RPL3

Summary

RPL3 (ribosomal protein L3, HGNC:10332) is a protein-coding gene on chromosome 22q13.1, encoding Large ribosomal subunit protein uL3 (P39023). Component of the large ribosomal subunit. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

Ribosomes, the complexes 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 60S subunit. The protein belongs to the L3P family of ribosomal proteins and it is located in the cytoplasm. The protein can bind to the HIV-1 TAR mRNA, and it has been suggested that the protein contributes to tat-mediated transactivation. This gene is co-transcribed with several small nucleolar RNA genes, which are located in several of this gene’s introns. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome.

Source: NCBI Gene 6122 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 75 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_000967

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10332
Approved symbol	RPL3
Name	ribosomal protein L3
Location	22q13.1
Locus type	gene with protein product
Status	Approved
Aliases	L3, uL3
Ensembl gene	ENSG00000100316
Ensembl biotype	protein_coding
OMIM	604163
Entrez	6122

Gene structure

Transcript identifiers

Ensembl transcripts: 39 — 26 protein_coding, 9 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000216146, ENST00000401609, ENST00000402527, ENST00000420536, ENST00000427905, ENST00000453303, ENST00000459859, ENST00000460589, ENST00000461967, ENST00000464182, ENST00000465618, ENST00000467105, ENST00000471290, ENST00000473638, ENST00000481985, ENST00000484358, ENST00000484615, ENST00000498462, ENST00000871468, ENST00000871469, ENST00000871470, ENST00000871471, ENST00000871472, ENST00000871473, ENST00000871474, ENST00000871475, ENST00000871476, ENST00000871477, ENST00000926227, ENST00000926228, ENST00000926229, ENST00000926230, ENST00000926231, ENST00000926232, ENST00000926233, ENST00000926234, ENST00000926235, ENST00000926236, ENST00000971220

RefSeq mRNA: 2 — MANE Select: NM_000967 NM_000967, NM_001033853

CCDS: CCDS13988

Canonical transcript exons

ENST00000216146 — 10 exons

Exon	Start	End
ENSE00000654709	39316706	39316841
ENSE00001555640	39312882	39312984
ENSE00003465930	39317461	39317629
ENSE00003521491	39313191	39313310
ENSE00003551427	39313634	39313729
ENSE00003597413	39314107	39314208
ENSE00003612364	39318400	39318592
ENSE00003639458	39314686	39314846
ENSE00003656428	39319595	39319623
ENSE00003788412	39315369	39315555

Expression profiles

Bgee: expression breadth ubiquitous, 307 present calls, max score 99.94.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 284.0083 / max 2417.5874, expressed in 1826 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194284	278.6855	1826
194279	1.9254	1026
194282	1.9124	1100
194281	1.3769	837
194283	0.0749	25
209481	0.0333	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ovary	UBERON:0002119	99.94	gold quality
right ovary	UBERON:0002118	99.93	gold quality
type B pancreatic cell	CL:0000169	99.92	gold quality
adenohypophysis	UBERON:0002196	99.92	gold quality
ventricular zone	UBERON:0003053	99.92	gold quality
upper arm skin	UBERON:0004263	99.92	gold quality
stromal cell of endometrium	CL:0002255	99.91	gold quality
pituitary gland	UBERON:0000007	99.91	gold quality
endocervix	UBERON:0000458	99.91	gold quality
ganglionic eminence	UBERON:0004023	99.91	gold quality
body of uterus	UBERON:0009853	99.91	gold quality
embryo	UBERON:0000922	99.90	gold quality
ovary	UBERON:0000992	99.90	gold quality
right uterine tube	UBERON:0001302	99.90	gold quality
skin of abdomen	UBERON:0001416	99.90	gold quality
skin of leg	UBERON:0001511	99.90	gold quality
right lobe of thyroid gland	UBERON:0001119	99.89	gold quality
left lobe of thyroid gland	UBERON:0001120	99.89	gold quality
mucosa of stomach	UBERON:0001199	99.89	gold quality
left uterine tube	UBERON:0001303	99.89	gold quality
cerebellar cortex	UBERON:0002129	99.89	gold quality
cerebellar hemisphere	UBERON:0002245	99.89	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.89	gold quality
ectocervix	UBERON:0012249	99.89	gold quality
zone of skin	UBERON:0000014	99.88	gold quality
left adrenal gland	UBERON:0001234	99.88	gold quality
left testis	UBERON:0004533	99.88	gold quality
cortical plate	UBERON:0005343	99.88	gold quality
metanephros cortex	UBERON:0010533	99.88	gold quality
lower esophagus	UBERON:0013473	99.88	gold quality

