TCOF1

Summary

TCOF1 (treacle ribosome biogenesis factor 1, HGNC:11654) is a protein-coding gene on chromosome 5q32-q33.1, encoding Treacle protein (Q13428). Nucleolar protein that acts as a regulator of RNA polymerase I by connecting RNA polymerase I with enzymes responsible for ribosomal processing and modification. It is a selective cancer dependency (DepMap: 55.0% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a nucleolar protein with a LIS1 homology domain. The protein is involved in ribosomal DNA gene transcription through its interaction with upstream binding factor (UBF). Mutations in this gene have been associated with Treacher Collins syndrome, a disorder which includes abnormal craniofacial development. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 6949 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Treacher-Collins syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 1,197 total — 168 pathogenic, 72 likely-pathogenic (top 2% of genes corpus-wide)
• GTEx eGene: eQTL in 14 tissues, sQTL in 29 (q < 0.05)
• Phenotypes (HPO): 87
• ChEMBL bioactivity: 1 clinical-phase molecule tested; no curated mechanism-of-action drug
• Cancer dependency (DepMap): dependent in 55.0% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.29 (highly constrained)
• MANE Select transcript: NM_001371623

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11654
Approved symbol	TCOF1
Name	treacle ribosome biogenesis factor 1
Location	5q32-q33.1
Locus type	gene with protein product
Status	Approved
Aliases	treacle, TCS
Ensembl gene	ENSG00000070814
Ensembl biotype	protein_coding
OMIM	606847
Entrez	6949

Gene structure

Transcript identifiers

Ensembl transcripts: 76 — 67 protein_coding, 5 nonsense_mediated_decay, 3 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000643257

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 2, TSL 4: 1, TSL 5: 9

ENST00000643257, ENST00000323668, ENST00000377797, ENST00000394269, ENST00000427724, ENST00000439160, ENST00000445265, ENST00000504761, ENST00000506063, ENST00000506630, ENST00000506767, ENST00000513346, ENST00000513538, ENST00000514442, ENST00000515035, ENST00000515516, ENST00000643812, ENST00000646961, ENST00000650162, ENST00000674413, ENST00000930540, ENST00000930541, ENST00000930542, ENST00000930543, ENST00000930544, ENST00000930545, ENST00000930546, ENST00000930547, ENST00000930548, ENST00000930549, ENST00000930550, ENST00000930551, ENST00000930552, ENST00000930553, ENST00000930554, ENST00000930555, ENST00000930556, ENST00000930557, ENST00000930558, ENST00000930559, ENST00000930560, ENST00000930561, ENST00000930562, ENST00000930563, ENST00000930564, ENST00000930565, ENST00000930566, ENST00000930567, ENST00000930568, ENST00000930569, ENST00000930570, ENST00000930571, ENST00000930572, ENST00000930573, ENST00000930574, ENST00000930575, ENST00000930576, ENST00000930577, ENST00000930578, ENST00000930579, ENST00000930580, ENST00000930581, ENST00000930582, ENST00000930583, ENST00000930584, ENST00000930585, ENST00000930586, ENST00000984679, ENST00000984680, ENST00000984681, ENST00001047711, ENST00001047712, ENST00001079184, ENST00001079185, ENST00001079186, ENST00001137918

RefSeq mRNA: 8 — MANE Select: NM_001371623 NM_000356, NM_001008657, NM_001135243, NM_001135244, NM_001135245, NM_001195141, NM_001371623, NM_001437406

CCDS: CCDS4306, CCDS43388, CCDS47305, CCDS47306, CCDS47307, CCDS54936, CCDS93805

Canonical transcript exons

ENST00000643257 — 27 exons

Exon	Start	End
ENSE00000972857	150374617	150374811
ENSE00001171398	150367844	150367917
ENSE00001198833	150368716	150368902
ENSE00001198956	150364113	150364252
ENSE00001198964	150361156	150361211
ENSE00001606922	150392705	150392790
ENSE00002204952	150398354	150398451
ENSE00002210082	150391544	150391657
ENSE00002223579	150391957	150392176
ENSE00002236001	150396282	150396842
ENSE00002300958	150393372	150393552
ENSE00002322879	150399022	150399070
ENSE00003507108	150376423	150376620
ENSE00003516904	150379229	150379408
ENSE00003535247	150374954	150375163
ENSE00003551581	150387902	150388088
ENSE00003573644	150372006	150372236
ENSE00003580151	150375721	150375909
ENSE00003594011	150378905	150379042
ENSE00003596631	150374174	150374386
ENSE00003611163	150376082	150376330
ENSE00003616935	150369529	150369602
ENSE00003642419	150379532	150379732
ENSE00003647292	150375339	150375554
ENSE00003648859	150389887	150390023
ENSE00003818116	150399810	150400293
ENSE00003897764	150357697	150357854

Expression profiles

Bgee: expression breadth ubiquitous, 265 present calls, max score 97.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 16.3216 / max 110.6306, expressed in 1775 samples.

Highest expression (Bgee): sural nerve, oocyte, dorsal motor nucleus of vagus nerve, granulocyte, pericardium.

