CTC1

Summary

CTC1 (CST telomere replication complex component 1, HGNC:26169) is a protein-coding gene on chromosome 17p13.1, encoding CST complex subunit CTC1 (Q2NKJ3). Component of the CST complex proposed to act as a specialized replication factor promoting DNA replication under conditions of replication stress or natural replication barriers such as the telomere duplex. It is a selective cancer dependency (DepMap: 35.5% of cell lines).

This gene encodes a component of the CST complex. This complex plays an essential role in protecting telomeres from degradation. This protein also forms a heterodimer with the CST complex subunit STN1 to form the enzyme alpha accessory factor. This enzyme regulates DNA replication. Mutations in this gene are the cause of cerebroretinal microangiopathy with calcifications and cysts. Alternate splicing results in both coding and non-coding variants.

Source: NCBI Gene 80169 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cerebroretinal microangiopathy with calcifications and cysts 1 (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 1,660 total — 88 pathogenic, 34 likely-pathogenic
• Phenotypes (HPO): 97
• Cancer dependency (DepMap): dependent in 35.5% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_025099

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26169
Approved symbol	CTC1
Name	CST telomere replication complex component 1
Location	17p13.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ22170, AAF132
Ensembl gene	ENSG00000178971
Ensembl biotype	protein_coding
OMIM	613129
Entrez	80169

Gene structure

Transcript identifiers

Ensembl transcripts: 33 — 15 retained_intron, 9 protein_coding, 8 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000449476, ENST00000578240, ENST00000578441, ENST00000578537, ENST00000579066, ENST00000580299, ENST00000581671, ENST00000581729, ENST00000581967, ENST00000583254, ENST00000584439, ENST00000584842, ENST00000643543, ENST00000651323, ENST00000699849, ENST00000699850, ENST00000699851, ENST00000699852, ENST00000699853, ENST00000699854, ENST00000699855, ENST00000699856, ENST00000699857, ENST00000699858, ENST00000699859, ENST00000699860, ENST00000699861, ENST00000699862, ENST00000868169, ENST00000932859, ENST00000932860, ENST00000932861, ENST00000968384

RefSeq mRNA: 2 — MANE Select: NM_025099 NM_001411067, NM_025099

CCDS: CCDS42259, CCDS92251

Canonical transcript exons

ENST00000651323 — 23 exons

Exon	Start	End
ENSE00001235008	8229891	8229968
ENSE00001334306	8232361	8232475
ENSE00001334309	8232906	8233032
ENSE00001334317	8235831	8235959
ENSE00001334319	8236058	8236342
ENSE00001334330	8242985	8243148
ENSE00001353475	8235053	8235285
ENSE00003458281	8229302	8229446
ENSE00003552048	8228727	8228892
ENSE00003554655	8234455	8234655
ENSE00003556017	8229142	8229206
ENSE00003564070	8231726	8231815
ENSE00003571009	8231903	8232227
ENSE00003581250	8234749	8234926
ENSE00003641946	8228503	8228629
ENSE00003658547	8230563	8230651
ENSE00003668315	8237375	8237519
ENSE00003678011	8231276	8231469
ENSE00003679303	8238392	8238629
ENSE00003689045	8238031	8238242
ENSE00003694372	8230294	8230468
ENSE00003841312	8224815	8228319
ENSE00003847394	8248004	8248056

Expression profiles

Bgee: expression breadth ubiquitous, 198 present calls, max score 96.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.0561 / max 150.6310, expressed in 1748 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
164425	11.0561	1748

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	96.20	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.40	gold quality
cerebellar hemisphere	UBERON:0002245	94.55	gold quality
cerebellar cortex	UBERON:0002129	94.30	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.74	gold quality
right uterine tube	UBERON:0001302	93.39	gold quality
spleen	UBERON:0002106	93.32	gold quality
mucosa of stomach	UBERON:0001199	93.17	gold quality
right lobe of thyroid gland	UBERON:0001119	93.13	gold quality
left ovary	UBERON:0002119	93.09	gold quality
right ovary	UBERON:0002118	92.72	gold quality
left lobe of thyroid gland	UBERON:0001120	92.53	gold quality
adenohypophysis	UBERON:0002196	92.34	gold quality
body of pancreas	UBERON:0001150	92.32	gold quality
upper lobe of left lung	UBERON:0008952	92.15	gold quality
body of uterus	UBERON:0009853	92.12	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.05	gold quality
lower esophagus muscularis layer	UBERON:0035833	91.69	gold quality
cerebellum	UBERON:0002037	91.67	gold quality
lower esophagus	UBERON:0013473	91.66	gold quality
endocervix	UBERON:0000458	91.64	gold quality
metanephros cortex	UBERON:0010533	91.53	gold quality
body of stomach	UBERON:0001161	91.45	gold quality
muscle layer of sigmoid colon	UBERON:0035805	91.20	gold quality
thyroid gland	UBERON:0002046	91.19	gold quality
apex of heart	UBERON:0002098	91.10	gold quality
tibial nerve	UBERON:0001323	91.09	gold quality
transverse colon	UBERON:0001157	91.03	gold quality
colonic epithelium	UBERON:0000397	91.02	gold quality
descending thoracic aorta	UBERON:0002345	91.01	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

