CTR9

Summary

CTR9 (CTR9 component of Paf1/RNA polymerase II complex, HGNC:16850) is a protein-coding gene on chromosome 11p15.4, encoding RNA polymerase-associated protein CTR9 homolog (Q6PD62). Component of the PAF1 complex (PAF1C) which has multiple functions during transcription by RNA polymerase II and is implicated in regulation of development and maintenance of embryonic stem cell pluripotency. It is a common-essential gene (DepMap: required in 92.6% of cancer cell lines).

The protein encoded by this gene is a component of the PAF1 complex, which associates with RNA polymerase II and functions in transcriptional regulation and elongation. This complex also plays a role in the modification of histones.

Source: NCBI Gene 9646 — RefSeq curated summary.

At a glance

• Gene–disease (curated): CTR9-related neurodevelopmental disorder (Moderate, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 779 total — 1 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 27
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 92.6% of screened cell lines (common-essential)
• MANE Select transcript: NM_014633

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16850
Approved symbol	CTR9
Name	CTR9 component of Paf1/RNA polymerase II complex
Location	11p15.4
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0155, TSBP, p150TSP
Ensembl gene	ENSG00000198730
Ensembl biotype	protein_coding
OMIM	609366
Entrez	9646

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 3 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000361367, ENST00000524523, ENST00000526874, ENST00000529355, ENST00000529898, ENST00000532365, ENST00000715696

RefSeq mRNA: 2 — MANE Select: NM_014633 NM_001346279, NM_014633

CCDS: CCDS7805

Canonical transcript exons

ENST00000361367 — 25 exons

Exon	Start	End
ENSE00000702613	10752672	10752770
ENSE00000702616	10754958	10755197
ENSE00000702618	10755678	10755795
ENSE00000702620	10756749	10756838
ENSE00000702622	10760173	10760321
ENSE00000702623	10761947	10762054
ENSE00000702624	10763431	10763538
ENSE00000702625	10763643	10763879
ENSE00000702628	10764112	10764201
ENSE00000702630	10764308	10764436
ENSE00000702632	10764548	10764731
ENSE00000702633	10766402	10766490
ENSE00000702639	10768343	10768491
ENSE00000702642	10770210	10770326
ENSE00000702644	10770487	10770632
ENSE00000702646	10771545	10771616
ENSE00000702649	10772520	10772655
ENSE00000702652	10774012	10774169
ENSE00000702653	10775207	10775303
ENSE00000702656	10775521	10775633
ENSE00003651921	10767806	10767991
ENSE00003653935	10773127	10773273
ENSE00003687098	10768074	10768161
ENSE00004027619	10751246	10751457
ENSE00004027620	10778679	10779746

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 96.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 35.1333 / max 291.2185, expressed in 1818 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
113070	24.7011	1811
113071	7.4430	1682
113068	2.3491	1111
113072	0.3881	203
113069	0.2522	106

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	96.64	gold quality
epithelium of nasopharynx	UBERON:0001951	96.27	gold quality
palpebral conjunctiva	UBERON:0001812	93.04	gold quality
bronchial epithelial cell	CL:0002328	92.82	gold quality
germinal epithelium of ovary	UBERON:0001304	92.70	gold quality
pigmented layer of retina	UBERON:0001782	92.68	gold quality
caput epididymis	UBERON:0004358	92.60	gold quality
oral cavity	UBERON:0000167	92.40	gold quality
jejunal mucosa	UBERON:0000399	92.37	gold quality
cauda epididymis	UBERON:0004360	92.35	gold quality
parietal pleura	UBERON:0002400	92.32	gold quality
islet of Langerhans	UBERON:0000006	92.30	gold quality
choroid plexus epithelium	UBERON:0003911	92.13	gold quality
endometrium	UBERON:0001295	92.09	gold quality
upper leg skin	UBERON:0004262	92.01	gold quality
ventricular zone	UBERON:0003053	92.00	gold quality
seminal vesicle	UBERON:0000998	91.73	gold quality
pleura	UBERON:0000977	91.48	gold quality
esophagus squamous epithelium	UBERON:0006920	91.44	gold quality
biceps brachii	UBERON:0001507	91.36	gold quality
epithelium of bronchus	UBERON:0002031	91.21	gold quality
sural nerve	UBERON:0015488	91.21	gold quality
bronchus	UBERON:0002185	91.11	gold quality
squamous epithelium	UBERON:0006914	91.06	gold quality
jejunum	UBERON:0002115	91.04	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	91.01	gold quality
gingiva	UBERON:0001828	91.00	gold quality
ganglionic eminence	UBERON:0004023	90.99	gold quality
lower lobe of lung	UBERON:0008949	90.91	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.89	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI2

miRNA regulators (miRDB)