Genetic regulation across tissues (GTEx eQTL / sQTL)

TCOF1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 14 tissues and its splicing (sQTL) in 29 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 43 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Adipose Subcutaneous	sqtl	9.8e-16	-0.73	5:150366222:G:A
Cells Cultured fibroblasts	sqtl	1.2e-15	-0.66	5:150392717:C:G
Artery Tibial	sqtl	1.8e-15	-0.66	5:150392717:C:G
Testis	sqtl	1.7e-14	-0.79	5:150359556:C:G
Skin Sun Exposed Lower leg	sqtl	2.8e-14	-0.64	5:150392717:C:G
Nerve Tibial	sqtl	4.5e-13	-0.95	5:150374425:G:A
Esophagus Muscularis	sqtl	3.6e-12	-0.68	5:150382362:G:GT
Esophagus Mucosa	sqtl	2.5e-11	-0.63	5:150366222:G:A
Muscle Skeletal	sqtl	2.9e-11	-0.85	5:150325822:C:T
Cells EBV-transformed lymphocytes	sqtl	4.1e-11	-1.37	5:150326230:A:G
Lung	sqtl	7.0e-11	-0.65	5:150366222:G:A
Skin Not Sun Exposed Suprapubic	sqtl	1.1e-10	-0.64	5:150366222:G:A
Thyroid	sqtl	3.7e-10	-0.86	5:150350382:C:T
Breast Mammary Tissue	sqtl	1.4e-09	-0.93	5:150313965:T:A
Prostate	sqtl	2.6e-06	-0.95	5:150341244:T:C
Colon Sigmoid	sqtl	3.7e-06	-0.87	5:150388818:G:A
Heart Atrial Appendage	sqtl	8.5e-06	-0.87	5:150380936:G:A
Artery Aorta	sqtl	1.1e-05	-1.06	5:150398890:C:A
Esophagus Gastroesophageal Junction	sqtl	1.7e-05	-0.65	5:150366222:G:A
Stomach	sqtl	3.0e-05	-0.67	5:150366222:G:A

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
59422	16.3216	1775

Top tissues by expression

showing 100 of 288 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	97.44	gold quality
oocyte	CL:0000023	91.14	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	88.15	gold quality
granulocyte	CL:0000094	87.72	gold quality
pericardium	UBERON:0002407	87.66	gold quality
lymph node	UBERON:0000029	87.21	gold quality
pylorus	UBERON:0001166	87.15	gold quality
lower esophagus muscularis layer	UBERON:0035833	86.72	gold quality
lower esophagus	UBERON:0013473	86.71	gold quality
apex of heart	UBERON:0002098	86.53	gold quality
tendon of biceps brachii	UBERON:0008188	86.39	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.36	gold quality
gastrocnemius	UBERON:0001388	86.33	gold quality
stromal cell of endometrium	CL:0002255	86.32	gold quality
muscle layer of sigmoid colon	UBERON:0035805	86.24	gold quality
ventricular zone	UBERON:0003053	86.22	gold quality
parotid gland	UBERON:0001831	86.04	silver quality
muscle of leg	UBERON:0001383	85.97	gold quality
popliteal artery	UBERON:0002250	85.90	gold quality
vena cava	UBERON:0004087	85.88	silver quality
tibial artery	UBERON:0007610	85.88	gold quality
calcaneal tendon	UBERON:0003701	85.81	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	85.72	gold quality
body of tongue	UBERON:0011876	85.68	gold quality
hindlimb stylopod muscle	UBERON:0004252	85.56	gold quality
pharyngeal mucosa	UBERON:0000355	85.55	gold quality
bone marrow cell	CL:0002092	85.54	gold quality
cortical plate	UBERON:0005343	85.49	gold quality
superior surface of tongue	UBERON:0007371	85.48	gold quality
nipple	UBERON:0002030	85.43	gold quality
inferior vagus X ganglion	UBERON:0005363	85.41	gold quality
saphenous vein	UBERON:0007318	85.39	gold quality
body of uterus	UBERON:0009853	85.32	gold quality
trachea	UBERON:0003126	85.13	gold quality
tongue	UBERON:0001723	85.12	gold quality
skin of leg	UBERON:0001511	84.90	gold quality
cardia of stomach	UBERON:0001162	84.83	gold quality
ganglionic eminence	UBERON:0004023	84.83	gold quality
pons	UBERON:0000988	84.81	gold quality
esophagus	UBERON:0001043	84.78	gold quality
secondary oocyte	CL:0000655	84.76	gold quality
aorta	UBERON:0000947	84.70	gold quality
ectocervix	UBERON:0012249	84.59	gold quality
tendon	UBERON:0000043	84.54	gold quality
spleen	UBERON:0002106	84.50	gold quality
fundus of stomach	UBERON:0001160	84.47	gold quality
right ovary	UBERON:0002118	84.38	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.29	gold quality
caecum	UBERON:0001153	84.22	gold quality
skin of abdomen	UBERON:0001416	84.22	gold quality
thymus	UBERON:0002370	84.20	silver quality
medulla oblongata	UBERON:0001896	84.14	gold quality
tonsil	UBERON:0002372	84.11	gold quality
lower esophagus mucosa	UBERON:0035834	84.11	gold quality
prefrontal cortex	UBERON:0000451	84.08	gold quality
left uterine tube	UBERON:0001303	84.04	gold quality
muscle organ	UBERON:0001630	84.04	gold quality
sigmoid colon	UBERON:0001159	84.03	gold quality
monocyte	CL:0000576	84.01	gold quality
leukocyte	CL:0000738	83.86	gold quality
body of stomach	UBERON:0001161	83.83	gold quality
coronary artery	UBERON:0001621	83.82	gold quality
tibial nerve	UBERON:0001323	83.79	gold quality
inferior olivary complex	UBERON:0002127	83.71	gold quality
mononuclear cell	CL:0000842	83.70	gold quality
left coronary artery	UBERON:0001626	83.66	gold quality
lateral globus pallidus	UBERON:0002476	83.63	gold quality
left ovary	UBERON:0002119	83.61	gold quality
cerebellar cortex	UBERON:0002129	83.61	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	83.58	silver quality
right frontal lobe	UBERON:0002810	83.57	gold quality
cerebellar hemisphere	UBERON:0002245	83.55	gold quality
ventral tegmental area	UBERON:0002691	83.54	gold quality
colonic epithelium	UBERON:0000397	83.51	gold quality
stomach	UBERON:0000945	83.38	gold quality
right hemisphere of cerebellum	UBERON:0014890	83.34	gold quality
mucosa of stomach	UBERON:0001199	83.32	gold quality
cerebellum	UBERON:0002037	83.24	gold quality
esophagus mucosa	UBERON:0002469	83.21	gold quality
ascending aorta	UBERON:0001496	83.14	gold quality
thoracic aorta	UBERON:0001515	83.14	gold quality
vermiform appendix	UBERON:0001154	83.11	gold quality
body of pancreas	UBERON:0001150	83.08	gold quality
superior vestibular nucleus	UBERON:0007227	83.01	gold quality
endocervix	UBERON:0000458	82.96	gold quality
right coronary artery	UBERON:0001625	82.96	gold quality
small intestine Peyer’s patch	UBERON:0003454	82.92	gold quality
cingulate cortex	UBERON:0003027	82.87	gold quality
dorsal plus ventral thalamus	UBERON:0001897	82.82	gold quality
upper lobe of left lung	UBERON:0008952	82.80	gold quality
gluteal muscle	UBERON:0002000	82.79	silver quality
subthalamic nucleus	UBERON:0001906	82.73	gold quality
anterior cingulate cortex	UBERON:0009835	82.71	gold quality
embryo	UBERON:0000922	82.69	gold quality
triceps brachii	UBERON:0001509	82.67	gold quality
myometrium	UBERON:0001296	82.61	gold quality
smooth muscle tissue	UBERON:0001135	82.58	gold quality
right lobe of thyroid gland	UBERON:0001119	82.54	gold quality
neocortex	UBERON:0001950	82.53	gold quality
frontal cortex	UBERON:0001870	82.48	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	954.42
E-ANND-3	yes	5.23
E-MTAB-9689	no	203.95

