TELO2

Summary

TELO2 (telomere maintenance 2, HGNC:29099) is a protein-coding gene on chromosome 16p13.3, encoding Telomere length regulation protein TEL2 homolog (Q9Y4R8). Regulator of the DNA damage response (DDR). It is a selective cancer dependency (DepMap: 71.8% of cell lines).

This gene encodes a protein that functions as an S-phase checkpoint protein in the cell cycle. The protein may also play a role in DNA repair.

Source: NCBI Gene 9894 — RefSeq curated summary.

At a glance

• Gene–disease (curated): TELO2-related intellectual disability-neurodevelopmental disorder (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 696 total — 12 pathogenic, 16 likely-pathogenic (top 5% of genes corpus-wide)
• GTEx eGene: eQTL in 49 tissues, sQTL in 46 (q < 0.05)
• Phenotypes (HPO): 68
• Cancer dependency (DepMap): dependent in 71.8% of screened cell lines
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.03 (unconstrained)
• MANE Select transcript: NM_016111

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29099
Approved symbol	TELO2
Name	telomere maintenance 2
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0683, hCLK2, TEL2
Ensembl gene	ENSG00000100726
Ensembl biotype	protein_coding
OMIM	611140
Entrez	9894

Gene structure

Transcript identifiers

Ensembl transcripts: 49 — 29 protein_coding, 15 nonsense_mediated_decay, 3 retained_intron, 2 protein_coding_CDS_not_defined

MANE Select: ENST00000262319

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

ENST00000262319, ENST00000497339, ENST00000563676, ENST00000564507, ENST00000567423, ENST00000567427, ENST00000568240, ENST00000569744, ENST00000889735, ENST00000889737, ENST00000889738, ENST00000889739, ENST00000889740, ENST00000889741, ENST00000889742, ENST00000889743, ENST00000889744, ENST00000914530, ENST00000914531, ENST00000914532, ENST00000914533, ENST00000914534, ENST00000914535, ENST00000962543, ENST00000962544, ENST00000962546, ENST00000962547, ENST00000962548, ENST00000962549, ENST00000962551, ENST00000999118, ENST00001033789, ENST00001033790, ENST00001033791, ENST00001033792, ENST00001033794, ENST00001033796, ENST00001033797, ENST00001033800, ENST00001033801, ENST00001065358, ENST00001065359, ENST00001065360, ENST00001065361, ENST00001065362, ENST00001110133, ENST00001116064, ENST00001116065, ENST00001136806

RefSeq mRNA: 2 — MANE Select: NM_016111 NM_001351846, NM_016111

CCDS: CCDS32363

Canonical transcript exons

ENST00000262319 — 21 exons

Exon	Start	End
ENSE00001164204	1501663	1501773
ENSE00001164214	1501420	1501499
ENSE00001389642	1493360	1493605
ENSE00001667433	1500096	1500164
ENSE00001677940	1500563	1500699
ENSE00001682957	1497361	1497508
ENSE00001689811	1495346	1495623
ENSE00001726905	1500347	1500488
ENSE00001730150	1497036	1497104
ENSE00001735679	1499231	1499333
ENSE00002722142	1494246	1494616
ENSE00003478260	1507601	1507716
ENSE00003501009	1509830	1510454
ENSE00003528878	1507306	1507370
ENSE00003541408	1506238	1506329
ENSE00003542697	1502645	1502761
ENSE00003550802	1506952	1507051
ENSE00003595778	1505410	1505601
ENSE00003631712	1502931	1503002
ENSE00003632324	1502313	1502404
ENSE00003649154	1502047	1502135

Expression profiles

Bgee: expression breadth ubiquitous, 234 present calls, max score 95.73.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.1498 / max 165.8223, expressed in 1785 samples.

Highest expression (Bgee): uterine tube, hemisphere of cerebellum, cerebellar hemisphere, apex of heart, cerebellar cortex.

Genetic regulation across tissues (GTEx eQTL / sQTL)