miRNA regulators (miRDB)

77 targeting CTC1, 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-5011-5P	100.00	83.46	5820
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-623	99.76	68.16	1170
HSA-MIR-3680-3P	99.75	72.51	3095

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 35.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 39)

• Ctc1-Stn1-Ten1 is a replication protein A (RPA)-like complex that is not directly involved in conventional DNA replication at forks but plays a role in DNA metabolism frequently required by telomeres. (PMID:19854130)
• CTC1 participates in telomere maintenance in diverse species and that a CST-like complex is required for telomere integrity in multicellular organisms. (PMID:19854131)
• Mutations in CTC1, encoding conserved telomere maintenance component 1, cause Coats plus. (PMID:22267198)
• Observed four recessively inherited compound heterozygous mutations in CTC1, which encodes the CTS telomere maintenance complex component 1. (PMID:22387016)
• CTC1 Mutations are associated with dyskeratosis congenita. (PMID:22532422)
• the human CST (CTC1, STN1 and TEN1) complex, previously implicated in telomere protection and DNA metabolism, inhibits telomerase activity through primer sequestration and physical interaction with the protection of telomeres 1 (POT1)-TPP1 telomerase processivity factor (PMID:22763445)
• CTC1-STN1-TEN1 complex rescues stalled replication forks during conditions of replication stress, such as those found at natural replication barriers, likely by facilitating dormant origin firing (PMID:22863775)
• Genome-wide meta-analysis points to CTC1 and ZNF676 as genes regulating telomere homeostasis in humans. (PMID:23001564)
• The mammalian CST (CTC1-STN1-TEN1) complex is directly involved at several stages of telomere end formation and CST seems to play critical roles in coordinating telomerase elongation and fill-in synthesis to complete telomere replication. (PMID:23851344)
• CTC1 mutations promote telomere dysfunction by decreasing the stability of STN1 to reduce its ability to interact with DNA Polalpha, thus highlighting a previously unknown mechanism to induce telomere dysfunction. (PMID:23869908)
• identify CTC1 disease mutations that disrupt CST complex formation, the physical interaction with DNA polymerase alpha-primase (polalpha-primase), telomeric ssDNA binding in vitro, accumulation in the nucleus, and/or telomere association in vivo (PMID:24115768)
• we explored two SNPs in genes associated either with telomere biology (OBFC1) or with LTL (OBCF1 and CTC1). Interestingly, we observed that genetic variation does not account for LTL at birth (PMID:25598199)
• CTC1 gene screening confirmed the diagnosis of cerebro-retinal microangiopathy with calcifications and cysts with the identification of heterozygous deleterious mutations (PMID:25843205)
• Coats plus syndrome also known as cerebroretinal microangiopathy with calcifications and cysts, is an autosomal recessive pleomorphic disorder caused by the CTS telomere maintenance complex component 1 gene. (PMID:25906927)
• an Indian family links Coats plus syndrome and dextrocardia with a homozygous novel CTC1 and a rare HES7 variation (PMID:25928698)
• HBV DNAPTP1 downregulated the expression of SWI5 and CTC1 at translation level. (PMID:27265469)
• CTC1/STN1/TEN1 (CST) deficiency diminishes HU-induced RAD51 foci formation. (PMID:27487043)
• TERT-mediated G-strand extension and Ctc1-Stn1-Ten1-mediated C-strand fill-in are equally important for telomere length maintenance. (PMID:28334750)
• The findings imply that theCTC1/STN1/TEN1 complex(CST )complex plays an important role in regulating telomere maintenance in alternative-lengthening of telomeres(ALT) cells. (PMID:28366536)
• Findings indicate the OB-fold domain contributes to efficient CST telomere replication complex component 1 (Ctc1) telomere localization and chromosome end maintenance. (PMID:29228254)
• Studies indicate telomere-binding proteins CTC1-STN1-TEN1 (CST) dysfunction and mutation is associated with several genetic diseases and cancers [Review]. (PMID:29293451)
• Results show that disease-causing CTC1 mutations induce spontaneous chromosome breakage and severe chromosome fragmentation that are further elevated by replication stress, leading to global genome instabilities. (PMID:29481669)
• Impaired interaction between CTC1(L1142H) :STN1 and DNA Pol-alpha results in increased telomerase recruitment to telomeres and further telomere elongation, revealing that C:S binding to DNA Pol-alpha is required to fully repress telomerase activity. (PMID:29774655)
• CTC1-STN1 terminates TERT while STN1-TEN1 enables C-strand synthesis during telomere replication in colon cancer cells. (PMID:30026550)
• CTC1 pathogenic variants can present with unusual manifestations of progeria accompanied with recurrent bone fractures. (PMID:30393977)
• CST functions in two distinct aspects of genome-wide DNA replication, namely, origin licensing and replisome assembly. CST interacts with additional replisome components, MCM and AND-1. (PMID:30979824)
• Ophthalmic findings and a novel CTC1 gene mutation in coats plus syndrome: a case report. (PMID:33034244)
• Human CST complex protects stalled replication forks by directly blocking MRE11 degradation of nascent-strand DNA. (PMID:33210317)
• Human CTC1 promotes TopBP1 stability and CHK1 phosphorylation in response to telomere dysfunction and global replication stress. (PMID:33269665)
• CST in maintaining genome stability: Beyond telomeres. (PMID:33780718)
• Structural genomics approach to investigate deleterious impact of nsSNPs in conserved telomere maintenance component 1. (PMID:33986331)
• The DNA-binding protein CST associates with the cohesin complex and promotes chromosome cohesion. (PMID:34339741)
• Primary Ovarian Failure in Addition to Classical Clinical Features of Coats Plus Syndrome in a Female Carrying 2 Truncating Variants of CTC1. (PMID:34706368)
• Pan-cancer analysis reveals that CTC1-STN1-TEN1 (CST) complex may have a key position in oncology. (PMID:35134616)
• Structures of the human CST-Polalpha-primase complex bound to telomere templates. (PMID:35830881)
• Reconstitution of a telomeric replicon organized by CST. (PMID:35831508)
• CTC1 OB-B interaction with TPP1 terminates telomerase and prevents telomere overextension. (PMID:37021555)
• A novel mutation of CTC1 leads to telomere shortening in a chinese family with interstitial lung disease. (PMID:37978541)
• CST-polymerase alpha-primase solves a second telomere end-replication problem. (PMID:38418884)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ctc1	ENSDARG00000070119
mus_musculus	Ctc1	ENSMUSG00000020898
rattus_norvegicus	Ctc1	ENSRNOG00000005357

