	1
Cellular response to starvation	1
SARS-CoV-1-host interactions	1
SARS-CoV-2-host interactions	1
Nonsense-Mediated Decay (NMD)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
ribosome	2
translation	1
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
ubiquitin-protein transferase activity	1
positive regulation of protein ubiquitination	1
positive regulation of catalytic activity	1
regulation of ubiquitin-protein transferase activity	1
nucleic acid binding	1
RNA binding	1
structural molecule activity	1
growth factor binding	1
protein binding	1
cell adhesion molecule binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
cell-substrate junction	1
cytosol	1
small ribosomal subunit	1
cytosolic ribosome	1
extracellular vesicle	1
intracellular membraneless organelle	1
ribosomal subunit	1
protein-containing complex	1

Protein interactions and networks

STRING

5518 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RPS2	RPS3	P23396	926
RPS2	RPS9	P46781	880
RPS2	RPS18	P25232	860
RPS2	RPS11	P04643	849
RPS2	PRMT3	O60678	843
RPS2	RPS19	P39019	839
RPS2	RPS20	P17075	833
RPS2	RPS3A	P33443	829
RPS2	RPS24	P16632	823
RPS2	RPS16	P17008	822
RPS2	RPS5	P46782	796
RPS2	RPS6	P08227	793
RPS2	RPS8	P09058	793
RPS2	RPL11	P25121	785
RPS2	RPL21	P46778	780

IntAct

414 interactions, top by confidence:

A	B	Type	Score
PRMT3	RPS2	psi-mi:“MI:0915”(physical association)	0.810
RPS2	PRMT3	psi-mi:“MI:0915”(physical association)	0.810
STAU1	RPLP0	psi-mi:“MI:0914”(association)	0.750
H2AX	PPM1G	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
NAT10	RPS2	psi-mi:“MI:0915”(physical association)	0.670
H1-1	RRP8	psi-mi:“MI:0914”(association)	0.640
IGF2BP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.640
RACK1	RPS17	psi-mi:“MI:0915”(physical association)	0.610
AKT1	MAPK13	psi-mi:“MI:0914”(association)	0.600
RPS9	RPS2	psi-mi:“MI:0915”(physical association)	0.560
NOM1	RPLP0	psi-mi:“MI:0914”(association)	0.530
MAPT	KIF2A	psi-mi:“MI:0914”(association)	0.530
H1-4	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
RPS2	MPHOSPH10	psi-mi:“MI:0914”(association)	0.530
ZCRB1	DKC1	psi-mi:“MI:0914”(association)	0.530
TSR1	PARN	psi-mi:“MI:0914”(association)	0.530
DHX57	APOD	psi-mi:“MI:0914”(association)	0.530
NAP1L5	RPS2	psi-mi:“MI:0914”(association)	0.530
rep	RPS2	psi-mi:“MI:0914”(association)	0.530
N	NOP56	psi-mi:“MI:0914”(association)	0.530
N	RBM47	psi-mi:“MI:0914”(association)	0.530
SYNGAP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
RPL13	RPLP1	psi-mi:“MI:0914”(association)	0.530
RPS18	RPS2	psi-mi:“MI:0914”(association)	0.530

BioGRID (1174): RPS2 (Affinity Capture-MS), RPS2 (Affinity Capture-MS), RPS2 (Affinity Capture-MS), RPS2 (Affinity Capture-MS), RPS2 (Biochemical Activity), RPS2 (Affinity Capture-MS), LARP7 (Affinity Capture-MS), RPL26L1 (Affinity Capture-MS), RPS27A (Affinity Capture-MS), YBX1 (Affinity Capture-MS), YBX2 (Affinity Capture-MS), KNOP1 (Affinity Capture-MS), SF3B1 (Affinity Capture-MS), GTF3C2 (Affinity Capture-MS), RPS10 (Affinity Capture-MS)