Single-cell (SCXA)

Detected in 50 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	7901.80
E-HCAD-9	yes	5203.70
E-CURD-112	yes	5117.58
E-MTAB-9221	yes	4097.41
E-HCAD-35	yes	1725.56
E-CURD-122	yes	101.02
E-CURD-88	yes	60.28
E-MTAB-9067	yes	32.41
E-MTAB-9543	yes	23.57
E-MTAB-10042	yes	15.62
E-MTAB-9801	yes	6.84
E-MTAB-7249	no	37468.38
E-HCAD-4	no	13757.71
E-MTAB-10885	no	11928.16
E-MTAB-7606	no	11361.45

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AR, KHSRP, MYC, NPM1

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 16)

• Involved in progression and regulation of telomerase (PMID:16364039)
• working model in which rpL3 recruits hnRNP H1 and, through cooperation with other splicing factors, promotes selection of the alternative splice site (PMID:20100605)
• NPM and KHSRP are two newly identified proteins involved in the regulation of rpL3 gene expression via alternative pre-mRNA splicing. (PMID:21705779)
• The rpL3 is able to modulate the protein amounts of p21 through a novel pathway independent from p53 involving Sp1 and NPM. (PMID:23255119)
• rpL3 participates in the cell response to chemotherapy acting as a critical regulator of cell cycle, apoptosis and DNA repair, by modulating p21 expression (PMID:25473889)
• nucleolar stress induced by 5-fluorouracil in colon cancer cells devoid of p53 leads to the activation of ribosomal protein L3 as proapoptotic factor (PMID:27385096)
• The sensitivity of p53 null colon cancer cells to 5-FU can be enhanced using proapoptotic rpL3 gene. (PMID:27835895)
• We found that uL3 down-regulation correlates positively with multidrug resistance. Restoration of the uL3 protein level re-sensitized the resistant cells to the drug by regulating the reactive oxygen species (ROS) levels, glutathione content, glutamate release, and cystine uptake. (PMID:28273808)
• Ribosomal protein uL3 targets E2F1 and Cyclin D1 in cancer cell response to nucleolar stress. (PMID:31659203)
• uL3 Mediated Nucleolar Stress Pathway as a New Mechanism of Action of Antiproliferative G-quadruplex TBA Derivatives in Colon Cancer Cells. (PMID:32290083)
• DUOX2 promotes the progression of colorectal cancer cells by regulating the AKT pathway and interacting with RPL3. (PMID:32531052)
• S-Adenosyl-l-Methionine Overcomes uL3-Mediated Drug Resistance in p53 Deleted Colon Cancer Cells. (PMID:33374288)
• Human METTL18 is a histidine-specific methyltransferase that targets RPL3 and affects ribosome biogenesis and function. (PMID:33693809)
• Suppression of RPL34 Inhibits Tumor Cell Proliferation and Promotes Apoptosis in Glioblastoma. (PMID:35377127)
• METTL18-mediated histidine methylation of RPL3 modulates translation elongation for proteostasis maintenance. (PMID:35674491)
• BAIAP2L1 accelerates breast cancer progression and chemoresistance by activating AKT signaling through binding with ribosomal protein L3. (PMID:36308067)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rpl3	ENSDARG00000003599
mus_musculus	Rpl3	ENSMUSG00000060036
rattus_norvegicus	Rpl3	ENSRNOG00000016896
drosophila_melanogaster	RpL3	FBGN0020910
caenorhabditis_elegans		WBGENE00004414

Paralogs (1): RPL3L (ENSG00000140986)

Protein

Protein identifiers

Large ribosomal subunit protein uL3 — P39023 (reviewed: P39023)

Alternative names: 60S ribosomal protein L3, HIV-1 TAR RNA-binding protein B

All UniProt accessions (6): P39023, B5MCW2, F8WCR1, G5E9G0, H7C3M2, H7C422

UniProt curated annotations — full annotation on UniProt →

Function. Component of the large ribosomal subunit. The ribosome is a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell.