Protein

Protein identifiers

CST complex subunit CTC1 — Q2NKJ3 (reviewed: Q2NKJ3)

Alternative names: Conserved telomere maintenance component 1, HBV DNAPTP1-transactivated protein B

All UniProt accessions (10): Q2NKJ3, A0A2R8Y574, A0A8V8TNY5, A0A8V8TP86, A0A8V8TQB6, A0A8V8TQN9, A0A8V8TQP4, J3KSR1, J3KSZ1, J3QKT7

UniProt curated annotations — full annotation on UniProt →

Function. Component of the CST complex proposed to act as a specialized replication factor promoting DNA replication under conditions of replication stress or natural replication barriers such as the telomere duplex. The CST complex binds single-stranded DNA with high affinity in a sequence-independent manner, while isolated subunits bind DNA with low affinity by themselves. Initially the CST complex has been proposed to protect telomeres from DNA degradation. However, the CST complex has been shown to be involved in several aspects of telomere replication. The CST complex inhibits telomerase and is involved in telomere length homeostasis; it is proposed to bind to newly telomerase-synthesized 3’ overhangs and to terminate telomerase action implicating the association with the ACD:POT1 complex thus interfering with its telomerase stimulation activity. The CST complex is also proposed to be involved in fill-in synthesis of the telomeric C-strand probably implicating recruitment and activation of DNA polymerase alpha. The CST complex facilitates recovery from many forms of exogenous DNA damage; seems to be involved in the re-initiation of DNA replication at repaired forks and/or dormant origins. Involved in telomere maintenance. Involved in genome stability. May be in involved in telomeric C-strand fill-in during late S/G2 phase.

