RTCB

Summary

RTCB (RNA 2’,3’-cyclic phosphate and 5’-OH ligase, HGNC:26935) is a protein-coding gene on chromosome 22q12.3, encoding RNA-splicing ligase RTCB (Q9Y3I0). 3’-5’ RNA ligase, catalytic subunit of the tRNA-splicing ligase complex (tRNA-LC), which is involved in the enzyme-dependent maturation of intron-containing pre-tRNAs. It is a selective cancer dependency (DepMap: 81.5% of cell lines).

Enables RNA ligase (GTP) activity and vinculin binding activity. Involved in tRNA splicing, via endonucleolytic cleavage and ligation. Located in cytosol and nucleoplasm. Part of tRNA-splicing ligase complex.

Source: NCBI Gene 51493 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 81 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 81.5% of screened cell lines
• MANE Select transcript: NM_014306

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26935
Approved symbol	RTCB
Name	RNA 2’,3’-cyclic phosphate and 5’-OH ligase
Location	22q12.3
Locus type	gene with protein product
Status	Approved
Aliases	HSPC117, FAAP
Ensembl gene	ENSG00000100220
Ensembl biotype	protein_coding
OMIM	613901
Entrez	51493

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000216038, ENST00000463455, ENST00000476619, ENST00000485373, ENST00000487704, ENST00000498434, ENST00000880534, ENST00000923679, ENST00000923680, ENST00000923681, ENST00000953018, ENST00000953019, ENST00000953020

RefSeq mRNA: 1 — MANE Select: NM_014306 NM_014306

CCDS: CCDS13905

Canonical transcript exons

ENST00000216038 — 12 exons

Exon	Start	End
ENSE00000879969	32387582	32388099
ENSE00001619596	32393892	32394002
ENSE00001639606	32397941	32398100
ENSE00001685272	32396074	32396249
ENSE00001781836	32395026	32395214
ENSE00001830068	32412064	32412247
ENSE00003464824	32406662	32406761
ENSE00003467851	32408755	32408833
ENSE00003552804	32408175	32408242
ENSE00003610841	32401747	32401903
ENSE00003634221	32399603	32399759
ENSE00003636338	32392240	32392359

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 97.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 63.3540 / max 1085.8300, expressed in 1822 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193747	63.3540	1822

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	97.48	gold quality
islet of Langerhans	UBERON:0000006	97.43	gold quality
ileal mucosa	UBERON:0000331	97.23	gold quality
duodenum	UBERON:0002114	97.17	gold quality
rectum	UBERON:0001052	97.08	gold quality
skin of leg	UBERON:0001511	96.80	gold quality
skin of abdomen	UBERON:0001416	96.63	gold quality
type B pancreatic cell	CL:0000169	96.38	gold quality
upper arm skin	UBERON:0004263	96.37	gold quality
zone of skin	UBERON:0000014	96.29	gold quality
smooth muscle tissue	UBERON:0001135	96.20	gold quality
mucosa of transverse colon	UBERON:0004991	95.80	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.77	gold quality
small intestine	UBERON:0002108	95.70	gold quality
stromal cell of endometrium	CL:0002255	95.59	gold quality
transverse colon	UBERON:0001157	95.55	gold quality
pancreas	UBERON:0001264	95.18	gold quality
intestine	UBERON:0000160	95.02	gold quality
parotid gland	UBERON:0001831	95.00	gold quality
calcaneal tendon	UBERON:0003701	94.99	gold quality
body of stomach	UBERON:0001161	94.87	gold quality
upper leg skin	UBERON:0004262	94.85	gold quality
large intestine	UBERON:0000059	94.81	gold quality
colon	UBERON:0001155	94.77	gold quality
minor salivary gland	UBERON:0001830	94.72	gold quality
body of pancreas	UBERON:0001150	94.70	gold quality
gastrocnemius	UBERON:0001388	94.68	gold quality
adult mammalian kidney	UBERON:0000082	94.67	gold quality
adult organism	UBERON:0007023	94.67	gold quality
muscle of leg	UBERON:0001383	94.61	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6379	no	1279.69
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): YY1

miRNA regulators (miRDB)