68 targeting CTR9, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-12129	99.72	67.45	1311

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 92.6% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 16)

• CTR9 participates in the transcription of IL-6-responsive genes through the regulation of DNA association of STAT3 and modification of histone methylation (PMID:17911113)
• MLL interacts directly with the polymerase associated factor complex (PAFc) via Paf1 and CTR9. PAFc augments MLL and MLL-AF9 mediated transcriptional activation of Hoxa9 and their interaction is essential for leukemogenesis. (PMID:20541477)
• CTR9, a component of PAF complex, controls elongation block at the c-Fos locus via signal-dependent regulation of chromatin-bound NELF dissociation. (PMID:23593388)
• CTR9 is a PAF1 complex gene whose germline mutations predispose to Wilms tumour (PMID:25099282)
• Ctr9, formerly identified as a nuclei protein, interacts with the dopamine transporter in the cytoplasmic compartment. (PMID:26048990)
• Ctr9, a key subunit of hPAFc, is a central regulator of estrogen signaling that drives ERalpha(+) breast tumorigenesis (PMID:26494790)
• Our data demonstrated that Ctr9, independent of other PAFc subunits, controls ERalpha-target gene expression by regulating global chromatin occupancies of ERalpha and RNAPII. (PMID:27829357)
• A novel CTR9 germline variant, located in a consensus splice acceptor site, was found to segregate with Wilms tumor in the family. (PMID:29292210)
• Study reports 2.53 A atomic structures of both the human PAF1/CTR9 and yeast Paf1/Ctr9 heterodimers. Results clearly reveal that the heterodimer of PAF1/CTR9 or Paf1/Ctr9 is the core component of evolutionarily conserved multifunctional polymerase-associated factor 1 complex (Paf1C) and is important for human PAF1C or yeast Paf1C assembly, yeast viability, and Paf1C-mediated histone modifications. (PMID:30228257)
• CTR9-mediated JAK2/STAT3 pathway promotes the proliferation, migration, and invasion of human glioma cells. (PMID:34369006)
• Transcriptional regulator CTR9 promotes hepatocellular carcinoma progression and metastasis via increasing PEG10 transcriptional activity. (PMID:34876700)
• MicroRNA-17-3p is upregulated in psoriasis and regulates keratinocyte hyperproliferation and pro-inflammatory cytokine secretion by targeting CTR9. (PMID:35016493)
• The transcriptional elongation factor CTR9 demarcates PRC2-mediated H3K27me3 domains by altering PRC2 subtype equilibrium. (PMID:35137163)
• Heterozygous variants in CTR9, which encodes a major component of the PAF1 complex, are associated with a neurodevelopmental disorder. (PMID:35499524)
• CTR9 drives osteochondral lineage differentiation of human mesenchymal stem cells via epigenetic regulation of BMP-2 signaling. (PMID:36383652)
• Inherited blood cancer predisposition through altered transcription elongation. (PMID:38218188)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ctr9	ENSDARG00000009170
mus_musculus	Ctr9	ENSMUSG00000005609
rattus_norvegicus	Ctr9	ENSRNOG00000017195
drosophila_melanogaster	Ctr9	FBGN0035205
caenorhabditis_elegans		WBGENE00007184

Protein

Protein identifiers

RNA polymerase-associated protein CTR9 homolog — Q6PD62 (reviewed: Q6PD62)

