RPS23

Summary

RPS23 (ribosomal protein S23, HGNC:10410) is a protein-coding gene on chromosome 5q14.2, encoding Small ribosomal subunit protein uS12 (P62266). 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 99.9% 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 S12P family of ribosomal proteins. It is located in the cytoplasm. The protein shares significant amino acid similarity with S. cerevisiae ribosomal protein S28. As is typical for genes encoding ribosomal proteins, there are multiple processed pseudogenes of this gene dispersed through the genome.

Source: NCBI Gene 6228 — RefSeq curated summary.

At a glance

• Gene–disease (curated): brachycephaly, trichomegaly, and developmental delay (Strong, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 24 total — 2 pathogenic
• Phenotypes (HPO): 29
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• MANE Select transcript: NM_001025

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10410
Approved symbol	RPS23
Name	ribosomal protein S23
Location	5q14.2
Locus type	gene with protein product
Status	Approved
Aliases	S23, uS12
Ensembl gene	ENSG00000186468
Ensembl biotype	protein_coding
OMIM	603683
Entrez	6228

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 10 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000296674, ENST00000503605, ENST00000504293, ENST00000507980, ENST00000510019, ENST00000510210, ENST00000511844, ENST00000512493, ENST00000651545, ENST00000912101, ENST00000912102, ENST00000912103

RefSeq mRNA: 1 — MANE Select: NM_001025 NM_001025

CCDS: CCDS47241

Canonical transcript exons

ENST00000296674 — 4 exons

Exon	Start	End
ENSE00001476080	82273320	82276255
ENSE00002021444	82278320	82278354
ENSE00003630242	82277693	82277852
ENSE00003640336	82276398	82276518

Expression profiles

Bgee: expression breadth ubiquitous, 305 present calls, max score 99.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 1048.9724 / max 17521.9650, expressed in 1828 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
62343	1041.6052	1828
62344	3.8867	1493
62342	3.4805	1490

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of hip	UBERON:0001554	99.99	gold quality
mammary duct	UBERON:0001765	99.99	gold quality
pleura	UBERON:0000977	99.98	gold quality
parietal pleura	UBERON:0002400	99.98	gold quality
visceral pleura	UBERON:0002401	99.98	gold quality
trabecular bone tissue	UBERON:0002483	99.98	gold quality
upper leg skin	UBERON:0004262	99.98	gold quality
lower lobe of lung	UBERON:0008949	99.98	gold quality
urethra	UBERON:0000057	99.97	gold quality
mammalian vulva	UBERON:0000997	99.97	gold quality
mucosa of urinary bladder	UBERON:0001259	99.97	gold quality
germinal epithelium of ovary	UBERON:0001304	99.97	gold quality
superficial temporal artery	UBERON:0001614	99.97	gold quality
epithelium of nasopharynx	UBERON:0001951	99.97	gold quality
vena cava	UBERON:0004087	99.97	gold quality
caput epididymis	UBERON:0004358	99.97	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.97	gold quality
adult organism	UBERON:0007023	99.97	gold quality
embryo	UBERON:0000922	99.96	gold quality
skin epidermis	UBERON:0001003	99.96	gold quality
nephron tubule	UBERON:0001231	99.96	gold quality
pigmented layer of retina	UBERON:0001782	99.96	gold quality
hair follicle	UBERON:0002073	99.96	gold quality
left ovary	UBERON:0002119	99.96	gold quality
tibia	UBERON:0000979	99.95	gold quality
penis	UBERON:0000989	99.95	gold quality
ovary	UBERON:0000992	99.95	gold quality
seminal vesicle	UBERON:0000998	99.95	gold quality
diaphragm	UBERON:0001103	99.95	gold quality
pylorus	UBERON:0001166	99.95	gold quality

Single-cell (SCXA)

Detected in 35 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	9453.79
E-CURD-112	yes	8901.92
E-CURD-88	yes	8280.44
E-CURD-122	yes	7520.83
E-MTAB-9221	yes	54.01
E-HCAD-31	yes	29.08
E-MTAB-9067	yes	28.91
E-HCAD-9	yes	15.90
E-HCAD-35	yes	8.84
E-GEOD-137537	yes	6.51
E-MTAB-6678	yes	4.39
E-MTAB-7407	no	10614.74
E-MTAB-8495	no	8981.18
E-GEOD-124263	no	8913.38
E-CURD-79	no	8551.23