28 targeting RTCB, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-34B-5P	99.78	67.56	1175
HSA-MIR-449C-5P	99.78	67.63	1168
HSA-MIR-2682-5P	99.73	67.38	1055
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-548AU-3P	99.70	68.22	1373
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-891B	99.59	69.81	1083
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-8064	99.45	66.92	875
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-455-3P	98.94	67.68	878
HSA-MIR-7114-5P	98.51	67.87	1349
HSA-MIR-6781-3P	97.44	66.85	970
HSA-MIR-4436B-5P	96.71	68.37	1346
HSA-MIR-627-5P	95.51	66.80	509
HSA-MIR-3615	95.04	65.37	109

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 81.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 8)

• study identified HSPC117, a member of the UPF0027 (RtcB) family, as the essential subunit of a tRNA ligase complex; RNA interference-mediated depletion of HSPC117 inhibited maturation of intron-containing pre-tRNA both in vitro and in living cells (PMID:21311021)
• hCLE/C14orf166 associates with DDX1, HSPC117, and FAM98B in a novel transcription-dependent shuttling RNA-transporting complex. (PMID:24608264)
• Over-expression of HSPC117 mRNA reduced MMP 2 and MMP 14 mRNA expression, while TIMP 2 mRNA expression was up-regulated. (PMID:24941254)
• RTCB, the catalytic subunit of the tRNA ligase complex, and its co-factor archease mediate XBP1 mRNA splicing both in vitro and in vivo. (PMID:25378478)
• This paper presents a homology model of human RtcB (hRtcB). The structure was analyzed in terms of stereochemical quality, folding reliability, secondary structure, druggability of the active site binding pocket and its metal-binding microenvironment. (PMID:28707320)
• Molecular architecture of the human tRNA ligase complex. (PMID:34854379)
• The RNA-Splicing Ligase RTCB Promotes Influenza A Virus Replication by Suppressing Innate Immunity via Interaction with RNA Helicase DDX1. (PMID:37556111)
• Structural and mechanistic insights into activation of the human RNA ligase RTCB by Archease. (PMID:38493148)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rtcb	ENSDARG00000101047
mus_musculus	Rtcb	ENSMUSG00000001783
rattus_norvegicus	Rtcb	ENSRNOG00000004813
drosophila_melanogaster	RtcB	FBGN0032781
caenorhabditis_elegans	rtcb-1	WBGENE00008877

Protein

Protein identifiers

RNA-splicing ligase RTCB — Q9Y3I0 (reviewed: Q9Y3I0)

Alternative names: 3’-phosphate/5’-hydroxy nucleic acid ligase, RNA 2’,3’-cyclic phosphate and 5’-OH ligase

All UniProt accessions (1): Q9Y3I0

UniProt curated annotations — full annotation on UniProt →

Function. 3’-5’ RNA ligase, catalytic subunit of the tRNA-splicing ligase complex (tRNA-LC), which is involved in the enzyme-dependent maturation of intron-containing pre-tRNAs. Functions downstream of the tRNA-splicing endonuclease that removes introns, ligating the two generated halves via phosphodiester bond formation. The ligation reaction, which requires guanosine triphosphate (GTP) and Mn(2+), proceeds through three metal-dependent steps. The first step requires ZBTB8OS/Archease and involves the guanylylation of RTCB at its active site histidine, forming a covalent GMP-histidine intermediate. Before the second step, RTCB also hydrolyzes the 2’,3’-cyclic phosphate (cP) at the 3’ end of the 5’ tRNA exon, typically generated by the tRNA-splicing endonuclease, producing a 3’ phosphate. The covalently bound GMP is then transferred to this 3’ phosphate to form an RNA(3’)-P-P-(5’)G intermediate. In the final step, the 5’-OH of the 3’ exon attacks the activated 3’ end of the 5’ exon, forming a 3’-5’ phosphodiester bond and releasing GMP. RTCB also functions in non-canonical, spliceosome-independent, cytoplasmic splicing of XBP1 mRNAs during the unfolded protein response (UPR). Upon endoplasmic reticulum (ER) stress, the endoribonuclease IRE1/ERN1 excises a short intron, generating free exon ends that are aligned by RNA-intrinsic, zipper-like stem-loop structures. These exon ends are then recognized and ligated by RTCB. This splicing event yields the active XBP1s transcription factor, which induces genes required to resolve protein folding defects in the endoplasmic reticulum.

Subunit / interactions. Catalytic component of the tRNA-splicing ligase core complex composed of RTCB and the accessory proteins DDX1, C2orf49/Ashwin, FAM98B and RTRAF/CGI-99. Interacts with PYROXD1; the interaction is direct and shields Cys-122 preventing oxidative inactivation of the catalytic center. The interaction could also regulate RTCB activation and depends on divalent cations. Interacts with ZBTB8OS/Archease; active site guanylylation reaction relies on the activation factor ZBTB8OS/Archease.