Alternative names: SH2 domain-binding protein 1

All UniProt accessions (3): Q6PD62, A0A2R8Y3S3, H0YCE8

UniProt curated annotations — full annotation on UniProt →

Function. Component of the PAF1 complex (PAF1C) which has multiple functions during transcription by RNA polymerase II and is implicated in regulation of development and maintenance of embryonic stem cell pluripotency. PAF1C associates with RNA polymerase II through interaction with POLR2A CTD non-phosphorylated and ‘Ser-2’- and ‘Ser-5’-phosphorylated forms and is involved in transcriptional elongation, acting both independently and synergistically with TCEA1 and in cooperation with the DSIF complex and HTATSF1. PAF1C is required for transcription of Hox and Wnt target genes. PAF1C is involved in hematopoiesis and stimulates transcriptional activity of KMT2A/MLL1; it promotes leukemogenesis through association with KMT2A/MLL1-rearranged oncoproteins, such as KMT2A/MLL1-MLLT3/AF9 and KMT2A/MLL1-MLLT1/ENL. PAF1C is involved in histone modifications such as ubiquitination of histone H2B and methylation on histone H3 ‘Lys-4’ (H3K4me3). PAF1C recruits the RNF20/40 E3 ubiquitin-protein ligase complex and the E2 enzyme UBE2A or UBE2B to chromatin which mediate monoubiquitination of ‘Lys-120’ of histone H2B (H2BK120ub1); UB2A/B-mediated H2B ubiquitination is proposed to be coupled to transcription. PAF1C is involved in mRNA 3’ end formation probably through association with cleavage and poly(A) factors. In case of infection by influenza A strain H3N2, PAF1C associates with viral NS1 protein, thereby regulating gene transcription. Required for mono- and trimethylation on histone H3 ‘Lys-4’ (H3K4me3) and dimethylation on histone H3 ‘Lys-79’ (H3K4me3). Required for Hox gene transcription. Required for the trimethylation of histone H3 ‘Lys-4’ (H3K4me3) on genes involved in stem cell pluripotency; this function is synergistic with CXXC1 indicative for an involvement of the SET1 complex. Involved in transcriptional regulation of IL6-responsive genes and in JAK-STAT pathway; may regulate DNA-association of STAT3.

Subunit / interactions. Component of the PAF1 complex, which consists of CDC73, PAF1, LEO1, CTR9, RTF1 and SKIC8. The PAF1 complex interacts with PHF5A. Interacts with KMT2A/MLL1. Interacts with STAT3. Interacts with SETD5. Interacts with ERCC6. (Microbial infection) The PAF1 complex interacts with Zika virus French Polynesia 10087PF/2013 non-structural protein 5/NS5. The interaction with viral NS5 proteins may reduce the antiviral immune response by inhibiting the recruitment of the PAF1 complex to interferon-stimulated genes, thus preventing their transcription. (Microbial infection) The PAF1 complex interacts with Dengue virus DENV2 16681 non-structural protein 5/NS5. The PAF1 complex interacts with Dengue virus DENV4 Dominica/814669/1981 non-structural protein 5/NS5. The interaction with viral NS5 proteins may reduce the antiviral immune response by inhibiting the recruitment of the PAF1 complex to interferon-stimulated genes, thus preventing their transcription.

Subcellular location. Nucleus speckle.

Tissue specificity. Widely expressed.

RefSeq proteins (2): NP_001333208, NP_055448* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR019734	TPR_rpt	Repeat
IPR031101	Ctr9	Family
IPR056836	ARM_TT21_4th	Domain

Pfam: PF13181, PF13374, PF14559, PF25068

UniProt features (110 total): helix 45, repeat 16, modified residue 15, strand 13, turn 10, compositionally biased region 9, chain 1, region of interest 1

Structure

Experimental structures (PDB)

21 structures.

PDB	Method	Resolution (Å)
9HVQ	ELECTRON MICROSCOPY	2
9MLC	ELECTRON MICROSCOPY	2.4
5ZYQ	X-RAY DIFFRACTION	2.53
7OOP	ELECTRON MICROSCOPY	2.9
9EGX	ELECTRON MICROSCOPY	2.9
9EGY	ELECTRON MICROSCOPY	2.9
9EGZ	ELECTRON MICROSCOPY	2.9
7OPC	ELECTRON MICROSCOPY	3
7OPD	ELECTRON MICROSCOPY	3
7UNC	ELECTRON MICROSCOPY	3
7UND	ELECTRON MICROSCOPY	3
6GMH	ELECTRON MICROSCOPY	3.1
6TED	ELECTRON MICROSCOPY	3.1
9EH1	ELECTRON MICROSCOPY	3.1
9EH2	ELECTRON MICROSCOPY	3.1
8A3Y	ELECTRON MICROSCOPY	3.3
9EH0	ELECTRON MICROSCOPY	3.6
9RTT	ELECTRON MICROSCOPY	4.01
9S3G	ELECTRON MICROSCOPY	6.4
9S0U	ELECTRON MICROSCOPY	6.72
9RZE	ELECTRON MICROSCOPY	8.53

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6PD62-F1	76.62	0.43

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 (15): 925, 932, 941, 943, 970, 1020, 1021, 1039, 1041, 1043, 1081, 1085, 1087, 1097, 1102

