STN1

Summary

STN1 (STN1 subunit of CST complex, HGNC:26200) is a protein-coding gene on chromosome 10q24.33, encoding CST complex subunit STN1 (Q9H668). 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: 41.0% of cell lines).

OBFC1 and C17ORF68 (MIM 613129) are subunits of an alpha accessory factor (AAF) that stimulates the activity of DNA polymerase-alpha-primase (see MIM 176636), the enzyme that initiates DNA replication (Casteel et al., 2009 [PubMed 19119139]). OBFC1 also appears to function in a telomere-associated complex with C17ORF68 and TEN1 (C17ORF106; MIM 613130) (Miyake et al., 2009 [PubMed 19854130]).

Source: NCBI Gene 79991 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cerebroretinal microangiopathy with calcifications and cysts 2 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 63
• Clinical variants (ClinVar): 317 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 39
• Cancer dependency (DepMap): dependent in 41.0% of screened cell lines
• MANE Select transcript: NM_024928

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26200
Approved symbol	STN1
Name	STN1 subunit of CST complex
Location	10q24.33
Locus type	gene with protein product
Status	Approved
Aliases	FLJ22559, bA541N10.2
Ensembl gene	ENSG00000107960
Ensembl biotype	protein_coding
OMIM	613128
Entrez	79991

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 23 protein_coding, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000224950, ENST00000369764, ENST00000466828, ENST00000472951, ENST00000698241, ENST00000698242, ENST00000698243, ENST00000698244, ENST00000698245, ENST00000698246, ENST00000698297, ENST00000698298, ENST00000698299, ENST00000698300, ENST00000698301, ENST00000698302, ENST00000698303, ENST00000698304, ENST00000698305, ENST00000698328, ENST00000893740, ENST00000893741, ENST00000893742, ENST00000970561, ENST00000970562, ENST00000970563, ENST00000970564

RefSeq mRNA: 1 — MANE Select: NM_024928 NM_024928

CCDS: CCDS7552

Canonical transcript exons

ENST00000224950 — 10 exons

Exon	Start	End
ENSE00001177572	103918100	103918184
ENSE00003477366	103897548	103897719
ENSE00003477522	103917462	103917656
ENSE00003498535	103889072	103889144
ENSE00003500216	103900062	103900223
ENSE00003501820	103892130	103892252
ENSE00003548614	103905091	103905156
ENSE00003585827	103910527	103910622
ENSE00003594884	103898877	103899000
ENSE00003973081	103877569	103882841

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 93.69.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.5910 / max 106.6443, expressed in 1795 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
111269	11.7396	1791
111267	0.9395	554
111268	0.4061	242
111266	0.2732	127
111264	0.2026	88
111265	0.0300	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	93.69	gold quality
oral cavity	UBERON:0000167	92.87	gold quality
esophagus mucosa	UBERON:0002469	92.59	gold quality
granulocyte	CL:0000094	91.13	gold quality
adrenal tissue	UBERON:0018303	91.01	gold quality
epithelium of esophagus	UBERON:0001976	90.97	gold quality
buccal mucosa cell	CL:0002336	90.89	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	90.75	gold quality
heart left ventricle	UBERON:0002084	90.48	gold quality
esophagus squamous epithelium	UBERON:0006920	90.34	gold quality
pharyngeal mucosa	UBERON:0000355	90.26	gold quality
cardiac ventricle	UBERON:0002082	90.23	gold quality
amniotic fluid	UBERON:0000173	90.16	gold quality
apex of heart	UBERON:0002098	90.08	gold quality
calcaneal tendon	UBERON:0003701	89.95	gold quality
islet of Langerhans	UBERON:0000006	89.67	gold quality
right lung	UBERON:0002167	89.55	gold quality
upper lobe of left lung	UBERON:0008952	89.50	gold quality
gall bladder	UBERON:0002110	89.32	gold quality
right adrenal gland	UBERON:0001233	89.23	gold quality
body of pancreas	UBERON:0001150	89.22	gold quality
left adrenal gland	UBERON:0001234	89.21	gold quality
esophagus	UBERON:0001043	89.14	gold quality
upper lobe of lung	UBERON:0008948	89.14	gold quality
left adrenal gland cortex	UBERON:0035825	89.13	gold quality
right adrenal gland cortex	UBERON:0035827	89.06	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.82	gold quality
pancreas	UBERON:0001264	88.69	gold quality
adrenal gland	UBERON:0002369	88.59	gold quality
heart	UBERON:0000948	88.56	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	10.61