TELO2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 49 tissues and its splicing (sQTL) in 46 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 95 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Thyroid	eqtl	1.6e-70	-0.98	16:1506499:A:G
Nerve Tibial	sqtl	1.0e-66	-1.52	16:1496729:T:C
Skin Not Sun Exposed Suprapubic	sqtl	4.1e-64	+1.41	16:1506499:A:G
Skin Sun Exposed Lower leg	sqtl	8.0e-64	+1.51	16:1506499:A:G
Nerve Tibial	eqtl	4.4e-63	-0.80	16:1506499:A:G
Skin Sun Exposed Lower leg	eqtl	2.7e-58	-0.78	16:1506499:A:G
Lung	sqtl	4.7e-52	-1.65	16:1496729:T:C
Adipose Subcutaneous	sqtl	7.4e-51	-1.39	16:1496729:T:C
Whole Blood	eqtl	8.3e-50	-0.45	16:1506499:A:G
Skin Not Sun Exposed Suprapubic	eqtl	8.5e-45	-0.65	16:1508914:C:T
Thyroid	sqtl	3.6e-43	+1.34	16:1506499:A:G
Adipose Visceral Omentum	eqtl	5.4e-43	-0.74	16:1510193:G:A
Testis	eqtl	1.3e-42	-0.96	16:1508934:T:C
Cells EBV-transformed lymphocytes	sqtl	5.2e-41	-1.97	16:1496729:T:C
Adipose Subcutaneous	eqtl	4.1e-40	-0.78	16:1508934:T:C
Breast Mammary Tissue	eqtl	2.8e-39	-0.72	16:1506499:A:G
Breast Mammary Tissue	sqtl	4.1e-35	-1.46	16:1496729:T:C
Brain Frontal Cortex BA9	eqtl	1.7e-34	-0.61	16:1493567:C:G
Esophagus Mucosa	sqtl	2.0e-34	+1.34	16:1506499:A:G
Colon Transverse	eqtl	3.7e-33	-0.66	16:1506499:A:G

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
152101	7.1800	1649
152104	5.5737	1708
152103	1.5756	697
152102	0.8204	440

Top tissues by expression

showing 100 of 277 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	95.73	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.16	gold quality
cerebellar hemisphere	UBERON:0002245	94.61	gold quality
apex of heart	UBERON:0002098	94.40	gold quality
cerebellar cortex	UBERON:0002129	94.36	gold quality
metanephros cortex	UBERON:0010533	93.91	gold quality
granulocyte	CL:0000094	93.51	gold quality
right lobe of liver	UBERON:0001114	93.23	gold quality
mucosa of stomach	UBERON:0001199	93.01	gold quality
mucosa of transverse colon	UBERON:0004991	92.75	gold quality
lower esophagus mucosa	UBERON:0035834	92.25	gold quality
spleen	UBERON:0002106	92.10	gold quality
endocervix	UBERON:0000458	91.99	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.98	gold quality
cerebellum	UBERON:0002037	91.92	gold quality
adenohypophysis	UBERON:0002196	91.92	gold quality
right lobe of thyroid gland	UBERON:0001119	91.90	gold quality
left uterine tube	UBERON:0001303	91.83	gold quality
tibial nerve	UBERON:0001323	91.82	gold quality
skin of leg	UBERON:0001511	91.52	gold quality
ectocervix	UBERON:0012249	91.51	gold quality
left ovary	UBERON:0002119	91.31	gold quality
left lobe of thyroid gland	UBERON:0001120	91.28	gold quality
skin of abdomen	UBERON:0001416	91.08	gold quality
right ovary	UBERON:0002118	91.06	gold quality
body of uterus	UBERON:0009853	90.97	gold quality
body of stomach	UBERON:0001161	90.87	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	90.75	gold quality
right adrenal gland	UBERON:0001233	90.65	gold quality
transverse colon	UBERON:0001157	90.59	gold quality
right adrenal gland cortex	UBERON:0035827	90.58	gold quality
upper lobe of left lung	UBERON:0008952	90.40	gold quality
pituitary gland	UBERON:0000007	90.21	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.20	gold quality
lower esophagus	UBERON:0013473	90.19	gold quality
left adrenal gland cortex	UBERON:0035825	90.15	gold quality
minor salivary gland	UBERON:0001830	90.09	gold quality
esophagus mucosa	UBERON:0002469	89.92	gold quality
ventricular zone	UBERON:0003053	89.79	gold quality
left adrenal gland	UBERON:0001234	89.72	gold quality
muscle layer of sigmoid colon	UBERON:0035805	89.70	gold quality
esophagus	UBERON:0001043	89.67	gold quality
thyroid gland	UBERON:0002046	89.67	gold quality
right frontal lobe	UBERON:0002810	89.44	gold quality
small intestine	UBERON:0002108	89.42	gold quality
omental fat pad	UBERON:0010414	89.39	gold quality
right atrium auricular region	UBERON:0006631	89.37	gold quality
peritoneum	UBERON:0002358	89.34	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	89.23	gold quality
sural nerve	UBERON:0015488	89.22	gold quality
body of pancreas	UBERON:0001150	89.07	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	89.01	gold quality
triceps brachii	UBERON:0001509	88.92	gold quality
adrenal cortex	UBERON:0001235	88.90	gold quality
right lung	UBERON:0002167	88.67	gold quality
upper lobe of lung	UBERON:0008948	88.64	gold quality
adipose tissue of abdominal region	UBERON:0007808	88.48	gold quality
left coronary artery	UBERON:0001626	88.34	gold quality
heart left ventricle	UBERON:0002084	88.31	gold quality
right coronary artery	UBERON:0001625	88.09	gold quality
saliva-secreting gland	UBERON:0001044	88.02	gold quality
cardiac ventricle	UBERON:0002082	87.94	gold quality
right testis	UBERON:0004534	87.94	gold quality
vagina	UBERON:0000996	87.93	gold quality
ascending aorta	UBERON:0001496	87.88	gold quality
cardiac atrium	UBERON:0002081	87.81	gold quality
thoracic aorta	UBERON:0001515	87.80	gold quality
mouth mucosa	UBERON:0003729	87.76	gold quality
ganglionic eminence	UBERON:0004023	87.76	gold quality
cortical plate	UBERON:0005343	87.72	gold quality
gluteal muscle	UBERON:0002000	87.66	gold quality
coronary artery	UBERON:0001621	87.57	gold quality
stomach	UBERON:0000945	87.48	gold quality
aorta	UBERON:0000947	87.47	gold quality
amygdala	UBERON:0001876	87.46	gold quality
popliteal artery	UBERON:0002250	87.41	gold quality
tibial artery	UBERON:0007610	87.40	gold quality
left testis	UBERON:0004533	87.38	gold quality
zone of skin	UBERON:0000014	87.35	gold quality
adrenal gland	UBERON:0002369	87.30	gold quality
gastrocnemius	UBERON:0001388	87.24	gold quality
cingulate cortex	UBERON:0003027	87.20	gold quality
monocyte	CL:0000576	87.19	gold quality
anterior cingulate cortex	UBERON:0009835	87.10	gold quality
nucleus accumbens	UBERON:0001882	87.08	gold quality
hindlimb stylopod muscle	UBERON:0004252	86.93	gold quality
mononuclear cell	CL:0000842	86.85	gold quality
sigmoid colon	UBERON:0001159	86.78	gold quality
spinal cord	UBERON:0002240	86.76	gold quality
leukocyte	CL:0000738	86.70	gold quality
colon	UBERON:0001155	86.58	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.42	gold quality
descending thoracic aorta	UBERON:0002345	86.42	gold quality
heart	UBERON:0000948	86.40	gold quality
caudate nucleus	UBERON:0001873	86.37	gold quality
prostate gland	UBERON:0002367	86.37	gold quality
subcutaneous adipose tissue	UBERON:0002190	86.36	gold quality
putamen	UBERON:0001874	86.27	gold quality
endometrium epithelium	UBERON:0004811	86.24	gold quality
intestine	UBERON:0000160	86.19	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.07