Subunit / interactions. Component of the CST complex, composed of TEN1/C17orf106, CTC1/C17orf68 and STN1; in the complex interacts directly with STN1. Interacts with ACD and POT1.

Subcellular location. Nucleus. Chromosome. Telomere.

Disease relevance. Cerebroretinal microangiopathy with calcifications and cysts 1 (CRMCC1) [MIM:612199] An autosomal recessive pleiomorphic disorder characterized primarily by intracranial calcifications, leukodystrophy, and brain cysts, resulting in spasticity, ataxia, dystonia, seizures, and cognitive decline. Patients also have retinal telangiectasia and exudates (Coats disease) as well as extraneurologic manifestations, including osteopenia with poor bone healing and a high risk of gastrointestinal bleeding and portal hypertension caused by vasculature ectasias in the stomach, small intestine, and liver. Some individuals also have hair, skin, and nail changes, as well as anemia and thrombocytopenia. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the CTC1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q2NKJ3-1	1	yes
Q2NKJ3-2	2

RefSeq proteins (2): NP_001397996, NP_079375* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029156	CTC1	Family
IPR042617	CTC1-like	Family

Pfam: PF15489

UniProt features (138 total): strand 72, helix 27, turn 15, sequence variant 13, sequence conflict 6, splice variant 3, chain 1, region of interest 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
5W2L	X-RAY DIFFRACTION	1.86
6W6W	ELECTRON MICROSCOPY	3
8D0B	ELECTRON MICROSCOPY	3.43
8SOJ	ELECTRON MICROSCOPY	3.8
8SOK	ELECTRON MICROSCOPY	4.1
8D0K	ELECTRON MICROSCOPY	4.27
7U5C	ELECTRON MICROSCOPY	4.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q2NKJ3-F1	78.01	0.20

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-174411	Polymerase switching on the C-strand of the telomere
R-HSA-174430	Telomere C-strand synthesis initiation

MSigDB gene sets: 416 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_UP, ATF_B, GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, GOBP_CHROMOSOME_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_DNA_REPLICATION, GOBP_NEGATIVE_REGULATION_OF_TELOMERE_MAINTENANCE_VIA_TELOMERASE, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_TELOMERE_CAPPING, GOBP_POSITIVE_REGULATION_OF_FIBROBLAST_PROLIFERATION, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_GROWTH, GOBP_THYMUS_DEVELOPMENT, GOBP_TELOMERE_MAINTENANCE_VIA_TELOMERE_LENGTHENING, GOBP_TELOMERE_ORGANIZATION, CREBP1_Q2

GO Biological Process (15): telomere maintenance (GO:0000723), DNA damage response (GO:0006974), regulation of G2/M transition of mitotic cell cycle (GO:0010389), telomere maintenance via telomere lengthening (GO:0010833), telomere capping (GO:0016233), negative regulation of telomere maintenance via telomerase (GO:0032211), multicellular organism growth (GO:0035264), positive regulation of DNA replication (GO:0045740), positive regulation of fibroblast proliferation (GO:0048146), spleen development (GO:0048536), thymus development (GO:0048538), bone marrow development (GO:0048539), hematopoietic stem cell proliferation (GO:0071425), replicative senescence (GO:0090399), chromosome organization (GO:0051276)

GO Molecular Function (5): single-stranded DNA binding (GO:0003697), telomeric repeat DNA binding (GO:0042162), G-rich strand telomeric DNA binding (GO:0098505), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (6): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), CST complex (GO:1990879), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Telomere C-strand (Lagging Strand) Synthesis	2

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
hematopoietic or lymphoid organ development	3
telomere maintenance	2
cellular anatomical structure	2
DNA metabolic process	1
telomere organization	1
cellular response to stress	1
G2/M transition of mitotic cell cycle	1
regulation of mitotic cell cycle phase transition	1
regulation of cell cycle G2/M phase transition	1
telomere maintenance via telomerase	1
regulation of telomere maintenance via telomerase	1
negative regulation of telomere maintenance via telomere lengthening	1
negative regulation of DNA biosynthetic process	1
multicellular organismal process	1
developmental growth	1
DNA replication	1
regulation of DNA replication	1
positive regulation of DNA metabolic process	1
positive regulation of cell population proliferation	1
fibroblast proliferation	1
regulation of fibroblast proliferation	1
gland development	1
tissue development	1
bone development	1
hemopoiesis	1
stem cell proliferation	1
cell cycle process	1
organelle organization	1
DNA binding	1
sequence-specific DNA binding	1
single-stranded telomeric DNA binding	1
nucleic acid binding	1
binding	1
chromosomal region	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
nuclear telomere cap complex	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