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

159 targeting STN1, 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-3120-5P	100.00	65.56	965
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-7845-5P	99.88	64.88	771

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 41.0% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 34)

• OBFC1 is identical to the previously described 44 kDa subunit of DNA-pol-alpha/primase associated factor (AAF) which increases polymerase-alpha/primase template affinity and stimulate both DNA primase and polymerase-alpha activities in vitro. (PMID:19119139)
• 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)
• Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology. (PMID:20421499)
• 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)
• The Stn1 deficiency leads to persistent and elevated association of DNA polymerase alpha to telomeres, suggesting that Stn1 may modulate the DNA synthesis activity of polalpha rather than controlling the loading of polalpha to telomeres. (PMID:22964711)
• the requirement for STN1/CST in telomere duplex replication correlates with increasing telomere length and replication stress. (PMID:23142664)
• 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 telomere replication. (PMID:23851344)
• A 2-SNP OBFC1 haplotype was associated with higher risk of CHD, and a 3-SNP TERC haplotype was associated with both higher risk of CHD and T2D. (PMID:24349443)
• 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)
• Mutations in STN1 cause Coats plus syndrome and are associated with genomic and telomere defects. (PMID:27432940)
• 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)
• The strongest association with prevalence of overall Cancer was observed for rs9420907 (OBFC1). (PMID:28728697)
• STN1-POLA2 interaction provides a basis for primase-polymerase alpha stimulation by human STN1. A disease-causing mutation in human STN1 engenders a selective defect in POLA2-binding. (PMID:28934486)
• Studies indicate telomere-binding proteins CTC1-STN1-TEN1 (CST) dysfunction and mutation is associated with several genetic diseases and cancers [Review]. (PMID:29293451)
• 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)
• Human STN1, like yeast STN1, is regulated by overlapping open reading frames that strongly reduce STN1 expression. We show that levels of Stn1 in yeast and human cells are reduced by the presence of an upstream overlapping open reading frame. (PMID:30067734)
• The CST complex (CTC1-STN1-TEN1) maintains genome integrity through resolution of G4 structures both ahead of the replication fork and on the lagging strand template (PMID:30976812)
• 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)
• Association of OBFC1 gene single nucleotide polymorphisms with laryngeal carcinoma in Chinese Han male population. (PMID:31016429)
• The study investigated whether six genetic variants previously associated with leukocyte telomere length are correlated with telomere length in peripheral blood mononuclear cells in a cohort of Africans living with and without HIV and undergoing evaluation for tuberculosis (TB). OBFC1 and the genetic sum score of the effect alleles across all six loci were found to be associated with shorter telomere length. (PMID:31388112)
• An Indian child with Coats plus syndrome due to mutations in STN1. (PMID:32627942)
• Human CST complex protects stalled replication forks by directly blocking MRE11 degradation of nascent-strand DNA. (PMID:33210317)
• CST in maintaining genome stability: Beyond telomeres. (PMID:33780718)
• Low frequency variants associated with leukocyte telomere length in the Singapore Chinese population. (PMID:33941849)
• Novel compound heterozygous STN1 variants are associated with Coats Plus syndrome. (PMID:34110109)
• 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)
• CaMKK2 and CHK1 phosphorylate human STN1 in response to replication stress to protect stalled forks from aberrant resection. (PMID:38036565)
• CST-polymerase alpha-primase solves a second telomere end-replication problem. (PMID:38418884)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	stn1	ENSDARG00000007734
mus_musculus	Stn1	ENSMUSG00000042694
rattus_norvegicus	Stn1	ENSRNOG00000020376

Paralogs (2): RPA2 (ENSG00000117748), RPA4 (ENSG00000204086)

Protein

Protein identifiers

CST complex subunit STN1 — Q9H668 (reviewed: Q9H668)

Alternative names: Oligonucleotide/oligosaccharide-binding fold-containing protein 1, Suppressor of cdc thirteen homolog