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Postcentral gyrus	tissue	35.4
Thymus	tissue	19.1
Locus coeruleus	tissue	18.3
Hippocampus	tissue	17.6	low
Lymph node	tissue	17.2	low
Tonsil	tissue	15.2	medium
Nucleus accumbens	tissue	14.2
Appendix	tissue	13.8	medium
Bone marrow	tissue	13.4	low
Skeletal muscle	tissue	13.3	medium
Choroid plexus	tissue	12.9
Vagina	tissue	12.8	medium
Spleen	tissue	12.6	medium
Skin 1	tissue	12.4	medium
Smooth muscle	tissue	10.9	low
Adipose tissue	tissue	10.4	medium
Seminal vesicle	tissue	10.2	low
Ovary	tissue	10.1	low
Salivary gland	tissue	10.1	low
Pituitary gland	tissue	9.9
Placenta	tissue	9.7	medium
Parathyroid gland	tissue	9.3	medium
Urinary bladder	tissue	9.2	medium
Colon	tissue	9.1	medium
Endometrium 1	tissue	9.1	low
Tongue	tissue	9.0
Retina	tissue	8.9
Fallopian tube	tissue	8.9	medium
Testis	tissue	8.8	medium
Pancreas	tissue	8.8	medium
Esophagus	tissue	8.4	medium
Frontal cortex	tissue	8.3
Rectum	tissue	8.2	medium
Stomach 1	tissue	7.8	medium
Prostate	tissue	7.6	low
Heart muscle	tissue	7.4	low
Lung	tissue	7.3	medium
Small intestine	tissue	7.3	medium
Adrenal gland	tissue	7.2	medium
Epididymis	tissue	7.0	medium
Cervix	tissue	6.9	medium
Breast	tissue	6.9	medium
Duodenum	tissue	6.9	medium
Thyroid gland	tissue	6.4	medium
Gallbladder	tissue	6.1	medium
Caudate putamen	tissue	6.1
Liver	tissue	5.4	low
Corpus callosum	tissue	5.4
Thalamus	tissue	4.9
Superior colliculi	tissue	4.9
Midbrain	tissue	4.8
Hypothalamus	tissue	4.7
Cerebellum	tissue	4.7	high
Cerebral cortex	tissue	4.4	medium
Somatosensory cortex	tissue	4.4
Pons	tissue	4.3
Substantia nigra	tissue	4.3
Kidney	tissue	4.2	medium
Hippocampal formation	tissue	4.2
Ventral forebrain	tissue	4.2

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Area striata (white matter) (30.3), Somatomor cortex, precentral gyrus (white matter) (30.3), Area parastriata, inferior (25.1), Premotor cortex, ventral (23.9), Subcentral gyrus, S2 (23.5).

Regulation

Is transcription factor: no

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.288, missense Z 1.53 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000643257 splits into 2 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
5:150,357,747–150,364,127	32 / 75.3	0.43	no
5:150,364,128–150,399,045	1696 / 1765.4	0.96	no
ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map
DepMap (CRISPR cell-line fitness): dependent in 55.0% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): OVTOKO (-1.661), HCC1187 (-1.607), COV644 (-1.53), U-118 MG (-1.409), NCI-H1092 (-1.336), SF126 (-1.319), HUP-T4 (-1.311), UACC-257 (-1.287), SNU-626 (-1.266), A-172 (-1.206), KMRC-1 (-1.171), Hey-A8 (-1.142), NCI-H2004 RT (-1.124), TE-5 (-1.112), SNU-840 (-1.11).