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 80 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Locus coeruleus	tissue	18.0
Hippocampus	tissue	17.6	low
Choroid plexus	tissue	16.2
Nucleus accumbens	tissue	14.9
Thalamus	tissue	13.1
Cerebellum	tissue	13.1	medium
Pons	tissue	13.0
Vagina	tissue	13.0	medium
Cerebral cortex	tissue	12.8	medium
Motor cortex	tissue	12.8
Substantia nigra	tissue	12.6
Prefrontal cortex	tissue	12.5
Midbrain	tissue	12.4
Hypothalamus	tissue	12.4
Hippocampal formation	tissue	12.4
Postcentral gyrus	tissue	12.2
Somatosensory cortex	tissue	12.2
Insular cortex	tissue	12.2
Medulla oblongata	tissue	12.0
Superior colliculi	tissue	12.0
Pituitary gland	tissue	11.9
Periaqueductal gray	tissue	11.9
Skin 1	tissue	11.8	low
Spinal cord	tissue	11.6
Corpus callosum	tissue	11.6
Entorhinal cortex	tissue	11.6
Retrosplenial and cingulate cortex	tissue	11.6
Temporal cortex	tissue	11.6
Amygdala	tissue	11.5
Retrosplenial cortex	tissue	11.5
Spleen	tissue	10.8	medium
Occipital cortex	tissue	10.8
Bone marrow	tissue	10.7	medium
Septum	tissue	10.7
Ventral forebrain	tissue	10.4
Olfactory bulb	tissue	10.3
Skeletal muscle	tissue	10.2	medium
Basal ganglia	tissue	10.2	medium
Putamen	tissue	9.5
Salivary gland	tissue	9.0	medium
Pancreas	tissue	8.8	medium
Duodenum	tissue	8.3	high
Small intestine	tissue	7.9	high
Lymph node	tissue	7.5	medium
Appendix	tissue	7.2	medium
Stomach 1	tissue	6.8	high
Adipose tissue	tissue	6.8	low
Frontal cortex	tissue	6.7
Thymus	tissue	5.4
Adrenal gland	tissue	5.1	high
Caudate putamen	tissue	4.9
Seminal vesicle	tissue	4.6	medium
Tongue	tissue	4.6
Heart muscle	tissue	4.5	not detected
Ovary	tissue	4.5	medium
Placenta	tissue	4.5	medium
Colon	tissue	4.4	medium
Endometrium 1	tissue	4.3	medium
Prostate	tissue	4.2	medium
Parathyroid gland	tissue	4.0	medium