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

58 targeting RPS23, 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-3134	100.00	66.43	777
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-651-5P	99.64	68.49	1104
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-182-3P	99.57	67.57	825
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-4519	99.48	66.10	859
HSA-MIR-12132	99.47	68.90	1341
HSA-MIR-5009-3P	99.45	69.43	1341
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-542-3P	99.34	67.58	1270
HSA-MIR-2116-5P	99.32	69.34	1273
HSA-MIR-5584-3P	99.23	68.79	1351
HSA-MIR-4426	99.17	66.74	1949
HSA-MIR-146A-3P	99.13	68.99	1881
HSA-MIR-7151-3P	99.04	69.72	2370

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 5)

• Rps23p hydroxylation can either increase or decrease translational accuracy in a stop codon context-dependent manner. (PMID:24550462)
• Report dysregulated expression of RPS23 in disc degeneration. (PMID:25893343)
• A missense mutation is reported in two unrelated individuals with microcephaly, hearing loss, and overlapping dysmorphic features. (PMID:28257692)
• The study results reveal a role for RPS23RG1 in maintaining synaptic integrity and function and provide a new mechanism for synaptic dysfunction in Alzheimer’s disease (AD) pathogenesis. (PMID:30292394)
• Identification of Hub Genes in Gastric Cancer with High Heterogeneity Based on Weighted Gene Co-Expression Network. (PMID:32558489)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rps23	ENSDARG00000021838
mus_musculus	Rps23	ENSMUSG00000049517
rattus_norvegicus	Rps23	ENSRNOG00000016580
drosophila_melanogaster	RpS23	FBGN0033912
caenorhabditis_elegans		WBGENE00004492

Paralogs (1): MRPS12 (ENSG00000128626)

Protein

Protein identifiers

Small ribosomal subunit protein uS12 — P62266 (reviewed: P62266)

Alternative names: 40S ribosomal protein S23

All UniProt accessions (6): A8K517, D6R9I7, D6RD47, D6RDJ2, D6RIX0, P62266

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 an important role in translational accuracy. Part of the small subunit (SSU) processome, first precursor of the small eukaryotic ribosomal subunit. During the assembly of the SSU processome in the nucleolus, many ribosome biogenesis factors, an RNA chaperone and ribosomal proteins associate with the nascent pre-rRNA and work in concert to generate RNA folding, modifications, rearrangements and cleavage as well as targeted degradation of pre-ribosomal RNA by the RNA exosome.

Subunit / interactions. Component of the 40S small ribosomal subunit. Part of the small subunit (SSU) processome, composed of more than 70 proteins and the RNA chaperone small nucleolar RNA (snoRNA) U3.

Subcellular location. Cytoplasm. Cytosol. Rough endoplasmic reticulum. Nucleus. Nucleolus.

Post-translational modifications. Hydroxylation at Pro-62 affects translation termination efficiency.

Disease relevance. Brachycephaly, trichomegaly, and developmental delay (BTDD) [MIM:617412] An autosomal dominant developmental disorder characterized by brachycephaly, ciliary trichomegaly, dysmorphic features of the face and hands, hearing loss, and developmental delay with short stature. Intellectual disability and autism spectrum disorder may be present in some patients. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the universal ribosomal protein uS12 family.

RefSeq proteins (1): NP_001016* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005680	Ribosomal_uS12_euk_arc	Family
IPR006032	Ribosomal_uS12	Family
IPR012340	NA-bd_OB-fold	Homologous_superfamily

Pfam: PF00164

UniProt features (26 total): strand 9, helix 5, modified residue 3, turn 2, sequence variant 2, initiator methionine 1, chain 1, region of interest 1, compositionally biased region 1, cross-link 1

Structure

Experimental structures (PDB)

205 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
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
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
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
8IFE	ELECTRON MICROSCOPY	2.57
9P7D	ELECTRON MICROSCOPY	2.57
9QLQ	ELECTRON MICROSCOPY	2.57
8IFD	ELECTRON MICROSCOPY	2.59
9P7E	ELECTRON MICROSCOPY	2.59
6ZLW	ELECTRON MICROSCOPY	2.6
6ZMI	ELECTRON MICROSCOPY	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P62266-F1	94.99	0.94

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 (4): 54, 62, 135, 37

Function

Pathways and Gene Ontology

Reactome pathways

53 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-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-9010553	Regulation of expression of SLITs and ROBOs
R-HSA-9629569	Protein hydroxylation
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-163841	Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation
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
R-HSA-2408522	Selenoamino acid metabolism