Subcellular location. Nucleus. Cytoplasm.

Activity regulation. ZBTB8OS/Archease stimulates the activity of the tRNA ligase complex by participating to RTCB active site guanylylation reaction. While Mg(2+), Ca(2+) and to a lesser extent Co(2+) show low levels of covalent incorporation of GMP the strongest guanylylation occurs in presence of Mn(2+) ions.

Cofactor. Binds 2 Mn(2+) per subunit. Three Mn(2+) ions are bound in the composite active site formed by RTCB and Archease. Two are exclusively coordinated by RTCB residues and the third one is solely coordinated by ZBTB8OS/Archease residues.

Similarity. Belongs to the RtcB family.

RefSeq proteins (1): NP_055121* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001233	RtcB	Family
IPR027513	RtcB_euk	Family
IPR036025	RtcB-like_sf	Homologous_superfamily

Pfam: PF01139

Enzyme classification (BRENDA):

• EC 6.5.1.8 — 3’-phosphate/5’-hydroxy nucleic acid ligase (BRENDA: 16 organisms, 45 substrates, 2 inhibitors, 0 Km, 5 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
(RIBONUCLEOTIDE)10-3’-PHOSPHATE	—	0
(RIBONUCLEOTIDE)20-3’-PHOSPHATE	—	0

Catalyzed reactions (Rhea), 6 shown:

• a 3’-end 2’,3’-cyclophospho-ribonucleotide-RNA + H2O = a 3’-end 3’-phospho-ribonucleotide-RNA + H(+) (RHEA:68056)
• a 3’-end 3’-phospho-ribonucleotide-RNA + a 5’-end dephospho-ribonucleoside-RNA + GTP = a ribonucleotidyl-ribonucleotide-RNA + GMP + diphosphate (RHEA:68076)
• a 3’-end 2’,3’-cyclophospho-ribonucleotide-RNA + a 5’-end dephospho-ribonucleoside-RNA + GTP + H2O = a ribonucleotidyl-ribonucleotide-RNA + GMP + diphosphate + H(+) (RHEA:68080)
• L-histidyl-[RNA ligase] + GTP = N(pros)-(5’-guanosyl-phosphono)-L-histidyl-[RNA ligase] + diphosphate (RHEA:68084)
• N(pros)-(5’-guanosyl-phosphono)-L-histidyl-[RNA ligase] + a 3’-end 3’-phospho-ribonucleotide-RNA + H(+) = a 3’-terminal ribonucleotide 3’-(5’-diphosphoguanosine)-RNA + L-histidyl-[RNA ligase] (RHEA:68088)
• a 3’-terminal ribonucleotide 3’-(5’-diphosphoguanosine)-RNA + a 5’-end dephospho-ribonucleoside-RNA = a ribonucleotidyl-ribonucleotide-RNA + GMP + H(+) (RHEA:68092)

UniProt features (90 total): binding site 27, helix 24, strand 23, mutagenesis site 5, sequence conflict 3, sequence variant 2, turn 2, chain 1, active site 1, modified residue 1, cross-link 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8ODO	X-RAY DIFFRACTION	2.2
7P3B	X-RAY DIFFRACTION	2.3
8ODP	X-RAY DIFFRACTION	2.3
8BTT	X-RAY DIFFRACTION	2.6
8ORJ	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y3I0-F1	95.66	0.89

Functional residue map

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

Catalytic / active sites (1): 428 (gmp-histidine intermediate)

Ligand- & substrate-binding residues (27): 230; 230; 259; 353; 354; 354; 375; 402; 402; 403; 92; 403 …

Post-translational modifications (2): 300, 496

Mutagenesis-validated functional residues (5):

Position	Phenotype
119	loss of rna ligase (gtp) activity.
122	loss of rna ligase (gtp) activity.
227	loss of rna ligase (gtp) activity.
259	loss of rna ligase (gtp) activity.
353	loss of rna ligase (gtp) activity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6784531	tRNA processing in the nucleus
R-HSA-72306	tRNA processing
R-HSA-8953854	Metabolism of RNA