Brain sub-regions (HPA Brain Atlas): detected in 192; highest nTPM — Nucleus ambiguus (25.8), Cerebellar cortex (22.4), Flocculonodular lobe (22.3), Vermis (21.6), Piriform cortex (20.8).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting TELO2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

8 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-4303	98.01	68.13	2304
HSA-MIR-6747-3P	97.73	64.84	1596
HSA-MIR-4793-3P	94.87	65.85	896
HSA-MIR-4258	90.68	62.19	164
HSA-MIR-1199-3P	79.56	60.75	34

Functional genomics

gnomAD constraint: pLI 9.42e-21, LOEUF 1.03, missense Z -0.881 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000262319 — one region, missense o/e 1.04. DepMap (CRISPR cell-line fitness): dependent in 71.8% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): PA-TU-8988T (-2.199), HSC-4 (-1.579), NCI-H2004 RT (-1.546), ONCO-DG-1 (-1.41), SW579 (-1.358), HEL 92.1.7 (-1.354), TC-71 (-1.352), TUHR14TKB (-1.33), SU-DHL-10 (-1.323), MPP 89 (-1.309), MHH-ES-1 (-1.309), SK-RC-52 (-1.285), SNU-475 (-1.261), HCC1428 (-1.233), KU812 (-1.22).

Literature-anchored findings (GeneRIF, showing 12)

• Data show that that knockdown of either Tti1 or Tel2 causes disassembly of mTORC1 and mTORC2. (PMID:20427287)
• TTI1 and TTI2 exist in multiple complexes, including a 2-MDa complex with TEL2 (telomere maintenance 2), called the Triple T complex, and phosphoinositide-3-kinase-related protein kinases (PIKKs) such as ataxia telangiectasia-mutated (ATM). (PMID:20810650)
• The CK2 phospho-dependent interaction between TEL2 and the R2TP complex affects phosphatidylinositol 3-kinase-related kinase functions and is essential for mTOR and SMG1 stability in vivo. (PMID:20864032)
• The SAM domain of human TEL2 can inhibit the transcriptional activities of ETS1/2 and TEL1. (PMID:22615925)
• IP7, formed by IP6K2, binds CK2 to enhance its phosphorylation of the Tti1/Tel2 complex, thereby stabilizing DNA-PKcs and ATM. This process stimulates p53 phosphorylation at serine 15 to activate the cell death program. (PMID:24657168)
• TELO2 missense variants result in loss of function, perturb TTT complex stability, and cause an autosomal-recessive syndromic form of Intellectual Disability Disorder. (PMID:27132593)
• Taken together, human high-grade gliomas increase TELO2 mRNA expression, and overexpression of TELO2 mRNA expression correlates with shorter survival outcome, supporting that TELO2 is an oncotarget in human gliomas. (PMID:27329594)
• Cataract in You-Hoover-Fong syndrome: TELO2 deficiency. (PMID:32940098)
• Milder presentation of TELO2-related syndrome in two sisters homozygous for the p.Arg609His pathogenic variant. (PMID:33307281)
• TELO2 induced progression of colorectal cancer by binding with RICTOR through mTORC2. (PMID:33416177)
• Structure of the Human TELO2-TTI1-TTI2 Complex. (PMID:34838521)
• TELO2-related syndrome (You-Hoover-Fong syndrome): Description of 14 new affected individuals and review of the literature. (PMID:36797513)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	telo2	ENSDARG00000000830
mus_musculus	Telo2	ENSMUSG00000024170
rattus_norvegicus	Telo2	ENSRNOG00000016774
caenorhabditis_elegans		WBGENE00000537

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1918968) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 7 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal cell cycle	1
early cellular replicative senescence	1
abnormal DNA repair	1
increased total body fat amount	1
embryonic lethality during organogenesis, complete penetrance	1
preweaning lethality, complete penetrance	1
embryonic lethality prior to organogenesis	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Xenopus tropicalis	Q08CY4	86.9%	Diamond
Xenopus laevis	Q6GPP1	86.9%	Diamond