Literature-anchored findings (GeneRIF, showing 40)

• The identification of a novel pathogenic missense change in exon 2 of the TCOF1 gene suggests that a functionally important domain of treacle exists near the N-terminus. (PMID:12114482)
• Patients with Goldenhar, Nager, or Miller syndromes may resemble Treacher-Collins, but are unlikely to have mutations at this locus. (PMID:12210332)
• Identification of 231-nucleotide(nt) exon 6A and 108-nt exon 16A and isoforms with exon 6A are up to 3.7-fold more abundant than alternatively spliced variants without exon 6A, but only minor isoforms contain exon 16A. (PMID:15019983)
• In this study we identified a TCOF1 1408delAG heterozygous mutation in a patient with the clinical diagnosis of TCS (treacher collins syndrome). (PMID:15039977)
• Results show that treacle is involved in ribosomal DNA gene transcription by interacting with upstream binding factor (UBF). (PMID:15249688)
• A novel mutation within exon 6A is associated with Treacher Collins syndrome. (PMID:15832313)
• The -346T allele impairs DNA-binding to the YY1 transcription factor, and this promoter variant represents a candidate allele to explain the clinical variability in patients bearing Treacher Collins syndrome. (PMID:16102917)
• A 5-bp deletion in exon 22 of the TCOF1 gene (3469del ACTCT) was found to cause a premature stop codon. (PMID:16801042)
• These observations strongly suggest that the TCOF1 genetic changes observed in these five patients might be related to oculo-auriculo-vertebral spectrum symptoms. (PMID:17786119)
• TCOF1 may influence risk of cleft palate through maternal transmission. (PMID:18688869)
• It has been hypothesized that mutations in Tcof1 disrupt ribosome biogenesis to a degree that is insufficient to meet the proliferative needs of the neuroepithelium and neural crest cells. (PMID:19027870)
• The novel mutation of Ala26Val is considered to affect the LisH domain, an important domain of treacle. All of the mutations thus far detected in exon 5 have resulted in frameshift, but a nonsense mutation was detected (Lys159Stop). (PMID:19067896)
• central repeated domain of treacle binds with RNA polymerase I, while that the treacle C-terminus is involved in rDNA promoter recognition and UBF recruitment. (PMID:19527688)
• We demonstrated that adult leucocytes and mesenchymal cells from TCS patients present significantly reduced levels of TCOF1 (PMID:20003452)
• 6 of 12 patients diagnosed with hemifacial microsomia exhibited a novel frameshift mutation c. 4127 ins G in exon 24 in the TCOF1 gene. (PMID:21848650)
• Fifteen mutations were reported, including twelve novel and three already described in 14 sporadic patients and in 3 familial cases of Treacher Collins syndrome. (PMID:21951868)
• Gene rearrangements in TCOF1 are responsible for Treacher-Collins-Franceschetti syndrome. (PMID:22317976)
• Presents the case of a male with Treacher Collins syndrome with a heterozygous de novo frameshift mutation within the TCOF1 gene (c.790_791delAG,p.Ser264GlnfsX7), as well as findings from three other individuals from two families with the same mutation. (PMID:22729243)
• we describe for the first time, two patients with MFD and ID and for whom a deletion encompassing TCOF1 and CAMK2A has been identified (PMID:23695276)
• TCOF1 genetic mutation can be a cause of Treacher Collins syndrome in Chinese patients. (PMID:23838542)
• Autosomal recessive POLR1D mutation with decrease of TCOF1 mRNA is responsible for Treacher Collins syndrome. (PMID:24603435)
• Mutations in TCOF1, POLR1C and POLR1D have all been implicated in causing TCS (PMID:24690222)
• Treacle-mediated NBS1 recruitment into the nucleoli regulates rRNA silencing in trans in the presence of distant chromosome breaks. (PMID:25064736)
• findings identify TCOF1 as a DDR factor that could cooperate with ATM and NBS1 to suppress inappropriate rDNA transcription and maintain genomic integrity after DNA damage. (PMID:25512513)
• We report a clinical and extensive molecular study, including TCOF1, POLR1D, POLR1C, and EFTUD2 genes, in a series of 146 patients with TCS. (PMID:25790162)
• The analysis results showed that the Tcof1-related genes were enriched in various biological processes, including cell proliferation, apoptosis, cell cycle, differentiation, and migration. (PMID:27300466)
• Performed mutational analysis of TCOF1, GSC, and HOXA2 to determine the mutational features of the 3 genes in Chinese patients with Treacher Collins syndrome. (PMID:27526242)
• Data indicate that Treacher Collins-Franceschetti syndrome 1 protein (TCOF1) was the main disease-causing gene for the Chinese Treacher Collins syndrome (TCS) population and its mutation spectrum. (PMID:29230583)
• Acinar Progenitor Cell Model Identifies Treacle-Dependent Radioresistance (PMID:31141469)
• POLR1B and neural crest cell anomalies in Treacher Collins syndrome type 4. (PMID:31649276)
• TOPBP1 recruitment is mediated by phosphorylation-dependent interactions between three of its BRCT domains and conserved phosphorylated Ser/Thr residues at the C-terminus of the nucleolar phosphoprotein Treacle. (PMID:31913317)
• Treacher Collins syndrome: A novel TCOF1 mutation and monopodial stapes. (PMID:32351010)
• TRF2 recruits nucleolar protein TCOF1 to coordinate telomere transcription and replication. (PMID:33082515)
• De novo TCOF1 mutation in Treacher Collins syndrome. (PMID:34058530)
• Treacle and TOPBP1 control replication stress response in the nucleolus. (PMID:34100862)
• TCOF1 upregulation in triple-negative breast cancer promotes stemness and tumour growth and correlates with poor prognosis. (PMID:34718356)
• TCOF1 coordinates oncogenic activation and rRNA production and promotes tumorigenesis in HCC. (PMID:34904330)
• The oncogenic role of treacle ribosome biogenesis factor 1 (TCOF1) in human tumors: a pan-cancer analysis. (PMID:35093935)
• Genetic mutations in ribosomal biogenesis gene TCOF1 identified in human neural tube defects. (PMID:36808708)
• [TCOF1 Gene variation in Treacher Collins syndrome and evaluation of speech rehabilitation after bone bridge surgery]. (PMID:37640998)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tcof1	ENSDARG00000087555
mus_musculus	Tcof1	ENSMUSG00000024613
rattus_norvegicus	Tcof1	ENSRNOG00000026108

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:892003) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 96 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal cranial ganglia morphology	3
abnormal neurocranium morphology	2
abnormal craniofacial morphology	2
mandible hypoplasia	2
exencephaly	2
anophthalmia	2
respiratory failure	2
neonatal lethality, complete penetrance	2
lowered ear position	1
abnormal tympanic ring morphology	1
short mandible	1
short premaxilla	1
short maxilla	1
abnormal nasal bone morphology	1
nasal bone hypoplasia	1
abnormal frontal bone morphology	1
cleft palate	1
rib fusion	1
microcephaly	1
shortened head	1
abnormal cranium morphology	1
domed cranium	1
abnormal maxilla morphology	1
maxilla hypoplasia	1
abnormal forebrain morphology	1

+71 more (showing top 25).