ESM2 similar proteins: A1A086, A2BTC1, A2BYS0, A2C4Y3, A3PF31, A5GIS9, A5IYW9, A8G745, B1AIN7, B3DQD1, B5ZB57, B7GNC3, C3PL26, O18789, O43992, O52349, P10128, P15880, P25443, P25444, P27685, P27952, P31009, P47414, P49493, P51403, Q2NIX1, Q318K0, Q3AMP6, Q46IS5, Q4A5D8, Q4A8I8, Q4AAF7, Q50301, Q5A900, Q5NQ48, Q601J7, Q6F1X7, Q6KI38, Q6MSP2

Diamond homologs: A0B9V0, A0R8J7, A0RUE7, A1RU37, A1RWR6, A2BMD9, A2SPM2, A3CT17, A3DNC7, A3MU88, A4FWA1, A4IJK5, A4WHQ8, A4XLR3, A4YCY6, A5UL68, A5USH2, A6UQ64, A6UWV8, A6VH05, A7I5Q9, A8AC00, A8MLF7, A9A9P4, B1AIN7, B2A4F6, B5ZB57, B9MKG4, C0QQP0, C3NH89, C5D3T4, G1SWM1, O05641, O18789, O26131, O28374, O43992, O59439, O67563, O74892

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
RPS2	“form complex”	“40S cytosolic small ribosomal subunit”	binding
“Host translation inhibitor nsp1”	“down-regulates activity”	RPS2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 212 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
Formation of the ternary complex, and subsequently, the 43S complex	12	17.1×	1e-10
Ribosomal scanning and start codon recognition	13	16.4×	3e-11
Eukaryotic Translation Initiation	8	16.4×	6e-07
Cap-dependent Translation Initiation	8	16.4×	6e-07
SARS-CoV-1 modulates host translation machinery	8	16.4×	6e-07
Translation initiation complex formation	12	15.1×	6e-10
Eukaryotic Translation Elongation	8	14.8×	1e-06
SRP-dependent cotranslational protein targeting to membrane	22	14.6×	5e-17

GO biological processes:

GO term	Partners	Fold	FDR
formation of cytoplasmic translation initiation complex	5	31.0×	8e-05
cytoplasmic translation	19	19.4×	2e-16
maturation of SSU-rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA)	5	18.6×	7e-04
stress granule assembly	5	16.6×	1e-03
translational initiation	8	15.8×	8e-06
ribosomal small subunit biogenesis	12	15.1×	8e-09
mRNA stabilization	6	12.1×	1e-03
intrinsic apoptotic signaling pathway	6	11.9×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	18
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

574 predictions. Top by Δscore:

Variant	Effect	Δscore
16:1962266:CTTGG:C	acceptor_gain	1.0000
16:1962267:TTGG:T	acceptor_gain	1.0000
16:1962268:TGG:T	acceptor_gain	1.0000
16:1962269:GG:G	acceptor_gain	1.0000
16:1962271:C:CC	acceptor_gain	1.0000
16:1962274:C:CT	acceptor_gain	1.0000
16:1962492:CCTA:C	donor_loss	1.0000
16:1962493:CTAC:C	donor_loss	1.0000
16:1962494:TA:T	donor_loss	1.0000
16:1962495:A:AC	donor_gain	1.0000
16:1962496:C:CA	donor_loss	1.0000
16:1962496:C:CC	donor_gain	1.0000
16:1962652:GTCAC:G	acceptor_gain	1.0000
16:1962653:TCAC:T	acceptor_gain	1.0000
16:1962654:CAC:C	acceptor_gain	1.0000
16:1962654:CACC:C	acceptor_gain	1.0000
16:1962655:AC:A	acceptor_gain	1.0000
16:1962656:CC:C	acceptor_gain	1.0000
16:1962656:CCTGG:C	acceptor_loss	1.0000
16:1962657:C:CC	acceptor_gain	1.0000
16:1962731:CCTA:C	donor_loss	1.0000
16:1962732:CTA:C	donor_loss	1.0000
16:1962733:TAC:T	donor_loss	1.0000
16:1962760:G:A	donor_gain	1.0000
16:1962905:AATGC:A	acceptor_gain	1.0000
16:1962906:ATGC:A	acceptor_gain	1.0000
16:1962907:TGC:T	acceptor_gain	1.0000
16:1962907:TGCC:T	acceptor_loss	1.0000
16:1962908:GC:G	acceptor_gain	1.0000
16:1962909:CC:C	acceptor_gain	1.0000