Subunit / interactions. Component of the large ribosomal subunit. Interacts with DHX33. Interacts with GRWD1.

Subcellular location. Nucleus. Nucleolus. Cytoplasm.

Post-translational modifications. Constitutively monomethylated at His-245 by METTL18. Methylation at His-245 regulates translation elongation by slowing ribosome traversal on tyrosine codons: slower elongation provides enough time for proper folding of synthesized proteins and prevents cellular aggregation of tyrosine-rich proteins. It is not required for incorporation of RPL3 into ribosomes.

Similarity. Belongs to the universal ribosomal protein uL3 family.

RefSeq proteins (2): NP_000958, NP_001029025 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000597	Ribosomal_uL3	Family
IPR009000	Transl_B-barrel_sf	Homologous_superfamily
IPR019926	Ribosomal_uL3_CS	Conserved_site
IPR044892	Ribosomal_L3_dom_3_arc_sf	Homologous_superfamily
IPR045077	L3_arc_euk	Family

Pfam: PF00297

UniProt features (25 total): cross-link 9, modified residue 8, sequence conflict 2, initiator methionine 1, chain 1, region of interest 1, sequence variant 1, mutagenesis site 1, compositionally biased region 1

Structure

Experimental structures (PDB)

193 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
8A3D	ELECTRON MICROSCOPY	1.67
8GLP	ELECTRON MICROSCOPY	1.67
8QYX	ELECTRON MICROSCOPY	1.78
8QOI	ELECTRON MICROSCOPY	1.9
9O3W	ELECTRON MICROSCOPY	1.9
8YOO	ELECTRON MICROSCOPY	2
9C3H	ELECTRON MICROSCOPY	2
9I2D	ELECTRON MICROSCOPY	2.19
9PBE	ELECTRON MICROSCOPY	2.19
8QFD	ELECTRON MICROSCOPY	2.2
8YOP	ELECTRON MICROSCOPY	2.2
9GUL	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
8FKV	ELECTRON MICROSCOPY	2.47
9QLO	ELECTRON MICROSCOPY	2.47
8FLE	ELECTRON MICROSCOPY	2.48
9P8B	ELECTRON MICROSCOPY	2.48
7XNY	ELECTRON MICROSCOPY	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P39023-F1	96.38	0.98

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 (17): 366, 373, 39, 224, 226, 286, 294, 366, 386, 393, 399, 13, 136, 245, 286, 294, 304

Mutagenesis-validated functional residues (1):

Position	Phenotype
246–249	no effect on methylation by mettl18.

Function

Pathways and Gene Ontology

Reactome pathways

16 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-6791226	Major pathway of rRNA processing in the nucleolus and cytosol
R-HSA-72689	Formation of a pool of free 40S subunits
R-HSA-72706	GTP hydrolysis and joining of the 60S ribosomal subunit
R-HSA-72764	Eukaryotic Translation Termination
R-HSA-9010553	Regulation of expression of SLITs and ROBOs
R-HSA-9633012	Response of EIF2AK4 (GCN2) to amino acid deficiency
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-9954709	Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide
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

MSigDB gene sets: 277 (showing top): GOBP_CYTOPLASMIC_TRANSLATION, HORIUCHI_WTAP_TARGETS_DN, SWEET_KRAS_ONCOGENIC_SIGNATURE, GOBP_RESPONSE_TO_INTERLEUKIN_4, GOBP_RESPONSE_TO_PEPTIDE, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, GCM_NPM1, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, HSIAO_HOUSEKEEPING_GENES, GOBP_MALE_GAMETE_GENERATION, KONG_E2F3_TARGETS, GOBP_TRANSLATION, MAHAJAN_RESPONSE_TO_IL1A_DN

GO Biological Process (3): cytoplasmic translation (GO:0002181), translation (GO:0006412), cellular response to interleukin-4 (GO:0071353)