954 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CTC1	STN1	Q9H668	999
CTC1	TEN1	Q86WV5	994
CTC1	TINF2	Q9BSI4	905
CTC1	NHP2	Q9NX24	888
CTC1	RTEL1	Q9NZ71	875
CTC1	WRAP53	Q9BUR4	871
CTC1	NOP10	Q9NPE3	855
CTC1	TERF1	P54274	817
CTC1	DKC1	O60832	815
CTC1	PARN	O95453	766
CTC1	TERT	O14746	733
CTC1	POT1	Q9NUX5	733
CTC1	ZNF676	Q8N7Q3	697
CTC1	POLA1	P09884	681
CTC1	ACD	Q96AP0	677

IntAct

99 interactions, top by confidence:

A	B	Type	Score
STN1	CTC1	psi-mi:“MI:0915”(physical association)	0.880
CTC1	STN1	psi-mi:“MI:0915”(physical association)	0.880
CTC1	STN1	psi-mi:“MI:0403”(colocalization)	0.880
TEN1	CTC1	psi-mi:“MI:0915”(physical association)	0.860
CTC1	TEN1	psi-mi:“MI:0915”(physical association)	0.860
TEN1	CTC1	psi-mi:“MI:0914”(association)	0.860
CTC1	TEN1	psi-mi:“MI:0914”(association)	0.860
KIF24	CCP110	psi-mi:“MI:0914”(association)	0.810
GMNN	MCIDAS	psi-mi:“MI:0914”(association)	0.770
DNAJC7	PLD2	psi-mi:“MI:0914”(association)	0.640
TFAP4	ANGPTL7	psi-mi:“MI:0914”(association)	0.640
USP4	PRPF3	psi-mi:“MI:0914”(association)	0.640
APPBP2	CTC1	psi-mi:“MI:0915”(physical association)	0.560
CTC1	APPBP2	psi-mi:“MI:0915”(physical association)	0.560
STN1	SMCO3	psi-mi:“MI:0914”(association)	0.530
CACNG5	ZNF316	psi-mi:“MI:0914”(association)	0.530
KCTD17	CBX4	psi-mi:“MI:0914”(association)	0.530
ZNF764	SH3PXD2B	psi-mi:“MI:0914”(association)	0.530

BioGRID (86): CTC1 (Affinity Capture-Western), CTC1 (Reconstituted Complex), CTC1 (Two-hybrid), CTC1 (Affinity Capture-MS), CTC1 (Affinity Capture-MS), CTC1 (Affinity Capture-MS), CTC1 (Affinity Capture-MS), CTC1 (Affinity Capture-MS), CTC1 (Affinity Capture-MS), CTC1 (Affinity Capture-MS), CTC1 (Affinity Capture-MS), CTC1 (Affinity Capture-MS), CTC1 (Affinity Capture-MS), CTC1 (Affinity Capture-MS), CTC1 (Affinity Capture-MS)

ESM2 similar proteins: A0JMF1, A2CI97, A3KNA7, A6NE52, B2GV47, E7FAW3, P60330, Q06ZW3, Q0VDN7, Q12769, Q1M161, Q2NKJ3, Q2YDQ5, Q3SYW0, Q3T1I9, Q3U6Q4, Q4FZR5, Q5EE38, Q5PNP6, Q5RDX3, Q5SUQ9, Q5TYP4, Q5ZIB8, Q6AYM1, Q6DG91, Q6IRN0, Q6NSI4, Q6NYX6, Q6P4K6, Q6PH58, Q6ZNJ1, Q6ZPG2, Q6ZQA0, Q7T006, Q7ZVM9, Q80TE0, Q80VA5, Q8BJW5, Q8BMG1, Q8C779

Diamond homologs: Q2NKJ3, Q5RDX3, Q5SUQ9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CTC1	“form complex”	“CST complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

1660 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	88
Likely pathogenic	34
Uncertain significance	828
Likely benign	534
Benign	57