All UniProt accessions (11): Q9H668, A0A8V8TLL1, A0A8V8TLN6, A0A8V8TM23, A0A8V8TM51, A0A8V8TM56, A0A8V8TN12, A0A8V8TN42, A0A8V8TNB0, A0A8V8TNE0, A0A8V8TNE6

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. Required for efficicient replication of the duplex region of the telomere. Promotes efficient replication of lagging-strand telomeres. Promotes general replication start following replication-fork stalling implicating new origin firing. May be in involved in C-strand fill-in during late S/G2 phase independent of its role in telomere duplex replication. Component of the CST complex, a complex that binds to single-stranded DNA and is required to protect telomeres from DNA degradation. 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. In addition to telomere protection, the CST complex has probably a more general role in DNA metabolism at non-telomeric sites.

Subunit / interactions. Component of the CST complex, composed of TEN1/C17orf106, CTC1/C17orf68 and STN1; in the complex interacts directly with TEN1 and CTC1. Interacts with ACD/TPP1, POT1 and POLA1.

Subcellular location. Nucleus. Chromosome. Telomere.

Disease relevance. Cerebroretinal microangiopathy with calcifications and cysts 2 (CRMCC2) [MIM:617341] An autosomal recessive, multisystemic disorder characterized by intrauterine growth retardation and, later in life, premature aging symptoms, including poor growth, graying hair, liver fibrosis, portal hypertension, esophageal varices, osteopenia, pancytopenia, hypocellular bone marrow, and vascular telangiectasia resulting in gastrointestinal bleeding. Brain calcifications and white matter changes are responsible for signs including spasticity, ataxia, or dystonia observed in some patients. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Cells expressing STN1 mutants defective for dimerization with TEN1 display elongated telomeres and telomere defects associated with telomere uncapping.

Similarity. Belongs to the STN1 family.

RefSeq proteins (1): NP_079204* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004365	NA-bd_OB_tRNA	Domain
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR014647	Stn1	Family
IPR015253	CST_STN1_C	Domain
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR040260	RFA2-like	Family
IPR042082	CST_Stn1_wHTH1_sf	Homologous_superfamily

Pfam: PF01336, PF09170

UniProt features (50 total): helix 19, strand 17, sequence variant 4, mutagenesis site 3, region of interest 3, turn 2, chain 1, DNA-binding region 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
4JQF	X-RAY DIFFRACTION	1.6
4JOI	X-RAY DIFFRACTION	2.05
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-Q9H668-F1	87.67	0.68

Functional residue map

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

Mutagenesis-validated functional residues (3):

Position	Phenotype
164	defective of ten1 binding; when associated with ala-78.
167	defective of ten1 binding; when associated with ala-78.
78	defective of ten1 binding; when associated with ala-164 or ala-167.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-174411	Polymerase switching on the C-strand of the telomere
R-HSA-174430	Telomere C-strand synthesis initiation
R-HSA-157579	Telomere Maintenance
R-HSA-1640170	Cell Cycle
R-HSA-174417	Telomere C-strand (Lagging Strand) Synthesis
R-HSA-180786	Extension of Telomeres
R-HSA-73886	Chromosome Maintenance

MSigDB gene sets: 250 (showing top): GOBP_RNA_TEMPLATED_DNA_BIOSYNTHETIC_PROCESS, GOBP_CHROMOSOME_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_DNA_REPLICATION, GOBP_NEGATIVE_REGULATION_OF_TELOMERE_MAINTENANCE_VIA_TELOMERASE, YANG_BREAST_CANCER_ESR1_LASER_UP, GOBP_TELOMERE_CAPPING, SP3_Q3, GOBP_TELOMERE_MAINTENANCE_VIA_TELOMERE_LENGTHENING, GOBP_TELOMERE_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_REGULATION_OF_TELOMERE_MAINTENANCE, GOBP_NEGATIVE_REGULATION_OF_DNA_BIOSYNTHETIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_TELOMERE_MAINTENANCE_VIA_TELOMERE_LENGTHENING, GOBP_NEGATIVE_REGULATION_OF_CHROMOSOME_ORGANIZATION, TGACATY_UNKNOWN