MSigDB gene sets: 308 (showing top): GOBP_CYTOPLASMIC_TRANSLATION, GOBP_RIBOSOME_BIOGENESIS, MODULE_151, GNF2_TPT1, GCM_NPM1, HSIAO_HOUSEKEEPING_GENES, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GOBP_TRANSLATION, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_RIBOSOMAL_SMALL_SUBUNIT_BIOGENESIS, GOMF_STRUCTURAL_CONSTITUENT_OF_RIBOSOME, GNF2_FBL, GOBP_ORGANELLE_ASSEMBLY, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_UP, GNF2_ST13

GO Biological Process (5): cytoplasmic translation (GO:0002181), translation (GO:0006412), stress granule assembly (GO:0034063), ribosomal small subunit biogenesis (GO:0042274), maintenance of translational fidelity (GO:1990145)

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

GO Cellular Component (15): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), rough endoplasmic reticulum (GO:0005791), cytosol (GO:0005829), ribosome (GO:0005840), membrane (GO:0016020), cytosolic ribosome (GO:0022626), cytosolic small ribosomal subunit (GO:0022627), small-subunit processome (GO:0032040), synapse (GO:0045202), nucleus (GO:0005634), nucleolus (GO:0005730), 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
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
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	1
Signaling by ROBO receptors	1
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1
Cellular response to starvation	1
SARS-CoV-1-host interactions	1
SARS-CoV-2-host interactions	1
Ribosome-associated quality control	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
translation	2
macromolecule biosynthetic process	2
ribosome	2
nuclear lumen	2
cytoplasm	2
intracellular membrane-bounded organelle	2
intracellular membraneless organelle	2
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
translational termination	1
protein metabolic process	1
protein biosynthetic process	1
membraneless organelle assembly	1
ribonucleoprotein complex biogenesis	1
ribosome biogenesis	1
nucleic acid binding	1
structural molecule activity	1
binding	1
intracellular anatomical structure	1
endomembrane system	1
endoplasmic reticulum	1
cytosol	1
small ribosomal subunit	1
cytosolic ribosome	1
nucleolus	1
preribosome	1
t-UTP complex	1
nuclear protein-containing complex	1
cell junction	1
ribosomal subunit	1
protein-containing complex	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

251 interactions, top by confidence:

A	B	Type	Score
YBX1	HNRNPR	psi-mi:“MI:0914”(association)	0.770
PIP4K2A	AHCYL1	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
Dcc	RPL5	psi-mi:“MI:0915”(physical association)	0.620
RACK1	RPS17	psi-mi:“MI:0915”(physical association)	0.610
DCC	RPL5	psi-mi:“MI:0915”(physical association)	0.610
OGFOD1	RPS23	psi-mi:“MI:0915”(physical association)	0.560
RPS23	OGFOD1	psi-mi:“MI:0915”(physical association)	0.560
RPL5	RPS23	psi-mi:“MI:0915”(physical association)	0.560
DDX6	MCRIP1	psi-mi:“MI:0914”(association)	0.510
ESR2		psi-mi:“MI:0914”(association)	0.500
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
PPP2R2B	DDX3X	psi-mi:“MI:0914”(association)	0.460
ESR1		psi-mi:“MI:0914”(association)	0.460
RPS23	DDX54	psi-mi:“MI:0915”(physical association)	0.400
RPS23	DCC	psi-mi:“MI:0915”(physical association)	0.400
	FER1L5	psi-mi:“MI:0915”(physical association)	0.400
UBE2W	RPS23	psi-mi:“MI:0915”(physical association)	0.370
		psi-mi:“MI:0914”(association)	0.350

BioGRID (594): RPS23 (Affinity Capture-MS), RPS23 (Affinity Capture-MS), RPS23 (Affinity Capture-MS), RPL10A (Co-fractionation), RPL12 (Co-fractionation), RPL13A (Co-fractionation), RPL14 (Co-fractionation), RPL15 (Co-fractionation), RPL17 (Co-fractionation), RPL23A (Co-fractionation), RPL27A (Co-fractionation), RPL28 (Co-fractionation), RPL30 (Co-fractionation), RPL31 (Co-fractionation), RPL37A (Co-fractionation)

ESM2 similar proteins: A5JSS2, A6H769, A6MZM2, E2RKA8, G1SHQ2, G1SNY0, G1SQH0, G1SVB0, G1SZ47, O09167, P12749, P14115, P18445, P20280, P30742, P46776, P46778, P47832, P49171, P49666, P61251, P61254, P61255, P61256, P61257, P62081, P62082, P62083, P62266, P62268, P62298, P62854, P62855, P62856, P62910, P62911, P62912, Q0D5W6, Q2I0I6, Q3SZQ6