AlphaMissense

1878 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:1962162:A:G	L273P	1.000
16:1962212:C:A	W256C	1.000
16:1962212:C:G	W256C	1.000
16:1962214:A:G	W256R	1.000
16:1962214:A:T	W256R	1.000
16:1962216:A:G	L255P	1.000
16:1962228:A:G	L251P	1.000
16:1962252:G:T	A243D	1.000
16:1962253:C:G	A243P	1.000
16:1962264:G:T	A239D	1.000
16:1962265:C:G	A239P	1.000
16:1962270:G:T	A237D	1.000
16:1962498:G:C	F236L	1.000
16:1962498:G:T	F236L	1.000
16:1962499:A:G	F236S	1.000
16:1962500:A:G	F236L	1.000
16:1962501:G:C	N235K	1.000
16:1962501:G:T	N235K	1.000
16:1962503:T:C	N235D	1.000
16:1962505:C:A	G234V	1.000
16:1962505:C:T	G234D	1.000
16:1962506:C:G	G234R	1.000
16:1962511:G:A	T232I	1.000
16:1962517:G:A	T230I	1.000
16:1962523:C:A	G228V	1.000
16:1962523:C:T	G228D	1.000
16:1962524:C:A	G228C	1.000
16:1962524:C:G	G228R	1.000
16:1962524:C:T	G228S	1.000
16:1962529:G:T	A226D	1.000

dbSNP variants (sampled 300 via entrez): RS1000994330 (16:1963995 G>A,C), RS1001008825 (16:1961652 A>C,G), RS1001274604 (16:1963822 C>G,T), RS1001537032 (16:1961599 G>A), RS1001591131 (16:1966634 G>T), RS1001755957 (16:1964845 G>A), RS1003181864 (16:1962554 C>T), RS1003786438 (16:1964877 T>A), RS1003892482 (16:1965717 C>T), RS1003900492 (16:1964001 A>G), RS1004016496 (16:1963026 C>T), RS1004409488 (16:1965811 G>A), RS1005073086 (16:1963589 G>A,C), RS1005172572 (16:1963730 A>G), RS1005302265 (16:1966692 C>A,T)

Disease associations

OMIM: gene MIM:603624 | 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
GCST006061_158	Atrial fibrillation	4.000000e-14
GCST010796_5218	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004327	electrocardiography

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3987582 (PROTEIN NUCLEIC-ACID COMPLEX), CHEMBL6066954 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds).