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
CRAMP1	protein-coding	57585
TMEM204	protein-coding	79652
JPT2	protein-coding	90861
IFT140	protein-coding	9742
PTX4	protein-coding	390667
CLCN7	protein-coding	1186
PERCC1	protein-coding	105371045
CCDC154	protein-coding	645811

Protein

Protein identifiers

Telomere length regulation protein TEL2 homolog — Q9Y4R8 (reviewed: Q9Y4R8)

Alternative names: Protein clk-2 homolog

All UniProt accessions (3): Q9Y4R8, H3BRS3, H3BU45

UniProt curated annotations — full annotation on UniProt →

Function. Regulator of the DNA damage response (DDR). Part of the TTT complex that is required to stabilize protein levels of the phosphatidylinositol 3-kinase-related protein kinase (PIKK) family proteins. The TTT complex is involved in the cellular resistance to DNA damage stresses, like ionizing radiation (IR), ultraviolet (UV) and mitomycin C (MMC). Together with the TTT complex and HSP90 may participate in the proper folding of newly synthesized PIKKs. Promotes assembly, stabilizes and maintains the activity of mTORC1 and mTORC2 complexes, which regulate cell growth and survival in response to nutrient and hormonal signals. May be involved in telomere length regulation.

Subunit / interactions. Component of the TTT complex composed of TELO2, TTI1 and TTI2. Interacts with ATM, ATR, MTOR, PRKDC, RUVBL2, TTI1, TTI2, SMG1 and TRRAP. Component of the mTORC1 and mTORC2 complexes. Interacts (phosphorylated form) with PIH1D1 which mediates interaction of TELO2 with the R2TP complex composed of RUVBL1, RUVBL2, PIH1D1, and RPAP3.

Subcellular location. Cytoplasm. Membrane. Nucleus. Chromosome. Telomere.

Post-translational modifications. Hydroxylation by PHD3 is required for a proper interaction with ATR, and activation of the ATR/CHK1/p53 pathway following DNA damage. Phosphorylated at Ser-485 by CK2 following growth factor deprivation, leading to its subsequent ubiquitination by the SCF(FBXO9) complex. Phosphorylation by CK2 only takes place when TELO2 is bound to mTORC1, not mTORC2; leading to selective ubiquitination of mTORC1-associated protein. Ubiquitinated by the SCF(FBXO9) complex following phosphorylation by CK2 in response to growth factor deprivation, leading to its degradation by the proteasome. Only mTORC1-associated protein is ubiquitinated and degraded, leading to selective inactivation of mTORC1 to restrain cell growth and protein translation, while mTORC2 is activated due to the relief of feedback inhibition by mTORC1.

Disease relevance. You-Hoover-Fong syndrome (YHFS) [MIM:616954] A syndrome characterized by severe global developmental delay, intellectual disability, dysmorphic facial features, microcephaly, abnormal movements, congenital heart disease comprising developmental abnormalities of the great vessels, and abnormal auditory and visual function. The transmission pattern is consistent with autosomal recessive inheritance. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Cells overexpressing TELO2 are hypersensitive to hydroxyurea (HU) and undergo apoptotic death in response to treatment with HU.

Similarity. Belongs to the TEL2 family.

RefSeq proteins (2): NP_001338775, NP_057195* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR016024	ARM-type_fold	Homologous_superfamily
IPR019337	Telomere_length_regulation_dom	Domain
IPR038528	TEL2_C_sf	Homologous_superfamily
IPR051970	TEL2	Family
IPR057348	TELO2_ARM	Domain

Pfam: PF10193, PF25320

UniProt features (51 total): helix 21, modified residue 10, sequence variant 10, site 3, region of interest 2, chain 1, mutagenesis site 1, sequence conflict 1, compositionally biased region 1, strand 1

Structure

Experimental structures (PDB)

4 structures by resolution:

PDB	Title	Method	Resolution (Å)
4PSI	PIH1D1/phospho-Tel2 complex	X-RAY DIFFRACTION	2.45
7OLE	Cryo-EM structure of the TELO2-TTI1-TTI2-RUVBL1-RUVBL2 complex	ELECTRON MICROSCOPY	3.41
9WJS	Tti1-Telo2 complex	ELECTRON MICROSCOPY	3.83
7F4U	Cryo-EM structure of TELO2-TTI1-TTI2 complex	ELECTRON MICROSCOPY	4.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y4R8-F1	84.74	0.63

Human Protein Atlas

Protein class: Predicted membrane proteins, Predicted intracellular proteins, Disease related genes, Human disease related genes, Congenital malformations, Congenital malformations of the nervous system, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; nuclear bodies

Antibody reliability (HPA): IH approved · IF supported

Functional residue map

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

Catalytic / active sites (3)

Position	Role
490	interaction with pih1d1
491	interaction with pih1d1
492	interaction with pih1d1

Post-translational modifications (10)

Type	Positions
Hydroxyproline	422, 374, 419
Phosphoserine	456, 485, 487, 491, 688, 836
N-acetylmethionine	1

Mutagenesis-validated functional residues (1)

Position	Phenotype
485	abolishes phosphorylation by ck2 in response to growth factor deprivation and subsequent ubiquitination and degradation.