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
ARSI	protein-coding	340075
CAMK2A	protein-coding	815
CD74	protein-coding	972
NDST1-AS1	ncRNA	102546298
RPS14	protein-coding	6208

Protein

Protein identifiers

Treacle protein — Q13428 (reviewed: Q13428)

Alternative names: Treacher Collins syndrome protein

All UniProt accessions (9): Q13428, A0A2R8Y4M7, A0A2R8Y857, A0A3B3IS06, A0A6I8PRA0, E7ETY2, H0Y8Y7, H0YA99, H0YAB7

UniProt curated annotations — full annotation on UniProt →

Function. Nucleolar protein that acts as a regulator of RNA polymerase I by connecting RNA polymerase I with enzymes responsible for ribosomal processing and modification. Required for neural crest specification: following monoubiquitination by the BCR(KBTBD8) complex, associates with NOLC1 and acts as a platform to connect RNA polymerase I with enzymes responsible for ribosomal processing and modification, leading to remodel the translational program of differentiating cells in favor of neural crest specification.

Subunit / interactions. Heterodimer; heterodimerizes with NOLC1 following monoubiquitination. Part of a large pre-ribosomal ribonucleoprotein (RNP) complex, that consists of at least 62 ribosomal proteins, 45 nonribosomal proteins and both pre-rRNA and mature rRNA species. Within this complex directly interacts with NOP56 in an RNA-independent manner.

Subcellular location. Nucleus. Nucleolus.

Post-translational modifications. Ubiquitinated. Monoubiquitination by the BCR(KBTBD8) complex promotes the formation of a NOLC1-TCOF1 complex that acts as a platform to connect RNA polymerase I with enzymes responsible for ribosomal processing and modification, leading to remodel the translational program of differentiating cells in favor of neural crest specification. Pyrophosphorylated by 5-diphosphoinositol pentakisphosphate (5-IP7). Serine pyrophosphorylation is achieved by Mg(2+)-dependent, but enzyme independent transfer of a beta-phosphate from a inositol pyrophosphate to a pre-phosphorylated serine residue.

Disease relevance. Treacher Collins syndrome 1 (TCS1) [MIM:154500] A form of Treacher Collins syndrome, a disorder of craniofacial development. Treacher Collins syndrome is characterized by a combination of bilateral downward slanting of the palpebral fissures, colobomas of the lower eyelids with a paucity of eyelashes medial to the defect, hypoplasia of the facial bones, cleft palate, malformation of the external ears, atresia of the external auditory canals, and bilateral conductive hearing loss. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Major. Minor.

Isoforms (8)

UniProt ID	Names	Canonical?
Q13428-1	1	yes
Q13428-2	2
Q13428-3	3
Q13428-4	4
Q13428-5	5
Q13428-6	6
Q13428-7	7
Q13428-8	8

RefSeq proteins (8): NP_000347, NP_001008657, NP_001128715, NP_001128716, NP_001128717, NP_001182070, NP_001358552, NP_001424335 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003993	Treacle_dom	Domain
IPR006594	LisH	Conserved_site
IPR017859	Treacle	Family

Pfam: PF03546

UniProt features (127 total): modified residue 68, compositionally biased region 24, cross-link 12, sequence variant 11, splice variant 6, sequence conflict 2, region of interest 2, chain 1, domain 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13428-F1	41.78	0.01

Human Protein Atlas

Protein class: Predicted intracellular proteins, Plasma proteins, Disease related genes, Human disease related genes, Other congenital disorders, Ribosomopathies, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoli fibrillar center

Antibody reliability (HPA): IH enhanced · IF enhanced

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 (80)

Type	Positions
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo2)	725, 732, 755, 1224, 1238, 1248, 1414, 126, 507, 600, 637
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo1)	755
Phosphoserine	83, 85, 87, 88, 107, 153, 156, 171, 233, 381, 413, 414, 446, 484, 503, 583, 620, 679, 762, 764, 765, 769, 771, 777, 868, 870, 871, 875, 877, 906, 967, 998, 1111, 1190, 1228, 1257, 1350, 1376, 1378, 1407 … (+3)
Phosphothreonine	84, 102, 173, 249, 310, 316, 533, 581, 914, 974, 983, 1175, 1222, 1234, 1358
N6-acetyllysine	134, 155, 296, 313, 322, 600, 716, 720, 755, 1414

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

MSigDB gene sets: 386 (showing top): MORF_RAGE, GOBP_RIBOSOME_BIOGENESIS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, MORF_CDK2, GOBP_RRNA_TRANSCRIPTION, PATIL_LIVER_CANCER, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, MUELLER_PLURINET, GOBP_MESENCHYMAL_CELL_DIFFERENTIATION, MYCMAX_01, BLALOCK_ALZHEIMERS_DISEASE_UP

GO Biological Process (6): skeletal system development (GO:0001501), regulation of translation (GO:0006417), neural crest formation (GO:0014029), neural crest cell development (GO:0014032), ribosome biogenesis (GO:0042254), nucleolar large rRNA transcription by RNA polymerase I (GO:0042790)

GO Molecular Function (5): RNA binding (GO:0003723), protein-macromolecule adaptor activity (GO:0030674), protein heterodimerization activity (GO:0046982), scaffold protein binding (GO:0097110), protein binding (GO:0005515)

GO Cellular Component (2): fibrillar center (GO:0001650), nucleolus (GO:0005730)

GO top-level categories

22 GO namespaces:

Category	Terms
protein binding	2
system development	1
animal gross anatomical part developmental process	1
translation	1
post-transcriptional regulation of gene expression	1
regulation of protein metabolic process	1
epithelial to mesenchymal transition	1
chordate embryonic development	1
anatomical structure formation involved in morphogenesis	1
neural crest cell differentiation	1
stem cell development	1
ribonucleoprotein complex biogenesis	1
transcription by RNA polymerase I	1
rRNA transcription	1
nucleic acid binding	1
molecular adaptor activity	1
protein dimerization activity	1
binding	1
nucleolus	1
cellular anatomical structure	1
nuclear lumen	1
intracellular membraneless organelle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 9 of 13 annotations. The rest are phylogenetic / computational / electronic (IEA).