GO Biological Process (6): telomere maintenance (GO:0000723), telomere maintenance via telomere lengthening (GO:0010833), telomere capping (GO:0016233), negative regulation of telomere maintenance via telomerase (GO:0032211), positive regulation of DNA replication (GO:0045740), regulation of DNA metabolic process (GO:0051052)

GO Molecular Function (6): single-stranded DNA binding (GO:0003697), telomeric repeat DNA binding (GO:0042162), single-stranded telomeric DNA binding (GO:0043047), nucleic acid binding (GO:0003676), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (7): chromosome, telomeric region (GO:0000781), fibrillar center (GO:0001650), nucleus (GO:0005634), nucleoplasm (GO:0005654), intermediate filament cytoskeleton (GO:0045111), CST complex (GO:1990879), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Telomere C-strand (Lagging Strand) Synthesis	2
Chromosome Maintenance	1
Extension of Telomeres	1
Telomere Maintenance	1
Cell Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA metabolic process	2
telomere maintenance	2
binding	2
cellular anatomical structure	2
telomere organization	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
DNA replication	1
regulation of DNA replication	1
positive regulation of DNA metabolic process	1
regulation of nucleobase-containing compound metabolic process	1
regulation of macromolecule metabolic process	1
DNA binding	1
sequence-specific DNA binding	1
telomeric repeat DNA binding	1
sequence-specific single stranded DNA binding	1
nucleic acid binding	1
chromosomal region	1
nucleolus	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoskeleton	1
nuclear telomere cap complex	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1560 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
STN1	CTC1	Q2NKJ3	999
STN1	RPA1	P27694	997
STN1	RPA3	P35244	996
STN1	TEN1	Q86WV5	986
STN1	SMARCAL1	Q9NZC9	926
STN1	XPA	P23025	858
STN1	PRKDC	P78527	849
STN1	RAD52	P43351	829
STN1	SERTAD3	Q9UJW9	783
STN1	ATRIP	Q8WXE1	774
STN1	SERTAD1	Q9UHV2	761
STN1	XRCC6	P12956	756
STN1	CHEK1	O14757	754
STN1	TP53BP1	Q12888	706
STN1	ZNF208	O43345	697

IntAct

148 interactions, top by confidence:

A	B	Type	Score
TEN1	STN1	psi-mi:“MI:0915”(physical association)	0.910
STN1	TEN1	psi-mi:“MI:0915”(physical association)	0.910
LDLRAP1	STN1	psi-mi:“MI:0915”(physical association)	0.890
STN1	LDLRAP1	psi-mi:“MI:0915”(physical association)	0.890
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
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
GMNN	MCIDAS	psi-mi:“MI:0914”(association)	0.770
TFAP4	ANGPTL7	psi-mi:“MI:0914”(association)	0.640
STN1	C14orf119	psi-mi:“MI:0915”(physical association)	0.600
C14orf119	STN1	psi-mi:“MI:0915”(physical association)	0.600
CTC1	STN1	psi-mi:“MI:0915”(physical association)	0.590

BioGRID (155): OBFC1 (Affinity Capture-Western), OBFC1 (Reconstituted Complex), OBFC1 (Two-hybrid), OBFC1 (Two-hybrid), TEN1 (Affinity Capture-MS), USP47 (Affinity Capture-MS), USP4 (Affinity Capture-MS), USP15 (Affinity Capture-MS), SPECC1L (Affinity Capture-MS), GRN (Affinity Capture-MS), LDLRAP1 (Affinity Capture-MS), CTC1 (Affinity Capture-MS), LRWD1 (Affinity Capture-MS), PRIM2 (Affinity Capture-MS), POLA1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8F8I9, A0A2R8QPS5, A1A5P5, A7S2N8, B0BM28, B4FGS2, B8AXB6, B8B624, B8JKF4, B9FM64, F1QNV4, F4IQJ2, P49842, P97564, Q08CY4, Q08DB2, Q0P5W1, Q0VA04, Q14AI0, Q2KI89, Q32PH0, Q3SYG4, Q3U0M1, Q4R804, Q5R629, Q61586, Q66I84, Q68F70, Q6DHG8, Q6GL75, Q6GMB0, Q6GN08, Q6GPP1, Q6NU25, Q6PA97, Q7T006, Q7XAM0, Q7Z3E5, Q811G0, Q8CIM8