Diamond homologs: A0A1D8PDU3, A0B562, A0RUR2, A1E9Q2, A1E9Y6, A1RSE4, A1RWW1, A2BN38, A2STX1, A3CXN0, A3DMP8, A3MXZ4, A4FWF2, A4WNA3, A5ULM8, A6UV46, A6VGV3, A7I4X6, A8A929, B0R8D1, G1SZ47, O15235, O27129, O28387, O35680, O59229, P06147, P0C460, P0C461, P0CT75, P0CT76, P0CX00, P0CX29, P0CX30, P0CY39, P0CY40, P10735, P11524, P12149, P12340

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RPS23	“form complex”	“40S cytosolic small ribosomal subunit”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 174 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	9	15.5×	2e-07
Ribosomal scanning and start codon recognition	10	15.2×	3e-08
SRP-dependent cotranslational protein targeting to membrane	18	14.4×	7e-14
GTP hydrolysis and joining of the 60S ribosomal subunit	18	14.4×	7e-14
Formation of a pool of free 40S subunits	16	14.3×	2e-12
L13a-mediated translational silencing of Ceruloplasmin expression	17	13.7×	8e-13
Translation initiation complex formation	9	13.7×	5e-07
Eukaryotic Translation Termination	14	13.5×	2e-10

GO biological processes:

GO term	Partners	Fold	FDR
formation of cytoplasmic translation initiation complex	5	36.7×	2e-05
stress granule assembly	7	27.5×	1e-06
cytoplasmic translation	17	20.6×	5e-15
translational initiation	8	18.8×	2e-06
mitophagy	6	12.5×	8e-04
negative regulation of translation	9	11.5×	2e-05
translation	16	10.8×	9e-10
ribosomal small subunit biogenesis	7	10.4×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	7
Likely benign	3
Benign	1

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
417763	NM_001025.5(RPS23):c.200G>A (p.Arg67Lys)	Pathogenic
417764	NM_001025.5(RPS23):c.358T>A (p.Phe120Ile)	Pathogenic

SpliceAI

351 predictions. Top by Δscore:

Variant	Effect	Δscore
5:82276394:TCA:T	donor_loss	1.0000
5:82276395:CA:C	donor_loss	1.0000
5:82276396:A:AC	donor_gain	1.0000
5:82276396:ACCT:A	donor_gain	1.0000
5:82276397:C:CC	donor_gain	1.0000
5:82276397:CCT:C	donor_gain	1.0000
5:82276397:CCTC:C	donor_gain	1.0000
5:82276514:CTCCT:C	acceptor_gain	1.0000
5:82276515:TCCT:T	acceptor_gain	1.0000
5:82276516:CCTC:C	acceptor_gain	1.0000
5:82276517:CT:C	acceptor_gain	1.0000
5:82276519:C:CA	acceptor_loss	1.0000
5:82276519:C:CC	acceptor_gain	1.0000
5:82276520:T:C	acceptor_loss	1.0000
5:82277686:GACTT:G	donor_loss	1.0000
5:82277688:CTTA:C	donor_loss	1.0000
5:82277691:A:AC	donor_gain	1.0000
5:82277691:ACACT:A	donor_loss	1.0000
5:82277692:C:CA	donor_gain	1.0000
5:82277692:CA:C	donor_gain	1.0000
5:82277692:CACT:C	donor_gain	1.0000
5:82277692:CACTT:C	donor_gain	1.0000
5:82277848:CTTGC:C	acceptor_gain	1.0000
5:82277853:C:CC	acceptor_gain	1.0000
5:82276175:A:AT	donor_gain	0.9900
5:82276253:TTCCT:T	acceptor_loss	0.9900
5:82276256:C:CG	acceptor_loss	0.9900
5:82276257:T:G	acceptor_loss	0.9900
5:82276396:AC:A	donor_gain	0.9900
5:82276397:CC:C	donor_gain	0.9900