9 experimentally-supported GO terms:

GO term	NS	Evidence
neural crest cell development	BP	mutant phenotype
neural crest formation	BP	mutant phenotype
regulation of translation	BP	mutant phenotype
fibrillar center	CC	direct assay
nucleolus	CC	direct assay
RNA binding	MF	high-throughput assay
protein heterodimerization activity	MF	physical interaction
protein-macromolecule adaptor activity	MF	direct assay
scaffold protein binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,662 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TCOF1	POLR1D	P0DPB6	939
TCOF1	OFD1	O75665	772
TCOF1	NOP56	O00567	759
TCOF1	MKLN1	Q9UL63	753
TCOF1	LNX2	Q8N448	753
TCOF1	UBTF	P17480	707
TCOF1	TBL1X	O60907	695
TCOF1	CDX1	P47902	673
TCOF1	RPS14	P06366	666
TCOF1	POLR1C	O15160	658
TCOF1	RPS19	P39019	630
TCOF1	NKX3-2	P78367	621
TCOF1	POLI	Q9UNA4	621
TCOF1	SUCLG2	Q96I99	618
TCOF1	SLC26A2	P50443	614

IntAct

Human interaction partners of TCOF1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

25 partners by confidence:

Partner	Interaction type	MIscore	Records
NBN	physical association	0.680	9
FGF12	association	0.610	8
SRPK2	phosphorylation reaction	0.590	1
CRK	direct interaction	0.440	1
APMAP	physical association	0.400	1
ARAF	physical association	0.400	1
ARHGAP44	physical association	0.400	1
BNIP5	physical association	0.400	1
CACNA2D3	physical association	0.400	1
COL16A1	physical association	0.400	1
FAM193A	physical association	0.400	1
FMR1	physical association	0.400	1
KMT2C	physical association	0.400	1
NOC3L	physical association	0.400	1
OBSCN	physical association	0.400	1
SF3A1	physical association	0.400	1
SSB	physical association	0.400	1
VSTM2B	physical association	0.400	1
ZNF462	physical association	0.400	1
TM9SF1	physical association	0.370	1
KBTBD8	association	0.350	1
ARRB1	physical association	0.000	2
ARRB2	physical association	0.000	2
PKNOX1	physical association	0.000	1
TTC4	physical association	0.000	1

BioGRID (395 interactions; top human partners by supporting records): KBTBD8 (Affinity Capture-Western; 9 records), ARRB1 (Affinity Capture-Western; 6 records), ARRB2 (Affinity Capture-Western; 6 records), CSNK2A1 (Affinity Capture-Western; 5 records), NOLC1 (Affinity Capture-Western; 5 records), TOPBP1 (Affinity Capture-Western; 4 records), CAMKV (Affinity Capture-MS; 3 records), CSNK2A2 (Affinity Capture-MS; 3 records), DENND2D (Affinity Capture-MS; 3 records), NOP56 (Affinity Capture-Western; 3 records), RPA3 (Negative Genetic; 3 records), BRD4 (Affinity Capture-MS; 2 records), CCNF (Affinity Capture-MS; 2 records), CHD4 (Affinity Capture-MS; 2 records), CIAO1 (Proximity Label-MS; 2 records)

SIGNOR signaling

2 signaling interactions:

A	Effect	B	Mechanism
TCOF1	“up-regulates activity”	NBN	relocalization
CSNK2A1	“up-regulates activity”	TCOF1	phosphorylation

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
★ Nop56p-associated pre-rRNA complex	104	LUC7L2, NCL, RPL27, RPL29, RPL39, RPL7, RPS23, RPS6, MYBBP1A, RPL21, RPL28, RPL5, RPS9, U2AF2, LYAR, RPL13, RPL23, RPL23A, RPL35A, RPL4, RPS24, HNRNPA1, EBNA1BP2, RPLP1, RPS17, U2AF1, DHX9, RPL30, SCYL2, RPL11, RPS11, NOLC1, RPL12, RPL14, RPL17, RPL19, RPL32, RPS13, RPS8, NOP58, RPL36A, RPLP2, RPS2, RPS29, SRP14, TCOF1, TUFM, ACTG2, RBM28, RPL10, RPL37A, RPS12, RPS7, TUBB1, BRIX1, DDX21, GNL3, IGF2BP1, ILF2, RPL10A, RPL15, RPLP0, EEF2, HNRNPU, NOP56, RPL26, RPL3, RPS14, RPS16, RSL1D1, ACTA2, EEF1A1, H1-3, RPL24, RPL6, RPL8, SRPK1, TOP1, FBL, HNRNPM, RPL13A, RPL31, RPL7A, RPS18, H1-10, ILF3, NPM1, RPS15A, TUBA1A, YBX1, H2BC14, PWP1, RPL18A, RPL22, RPL27A, RPS15, RPS3A, SLC25A5, NAP1L1, RPL18, RPL35, RPL36, RPL9, SNU13

Disease & clinical

Genetic variants

Variant evidence for TCOF1: 1,197 ClinVar records (240 pathogenic / likely pathogenic); 2 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