MSigDB gene sets: 193 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_IRE1_MEDIATED_UNFOLDED_PROTEIN_RESPONSE, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_TRNA_METABOLIC_PROCESS, MORF_HDAC2, RIZKI_TUMOR_INVASIVENESS_3D_DN, GOBP_CELLULAR_RESPONSE_TO_TOPOLOGICALLY_INCORRECT_PROTEIN, MORF_RAF1, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, GOBP_RNA_SPLICING_VIA_ENDONUCLEOLYTIC_CLEAVAGE_AND_LIGATION, GOBP_RNA_SPLICING, SCHLOSSER_SERUM_RESPONSE_DN, GOBP_EMBRYO_DEVELOPMENT, MORF_AATF, HU_GENOTOXIN_ACTION_DIRECT_VS_INDIRECT_24HR

GO Biological Process (9): RNA splicing, via endonucleolytic cleavage and ligation (GO:0000394), tRNA exon ligation (GO:0000968), in utero embryonic development (GO:0001701), placenta development (GO:0001890), tRNA splicing, via endonucleolytic cleavage and ligation (GO:0006388), IRE1-mediated unfolded protein response (GO:0036498), mRNA splicing, via endonucleolytic cleavage and ligation (GO:0070054), RNA processing (GO:0006396), tRNA processing (GO:0008033)

GO Molecular Function (10): RNA binding (GO:0003723), GTP binding (GO:0005525), vinculin binding (GO:0017166), metal ion binding (GO:0046872), RNA ligase (GTP) activity (GO:0170057), nucleotide binding (GO:0000166), protein binding (GO:0005515), RNA ligase activity (GO:0008452), ligase activity (GO:0016874), ligase activity, forming phosphoric ester bonds (GO:0016886)

GO Cellular Component (8): nucleus (GO:0005634), nuclear envelope (GO:0005635), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), tRNA-splicing ligase complex (GO:0072669), catalytic complex (GO:1902494)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
tRNA processing	1
Metabolism of RNA	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
RNA splicing, via endonucleolytic cleavage and ligation	2
RNA splicing	1
RNA exon ligation	1
tRNA splicing, via endonucleolytic cleavage and ligation	1
chordate embryonic development	1
animal organ development	1
tRNA processing	1
endoplasmic reticulum unfolded protein response	1
mRNA processing	1
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
RNA processing	1
tRNA metabolic process	1
nucleic acid binding	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cytoskeletal protein binding	1
cation binding	1
RNA ligase activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
ligase activity, forming phosphoric ester bonds	1
catalytic activity, acting on RNA	1
catalytic activity	1
ligase activity	1
intracellular membrane-bounded organelle	1
nucleus	1
endomembrane system	1
organelle envelope	1
nuclear lumen	1
intracellular anatomical structure	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cytoplasm	1
intracellular protein-containing complex	1
catalytic complex	1

Protein interactions and networks

STRING

1976 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RTCB	DDX1	Q92499	987
RTCB	FAM98B	Q52LJ0	950
RTCB	RTRAF	Q9Y224	943
RTCB	ZBTB8OS	Q8IWT0	874
RTCB	RTCA	O00442	851
RTCB	C2orf49	Q9BVC5	743
RTCB	FAM98A	Q8NCA5	729
RTCB	XBP1	P17861	716
RTCB	TRPT1	Q86TN4	604
RTCB	TSEN34	Q9BSV6	587
RTCB	VCL	P18206	579
RTCB	DDX3X	O00571	568
RTCB	ERN1	O75460	556
RTCB	PXN	P49023	543
RTCB	CLP1	Q92989	543

IntAct

199 interactions, top by confidence:

A	B	Type	Score
NS	PIK3R2	psi-mi:“MI:0914”(association)	0.750
RTRAF	RTCB	psi-mi:“MI:0915”(physical association)	0.750
RTCB	RTRAF	psi-mi:“MI:0915”(physical association)	0.750
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
DDX1	FAM98B	psi-mi:“MI:0915”(physical association)	0.670
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
	DDX3X	psi-mi:“MI:0914”(association)	0.630
APPL1	RTCB	psi-mi:“MI:0915”(physical association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
LIN28A	EIF3D	psi-mi:“MI:0914”(association)	0.550
N	RBM47	psi-mi:“MI:0914”(association)	0.530
DDX1	FAM98C	psi-mi:“MI:0914”(association)	0.530
DDX6	MCRIP1	psi-mi:“MI:0914”(association)	0.510
ZBTB8OS	RTCB	psi-mi:“MI:0915”(physical association)	0.500
RTCB	CRK	psi-mi:“MI:0915”(physical association)	0.490
FUS	DDX3X	psi-mi:“MI:0914”(association)	0.430
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
YWHAZ	RTCB	psi-mi:“MI:0915”(physical association)	0.400
Rpl35	RPS6	psi-mi:“MI:0914”(association)	0.350
Eif3a	RPSA	psi-mi:“MI:0914”(association)	0.350
RPL10	RPS6	psi-mi:“MI:0914”(association)	0.350
Gspt1	MRPL27	psi-mi:“MI:0914”(association)	0.350
Rrbp1	PIPSL	psi-mi:“MI:0914”(association)	0.350