Molecule	Name	Phase	Patents
CHEMBL6067484	GENTAMICIN SULFATE	4

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

ChEMBL bioactivities

50 potent at pChembl≥5 of 54 total, top 49 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.09	Kd	80.43	nM	CHEMBL3752910
7.09	ED50	80.43	nM	CHEMBL3752910
6.52	IC50	300	nM	CHEMBL4109308
6.42	IC50	380	nM	CHEMBL4109308
6.42	IC50	380	nM	CHEMBL4574496
6.41	IC50	390	nM	CHEMBL4126894
6.39	IC50	410	nM	CHEMBL4114159
6.35	IC50	450	nM	CHEMBL4126496
6.30	IC50	500	nM	CHEMBL4574496
6.30	IC50	500	nM	CHEMBL4560206
6.16	IC50	690	nM	CHEMBL4130157
6.15	IC50	710	nM	CHEMBL4108338
6.11	IC50	780	nM	CHEMBL4114159
6.09	IC50	820	nM	CHEMBL4109308
6.07	IC50	850	nM	CHEMBL4107559
6.07	IC50	850	nM	CHEMBL4533299
6.05	IC50	900	nM	CHEMBL4126894
6.05	IC50	900	nM	CHEMBL4126496
6.04	IC50	920	nM	CHEMBL4554909
5.97	IC50	1060	nM	CHEMBL4128388
5.89	IC50	1290	nM	CHEMBL4130157
5.86	IC50	1370	nM	CHEMBL4107559
5.84	IC50	1440	nM	CHEMBL4108338
5.81	IC50	1540	nM	CHEMBL4534859
5.76	IC50	1730	nM	CHEMBL4534859
5.74	Kd	1825	nM	CHEMBL5653589
5.74	ED50	1825	nM	CHEMBL5653589
5.69	IC50	2050	nM	CHEMBL4566239
5.68	IC50	2080	nM	CHEMBL4446635
5.66	IC50	2210	nM	CHEMBL4446635
5.66	EC50	2200	nM	CHEMBL4464929
5.64	IC50	2270	nM	CHEMBL4533299
5.63	IC50	2330	nM	CHEMBL4566239
5.62	IC50	2380	nM	CHEMBL4128388
5.58	IC50	2630	nM	CHEMBL4128250
5.55	IC50	2820	nM	CHEMBL4127458
5.53	IC50	2970	nM	CHEMBL4127311
5.51	IC50	3080	nM	CHEMBL4126072
5.46	IC50	3500	nM	CHEMBL4525277
5.44	IC50	3630	nM	CHEMBL4469712
5.39	IC50	4100	nM	CHEMBL4128560
5.37	IC50	4300	nM	CHEMBL4127016
5.36	IC50	4380	nM	CHEMBL4527910
5.16	IC50	7000	nM	CHEMBL4109308
5.13	IC50	7400	nM	CHLORAMPHENICOL SULFATE SALT
5.09	IC50	8040	nM	CHEMBL4128250
5.08	IC50	8370	nM	CHEMBL4128250
5.03	IC50	9320	nM	CHEMBL4127016
5.03	IC50	9240	nM	CHEMBL4128560