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: 284 (showing top): GOBP_REGULATION_OF_CELL_CYCLE_CHECKPOINT, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_PROTEIN_MATURATION, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE, GOBP_PROTEIN_STABILIZATION, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_DNA_DAMAGE_RESPONSE, GARCIA_TARGETS_OF_FLI1_AND_DAX1_DN, GOBP_PROTEIN_FOLDING, GOBP_REGULATION_OF_PROTEIN_STABILITY, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_DNA_DAMAGE_CHECKPOINT, GOBP_SIGNAL_TRANSDUCTION_IN_RESPONSE_TO_DNA_DAMAGE

GO Biological Process (3): protein stabilization (GO:0050821), ‘de novo’ cotranslational protein folding (GO:0051083), positive regulation of DNA damage checkpoint (GO:2000003)

GO Molecular Function (8): kinase binding (GO:0019900), protein kinase binding (GO:0019901), telomeric repeat DNA binding (GO:0042162), protein-containing complex binding (GO:0044877), Hsp90 protein binding (GO:0051879), molecular adaptor activity (GO:0060090), protein-containing complex stabilizing activity (GO:0140777), protein binding (GO:0005515)

GO Cellular Component (6): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), nuclear body (GO:0016604)

GO top-level categories

18 GO namespaces:

Category	Terms
binding	3
cellular anatomical structure	3
molecular_function	2
regulation of protein stability	1
‘de novo’ protein folding	1
DNA damage checkpoint signaling	1
positive regulation of cell cycle checkpoint	1
regulation of DNA damage checkpoint	1
enzyme binding	1
kinase binding	1
sequence-specific DNA binding	1
heat shock protein binding	1
chromosomal region	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
nucleoplasm	1
intracellular membraneless organelle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 10 of 17 annotations. The rest are phylogenetic / computational / electronic (IEA).

10 experimentally-supported GO terms:

GO term	NS	Evidence
protein stabilization	BP	direct assay
cytoplasm	CC	direct assay
cytosol	CC	direct assay
nuclear body	CC	direct assay
nucleus	CC	direct assay
Hsp90 protein binding	MF	physical interaction
kinase binding	MF	physical interaction
protein kinase binding	MF	physical interaction
protein-containing complex binding	MF	direct assay
protein-containing complex stabilizing activity	MF	mutant phenotype

Protein interactions and networks

STRING

showing 15 of 1,084 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TELO2	FAAP24	Q9BTP7	862
TELO2	TTI1	O43156	827
TELO2	COQ7	Q99807	827
TELO2	FANCM	Q8IYD8	795
TELO2	CLK3	P49761	759
TELO2	TTI2	Q6NXR4	731
TELO2	SMG1	Q96Q15	708
TELO2	CHEK1	O14757	703
TELO2	TRRAP	Q9Y4A5	695
TELO2	RMI1	Q9H9A7	645
TELO2	FANCD2	Q9BXW9	610
TELO2	IMMT	Q16891	600
TELO2	PRKDC	P78527	549
TELO2	TOP3A	Q13472	519
TELO2	PIH1D1	Q9NWS0	511

IntAct

Human interaction partners of TELO2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

14 partners by confidence:

Partner	Interaction type	MIscore	Records
TTI1	physical association	0.760	6
PIH1D1	physical association	0.700	10
ATM	direct interaction	0.680	1
FBXO9	physical association	0.610	3
MTOR	association	0.600	2
PRKDC	association	0.600	1
ATXN3	physical association	0.560	3
RPAP3	association	0.530	2
CACNA1A	physical association	0.370	1
KRT15	physical association	0.370	1
KAT5	physical association	0.000	1
MAGED1	physical association	0.000	1
PSMD6	physical association	0.000	1
TSC22D1	physical association	0.000	1

BioGRID (221 interactions; top human partners by supporting records): ATR (Affinity Capture-Western; 12 records), TTI1 (Affinity Capture-Western; 9 records), ATM (Affinity Capture-Western; 5 records), PRKDC (Affinity Capture-Western; 5 records), ARHGEF12 (Two-hybrid; 4 records), BSG (Affinity Capture-MS; 4 records), EGLN3 (Affinity Capture-MS; 4 records), MTOR (Affinity Capture-MS; 4 records), TTI2 (Affinity Capture-Western; 4 records), C19orf40 (Co-fractionation; 3 records), FANCM (Affinity Capture-MS; 3 records), RUVBL2 (Affinity Capture-MS; 3 records), CCNF (Affinity Capture-MS; 2 records), EGFR (Negative Genetic; 2 records), PTPRN2 (Affinity Capture-MS; 2 records)