BioGRID (475): RTCB (Affinity Capture-MS), RTCB (Affinity Capture-MS), RTCB (Affinity Capture-MS), RTCB (Affinity Capture-MS), RTCB (Affinity Capture-MS), RTCB (Reconstituted Complex), RTCB (Affinity Capture-MS), RTCB (Affinity Capture-MS), RTCB (Affinity Capture-MS), RTCB (Affinity Capture-RNA), C14orf166 (Co-fractionation), CCDC22 (Co-fractionation), DPH2 (Co-fractionation), FAM98B (Co-fractionation), HNRNPH1 (Co-fractionation)

ESM2 similar proteins: A0B8K5, A0B8Q8, A0RYM0, A2ST90, A2SU54, A3CXE7, A4G0G9, A6URH2, A6VI14, A7RKF6, A9A8R5, A9CB42, A9UXG6, B0WCT9, B2UKT4, C3YN79, O27579, O27634, O28552, O29399, O84834, P90838, Q0W5U6, Q12TF2, Q17FP1, Q19PY3, Q1IJG7, Q2FQD6, Q2FSF9, Q2NHG2, Q46CS0, Q46E19, Q4R6X4, Q561P3, Q59024, Q5E9T9, Q5JET0, Q5PAH7, Q6L1K9, Q6M191

Diamond homologs: A4S3S3, A7RKF6, A8JC00, A8QC60, A9CB42, A9UXG6, B0EAV2, B0EIW5, B0WCT9, B0XKF3, B3L4K9, B3RID0, B8LBM8, C1E9Y5, C1MI97, C3YN79, C4M244, C4M6T2, O27634, O29399, O59245, P59975, P90838, P9WGW4, P9WGW5, Q00ZY2, Q17FP1, Q19PY3, Q4N1R8, Q4R6X4, Q4U923, Q4YUZ9, Q54Y09, Q561P3, Q58095, Q5E9T9, Q5JCZ1, Q6AYT3, Q6LXF9, Q6NZS4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 183 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
Signaling by high-kinase activity BRAF mutants	5	13.8×	1e-03
MAP2K and MAPK activation	5	12.4×	2e-03
SARS-CoV-1-host interactions	8	12.2×	1e-04
Signaling by RAF1 mutants	5	12.1×	2e-03
SARS-CoV-1 Infection	9	11.2×	7e-05
Signaling by moderate kinase activity BRAF mutants	5	11.0×	3e-03
Paradoxical activation of RAF signaling by kinase inactive BRAF	5	11.0×	3e-03
Signaling downstream of RAS mutants	5	11.0×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
autophagosome maturation	7	16.3×	7e-05
mRNA stabilization	5	12.1×	9e-03
translational initiation	5	11.9×	9e-03
intrinsic apoptotic signaling pathway	5	11.9×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	55
Likely benign	4
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

1511 predictions. Top by Δscore:

Variant	Effect	Δscore
22:32392235:CTTA:C	donor_loss	1.0000
22:32392236:TTACC:T	donor_loss	1.0000
22:32392237:TACC:T	donor_loss	1.0000
22:32392238:A:AC	donor_gain	1.0000
22:32392238:A:AT	donor_loss	1.0000
22:32392238:AC:A	donor_gain	1.0000
22:32392238:ACCT:A	donor_gain	1.0000
22:32392239:C:CG	donor_gain	1.0000
22:32392239:CC:C	donor_gain	1.0000
22:32392239:CCT:C	donor_gain	1.0000
22:32392239:CCTC:C	donor_gain	1.0000
22:32392239:CCTCT:C	donor_gain	1.0000
22:32392355:CGGCC:C	acceptor_gain	1.0000
22:32392358:CC:C	acceptor_gain	1.0000
22:32392359:CC:C	acceptor_gain	1.0000
22:32392360:C:CC	acceptor_gain	1.0000
22:32392361:T:A	acceptor_loss	1.0000
22:32392365:A:AC	acceptor_gain	1.0000
22:32393891:CCG:C	donor_gain	1.0000
22:32395024:A:AC	donor_gain	1.0000
22:32395025:C:CC	donor_gain	1.0000
22:32395082:T:TA	donor_gain	1.0000
22:32395094:A:AC	donor_gain	1.0000
22:32395095:C:CC	donor_gain	1.0000
22:32395105:T:A	donor_gain	1.0000
22:32395213:GCC:G	acceptor_loss	1.0000
22:32395215:C:CC	acceptor_gain	1.0000
22:32395215:C:CG	acceptor_loss	1.0000
22:32395216:T:G	acceptor_loss	1.0000
22:32396069:TGTAC:T	donor_loss	1.0000