Diamond homologs: B8JKF4, C1C4M3, D2GXY4, Q08DB2, Q4R804, Q6AYD2, Q6DJ48, Q8K2X3, Q9H668, Q9LMK5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
STN1	“form complex”	“CST complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 97 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
Telomere C-strand (Lagging Strand) Synthesis	7	106.6×	1e-11
Processive synthesis on the C-strand of the telomere	6	91.4×	2e-09
Removal of the Flap Intermediate from the C-strand	6	76.1×	4e-09
Extension of Telomeres	6	72.1×	5e-09
Base Excision Repair	5	71.4×	1e-07
Polymerase switching on the C-strand of the telomere	8	67.7×	1e-11
Telomere Extension By Telomerase	6	54.8×	3e-08
Telomere Maintenance	6	44.2×	9e-08

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of telomere maintenance via telomerase	7	59.0×	6e-09
telomere maintenance via telomerase	5	42.1×	1e-05
positive regulation of telomere maintenance	6	35.2×	3e-06
telomere maintenance	6	18.4×	7e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	161
Likely benign	131
Benign	6

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
375591	NM_024928.5(STN1):c.404G>C (p.Arg135Thr)	Pathogenic
4072187	NM_024928.5(STN1):c.707T>C (p.Leu236Pro)	Likely pathogenic

SpliceAI

1558 predictions. Top by Δscore:

Variant	Effect	Δscore
10:103889070:A:AC	donor_gain	1.0000
10:103889071:C:CC	donor_gain	1.0000
10:103889071:CG:C	donor_gain	1.0000
10:103889071:CGA:C	donor_gain	1.0000
10:103889071:CGAT:C	donor_gain	1.0000
10:103889071:CGATT:C	donor_gain	1.0000
10:103892124:TCTTA:T	donor_loss	1.0000
10:103892125:CTTA:C	donor_loss	1.0000
10:103892126:TTACA:T	donor_loss	1.0000
10:103892127:TAC:T	donor_loss	1.0000
10:103892128:A:AC	donor_gain	1.0000
10:103892128:A:AT	donor_loss	1.0000
10:103892129:C:CC	donor_gain	1.0000
10:103892129:C:CG	donor_loss	1.0000
10:103892129:CATA:C	donor_gain	1.0000
10:103897546:A:AC	donor_gain	1.0000
10:103897547:C:CC	donor_gain	1.0000
10:103900060:A:AC	donor_gain	1.0000
10:103900061:C:CC	donor_gain	1.0000
10:103900224:C:CC	acceptor_gain	1.0000
10:103900230:T:TC	acceptor_gain	1.0000
10:103900232:G:GC	acceptor_gain	1.0000
10:103900234:T:C	acceptor_gain	1.0000
10:103900234:T:TC	acceptor_gain	1.0000
10:103900241:C:CT	acceptor_gain	1.0000
10:103900241:C:T	acceptor_gain	1.0000
10:103900242:A:T	acceptor_gain	1.0000
10:103905157:C:CC	acceptor_gain	1.0000
10:103889064:CCACT:C	donor_loss	0.9900
10:103889067:CTT:C	donor_loss	0.9900

AlphaMissense

2443 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:103910568:A:T	V63D	0.993
10:103905151:C:G	D79H	0.986
10:103917546:A:G	W17R	0.984
10:103917546:A:T	W17R	0.984
10:103900113:C:G	G136R	0.983
10:103910574:C:T	G61E	0.983
10:103910575:C:G	G61R	0.982
10:103910575:C:T	G61R	0.982
10:103905130:A:G	C86R	0.981
10:103900118:A:T	V134D	0.980
10:103892198:C:G	A270P	0.979
10:103905149:G:C	D79E	0.979
10:103905149:G:T	D79E	0.979
10:103900112:C:T	G136D	0.977
10:103892167:A:T	V280D	0.976
10:103905156:A:T	V77E	0.975
10:103897629:A:C	F224L	0.973
10:103897629:A:T	F224L	0.973
10:103897631:A:G	F224L	0.973
10:103905135:A:T	I84K	0.973
10:103905150:T:A	D79V	0.972
10:103905150:T:G	D79A	0.971
10:103910602:G:C	H52D	0.971
10:103905128:G:C	C86W	0.970
10:103900079:A:C	I147S	0.969
10:103910574:C:A	G61V	0.969
10:103910580:A:T	V59D	0.969
10:103900079:A:T	I147N	0.967
10:103900133:C:A	G129V	0.967
10:103910586:A:T	V57E	0.967