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1060669	NM_025099.6(CTC1):c.3538C>T (p.Gln1180Ter)	Pathogenic
1072838	NM_025099.6(CTC1):c.458G>A (p.Trp153Ter)	Pathogenic
1076259	NM_025099.6(CTC1):c.591del (p.Val198fs)	Pathogenic
1322170	NM_025099.6(CTC1):c.2581G>T (p.Glu861Ter)	Pathogenic
1338425	NM_025099.6(CTC1):c.2847_2850del (p.Val948_Tyr949insTer)	Pathogenic
1342131	NM_025099.6(CTC1):c.2T>C (p.Met1Thr)	Pathogenic
1397961	NM_025099.6(CTC1):c.812G>A (p.Trp271Ter)	Pathogenic
1405899	NM_025099.6(CTC1):c.2291_2292del (p.Tyr764fs)	Pathogenic
1433246	NM_025099.6(CTC1):c.2978_2981dup (p.Leu995fs)	Pathogenic
1439373	NM_025099.6(CTC1):c.1918C>T (p.Gln640Ter)	Pathogenic
1442522	NM_025099.6(CTC1):c.1042del (p.Ser348fs)	Pathogenic
1447492	NM_025099.6(CTC1):c.2880dup (p.Leu961fs)	Pathogenic
1451275	NM_025099.6(CTC1):c.880C>T (p.Gln294Ter)	Pathogenic
1453166	NM_025099.6(CTC1):c.1156C>T (p.Gln386Ter)	Pathogenic
1454320	NC_000017.10:g.(?8131498)(8151354_?)del	Pathogenic
1455096	NM_025099.6(CTC1):c.1683dup (p.Lys562Ter)	Pathogenic
1456511	NM_025099.6(CTC1):c.303_316del (p.Asn102fs)	Pathogenic
1521413	NM_025099.6(CTC1):c.3456_3462del (p.Arg1153fs)	Pathogenic
1685681	NM_025099.6(CTC1):c.2346del (p.Leu783fs)	Pathogenic
2021605	NM_025099.6(CTC1):c.58C>T (p.Gln20Ter)	Pathogenic
2037045	NM_025099.6(CTC1):c.341del (p.Leu113_Leu114insTer)	Pathogenic
2043467	NM_025099.6(CTC1):c.1623_1624del (p.Arg542fs)	Pathogenic
2053060	NM_025099.6(CTC1):c.2071C>T (p.Gln691Ter)	Pathogenic
2066906	NM_025099.6(CTC1):c.1814_1818del (p.Ala605fs)	Pathogenic
2091505	NM_025099.6(CTC1):c.1934dup (p.Arg646fs)	Pathogenic
2096265	NM_025099.6(CTC1):c.1774_1784dup (p.Cys596fs)	Pathogenic
2153209	NM_025099.6(CTC1):c.694C>T (p.Arg232Ter)	Pathogenic
2156625	NM_025099.6(CTC1):c.1190dup (p.Gly398fs)	Pathogenic
2175491	NM_025099.6(CTC1):c.2605C>T (p.Gln869Ter)	Pathogenic
2175818	NM_025099.6(CTC1):c.2770dup (p.Ala924fs)	Pathogenic

SpliceAI

3738 predictions. Top by Δscore:

Variant	Effect	Δscore
17:8228497:CCTTA:C	donor_loss	1.0000
17:8228498:CTTA:C	donor_loss	1.0000
17:8228499:TTAC:T	donor_loss	1.0000
17:8228500:TACCT:T	donor_loss	1.0000
17:8228501:A:AT	donor_loss	1.0000
17:8228502:C:T	donor_loss	1.0000
17:8228628:GA:G	acceptor_gain	1.0000
17:8228630:C:CC	acceptor_gain	1.0000
17:8231274:A:AC	donor_gain	1.0000
17:8231275:C:CC	donor_gain	1.0000
17:8231275:CTTG:C	donor_gain	1.0000
17:8231276:TTGT:T	donor_gain	1.0000
17:8231277:TGTC:T	donor_gain	1.0000
17:8232057:CG:C	donor_gain	1.0000
17:8232061:T:TA	donor_gain	1.0000
17:8232072:T:TA	donor_gain	1.0000
17:8232226:CT:C	acceptor_gain	1.0000
17:8232476:C:CC	acceptor_gain	1.0000
17:8232908:ATCAG:A	donor_gain	1.0000
17:8232909:T:C	donor_gain	1.0000
17:8235042:AGCCT:A	donor_gain	1.0000
17:8235046:T:TA	donor_gain	1.0000
17:8235051:A:AC	donor_gain	1.0000
17:8235052:C:CC	donor_gain	1.0000
17:8235108:A:C	donor_gain	1.0000
17:8236095:T:A	donor_gain	1.0000
17:8228316:GGTT:G	acceptor_gain	0.9900
17:8228320:C:CC	acceptor_gain	0.9900
17:8228325:G:GC	acceptor_gain	0.9900
17:8228501:A:AC	donor_gain	0.9900