SIGNOR signaling

showing 5 of 8 signaling interactions:

A	Effect	B	Mechanism
CSNK2A1	down-regulates	TELO2	phosphorylation
FBXO9	“down-regulates quantity by destabilization”	TELO2	binding
“Cullin 1-RBX1-Skp1”	“down-regulates quantity by destabilization”	TELO2	polyubiquitination
TELO2	“up-regulates quantity by stabilization”	mTORC1	binding
TELO2	“up-regulates quantity by stabilization”	mTORC2	binding

Protein complexes (CORUM) (3)

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

3 complexes by size:

Complex	Subunits	Members
★ mTORC1-TELO2-TTI1 complex	5	RPTOR, TELO2, TTI1, MLST8, MTOR
★ mTORC2-TELO2-TTI1 complex	5	RICTOR, TELO2, TTI1, MLST8, MTOR
TELO2-TTI1-TTI2 complex	3	TELO2, TTI1, TTI2

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 14 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.

GO biological processes:

GO term	Partners	Fold	FDR
protein stabilization	5	23.9×	3e-04

Disease & clinical

Genetic variants

Variant evidence for TELO2: 696 ClinVar records (28 pathogenic / likely pathogenic); 1 GWAS association. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	12
Likely pathogenic	16
Uncertain significance	257
Likely benign	289
Benign	44

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 28 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
2446177	NM_016111.4(TELO2):c.1652del (p.Glu551fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
4532811	NM_016111.4(TELO2):c.800_801del (p.Val267fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
2072846	NM_016111.4(TELO2):c.2291+1G>C	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
4086194	NM_016111.4(TELO2):c.2034+2T>C	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
1686256	NM_016111.4(TELO2):c.1825C>T (p.Arg609Cys)	Pathogenic	criteria provided, single submitter	1
2015550	NM_016111.4(TELO2):c.2121dup (p.Asp708Ter)	Pathogenic	criteria provided, single submitter	1
2103874	NM_016111.4(TELO2):c.460dup (p.Glu154fs)	Pathogenic	criteria provided, single submitter	1
2783244	NM_016111.4(TELO2):c.418C>T (p.Gln140Ter)	Pathogenic	criteria provided, single submitter	1
2980637	NM_016111.4(TELO2):c.569_570del (p.Glu190fs)	Pathogenic	criteria provided, single submitter	1
3339339	NM_016111.4(TELO2):c.1612_1621dup (p.Leu541delinsProTer)	Pathogenic	criteria provided, single submitter	1
3661655	NM_016111.4(TELO2):c.1922dup (p.Asn641fs)	Pathogenic	criteria provided, single submitter	1
3907641	NM_016111.4(TELO2):c.434del (p.Thr145fs)	Pathogenic	criteria provided, single submitter	1
4887695	NM_016111.4(TELO2):c.2184_2191dup (p.Leu731fs)	Pathogenic	criteria provided, single submitter	1
452017	NM_016111.4(TELO2):c.561del (p.Leu188fs)	Likely pathogenic	criteria provided, single submitter	1
1319744	NM_016111.4(TELO2):c.1110del (p.Gln370fs)	Likely pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore TELO2’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; 35 predictions of 2,078):

Position(s)	Effect	Δscore	Sites
16:1495624–1495625	donor_loss	1.0000	4
16:1497509–1497510	donor_loss	1.0000	4
16:1500165–1500166	donor_loss	1.0000	4
16:1500345–1500346	acceptor_loss	1.0000	2
16:1500561–1500562	acceptor_loss	1.0000	6
16:1500700–1500701	donor_loss	1.0000	3
16:1501661	acceptor_gain	1.0000
16:1501661–1501662	acceptor_loss	1.0000	5
16:1501774–1501775	donor_loss	1.0000	5
16:1502044	acceptor_gain	1.0000

AlphaMissense

1,005 missense substitutions predicted likely pathogenic (of 5,338 scored), across 350 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
M407	9	0.822	0.968
F426	8	0.939	0.993
F700	8	0.810	0.948
F91	8	0.806	0.932
D720	8	0.803	0.926
D808	8	0.792	0.938
F100	8	0.773	0.946
W343	7	0.940	0.989
W800	7	0.906	0.976
F127	7	0.899	0.972
F54	7	0.884	0.970
F701	7	0.883	0.933
F572	7	0.881	0.972
F699	7	0.854	0.959
F599	7	0.842	0.972
F692	7	0.840	0.948
F213	7	0.831	0.948
F179	7	0.821	0.952
F185	7	0.776	0.943
D611	7	0.667	0.840