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-112382	Formation of RNA Pol II elongation complex
R-HSA-674695	RNA Polymerase II Pre-transcription Events
R-HSA-75955	RNA Polymerase II Transcription Elongation
R-HSA-8866654	E3 ubiquitin ligases ubiquitinate target proteins
R-HSA-9920588	Dengue virus activates/modulates innate and adaptive immune responses
R-HSA-9943411	CHD1 and CHD2 subfamily

MSigDB gene sets: 288 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_RESPONSE_TO_PEPTIDE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_FORMATION_OF_PRIMARY_GERM_LAYER, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, CGGAARNGGCNG_UNKNOWN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_GROWTH, GOBP_BLASTOCYST_FORMATION, GOBP_CELL_SURFACE_RECEPTOR_SIGNALING_PATHWAY_VIA_JAK_STAT, ACTGCAG_MIR173P, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, SP1_Q2_01

GO Biological Process (18): negative regulation of transcription by RNA polymerase II (GO:0000122), endodermal cell fate commitment (GO:0001711), inner cell mass cell differentiation (GO:0001826), trophectodermal cell differentiation (GO:0001829), blastocyst growth (GO:0001832), blastocyst hatching (GO:0001835), transcription elongation by RNA polymerase II (GO:0006368), cell surface receptor signaling pathway via JAK-STAT (GO:0007259), Wnt signaling pathway (GO:0016055), stem cell population maintenance (GO:0019827), negative regulation of myeloid cell differentiation (GO:0045638), negative regulation of gene expression, epigenetic (GO:0045814), positive regulation of transcription by RNA polymerase II (GO:0045944), interleukin-6-mediated signaling pathway (GO:0070102), cellular response to lipopolysaccharide (GO:0071222), chromatin organization (GO:0006325), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357)

GO Molecular Function (3): RNA polymerase II complex binding (GO:0000993), SH2 domain binding (GO:0042169), protein binding (GO:0005515)

GO Cellular Component (5): euchromatin (GO:0000791), nucleoplasm (GO:0005654), Cdc73/Paf1 complex (GO:0016593), nuclear speck (GO:0016607), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
RNA Polymerase II Transcription	2
RNA Polymerase II Transcription Elongation	1
Protein ubiquitination	1
Dengue Virus-Host Interactions	1
CHD chromatin remodelers	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transcription by RNA polymerase II	4
regulation of transcription by RNA polymerase II	2
blastocyst formation	2
cell differentiation	2
blastocyst development	2
negative regulation of DNA-templated transcription	1
endodermal cell differentiation	1
cell fate commitment involved in formation of primary germ layer	1
developmental growth	1
hatching	1
DNA-templated transcription elongation	1
cell surface receptor signaling pathway via STAT	1
cell surface receptor signaling pathway	1
multicellular organismal process	1
maintenance of cell number	1
myeloid cell differentiation	1
negative regulation of cell differentiation	1
regulation of myeloid cell differentiation	1
negative regulation of gene expression	1
epigenetic regulation of gene expression	1
positive regulation of DNA-templated transcription	1
cytokine-mediated signaling pathway	1
cellular response to interleukin-6	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
cellular component organization	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
regulation of DNA-templated transcription	1
RNA polymerase core enzyme binding	1
protein domain specific binding	1
binding	1
chromatin	1
nuclear lumen	1
cellular anatomical structure	1
transcription elongation factor complex	1
RNA polymerase II, holoenzyme	1

Protein interactions and networks

STRING

3819 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CTR9	LEO1	Q8WVC0	999
CTR9	CDC73	Q6P1J9	999
CTR9	RTF1	Q92541	998
CTR9	SKIC8	Q9GZS3	997
CTR9	POLR2A	P24928	862
CTR9	SUPT5H	O00267	831
CTR9	SUPT6H	Q7KZ85	805
CTR9	PAF1	Q8N7H5	798
CTR9	RNF20	Q5VTR2	764
CTR9	DHX9	Q08211	749
CTR9	PHF6	Q8IWS0	731
CTR9	RNF40	O75150	722
CTR9	DDX5	P17844	698
CTR9	JAG2	Q9Y219	686
CTR9	SUPT16H	Q9Y5B9	666

IntAct

190 interactions, top by confidence:

A	B	Type	Score
CCNT1	CDK9	psi-mi:“MI:0914”(association)	0.980
PAF1	CDC73	psi-mi:“MI:0914”(association)	0.960
CDC73	CTR9	psi-mi:“MI:0914”(association)	0.940
CTR9	CDC73	psi-mi:“MI:0914”(association)	0.940
CDC73	CTR9	psi-mi:“MI:0915”(physical association)	0.940

BioGRID (358): CTR9 (Affinity Capture-RNA), CTR9 (Affinity Capture-MS), CTR9 (Affinity Capture-MS), CTR9 (Affinity Capture-Western), CTR9 (Affinity Capture-Western), CTR9 (Reconstituted Complex), CTR9 (Affinity Capture-MS), CTR9 (Affinity Capture-MS), CTR9 (Two-hybrid), CDC73 (Co-fractionation), CHD1 (Co-fractionation), CHD2 (Co-fractionation), CTR9 (Co-fractionation), CTR9 (Co-fractionation), CTR9 (Co-fractionation)

ESM2 similar proteins: A1A4R8, B0BNG0, B3DNN5, E7F590, F8VPK0, O89079, P45432, P49754, P62944, P63009, P63010, Q12996, Q15006, Q28G25, Q2KJ25, Q4QR29, Q5E993, Q5F3K0, Q5KU39, Q5M7J9, Q5R4J9, Q5R882, Q5RBI3, Q5RDW9, Q60445, Q62018, Q6DEU9, Q6DFB8, Q6INS3, Q6N069, Q6PD62, Q6PGP7, Q6TGY8, Q80UM3, Q8AVU9, Q8BGZ4, Q8TAM2, Q8VD72, Q8VY89, Q8VZM1

Diamond homologs: B5X0I6, Q4QR29, Q62018, Q6DEU9, Q6PD62, Q03560

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CTR9	“form complex”	PAF1C	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 173 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
HIV elongation arrest and recovery	13	37.2×	8e-16
Pausing and recovery of HIV elongation	13	37.2×	8e-16
Pausing and recovery of Tat-mediated HIV elongation	12	36.5×	1e-14
Tat-mediated HIV elongation arrest and recovery	12	36.5×	1e-14
FGFR2 mutant receptor activation	5	31.5×	4e-06
HIV Transcription Elongation	11	30.5×	1e-12
Formation of RNA Pol II elongation complex	19	30.4×	2e-21
RNA Polymerase II Transcription Elongation	19	30.4×	2e-21

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of transcription by RNA polymerase III	5	30.6×	8e-05
transcription elongation by RNA polymerase II	10	29.0×	6e-10
mRNA 3’-end processing	5	18.4×	8e-04
transcription initiation at RNA polymerase II promoter	6	14.7×	4e-04
positive regulation of transcription elongation by RNA polymerase II	7	13.8×	1e-04
stem cell population maintenance	5	13.8×	3e-03
mRNA transcription by RNA polymerase II	5	10.8×	8e-03
Wnt signaling pathway	11	7.2×	8e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	14
Uncertain significance	375
Likely benign	290
Benign	53

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
4531690	NM_014633.5(CTR9):c.46-1G>T	Pathogenic
1173018	NM_014633.5(CTR9):c.43G>A (p.Glu15Lys)	Likely pathogenic
1173019	NM_014633.5(CTR9):c.109G>C (p.Glu37Gln)	Likely pathogenic
1173021	NM_014633.5(CTR9):c.1405G>A (p.Glu469Lys)	Likely pathogenic
1173022	NM_014633.5(CTR9):c.254G>A (p.Cys85Tyr)	Likely pathogenic
1173023	NM_014633.5(CTR9):c.76G>C (p.Glu26Gln)	Likely pathogenic
1173024	NM_014633.5(CTR9):c.1364A>G (p.Asn455Ser)	Likely pathogenic
1173027	NM_014633.5(CTR9):c.2633G>A (p.Arg878Gln)	Likely pathogenic
1806792	NM_014633.4(CTR9):c.1286del	Likely pathogenic
2575015	NM_014633.5(CTR9):c.110A>G (p.Glu37Gly)	Likely pathogenic
2576938	NM_014633.5(CTR9):c.85G>C (p.Glu29Gln)	Likely pathogenic
3078716	NM_014633.5(CTR9):c.44A>G (p.Glu15Gly)	Likely pathogenic
3078720	NM_014633.5(CTR9):c.56T>A (p.Leu19His)	Likely pathogenic
4008093	NM_014633.5(CTR9):c.98T>C (p.Ile33Thr)	Likely pathogenic
4814031	NM_014633.5(CTR9):c.2801A>G (p.Lys934Arg)	Likely pathogenic