dbSNP variants (sampled 300 via entrez): RS1000091453 (10:103906711 C>A), RS1000201197 (10:103920052 A>G), RS1000211420 (10:103882112 G>A), RS1000265267 (10:103916510 C>T), RS1000364052 (10:103913820 T>C), RS1000406935 (10:103900464 G>A,T), RS1000472359 (10:103903025 GA>G), RS1000499664 (10:103895626 C>T), RS1000521333 (10:103902800 G>T), RS1000544248 (10:103903288 C>T), RS1000615687 (10:103895425 T>C,G), RS1000655204 (10:103881919 C>T), RS1000770353 (10:103888769 C>A,T), RS1000807624 (10:103908510 G>A), RS1000834967 (10:103889929 C>T)

Disease associations

OMIM: gene MIM:613128 | disease phenotypes: MIM:617341

GenCC curated gene-disease

Disease	Classification	Inheritance
cerebroretinal microangiopathy with calcifications and cysts 2	Strong	Autosomal recessive
Coats plus syndrome	Supportive	Autosomal recessive

Mondo (3): cerebroretinal microangiopathy with calcifications and cysts 2 (MONDO:0015026), brain disorder (MONDO:0005560), Coats plus syndrome (MONDO:0012815)

Orphanet (0):

HPO phenotypes

39 total (30 of 39 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000938	Osteopenia
HP:0001063	Acrocyanosis
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001332	Dystonia
HP:0001395	Hepatic fibrosis
HP:0001409	Portal hypertension
HP:0001510	Growth delay
HP:0001511	Intrauterine growth retardation
HP:0001876	Pancytopenia
HP:0002020	Gastroesophageal reflux
HP:0002040	Esophageal varix
HP:0002110	Bronchiectasis
HP:0002206	Pulmonary fibrosis
HP:0002216	Premature graying of hair
HP:0002239	Gastrointestinal hemorrhage
HP:0002875	Exertional dyspnea
HP:0003546	Exercise intolerance
HP:0003621	Juvenile onset
HP:0005528	Bone marrow hypocellularity
HP:0006530	Abnormal pulmonary interstitial morphology
HP:0007763	Retinal telangiectasia
HP:0010444	Pulmonic regurgitation
HP:0011463	Childhood onset
HP:0012378	Fatigue
HP:0012735	Cough
HP:0025175	Honeycomb lung
HP:0025179	Ground-glass opacification
HP:0025390	Reticular pattern on pulmonary HRCT

GWAS associations

63 associations (top):

Study	Trait	p-value
GCST000102_1	Endothelial function traits	9.000000e-07
GCST000669_3	Telomere length	2.000000e-11
GCST001027_1	Uterine fibroids	9.000000e-14
GCST001697_3	Telomere length	9.000000e-11
GCST001936_2	Telomere length	7.000000e-11
GCST001968_11	Interstitial lung disease	2.000000e-08
GCST002875_131	Diisocyanate-induced asthma	1.000000e-06
GCST002875_3	Diisocyanate-induced asthma	1.000000e-06
GCST003061_5	Cutaneous malignant melanoma	2.000000e-09
GCST003726_31	Basal cell carcinoma	5.000000e-09
GCST004142_16	Melanoma	2.000000e-09
GCST004144_9	Thyroid cancer	5.000000e-11
GCST004347_3	Glioma	3.000000e-07
GCST004348_17	Non-glioblastoma glioma	3.000000e-08
GCST004710_5	Renal cell carcinoma	4.000000e-08
GCST004744_57	Lung adenocarcinoma	6.000000e-11
GCST004748_17	Lung cancer	7.000000e-06
GCST004777_21	Diastolic blood pressure	4.000000e-06
GCST004798_1	Differentiated thyroid cancer	9.000000e-06
GCST005196_37	Coronary artery disease	3.000000e-09
GCST005978_2	Diastolic blood pressure	2.000000e-08
GCST005993_49	Mean corpuscular hemoglobin	4.000000e-11
GCST006011_81	Mean corpuscular volume	5.000000e-12
GCST006020_10	Diastolic blood pressure	4.000000e-10
GCST006021_42	Systolic blood pressure	9.000000e-10
GCST006023_4	Hypertension	2.000000e-08
GCST006462_33	Uterine fibroids	3.000000e-09
GCST006479_27	Diverticular disease	3.000000e-06
GCST007045_34	PR interval	6.000000e-18
GCST007429_112	Lung function (FVC)	8.000000e-09