AlphaMissense

7776 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:8236324:A:G	W271R	0.994
17:8236324:A:T	W271R	0.994
17:8238191:A:G	W163R	0.993
17:8238191:A:T	W163R	0.993
17:8228879:C:G	D1079H	0.992
17:8228864:C:G	A1084P	0.990
17:8236240:A:G	W299R	0.987
17:8236240:A:T	W299R	0.987
17:8231748:C:G	R818P	0.985
17:8230321:A:G	F969S	0.983
17:8230429:A:T	V933D	0.983
17:8237432:G:C	F245L	0.983
17:8237432:G:T	F245L	0.983
17:8237434:A:G	F245L	0.983
17:8238578:G:C	S83R	0.981
17:8238578:G:T	S83R	0.981
17:8238580:T:G	S83R	0.981
17:8228804:A:G	W1104R	0.980
17:8228804:A:T	W1104R	0.980
17:8236322:C:A	W271C	0.980
17:8236322:C:G	W271C	0.980
17:8238418:C:G	D137H	0.980
17:8228852:A:G	C1088R	0.979
17:8228878:T:A	D1079V	0.979
17:8229373:A:G	C1029R	0.979
17:8231782:A:G	W807R	0.979
17:8231782:A:T	W807R	0.979
17:8228877:A:C	D1079E	0.978
17:8228877:A:T	D1079E	0.978
17:8230327:A:T	V967D	0.978

dbSNP variants (sampled 300 via entrez): RS1000047631 (17:8226083 A>G), RS1000063340 (17:8227125 T>C), RS1000073790 (17:8238850 G>T), RS1000087399 (17:8244586 C>T), RS1000241243 (17:8247064 G>A,C), RS1000619547 (17:8240547 G>A,T), RS1000787486 (17:8249720 T>A,C), RS1000921938 (17:8234009 G>T), RS1001094257 (17:8245750 A>G), RS1001178402 (17:8248685 G>A,C), RS1001478544 (17:8242603 C>T), RS1001614237 (17:8226108 A>G), RS1001797761 (17:8229172 G>A), RS1002077441 (17:8241561 A>C,G), RS1002216604 (17:8230874 G>A)

Disease associations

OMIM: gene MIM:613129 | disease phenotypes: MIM:127550, MIM:612199, MIM:178500

GenCC curated gene-disease

Disease	Classification	Inheritance
cerebroretinal microangiopathy with calcifications and cysts 1	Definitive	Autosomal recessive
dyskeratosis congenita	Definitive	Autosomal recessive
Coats plus syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
cerebroretinal microangiopathy with calcifications and cysts 1	Definitive	AR

Mondo (4): dyskeratosis congenita (MONDO:0015780), cerebroretinal microangiopathy with calcifications and cysts 1 (MONDO:0024564), Coats plus syndrome (MONDO:0012815), interstitial lung disease 2 (MONDO:0800497)

Orphanet (4): Dyskeratosis congenita (Orphanet:1775), Coats plus syndrome (Orphanet:313838), Idiopathic pulmonary fibrosis (Orphanet:2032), Acute interstitial pneumonia (Orphanet:79126)

HPO phenotypes

97 total (30 of 97 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000008	Abnormal morphology of female internal genitalia
HP:0000035	Abnormal testis morphology
HP:0000164	Abnormality of the dentition
HP:0000327	Hypoplasia of the maxilla
HP:0000365	Hearing impairment
HP:0000498	Blepharitis
HP:0000499	Abnormal eyelash morphology
HP:0000518	Cataract
HP:0000534	Abnormal eyebrow morphology
HP:0000600	Abnormality of the pharynx
HP:0000618	Blindness
HP:0000648	Optic atrophy
HP:0000668	Hypodontia
HP:0000670	Carious teeth
HP:0000679	Taurodontia
HP:0000704	Periodontitis
HP:0000819	Diabetes mellitus
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0000963	Thin skin
HP:0000975	Hyperhidrosis
HP:0000982	Palmoplantar keratoderma
HP:0001034	Hypermelanotic macule
HP:0001053	Hypopigmented skin patches
HP:0001231	Abnormal fingernail morphology
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001260	Dysarthria