SpliceAI

3587 predictions. Top by Δscore:

Variant	Effect	Δscore
11:10751454:CGAGG:C	donor_loss	1.0000
11:10751455:GAG:G	donor_gain	1.0000
11:10751458:GT:G	donor_loss	1.0000
11:10752666:TTTTA:T	acceptor_loss	1.0000
11:10752667:TTTA:T	acceptor_loss	1.0000
11:10752668:TTA:T	acceptor_loss	1.0000
11:10752669:TA:T	acceptor_loss	1.0000
11:10752671:GGT:G	acceptor_gain	1.0000
11:10752671:GGTC:G	acceptor_gain	1.0000
11:10752767:GGCG:G	donor_gain	1.0000
11:10752768:GCG:G	donor_gain	1.0000
11:10752768:GCGG:G	donor_gain	1.0000
11:10752771:G:GG	donor_gain	1.0000
11:10752771:GTCA:G	donor_loss	1.0000
11:10752772:T:A	donor_loss	1.0000
11:10752774:A:AG	donor_gain	1.0000
11:10752775:G:GG	donor_gain	1.0000
11:10754949:A:AG	acceptor_gain	1.0000
11:10754950:C:G	acceptor_gain	1.0000
11:10754953:TATA:T	acceptor_loss	1.0000
11:10754954:A:AG	acceptor_gain	1.0000
11:10754955:T:G	acceptor_gain	1.0000
11:10754955:TAGC:T	acceptor_loss	1.0000
11:10754956:A:AC	acceptor_loss	1.0000
11:10754956:A:AG	acceptor_gain	1.0000
11:10754956:AGCT:A	acceptor_gain	1.0000
11:10754956:AGCTG:A	acceptor_gain	1.0000
11:10754957:G:A	acceptor_loss	1.0000
11:10754957:G:GG	acceptor_gain	1.0000
11:10754957:GC:G	acceptor_gain	1.0000

AlphaMissense

7759 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:10751435:T:A	I8N	1.000
11:10751435:T:C	I8T	1.000
11:10751435:T:G	I8S	1.000
11:10751441:T:A	L10H	1.000
11:10751441:T:C	L10P	1.000
11:10751455:G:A	E15K	1.000
11:10752676:T:A	I17N	1.000
11:10752676:T:G	I17S	1.000
11:10752682:T:A	L19H	1.000
11:10752682:T:C	L19P	1.000
11:10752697:T:C	L24S	1.000
11:10752724:T:A	I33N	1.000
11:10752724:T:C	I33T	1.000
11:10752724:T:G	I33S	1.000
11:10752727:T:A	L34Q	1.000
11:10752727:T:C	L34P	1.000
11:10752735:G:A	E37K	1.000
11:10752736:A:T	E37V	1.000
11:10752737:A:C	E37D	1.000
11:10752737:A:T	E37D	1.000
11:10752756:T:A	W44R	1.000
11:10752756:T:C	W44R	1.000
11:10755061:T:G	M83R	1.000
11:10755072:G:C	D87H	1.000
11:10755072:G:T	D87Y	1.000
11:10755073:A:C	D87A	1.000
11:10755073:A:T	D87V	1.000
11:10755081:G:C	A90P	1.000
11:10755082:C:A	A90E	1.000
11:10755084:G:C	A91P	1.000

dbSNP variants (sampled 300 via entrez): RS1000085934 (11:10752882 T>A,C), RS1000154224 (11:10760381 T>C), RS1000181715 (11:10751440 C>T), RS1000218360 (11:10769752 G>T), RS1000450086 (11:10771844 T>C), RS1000515990 (11:10750486 C>G,T), RS1000569032 (11:10769900 G>C), RS1000572541 (11:10750707 A>G), RS1000682465 (11:10763125 C>G), RS1000855990 (11:10758596 A>G), RS1000961694 (11:10765404 A>C), RS1000979184 (11:10756364 T>C), RS1001041392 (11:10777210 C>T), RS1001058114 (11:10751647 C>T), RS1001101235 (11:10765184 A>T)

Disease associations

OMIM: gene MIM:609366 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
childhood kidney Wilms tumor	Moderate	Autosomal dominant
CTR9-related neurodevelopmental disorder	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
CTR9-related neurodevelopmental disorder	Moderate	AD