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Disease associations

OMIM: gene MIM:611140 | disease phenotypes: MIM:616954

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
TELO2-related intellectual disability-neurodevelopmental disorder	Definitive	Autosomal recessive	5

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
TELO2-related intellectual disability-neurodevelopmental disorder	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (9 panels, 6 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

9 panels:

Panel	Rating
Clefting	green
DDG2P	green
Fetal anomalies	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Early onset or syndromic epilepsy	amber
Paediatric disorders	amber
Unexplained death in infancy and sudden unexplained death in childhood	amber

Mondo (1): TELO2-related intellectual disability-neurodevelopmental disorder (MONDO:0014848)

Orphanet (1): TELO2-related intellectual disability-neurodevelopmental disorder (Orphanet:488642)

HPO phenotypes

showing 60 of 68 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000081	Duplicated collecting system
HP:0000175	Cleft palate
HP:0000191	Accessory oral frenulum
HP:0000252	Microcephaly
HP:0000308	Microretrognathia
HP:0000316	Hypertelorism
HP:0000365	Hearing impairment
HP:0000510	Rod-cone dystrophy
HP:0000519	Developmental cataract
HP:0000582	Upslanted palpebral fissure
HP:0000592	Blue sclerae
HP:0000749	Paroxysmal bursts of laughter
HP:0000767	Pectus excavatum
HP:0000768	Pectus carinatum
HP:0001156	Brachydactyly
HP:0001182	Tapered finger
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001344	Absent speech
HP:0001382	Joint hypermobility
HP:0001511	Intrauterine growth retardation
HP:0001583	Rotary nystagmus
HP:0001680	Coarctation of aorta
HP:0001734	Annular pancreas
HP:0001773	Short foot
HP:0001800	Hypoplastic toenails
HP:0001838	Rocker bottom foot
HP:0001845	Overlapping toe
HP:0001999	Abnormal facial shape
HP:0002141	Gait imbalance
HP:0002360	Sleep disturbance
HP:0002465	Poor speech
HP:0002540	Inability to walk
HP:0002714	Downturned corners of mouth
HP:0002751	Kyphoscoliosis
HP:0003273	Hip contracture
HP:0003577	Congenital onset
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0004209	Clinodactyly of the 5th finger
HP:0004322	Short stature
HP:0004692	4-5 toe syndactyly
HP:0006380	Knee flexion contracture
HP:0006979	Sleep-wake cycle disturbance
HP:0007598	Bilateral single transverse palmar creases
HP:0008513	Bilateral conductive hearing impairment
HP:0008780	Congenital bilateral hip dislocation
HP:0008947	Floppy infant
HP:0010296	Ankyloglossia
HP:0010775	Vascular ring
HP:0010864	Severe intellectual disability
HP:0011344	Severe global developmental delay
HP:0011451	Primary microcephaly
HP:0011590	Double aortic arch

GWAS associations

1 associations:

Study	Trait	p-value
GCST007843_25	Rheumatoid arthritis	2e-8

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066377 (SINGLE PROTEIN)

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
9.50	Kd	0.314	nM	CHEMBL5653589
9.50	ED50	0.314	nM	CHEMBL5653589
6.18	Kd	664.8	nM	CHEMBL3752910
6.18	ED50	664.8	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 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
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149569: Binding affinity to human TELO2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0003	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149569: Binding affinity to human TELO2 incubated for 45 mins by Kinobead based pull down assay	kd	0.6648	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
Cadmium	decreases expression, increases expression	2
Valproic Acid	affects expression, increases methylation	2
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
propylparaben	increases expression	1
bisphenol A	increases methylation	1
lead acetate	increases expression	1
potassium perchlorate	decreases expression	1
methylparaben	increases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
perfluorooctanoic acid	decreases expression	1
cupric chloride	increases expression	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
perfluorohexanesulfonic acid	decreases expression	1
jinfukang	increases expression	1
MT19c compound	decreases expression	1
Pioglitazone	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Boron Compounds	decreases expression	1
Caffeine	decreases phosphorylation	1
Cannabinoids	affects methylation, increases abundance	1
Cisplatin	decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Estradiol	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652611	Binding	Binding affinity to human TELO2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — *ChemMedChem*

Clinical trials (associated diseases)

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

1 trials:

NCT	Phase	Status	Title
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for TELO2 across ~30M SureChEMBL compounds — explore on Sugi Predict.