EFO canonical traits (23, from GWAS)

EFO ID	Trait name
EFO:0004298	cardiovascular measurement
EFO:0006995	response to diisocyanate
EFO:0006336	diastolic blood pressure
EFO:0004527	mean corpuscular hemoglobin
EFO:0006335	systolic blood pressure
EFO:0009959	diverticular disease
EFO:0004462	PR interval
EFO:0004312	vital capacity
EFO:0009718	peak expiratory flow
EFO:0004314	forced expiratory volume
EFO:0008392	triiodothyronine measurement
EFO:0005763	pulse pressure measurement
EFO:0010176	keratinocyte carcinoma
EFO:0005420	grey matter volume measurement
EFO:0000768	idiopathic pulmonary fibrosis
EFO:0004641	white matter integrity
EFO:0004632	nevus count
EFO:0004346	neuroimaging measurement
EFO:0005665	white matter hyperintensity measurement
EFO:0004327	electrocardiography
EFO:0007985	platelet crit
EFO:0004309	platelet count
EFO:0004305	erythrocyte count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D001927	Brain Diseases	C10.228.140
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)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs4387287	Efficacy	3	atenolol	Hypertension

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4387287	STN1	3	3.00	1	atenolol

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, decreases methylation	4
cobaltous chloride	decreases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
bisphenol F	affects cotreatment, increases expression	1
sotorasib	affects cotreatment, decreases expression	1
bufotalin	decreases expression	1
methylmercuric chloride	decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
trichostatin A	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
potassium chromate(VI)	decreases expression	1
beta-methylcholine	affects expression	1
CGP 52608	increases reaction, affects binding	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	decreases methylation	1
jinfukang	increases expression, affects cotreatment	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Arsenic	decreases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cisplatin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00570973	PHASE4	COMPLETED	Band Ligation Versus Transjugular Intrahepatic Portosystemic Stent Shunt (TIPS) in Cirrhotics With Recurrent Variceal Bleeding Non Responding to Medical Therapy
NCT01613417	PHASE4	COMPLETED	Comparison of Prohance® With Gadovist®/Gadavist™ in Magnetic Resonance Imaging (MRI) of the Brain
NCT01662414	PHASE4	COMPLETED	Effect of Undenatured Cysteine-Rich Whey Protein Isolate (HMS 90®) in Patients With Parkinson’s Disease
NCT02070380	PHASE4	COMPLETED	Crossover Comparison of MultiHance and Dotarem
NCT02776189	PHASE4	COMPLETED	Dexmedetomidine Verses Propofol for Paediatric MRI Brain
NCT02951559	PHASE4	UNKNOWN	SOLFAMU Study of Nasal Brushing Collected OLFActory MUcosa Samples in the Diagnosis of Human Encephalopathies
NCT04871464	PHASE4	UNKNOWN	Role and Mechanism of Probiotics in Improving Motor Symptoms in Mild to Moderate Parkinson’s Disease
NCT05812755	PHASE4	RECRUITING	SGC Stimulation, Perioperative Vascular Reactivity, and Organ Injury in Cardiac Surgery
NCT06244823	PHASE4	UNKNOWN	The FreMRI Study: Advanced MRI on Migraine Patients Treated With Fremanezumab
NCT00216502	PHASE3	COMPLETED	A Study of the Safety and Effectiveness of Galantamine in Patients With Alzheimer’s Disease