PubChem BioAssay actives

48 with measured affinity, of 209 total; 28 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149293: Binding affinity to human RPS2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0804	uM
N-(3-chloro-2-pyridinyl)-N-[(3R)-piperidin-3-yl]-4-(triazolo[4,5-b]pyridin-3-yl)benzamide	1585498: Binding affinity to 80S ribosome in human HuH7 cells expressing human C-terminal V5/6-His-tagged PCSK9 assessed as inhibition of PCSK9 secretion after 16 to 24 hrs by AlphaLISA method	ic50	0.3000	uM
N-(3-chloro-2-pyridinyl)-N-[(3R)-piperidin-3-yl]-3-[4-(triazolo[4,5-b]pyridin-3-yl)phenyl]propanamide	1532845: Binding affinity to 80S ribosome in human HuH7 cells harboring human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	0.3800	uM
N-isoquinolin-1-yl-N-[(3R)-piperidin-3-yl]-4-(triazolo[4,5-b]pyridin-3-yl)benzamide	1497947: Binding affinity to 80S ribosome in human HuH7 cells harboring pCMV-truncated human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	0.3900	uM
N-(3-chloro-2-pyridinyl)-4-(6-methyltriazolo[4,5-b]pyridin-3-yl)-N-[(3R)-piperidin-3-yl]benzamide	1497947: Binding affinity to 80S ribosome in human HuH7 cells harboring pCMV-truncated human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	0.4100	uM
N-(3-chloro-2-pyridinyl)-4-(5-methyltriazolo[4,5-b]pyridin-3-yl)-N-[(3R)-piperidin-3-yl]benzamide	1497947: Binding affinity to 80S ribosome in human HuH7 cells harboring pCMV-truncated human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	0.4500	uM
N-(1-methylpyrrolo[2,3-c]pyridin-7-yl)-4-phenyl-N-[(3R)-piperidin-3-yl]piperidine-1-carboxamide	1532846: Binding affinity to 80S ribosome in human HeLa cells lysates using human full length PCSK9 encoding mRNAs assessed as inhibition of PCSK9 mRNA translation after 45 mins by Steady-Glo luciferase reporter gene assay	ic50	0.5000	uM
N-isoquinolin-1-yl-N-[(3R)-piperidin-3-yl]-4-pyrazolo[1,5-a]pyrimidin-3-ylbenzamide	1497947: Binding affinity to 80S ribosome in human HuH7 cells harboring pCMV-truncated human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	0.6900	uM
N-(3-chloro-2-pyridinyl)-N-[(3R)-piperidin-3-yl]-5-(triazolo[4,5-b]pyridin-3-yl)pyridine-2-carboxamide	1497947: Binding affinity to 80S ribosome in human HuH7 cells harboring pCMV-truncated human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	0.7100	uM
N-(3-chloro-2-pyridinyl)-3-[5-(6-methyltriazolo[4,5-b]pyridin-3-yl)-2-pyridinyl]-N-[(3R)-piperidin-3-yl]propanamide	1532845: Binding affinity to 80S ribosome in human HuH7 cells harboring human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	0.8500	uM
N-(3-chloro-2-pyridinyl)-5-(6-methyltriazolo[4,5-b]pyridin-3-yl)-N-[(3R)-piperidin-3-yl]pyridine-2-carboxamide	1497947: Binding affinity to 80S ribosome in human HuH7 cells harboring pCMV-truncated human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	0.8500	uM
N-(3-methyl-2-pyridinyl)-N-[(3R)-piperidin-3-yl]-4-pyrazolo[1,5-a]pyrimidin-3-ylpiperidine-1-carboxamide	1532846: Binding affinity to 80S ribosome in human HeLa cells lysates using human full length PCSK9 encoding mRNAs assessed as inhibition of PCSK9 mRNA translation after 45 mins by Steady-Glo luciferase reporter gene assay	ic50	0.9200	uM
N-isoquinolin-1-yl-4-(1-methylpyrazol-4-yl)-N-[(3R)-piperidin-3-yl]benzamide	1497947: Binding affinity to 80S ribosome in human HuH7 cells harboring pCMV-truncated human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	1.0600	uM
N-isoquinolin-1-yl-4-phenyl-N-[(3R)-piperidin-3-yl]piperidine-1-carboxamide	1532846: Binding affinity to 80S ribosome in human HeLa cells lysates using human full length PCSK9 encoding mRNAs assessed as inhibition of PCSK9 mRNA translation after 45 mins by Steady-Glo luciferase reporter gene assay	ic50	1.5400	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149293: Binding affinity to human RPS2 incubated for 45 mins by Kinobead based pull down assay	kd	1.8254	uM
N-(3-methyl-2-pyridinyl)-4-phenyl-N-[(3R)-piperidin-3-yl]piperidine-1-carboxamide	1532845: Binding affinity to 80S ribosome in human HuH7 cells harboring human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	2.0500	uM
N-(3-chloro-2-pyridinyl)-4-phenyl-N-[(3R)-piperidin-3-yl]piperidine-1-carboxamide	1532846: Binding affinity to 80S ribosome in human HeLa cells lysates using human full length PCSK9 encoding mRNAs assessed as inhibition of PCSK9 mRNA translation after 45 mins by Steady-Glo luciferase reporter gene assay	ic50	2.0800	uM