Mondo (4): CTR9-related neurodevelopmental disorder (MONDO:1040006), neurodevelopmental disorder (MONDO:0700092), exocrine pancreatic insufficiency (MONDO:0001684), childhood kidney Wilms tumor (MONDO:0024676)

Orphanet (0):

HPO phenotypes

27 total (27 of 27 shown, HPO-id order):

HPO	Term
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000085	Horseshoe kidney
HP:0000086	Ectopic kidney
HP:0000526	Aniridia
HP:0000822	Hypertension
HP:0001528	Hemihypertrophy
HP:0001824	Weight loss
HP:0001901	Polycythemia
HP:0001903	Anemia
HP:0001945	Fever
HP:0002027	Abdominal pain
HP:0002094	Dyspnea
HP:0002664	Neoplasm
HP:0002667	Nephroblastoma
HP:0002716	Lymphadenopathy
HP:0002896	Neoplasm of the liver
HP:0002907	Microscopic hematuria
HP:0003072	Hypercalcemia
HP:0005580	Duplication of renal pelvis
HP:0008330	Reduced von Willebrand factor activity
HP:0012587	Macroscopic hematuria
HP:0012871	Varicocele
HP:0031105	Abnormal uterus morphology
HP:0031500	Abdominal mass
HP:0033834	Malaise
HP:0100526	Neoplasm of the lung

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003986_13	Migraine	2.000000e-09
GCST012033_13	Sleep (1/3-day periodicity)	4.000000e-08

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D010188	Exocrine Pancreatic Insufficiency	C06.689.276
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724759 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.66	Kd	22	nM	MOLIBRESIB
5.24	Kd	5719	nM	CHEMBL3752910
5.24	ED50	5719	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 9 total; 2 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
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2179166: Binding affinity against CTR9 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.0220	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148173: Binding affinity to human CTR9 incubated for 45 mins by Kinobead based pull down assay	kd	5.7186	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
(+)-JQ1 compound	increases expression	2
Resveratrol	affects cotreatment, increases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Air Pollutants, Occupational	increases abundance, increases expression, affects expression, decreases expression	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
ICG 001	decreases expression	1
Arsenic	affects methylation	1
Vehicle Emissions	increases abundance, increases expression	1
Cannabidiol	increases expression	1
Cisplatin	increases expression	1
Coumestrol	affects cotreatment, increases expression	1
Dimethyl Sulfoxide	decreases expression	1
Estradiol	increases expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Nickel	decreases expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1
Ribonucleotides	affects binding	1
Rotenone	decreases expression	1
Smoke	decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	increases expression	1
Valproic Acid	affects expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651215	Binding	Binding affinity to human CTR9 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