1,197 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	168
Likely pathogenic	72
Uncertain significance	429
Likely benign	309
Benign	48

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 240 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
3963	NM_001371623.1(TCOF1):c.4372_4376del (p.Lys1458fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	16
436967	NM_001371623.1(TCOF1):c.4368dup (p.Glu1457fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
575776	NM_001371623.1(TCOF1):c.4221dup (p.Ser1408fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	5
3965	NM_001371623.1(TCOF1):c.1639_1640del (p.Ser547fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	4
3966	NM_001371623.1(TCOF1):c.2962C>T (p.Arg988Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
477617	NM_001371623.1(TCOF1):c.2796_2797del (p.Gly933fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
947528	NM_001371623.1(TCOF1):c.1021_1022del (p.Ser341fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
1705551	NM_001371623.1(TCOF1):c.2112_2116del (p.Glu704fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
280270	NM_001371623.1(TCOF1):c.1278+1G>A	Pathogenic	criteria provided, multiple submitters, no conflicts	2
419066	NM_001371623.1(TCOF1):c.3973dup (p.Glu1325fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
432771	NM_001371623.1(TCOF1):c.1990C>T (p.Gln664Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
452124	NM_001371623.1(TCOF1):c.4132_4133del (p.Val1378fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
452460	NM_001371623.1(TCOF1):c.4360_4363del (p.Glu1454fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
477616	NM_001371623.1(TCOF1):c.2285_2286del (p.Asp761_Ser762insTer)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
931320	NM_001371623.1(TCOF1):c.1204C>T (p.Gln402Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2

Per-variant reference — Sugi Variant

Explore TCOF1’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 40 predictions of 2,601):

Position(s)	Effect	Δscore	Sites
5:150357855–150357856	donor_loss	1.0000	4
5:150368714–150368715	acceptor_loss	1.0000	6
5:150369603–150369604	donor_loss	1.0000	3
5:150374615–150374616	acceptor_loss	1.0000	2
5:150374812–150374813	donor_loss	1.0000	5
5:150375910–150375911	donor_loss	1.0000	5
5:150376080–150376081	acceptor_loss	1.0000	4
5:150376331–150376332	donor_loss	1.0000	5
5:150378900	acceptor_gain	1.0000
5:150378903–150378904	acceptor_loss	1.0000	5

AlphaMissense

758 missense substitutions predicted likely pathogenic (of 9,554 scored), across 224 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
H17	8	0.948	0.990
F961	8	0.883	0.987
D48	8	0.870	0.980
D80	8	0.816	0.906
W53	7	0.993	0.999
E9	7	0.904	0.972
I14	7	0.846	0.996
H52	7	0.826	0.977
E3	7	0.802	0.913
E29	7	0.802	0.910
D963	7	0.752	0.812
E86	7	0.671	0.783
G22	6	0.975	0.993
K6	6	0.927	0.983
I49	6	0.925	0.994
P12	6	0.919	0.954
R25	6	0.895	0.974
A26	6	0.890	0.986
K31	6	0.884	0.987
A27	6	0.870	0.994

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

5 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	6.41e-13
Lung Adenocarcinoma (validation)	unfavorable	3.93e-05
Prostate Adenocarcinoma (TCGA)	unfavorable	0.000485
Pancreatic Adenocarcinoma (validation)	unfavorable	0.000629
Liver Hepatocellular Carcinoma (validation)	unfavorable	0.000826

Disease associations

OMIM: gene MIM:606847 | disease phenotypes: MIM:154500, MIM:612998

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
Treacher-Collins syndrome	Definitive	Autosomal dominant	2
Treacher Collins syndrome 1	Definitive	Autosomal dominant	3

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
Treacher-Collins syndrome	Definitive	AD

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (7 panels, 6 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

7 panels:

Panel	Rating
Clefting	green
DDG2P	green
Deafness and congenital structural abnormalities	green
Fetal anomalies	green
Paediatric disorders	green
Skeletal dysplasia	green
Structural eye disease	amber

Mondo (3): Treacher Collins syndrome 1 (MONDO:0007944), Treacher-Collins syndrome (MONDO:0002457), Emery-Dreifuss muscular dystrophy 4, autosomal dominant (MONDO:0013071)

Orphanet (2): Treacher-Collins syndrome (Orphanet:861), Emery-Dreifuss muscular dystrophy (Orphanet:261)

HPO phenotypes

showing 60 of 87 phenotypes (HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000046	Small scrotum
HP:0000143	Rectovaginal fistula
HP:0000154	Wide mouth
HP:0000160	Narrow mouth
HP:0000162	Glossoptosis
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000185	Cleft soft palate
HP:0000197	Abnormal parotid gland morphology
HP:0000204	Cleft upper lip
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000248	Brachycephaly
HP:0000272	Malar flattening
HP:0000278	Retrognathia
HP:0000294	Low anterior hairline
HP:0000316	Hypertelorism
HP:0000327	Hypoplasia of the maxilla
HP:0000347	Micrognathia
HP:0000356	Abnormality of the outer ear
HP:0000358	Posteriorly rotated ears
HP:0000370	Abnormality of the middle ear
HP:0000377	Abnormal pinna morphology
HP:0000384	Preauricular skin tag
HP:0000405	Conductive hearing impairment
HP:0000413	Atresia of the external auditory canal
HP:0000431	Wide nasal bridge
HP:0000453	Choanal atresia
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000561	Absent eyelashes
HP:0000568	Microphthalmia
HP:0000572	Visual loss
HP:0000612	Iris coloboma
HP:0000625	Eyelid coloboma
HP:0000636	Upper eyelid coloboma
HP:0000643	Blepharospasm
HP:0000652	Lower eyelid coloboma
HP:0000682	Abnormal dental enamel morphology
HP:0000689	Dental malocclusion
HP:0000750	Delayed speech and language development
HP:0000778	Hypoplasia of the thymus
HP:0000834	Abnormality of the adrenal glands
HP:0000925	Abnormality of the vertebral column
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0001508	Failure to thrive
HP:0001627	Abnormal heart morphology
HP:0001643	Patent ductus arteriosus
HP:0001999	Abnormal facial shape
HP:0002006	Tessier cleft
HP:0002007	Frontal bossing
HP:0002084	Encephalocele
HP:0002093	Respiratory insufficiency
HP:0002381	Aphasia