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001546_5	Parkinson’s disease (motor and cognition)	9.000000e-06
GCST001697_2	Telomere length	2.000000e-08
GCST004139_15	Bipolar disorder	2.000000e-07

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D019871	Dyskeratosis Congenita	C15.378.190.223.500.750; C16.131.831.150; C16.320.322.108; C16.320.850.235; C17.800.804.150; C17.800.827.235
C567401	Cerebroretinal Microangiopathy with Calcifications and Cysts (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Formaldehyde	affects response to substance, decreases expression	2
Cyclosporine	increases expression, increases methylation	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
dicrotophos	increases expression	1
alpha-pinene	increases abundance, affects cotreatment, decreases expression	1
hydroxyhydroquinone	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects cotreatment, increases methylation	1
jinfukang	increases expression	1
(+)-JQ1 compound	increases expression	1
Sunitinib	increases expression	1
Fulvestrant	increases methylation, decreases methylation, affects cotreatment	1
Acetaminophen	increases expression	1
Acrolein	increases abundance, affects cotreatment, decreases expression	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance	1
Amiodarone	increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Doxorubicin	decreases expression	1
Manganese	decreases expression, increases abundance	1
Methyl Methanesulfonate	decreases expression	1
Ozone	affects cotreatment, decreases expression, increases abundance	1
Quercetin	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Vincristine	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00004787	PHASE2	COMPLETED	Phase II Pilot Study of Granulocyte Colony-Stimulating Factor for Inherited Bone Marrow Failure Syndromes
NCT01659606	PHASE2	ACTIVE_NOT_RECRUITING	Radiation- and Alkylator-free Bone Marrow Transplantation Regimen for Patients With Dyskeratosis Congenita
NCT03579875	PHASE2	RECRUITING	Alpha/Beta TCD HCT in Patients With Inherited BMF Disorders
NCT04232085	PHASE2	RECRUITING	Regenerative Medicine to Restore Hematopoiesis and Immune Function in Immunodeficiencies and Inherited Bone Marrow Failures
NCT04638517	PHASE2	TERMINATED	The TELO-SCOPE Study: Attenuating Telomere Attrition With Danazol. Is There Scope to Dramatically Improve Health Outcomes for Adults and Children With Pulmonary Fibrosis
NCT01917708	PHASE1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT06477614	PHASE1	RECRUITING	Anti-cancer DC Cell Vaccination to Treat Solid Tumors
NCT06817590	PHASE1	RECRUITING	Nucleoside Therapy in Patients With Telomere Biology Disorders
NCT00455312	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant (SCT) for Dyskeratosis Congenita or SAA
NCT01001598	PHASE1/PHASE2	TERMINATED	Safety and Efficacy Trial of Danazol in Patients With Fanconi Anemia or Dyskeratosis Congenita
NCT00027274	Not specified	RECRUITING	Cancer in Inherited Bone Marrow Failure Syndromes
NCT00499070	Not specified	COMPLETED	Assessing Immune Function in Young Patients With Cytopenia That Did Not Respond to Treatment
NCT01319851	Not specified	TERMINATED	Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation
NCT02162420	Not specified	COMPLETED	Hematopoietic Stem Cell Transplant for Dyskeratosis Congenita or Severe Aplastic Anemia
NCT02720679	Not specified	RECRUITING	Investigation of the Genetics of Hematologic Diseases
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT04959188	Not specified	COMPLETED	Needs Assessment for Individuals and Families Affected by Dyskeratosis Congenita (DC) and Related Telomere Biology Disorders (TBD)
NCT06731036	Not specified	AVAILABLE	Expanded Access to CD34+ Selection Utilizing Miltenyi CliniMACS Prodigy® for Patients Receiving Peripheral Blood Stem Cell Transplantations and Stem Cell Boosts
NCT06372353	Not specified	COMPLETED	The Effect Of Baduanjin Exercises In Patients With Idiopathic Pulmonary Fibrosis
NCT06644144	Not specified	RECRUITING	P4O2 ILD Extension