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00336531	PHASE4	COMPLETED	Efficacy of Prophylactic Itraconazole in High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00744250	PHASE4	TERMINATED	Intraduodenal Aspiration Study to Assess the Bioavailability of Oral Pancrecarb® Compared to Placebo Control
NCT01100606	PHASE4	COMPLETED	A Study to Evaluate the Mode of Administration and Safety of EUR-1008 (APT-1008) in Infants 1 to 12 Months of Age
NCT01131507	PHASE4	COMPLETED	PR-018: An Open-Label, Safety Extension of Study PR-011
NCT01327703	PHASE4	COMPLETED	Control of Steatorrhea in Participants With Cystic Fibrosis and Exocrine Pancreatic Insufficiency
NCT01430234	PHASE4	COMPLETED	Enzyme Suppletion in Exocrine Pancreatic Dysfunction
NCT02823964	PHASE4	COMPLETED	EASY: Extended Access to Sollpura Over Years
NCT03859869	PHASE4	TERMINATED	A Study of Creon (Pancrelipase) in Resected and Non-resected Pancreatic Cancer Participants With Exocrine Pancreatic Insufficiency (EPI)
NCT04315311	PHASE4	WITHDRAWN	Study Of Effects Of Oral CREON Capsules In Adult Participants With Exocrine Pancreatic Insufficiency Not Due To Cystic Fibrosis, Chronic Pancreatitis, Pancreatectomy, Or Pancreatic Cancer
NCT06477159	PHASE4	RECRUITING	Pancreatic Enzyme Replacement Therapy for Acute Pancreatitis-Associated Exocrine Pancreatic Insufficiency
NCT07285863	PHASE4	RECRUITING	A Study Of Effect Of Secretin For In Injection (Chirostim) On Pancreatic Fluid Composition In Healthy Subjects
NCT07418593	PHASE4	RECRUITING	Malabsorption Blood Test (MBT) to Determine Exocrine Pancreatic Function and Related Quality of Life in Chronic Pancreatitis
NCT00352534	PHASE3	ACTIVE_NOT_RECRUITING	Vincristine, Dactinomycin, and Doxorubicin With or Without Radiation Therapy or Observation Only in Treating Younger Patients Who Are Undergoing Surgery for Newly Diagnosed Stage I, Stage II, or Stage III Wilms’ Tumor
NCT00379340	PHASE3	ACTIVE_NOT_RECRUITING	Combination Chemotherapy With or Without Radiation Therapy in Treating Young Patients With Newly Diagnosed Stage III or Stage IV Wilms’ Tumor
NCT00945009	PHASE3	ACTIVE_NOT_RECRUITING	Combination Chemotherapy and Surgery in Treating Young Patients With Wilms Tumor
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT00297167	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of EUR-1008 (APT-1008) Pancreatic Enzyme Product in Participants With Cystic Fibrosis and Exocrine Pancreatic Insufficiency
NCT00408317	PHASE3	COMPLETED	Safety and Efficacy Study of ULTRASE® MT20 in Participants With Cystic Fibrosis (CF) and Exocrine Pancreatic Insufficiency (PI)
NCT00449878	PHASE3	COMPLETED	Liprotamase Efficacy Trial in Patients With Cystic Fibrosis-Related Exocrine Pancreatic Insufficiency
NCT00449904	PHASE3	COMPLETED	Open-Label Phase III Long-Term Safety Trial of Liprotamase
NCT00500084	PHASE3	TERMINATED	Phase III ALTU-135 CP Safety Trial
NCT00559364	PHASE3	COMPLETED	Safety and Efficacy Study of Viokase® 16 for the Correction of Steatorrhea
NCT00662675	PHASE3	COMPLETED	A Study of the Efficacy and Tolerability of Pancrelipase Microtablet (MT) Capsules for the Treatment of Cystic Fibrosis-dependent Exocrine Pancreatic Insufficiency
NCT00788593	PHASE3	COMPLETED	A Randomized, Double-Blind, Dose Response-Control, Crossover Study to Evaluate the Safety and Efficacy of Two Doses of EUR-1008 (APT-1008) in Chronic Pancreatitis (CP) Participants With Exocrine Pancreatic Insufficiency (EPI)
NCT00981214	PHASE3	COMPLETED	Study of Pancreatic Enzyme Product in Pediatric Participants With Cystic Fibrosis and Exocrine Pancreatic Insufficiency
NCT02279498	PHASE3	COMPLETED	SOLUTION: Study of Oral Liprotamase Unit-Matched Therapy Of Non-Porcine Origin in Patients With Cystic Fibrosis
NCT02734810	PHASE3	COMPLETED	SIMPLICITY: Studying Impacts on Malabsorption With Liprotamase in Cystic Fibrosis
NCT03051490	PHASE3	UNKNOWN	RESULT: Reliable, Emergent Solution Using Liprotamase Treatment
NCT06691893	PHASE3	RECRUITING	Evaluating the Efficacy of RELiZORB in Managing Exocrine Pancreatic Insufficiency in Tube-fed Pancreatitis Patients
NCT00141765	PHASE2	COMPLETED	Study of High-Dose Chemotherapy With Bone Marrow or Stem Cell Transplant for Rare Poor-Prognosis Cancers
NCT00187031	PHASE2	COMPLETED	A Phase II Study of Topotecan in Children With Recurrent Wilms Tumor
NCT01095926	PHASE2	COMPLETED	Pharmacokinetic Study of Doxorubicin in Children With Cancer
NCT02452554	PHASE2	COMPLETED	Lorvotuzumab Mertansine in Treating Younger Patients With Relapsed or Refractory Wilms Tumor, Rhabdomyosarcoma, Neuroblastoma, Pleuropulmonary Blastoma, Malignant Peripheral Nerve Sheath Tumor, or Synovial Sarcoma
NCT02624388	PHASE2	TERMINATED	Study of Genistein in Pediatric Oncology Patients (UVA-Gen001)
NCT02689336	PHASE2	WITHDRAWN	Erlotinib in Combination With Temozolomide in Treating Relapsed/Recurrent/Refractory Pediatric Solid Tumors