N-(5,8-dihydroisoquinolin-1-yl)-3-(4-methoxyphenyl)-N-[(3R)-piperidin-3-yl]propanamide	1584424: Inhibition of human 80S ribosome-mediated PCSK9 translation expressed in CHO-K1 cells assessed as reduction in PCSK9 secretion	ec50	2.2000	uM
N-isoquinolin-1-yl-3-(4-methoxyphenyl)-N-[(3R)-piperidin-3-yl]propanamide	1497947: Binding affinity to 80S ribosome in human HuH7 cells harboring pCMV-truncated human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	2.6300	uM
N-(3-chloro-2-pyridinyl)-4-(6-methylpyrazin-2-yl)-N-[(3R)-piperidin-3-yl]benzamide	1497963: Binding affinity to 80S ribosome in human HuH7 cells assessed as inhibition of PCSK9 mRNA translation after overnight incubation by ELISA	ic50	2.8200	uM
N-(3-chloro-2-pyridinyl)-4-[6-(dimethylamino)pyrazin-2-yl]-N-[(3R)-piperidin-3-yl]benzamide	1497963: Binding affinity to 80S ribosome in human HuH7 cells assessed as inhibition of PCSK9 mRNA translation after overnight incubation by ELISA	ic50	2.9700	uM
N-(3-chloro-2-pyridinyl)-4-[6-(methylamino)pyrazin-2-yl]-N-[(3R)-piperidin-3-yl]benzamide	1497963: Binding affinity to 80S ribosome in human HuH7 cells assessed as inhibition of PCSK9 mRNA translation after overnight incubation by ELISA	ic50	3.0800	uM
N-isoquinolin-1-yl-4-(6-methyl-1,2-benzoxazol-3-yl)-N-[(3R)-piperidin-3-yl]piperazine-1-carboxamide	1532845: Binding affinity to 80S ribosome in human HuH7 cells harboring human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	3.5000	uM
N-(3-methylpyrazin-2-yl)-4-phenyl-N-[(3R)-piperidin-3-yl]piperidine-1-carboxamide	1532846: Binding affinity to 80S ribosome in human HeLa cells lysates using human full length PCSK9 encoding mRNAs assessed as inhibition of PCSK9 mRNA translation after 45 mins by Steady-Glo luciferase reporter gene assay	ic50	3.6300	uM
N-(3-chloro-2-pyridinyl)-N-[(3R)-piperidin-3-yl]-6-(triazolo[4,5-b]pyridin-3-yl)pyridine-3-carboxamide	1497947: Binding affinity to 80S ribosome in human HuH7 cells harboring pCMV-truncated human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	4.1000	uM
N-isoquinolin-1-yl-N-[(3R)-piperidin-3-yl]-4-pyrazin-2-ylbenzamide	1497947: Binding affinity to 80S ribosome in human HuH7 cells harboring pCMV-truncated human PCSK9 (1 to 152 residues)-proLuc assessed as inhibition of PCSK9 mRNA translation after overnight incubation by luciferase reporter gene assay	ic50	4.3000	uM
4-(2-fluorophenyl)-N-(3-methyl-2-pyridinyl)-N-[(3R)-piperidin-3-yl]piperidine-1-carboxamide	1532846: Binding affinity to 80S ribosome in human HeLa cells lysates using human full length PCSK9 encoding mRNAs assessed as inhibition of PCSK9 mRNA translation after 45 mins by Steady-Glo luciferase reporter gene assay	ic50	4.3800	uM
2,2-dichloro-N-[(1R,2R)-1,3-dihydroxy-1-(4-nitrophenyl)propan-2-yl]acetamide;sulfuric acid	717551: Inhibition of mitochondrial ribosome-mediated protein synthesis in human HeLa cells assessed as {35S]methionine incorporation by autoradiography	ic50	7.4000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, affects cotreatment	6
sodium arsenite	affects binding, decreases reaction, decreases expression	2
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	2
chloropicrin	decreases expression	2
Acrolein	affects cotreatment, increases expression, increases abundance	2
Ozone	affects cotreatment, increases expression, increases abundance	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
alpha-pinene	increases abundance, affects cotreatment, increases expression	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
diisononyl phthalate	affects cotreatment, increases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, increases reaction	1
lead nitrate	affects cotreatment, increases expression	1
perfluorooctanoic acid	decreases expression	1
butylbenzyl phthalate	affects cotreatment, increases expression	1
cupric oxide	increases expression	1
epigallocatechin gallate	increases expression	1
arsenic trichloride	decreases expression, increases abundance	1
tamibarotene	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
azoxystrobin	increases expression	1
CD 437	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
deguelin	increases expression	1
K 7174	decreases expression	1

ChEMBL screening assays

90 unique, capped per target: 90 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1920845	Binding	Induction of ribosome to readthrough in human A-T lymphoblastoid cells assessed as ATM ser1981 autophosphorylation at 30 uM after 4 days by PTT-ELISA assay	Synthesis and evaluation of compounds that induce readthrough of premature termination codons. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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