GO Molecular Function (3): RNA binding (GO:0003723), structural constituent of ribosome (GO:0003735), protein binding (GO:0005515)

GO Cellular Component (11): nucleus (GO:0005634), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), focal adhesion (GO:0005925), cytosolic large ribosomal subunit (GO:0022625), cytosolic ribosome (GO:0022626), protein-containing complex (GO:0032991), extracellular exosome (GO:0070062), ribosome (GO:0005840), ribonucleoprotein complex (GO:1990904)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Ribosome-associated quality control	3
Translation	2
Cap-dependent Translation Initiation	2
Nonsense-Mediated Decay (NMD)	2
Eukaryotic Translation Initiation	1
Eukaryotic Translation Elongation	1
Influenza Viral RNA Transcription and Replication	1
Selenoamino acid metabolism	1
rRNA processing in the nucleus and cytosol	1
Signaling by ROBO receptors	1
Cellular response to starvation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
ribosome	2
intracellular membraneless organelle	2
cellular anatomical structure	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
response to interleukin-4	1
cellular response to cytokine stimulus	1
nucleic acid binding	1
structural molecule activity	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
cell-substrate junction	1
large ribosomal subunit	1
cytosolic ribosome	1
cytosol	1
cellular_component	1
extracellular vesicle	1
protein-containing complex	1

Protein interactions and networks

STRING

5595 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RPL3	GRWD1	Q9BQ67	952
RPL3	RPS3	P23396	878
RPL3	RPL12	P30050	855
RPL3	RPL4	P36578	852
RPL3	RPL8	P25120	828
RPL3	MRPL3	P09001	823
RPL3	RPS8	P09058	805
RPL3	RPL11	P25121	804
RPL3	RPL6	Q02878	796
RPL3	RPL18	Q07020	786
RPL3	RPL14	P50914	779
RPL3	RPS19	P39019	778
RPL3	RPL7	P18124	768
RPL3	RPS6	P08227	765
RPL3	RPL5	P46777	759

IntAct

262 interactions, top by confidence:

A	B	Type	Score
MAP3K14	CHUK	psi-mi:“MI:0914”(association)	0.950
PPP1CC	CCDC85C	psi-mi:“MI:0914”(association)	0.740
PPP1CC	CCDC85C	psi-mi:“MI:2364”(proximity)	0.740
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
FAM90A1	KPNA3	psi-mi:“MI:0914”(association)	0.670
NOP53	RRP8	psi-mi:“MI:0914”(association)	0.640
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
RACK1	RPS17	psi-mi:“MI:0915”(physical association)	0.610
RPL3	WFS1	psi-mi:“MI:0915”(physical association)	0.560
RPL3	SHANK3	psi-mi:“MI:0915”(physical association)	0.550
NOM1	RPLP0	psi-mi:“MI:0914”(association)	0.530
MAPT	KIF2A	psi-mi:“MI:0914”(association)	0.530
PLEKHO1	UBA6	psi-mi:“MI:0914”(association)	0.530
MECP2	GTPBP10	psi-mi:“MI:0914”(association)	0.530
MAGEB10	GTPBP10	psi-mi:“MI:0914”(association)	0.530
ZNF324B	ZNF316	psi-mi:“MI:0914”(association)	0.530
RBM34	NVL	psi-mi:“MI:0914”(association)	0.530
RRP8	NVL	psi-mi:“MI:0914”(association)	0.530

BioGRID (1121): RPL3 (Affinity Capture-MS), RPL3 (Affinity Capture-MS), RPL3 (Affinity Capture-MS), RPL3 (Affinity Capture-MS), RPL3 (Affinity Capture-MS), RPL3 (Affinity Capture-MS), RPL3 (Affinity Capture-MS), RPL3 (Reconstituted Complex), RPL3 (Affinity Capture-MS), RPL3 (Affinity Capture-MS), RPL3 (Affinity Capture-MS), RPL3 (Affinity Capture-MS), RPL3 (Affinity Capture-MS), RPL3 (Affinity Capture-MS), RPL3 (Affinity Capture-MS)