AlphaMissense

3337 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:32387996:C:T	G505E	1.000
22:32387997:C:G	G505R	1.000
22:32387997:C:T	G505R	1.000
22:32387998:T:A	K504N	1.000
22:32387998:T:G	K504N	1.000
22:32387999:T:A	K504I	1.000
22:32388000:T:C	K504E	1.000
22:32388082:C:A	K476N	1.000
22:32388082:C:G	K476N	1.000
22:32388084:T:C	K476E	1.000
22:32388087:A:G	Y475H	1.000
22:32388099:C:G	A471P	1.000
22:32392240:C:A	E470D	1.000
22:32392240:C:G	E470D	1.000
22:32392241:T:A	E470V	1.000
22:32392242:C:G	E470Q	1.000
22:32392242:C:T	E470K	1.000
22:32392244:T:A	E469V	1.000
22:32392245:C:T	E469K	1.000
22:32392253:A:G	L466P	1.000
22:32392344:G:C	R436G	1.000
22:32392355:C:G	R432P	1.000
22:32392355:C:T	R432H	1.000
22:32392356:G:A	R432C	1.000
22:32392356:G:T	R432S	1.000
22:32392358:C:A	G431V	1.000
22:32392358:C:T	G431D	1.000
22:32392359:C:A	G431C	1.000
22:32392359:C:G	G431R	1.000
22:32392359:C:T	G431S	1.000

dbSNP variants (sampled 300 via entrez): RS1000096523 (22:32413266 A>G), RS1000393652 (22:32411813 GTATT>G), RS1000395900 (22:32405839 G>C), RS1000548359 (22:32391020 T>G), RS1000588958 (22:32409222 T>C), RS1000685925 (22:32403338 C>T), RS1000743635 (22:32411475 A>C), RS1000880271 (22:32387156 C>A,G), RS1000985852 (22:32391276 GAC>G), RS1001043198 (22:32409449 T>C), RS1001263626 (22:32395837 T>C,G), RS1001408946 (22:32402205 A>AT), RS1001520776 (22:32411859 G>A), RS1001531076 (22:32403162 T>C), RS1001580261 (22:32411981 G>A,T)

Disease associations

OMIM: gene MIM:613901 | 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
GCST005756_10	Dimensional psychopathology (Negative)	7.000000e-07
GCST005758_7	Dimensional psychopathology (Arousal)	2.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009096	negative domain measurement
EFO:0009099	arousal domain measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067243 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.42	Kd	38.31	nM	CHEMBL5653589
7.42	ED50	38.31	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 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	2149326: Binding affinity to human RTCB incubated for 45 mins by Kinobead based pull down assay	kd	0.0383	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol F	increases expression, affects cotreatment, decreases expression	2
sodium arsenite	affects binding, increases reaction, increases expression	2
FR900359	increases phosphorylation	1
bisphenol A	decreases expression	1
sodium arsenate	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
methylparaben	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	increases secretion, affects cotreatment	1
bisphenol B	increases expression	1
abrine	increases expression	1
bisphenol S	increases expression	1
LDN 193189	increases expression, affects cotreatment	1
bisphenol AF	increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases methylation	1
Cadmium	increases abundance, increases expression	1
Clozapine	increases expression	1
Dactinomycin	increases secretion, affects cotreatment	1
Dexamethasone	affects cotreatment, decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Furaldehyde	affects cotreatment, affects localization, increases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Lead	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652368	Binding	Binding affinity to human RTCB incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D9R2	Ubigene HEK293 RTCB KO	Transformed cell line	Female

Clinical trials (associated diseases)

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