AlphaMissense

924 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:82276181:A:C	F120L	1.000
5:82276181:A:T	F120L	1.000
5:82276183:A:G	F120L	1.000
5:82276188:A:T	V118D	1.000
5:82276191:C:T	G117E	1.000
5:82276192:C:G	G117R	1.000
5:82276192:C:T	G117R	1.000
5:82276199:A:C	D114E	1.000
5:82276199:A:T	D114E	1.000
5:82276200:T:A	D114V	1.000
5:82276200:T:C	D114G	1.000
5:82276200:T:G	D114A	1.000
5:82276201:C:G	D114H	1.000
5:82276203:C:A	G113V	1.000
5:82276203:C:T	G113D	1.000
5:82276204:C:A	G113C	1.000
5:82276204:C:G	G113R	1.000
5:82276224:C:A	G106V	1.000
5:82276224:C:T	G106D	1.000
5:82276225:C:G	G106R	1.000
5:82276230:C:T	G104E	1.000
5:82276236:A:T	V102D	1.000
5:82276421:C:G	D88H	1.000
5:82276429:A:T	V85E	1.000
5:82276431:A:C	F84L	1.000
5:82276431:A:T	F84L	1.000
5:82276433:A:G	F84L	1.000
5:82276435:G:T	A83D	1.000
5:82276462:A:G	L74P	1.000
5:82276468:A:T	V72D	1.000

dbSNP variants (sampled 300 via entrez): RS1000912449 (5:82274241 T>C), RS1001150651 (5:82277554 C>T), RS1002144614 (5:82273243 G>A), RS1002153132 (5:82278454 G>T), RS1002360698 (5:82279846 A>G), RS1002412110 (5:82273470 G>A,T), RS1002425970 (5:82274871 C>A,T), RS1003002153 (5:82274663 T>C), RS1003185571 (5:82279998 T>A), RS1003192571 (5:82275779 G>T), RS1003548302 (5:82274492 G>C), RS1004153819 (5:82275503 T>C,G), RS1004805570 (5:82277868 T>C), RS1004874436 (5:82276551 G>C), RS1004933835 (5:82273682 T>C)

Disease associations

OMIM: gene MIM:603683 | disease phenotypes: MIM:617412

GenCC curated gene-disease

Disease	Classification	Inheritance
brachycephaly, trichomegaly, and developmental delay	Strong	Autosomal dominant

Mondo (1): brachycephaly, trichomegaly, and developmental delay (MONDO:0044311)

Orphanet (0):

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000176	Submucous cleft hard palate
HP:0000179	Thick lower lip vermilion
HP:0000193	Bifid uvula
HP:0000194	Open mouth
HP:0000218	High palate
HP:0000233	Thin vermilion border
HP:0000252	Microcephaly
HP:0000286	Epicanthus
HP:0000369	Low-set ears
HP:0000396	Overfolded helix
HP:0000405	Conductive hearing impairment
HP:0000527	Long eyelashes
HP:0000574	Thick eyebrow
HP:0000592	Blue sclerae
HP:0000629	Periorbital fullness
HP:0000664	Synophrys
HP:0000729	Autistic behavior
HP:0000954	Single transverse palmar crease
HP:0001212	Prominent fingertip pads
HP:0001270	Motor delay
HP:0001290	Generalized hypotonia
HP:0001328	Specific learning disability
HP:0002299	Brittle hair
HP:0002553	Highly arched eyebrow
HP:0004322	Short stature
HP:0005280	Depressed nasal bridge
HP:0005469	Flat occiput
HP:0011069	Supernumerary tooth

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009921_1	Carotid intima media thickness (mean)	3.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3987582 (PROTEIN NUCLEIC-ACID COMPLEX), CHEMBL6067555 (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
9.21	Kd	0.624	nM	CHEMBL5653589
9.21	ED50	0.624	nM	CHEMBL5653589
8.06	Kd	8.732	nM	CHEMBL3752910
8.06	ED50	8.732	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
5.69	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-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149296: Binding affinity to human RPS23 incubated for 45 mins by Kinobead based pull down assay	kd	0.0006	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149296: Binding affinity to human RPS23 incubated for 45 mins by Kinobead based pull down assay	kd	0.0087	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
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

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression, affects expression	4
bisphenol A	decreases expression	3
sodium arsenite	decreases expression, increases activity	3
Particulate Matter	decreases expression, increases expression	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	2
TAK-243	increases sumoylation	1
methylmercuric chloride	decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
methylparaben	decreases expression	1
perfluorodecanoic acid	decreases expression	1
chloropicrin	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Dactinomycin	affects cotreatment, increases secretion	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Furaldehyde	decreases expression, affects cotreatment, affects localization	1
Isoniazid	decreases expression	1
Ivermectin	decreases expression	1
Lipopolysaccharides	affects expression, affects response to substance	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.