ESM2 similar proteins: A5JSW9, B2CAZ2, B7XMD2, E9PWZ3, G1TL06, O01727, O14049, O16797, O96774, P0CX39, P0CX40, P14126, P17094, P21531, P22738, P27659, P29327, P34113, P35684, P36584, P39023, P39872, P40372, P49149, P50880, P59671, P62247, Q29293, Q3SZ10, Q4N3P0, Q4R5Q0, Q4UFS9, Q54E24, Q59LS1, Q5DAA3, Q64FN2, Q6BXM5, Q6CJR7, Q6FTJ2, Q759R7

Diamond homologs: A0B9X0, A0LIJ0, A1RVG3, A2SPK3, A3CSZ7, A3DNA4, A3MWI4, A4FVY2, A4WMH5, A4YCW6, A5UL89, A6UQJ0, A6UV68, A6VHD2, A7I5N9, A7Z0N8, A8M529, A8MB75, A9A9B8, B0R656, B1YD88, B2GIL4, B6YSL3, B8GKD3, C3MQ59, C3MVH8, C3N5S7, C3NEE3, C3NHA9, C4KHF6, C5A286, C6A159, E9PWZ3, G1TL06, G7WMS7, O16797, O26110, O28354, O59418, O96774

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RPL3	“form complex”	“60S cytosolic large ribosomal subunit”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 201 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
Peptide chain elongation	15	14.9×	8e-12
Viral mRNA Translation	15	14.9×	8e-12
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	16	14.7×	3e-12
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	15	14.7×	8e-12
Selenocysteine synthesis	15	14.1×	1e-11
Eukaryotic Translation Termination	15	14.1×	1e-11
ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA	15	13.8×	1e-11
SRP-dependent cotranslational protein targeting to membrane	17	13.3×	3e-12

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic translation	17	17.9×	7e-14
ribosomal large subunit biogenesis	7	17.6×	2e-05
mRNA stabilization	7	14.6×	8e-05
intrinsic apoptotic signaling pathway	7	14.3×	9e-05
rRNA processing	16	12.9×	7e-11
mitophagy	7	12.7×	2e-04
ribosomal small subunit biogenesis	9	11.7×	2e-05
translation	17	9.9×	6e-10

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	52
Likely benign	3
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1263 predictions. Top by Δscore:

Variant	Effect	Δscore
22:39312984:CCTG:C	acceptor_loss	1.0000
22:39313187:TCAC:T	donor_loss	1.0000
22:39313188:CA:C	donor_loss	1.0000
22:39313189:A:AC	donor_gain	1.0000
22:39313189:AC:A	donor_gain	1.0000
22:39313190:C:CT	donor_gain	1.0000
22:39313190:CC:C	donor_gain	1.0000
22:39313190:CCA:C	donor_gain	1.0000
22:39313190:CCATG:C	donor_gain	1.0000
22:39313306:AAGGA:A	acceptor_gain	1.0000
22:39313307:AGGA:A	acceptor_gain	1.0000
22:39313308:GGA:G	acceptor_gain	1.0000
22:39313309:GA:G	acceptor_gain	1.0000
22:39313311:C:CC	acceptor_gain	1.0000
22:39313313:A:C	acceptor_gain	1.0000
22:39313319:C:T	acceptor_gain	1.0000
22:39313628:CCTCA:C	donor_loss	1.0000
22:39313629:CTCA:C	donor_loss	1.0000
22:39313633:C:CA	donor_loss	1.0000
22:39313725:CCACC:C	acceptor_gain	1.0000
22:39313726:CACC:C	acceptor_gain	1.0000
22:39313726:CACCC:C	acceptor_gain	1.0000
22:39313728:CC:C	acceptor_gain	1.0000
22:39313729:CC:C	acceptor_gain	1.0000
22:39313730:C:CC	acceptor_gain	1.0000
22:39314103:TTA:T	donor_loss	1.0000
22:39314105:A:AC	donor_gain	1.0000
22:39314105:A:AT	donor_loss	1.0000
22:39314105:AC:A	donor_gain	1.0000
22:39314106:C:CG	donor_gain	1.0000