GWAS associations

2 associations:

Study	Trait	p-value
GCST004132_118	Crohn’s disease	2e-19
GCST004131_47	Inflammatory bowel disease	3e-15

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
C567831	Emery-Dreifuss Muscular Dystrophy 4 *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5725056 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,601 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

1 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,601

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (2 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
8.00	IC50	10	nM	MOLIBRESIB
7.75	Kd	18	nM	MOLIBRESIB
5.30	Kd	4983	nM	CHEMBL5653589
5.30	ED50	4983	nM	CHEMBL5653589

PubChem BioAssay actives

3 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	2178454: Inhibition of TCOF1 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.0100	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149565: Binding affinity to human TCOF1 incubated for 45 mins by Kinobead based pull down assay	kd	4.9835	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases abundance, decreases expression, decreases methylation, affects cotreatment, affects expression	5
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	4
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	3
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	2
Acrolein	increases abundance, affects cotreatment, increases oxidation	2
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
Estradiol	increases expression	2
Ozone	increases oxidation, increases abundance, affects cotreatment	2
Tretinoin	decreases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
TAK-243	decreases sumoylation	1
ginger extract	affects cotreatment, affects expression, increases abundance	1
dicrotophos	increases expression	1
testosterone enanthate	affects expression	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
methylparaben	increases expression	1
potassium chromate(VI)	increases expression	1
aflatoxin B2	increases methylation	1
cupric chloride	increases expression	1
coumarin	affects phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
NSC 689534	affects binding, decreases 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
CHEMBL5652607	Binding	Binding affinity to human TCOF1 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 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A8ZG	PSHi002-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 301 trials:

NCT	Phase	Status	Title
NCT00205881	Phase 4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	Phase 4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	Phase 4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	Phase 4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	Phase 4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	Phase 3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	Phase 3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	Phase 3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	Phase 3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	Phase 2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	Phase 2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	Phase 2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	Phase 2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	Phase 2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	Phase 2	WITHDRAWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	Phase 2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	Phase 2	UNKNOWN	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	Phase 2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	Phase 2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	Phase 2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	Phase 2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	Phase 1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	Phase 1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	Phase 1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	Phase 1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	Phase 1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	Phase 1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	Phase 1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	Phase 1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	Phase 1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT04931056	Not specified	COMPLETED	A Post Market Clinical Follow-up Study on Biomet Microfixation HTR PEKK (Midface), Facial & Mandibular Plates.
NCT00486577	Phase 2/3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	Phase 2/3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	Phase 2/3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	Phase 2/3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	Phase 1/2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	Phase 1/2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	Phase 1/2	ACTIVE_NOT_RECRUITING	A Phase I/II Clinical Trial With SENS-501 in Children Suffering From Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	Phase 1/2	ACTIVE_NOT_RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	Phase 1/2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound
NCT01109576	Early Phase 1	COMPLETED	Workshops for Veterans With Vision and Hearing Loss
NCT03300687	Early Phase 1	COMPLETED	First in Human Safety Study of FX-322 in Adults Undergoing Cochlear Implantation
NCT04777669	Early Phase 1	UNKNOWN	Removing Background Talker Noise for Cochlear Implant Users
NCT06025032	Early Phase 1	WITHDRAWN	a Study in Subjects With Otoferlin Mutation-related Hearing Loss Using RNA Base-eDiting Therapy(SOUND)
NCT00001668	Not specified	COMPLETED	Endolymphatic Sac Tumors in a Population of Patients With Von Hippel-Lindau Disease:The Natural History and Pathobiology, and a Prospective Non-Randomized Clinical Trial of Hearing Preservation Surgery in Patients With Early Stage Endolymphatic Sac Tumors
NCT00001782	Not specified	COMPLETED	Areas of Brain Responsible for Understanding American Sign Language
NCT00013468	Not specified	COMPLETED	Early Diagnosis of Steroid-Responsive & No-Responsive Hearing Loss
NCT00016471	Not specified	COMPLETED	A Genetic Analysis of Usher Syndrome in Ashkenazi Jews
NCT00018486	Not specified	COMPLETED	Epidemiology of Hearing Loss in Diabetic and Non-Diabetic Veterans
NCT00106743	Not specified	COMPLETED	Natural History and Genetic Studies of Usher Syndrome
NCT00110604	Not specified	COMPLETED	The Effect of Folic Acid on Atherosclerosis, Cognitive Performance and Hearing
NCT00126113	Not specified	COMPLETED	The Performance-Perceptual Test as a Counseling Tool
NCT00260663	Not specified	COMPLETED	The Hearing Aid Effectiveness After Aural Rehabilitation (HEAR) Trial
NCT00371436	Not specified	COMPLETED	Progressive Intervention Program for Tinnitus Management
NCT00371449	Not specified	COMPLETED	Predicting Success With Hearing Aids
NCT00371839	Not specified	COMPLETED	Clinical Applications for Time-Compressed Speech Tests
NCT00400413	Not specified	COMPLETED	Neuroanatomy of Reading in Congenital Deafness.
NCT00438334	Not specified	COMPLETED	Real-World Benefit From Directional Hearing Aids
NCT00451503	Not specified	COMPLETED	Evaluation of Middle Ear Implantation
NCT00484224	Not specified	UNKNOWN	Audiological Disturbances in Vitiligo

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for TCOF1 across ~30M SureChEMBL compounds — explore on Sugi Predict.