NCT00240695	PHASE3	COMPLETED	A Follow-up Study to Assess Safety and Tolerability of Galantamine Treatment in Individuals With Mild Cognitive Impairment
NCT04639310	PHASE3	TERMINATED	XEN496 (Ezogabine) in Children With KCNQ2 Developmental and Epileptic Encephalopathy
NCT04912856	PHASE3	TERMINATED	An Open-Label Extension of the Study XEN496 (Ezogabine) in Children With KCNQ2-DEE
NCT05395195	PHASE3	RECRUITING	Erythropoietin for Neonatal Encephalopathy in LMIC (EMBRACE Trial)
NCT05508789	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Donanemab (LY3002813) in Participants With Early Symptomatic Alzheimer’s Disease (TRAILBLAZER-ALZ 5)
NCT05738486	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Different Donanemab (LY3002813) Dosing Regimens in Adults With Early Alzheimer’s Disease (TRAILBLAZER-ALZ 6)
NCT06447701	PHASE3	NOT_YET_RECRUITING	Interleukin-6 Receptor Inhibition for Symptomatic Intracranial Atherosclerosis
NCT00000982	PHASE2	COMPLETED	A Study of Azidothymidine in HIV-Infected Children
NCT00406029	PHASE2	COMPLETED	Dyskinesia in Parkinson’s Disease (Study P04501)
NCT00537017	PHASE2	COMPLETED	Follow Up Safety Study of SCH 420814 in Subjects With Parkinson’s Disease (P05175)
NCT00862459	PHASE2	COMPLETED	Dose Finding Study of Gadavist in Central Nervous System (CNS) Magnetic Resonance Imaging (MRI)
NCT03448159	PHASE2	COMPLETED	Fluoxetine Opens Window to Improve Motor Recovery After Stroke
NCT03926351	PHASE2	UNKNOWN	High Dose Omega 3 in People at Risk for Dementia
NCT04640077	PHASE2	COMPLETED	A Follow-On Study of Donanemab (LY3002813) With Video Assessments in Participants With Alzheimer’s Disease (TRAILBLAZER-EXT)
NCT04755920	PHASE2	RECRUITING	SGM-101 in Colorectal Brain Metastases.
NCT04937452	PHASE2	COMPLETED	Dopaminergic Therapy for Frontotemporal Dementia Patients
NCT04970355	PHASE2	COMPLETED	Efficacy of Erenumab in Chronic Cluster Headache
NCT05318976	PHASE2	COMPLETED	A Study of XPro1595 in Patients With Early Alzheimer’s Disease With Biomarkers of Inflammation
NCT05321498	PHASE2	WITHDRAWN	Study to Assess the Efficacy of XPro1595 in Patients With Mild Cognitive Impairment With Biomarkers of Inflammation
NCT05375240	PHASE2	UNKNOWN	Propranolol on Post Stroke Immune Status and Infection
NCT05522387	PHASE2	TERMINATED	An Open-Label Extension of XPro1595 in Patients With Alzheimer’s Disease
NCT05920889	PHASE2	COMPLETED	Glucagon-like Peptide 1 Receptor Agonist in Acute Large Vessel Occlusion Stroke Treated by Reperfusion Therapies
NCT06712004	PHASE2	RECRUITING	A Dose-Response Controlled Trial of Bevifibatide for Acute Ischemic Stroke
NCT00000856	PHASE1	WITHDRAWN	A Phase I/II Pilot Treatment Study Of CSF Penetration And Response To Ganciclovir And Foscarnet In CMV Neurologic Disease.
NCT00649207	PHASE1	COMPLETED	A Phase I Study of ABT-888 in Combination With Conventional Whole Brain Radiation Therapy (WBRT) in Cancer Patients With Brain Metastases
NCT00895960	PHASE1	TERMINATED	Dasatinib Plus Radiation Therapy/Temozolomide in Newly-Diagnosed Glioblastoma
NCT03065192	PHASE1	COMPLETED	Safety and Efficacy Study of VY-AADC01 for Advanced Parkinson’s Disease
NCT03776994	PHASE1	UNKNOWN	Venezuelan Equine Encephalitis Monovalent Virus-Like Particle Vaccine
NCT03911388	PHASE1	RECRUITING	HSV G207 in Children With Recurrent or Refractory Cerebellar Brain Tumors
NCT05921929	PHASE1	WITHDRAWN	First-In-Human (FIH), Single Ascending Dose (SAD) Study of FluoroEthylNorMemantine (FENM)