AlphaMissense

2665 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:39313221:G:C	F379L	1.000
22:39313221:G:T	F379L	1.000
22:39313223:A:G	F379L	1.000
22:39313257:G:C	F367L	1.000
22:39313257:G:T	F367L	1.000
22:39313259:A:G	F367L	1.000
22:39313665:C:T	G339E	1.000
22:39313666:C:G	G339R	1.000
22:39313666:C:T	G339R	1.000
22:39313678:C:G	G335R	1.000
22:39313721:A:C	F320L	1.000
22:39313721:A:T	F320L	1.000
22:39313723:A:G	F320L	1.000
22:39314726:C:A	G270V	1.000
22:39314726:C:T	G270E	1.000
22:39314760:G:A	P259S	1.000
22:39314764:C:A	W257C	1.000
22:39314764:C:G	W257C	1.000
22:39314766:A:G	W257R	1.000
22:39314766:A:T	W257R	1.000
22:39314771:C:A	G255V	1.000
22:39314771:C:T	G255E	1.000
22:39314772:C:A	G255W	1.000
22:39314772:C:G	G255R	1.000
22:39314772:C:T	G255R	1.000
22:39314774:A:T	I254N	1.000
22:39314776:A:C	C253W	1.000
22:39314777:C:T	C253Y	1.000
22:39314778:A:G	C253R	1.000
22:39314780:G:T	A252D	1.000

dbSNP variants (sampled 300 via entrez): RS1000169001 (22:39318975 G>A), RS1000192525 (22:39316190 G>A), RS1000218282 (22:39314088 C>A,T), RS1000404930 (22:39314290 G>A,C,T), RS1000428722 (22:39316470 G>A), RS1000536117 (22:39321609 G>T), RS1000606715 (22:39318835 T>C), RS1000663145 (22:39312687 A>T), RS1000826106 (22:39317388 C>G,T), RS1000933539 (22:39317147 G>A), RS1001308108 (22:39313182 G>C), RS1001371968 (22:39313536 T>TC,TCC), RS1002052109 (22:39316707 T>C), RS1002117135 (22:39313174 C>A,G,T), RS1002279606 (22:39317970 C>A,T)

Disease associations

OMIM: gene MIM:604163 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST004131_35	Inflammatory bowel disease	5.000000e-24
GCST004132_19	Crohn’s disease	8.000000e-21
GCST004133_57	Ulcerative colitis	3.000000e-10
GCST004302_11	Primary biliary cholangitis	3.000000e-08
GCST005581_18	Primary biliary cirrhosis	1.000000e-13
GCST007445_2	Factor VIII levels	2.000000e-07
GCST007445_31	Factor VIII levels	9.000000e-09
GCST007445_47	Factor VIII levels	2.000000e-06
GCST007446_84	vWF levels	6.000000e-14

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004630	factor VIII measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3987582 (PROTEIN NUCLEIC-ACID COMPLEX), CHEMBL6066907 (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

48 potent at pChembl≥5 of 54 total, top 47 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
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
5.69	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
5.58	Kd	2639	nM	CHEMBL3752910
5.58	ED50	2639	nM	CHEMBL3752910
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

47 with measured affinity, of 209 total; 27 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
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
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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149260: Binding affinity to human RPL3 incubated for 45 mins by Kinobead based pull down assay	kd	2.6389	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

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, decreases expression	4
bisphenol A	decreases expression	2
perfluorooctane sulfonic acid	increases expression, decreases expression	2
Fluorouracil	decreases expression	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
bisphenol F	increases expression	1
TAK-243	increases sumoylation	1
2,4,6-tribromophenol	decreases expression	1
deoxynivalenol	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
decabromobiphenyl ether	decreases expression	1
beta-lapachone	increases expression	1
perfluorooctanoic acid	decreases expression	1
ochratoxin A	increases expression	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
chloropicrin	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
deguelin	increases expression	1
perfluorohexanesulfonic acid	decreases expression	1
pyrimidifen	increases expression	1
bisphenol B	increases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pyrachlostrobin	increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	increases expression	1
jinfukang	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1

ChEMBL screening assays

90 unique, capped per target: 90 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
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.