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): 680 total — 11 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 68
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 71.8% of screened cell lines
• 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: 33 — 27 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000262319, ENST00000497339, ENST00000563676, ENST00000564507, ENST00000567423, ENST00000567427, ENST00000568240, ENST00000569744, ENST00000889735, ENST00000889736, ENST00000889737, ENST00000889738, ENST00000889739, ENST00000889740, ENST00000889741, ENST00000889742, ENST00000889743, ENST00000889744, ENST00000914530, ENST00000914531, ENST00000914532, ENST00000914533, ENST00000914534, ENST00000914535, ENST00000962543, ENST00000962544, ENST00000962545, ENST00000962546, ENST00000962547, ENST00000962548, ENST00000962549, ENST00000962550, ENST00000962551

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.

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

277 total, 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

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

8 targeting TELO2, 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-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

DepMap (CRISPR cell-line fitness): dependent in 71.8% of screened cell lines.

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

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_Regulation	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)

3 structures.

PDB	Method	Resolution (Å)
4PSI	X-RAY DIFFRACTION	2.45
7OLE	ELECTRON MICROSCOPY	3.41
7F4U	ELECTRON MICROSCOPY	4.2

Predicted structure (AlphaFold)

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

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): 490 (interaction with pih1d1); 491 (interaction with pih1d1); 492 (interaction with pih1d1)

Post-translational modifications (10): 422, 456, 485, 487, 491, 688, 836, 1, 374, 419

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 pathways

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 (8): chromosome, telomeric region (GO:0000781), nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), nuclear body (GO:0016604), TTT Hsp90 cochaperone complex (GO:0110078), chromosome (GO:0005694)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	3
cellular anatomical structure	3
molecular_function	2
intracellular membraneless organelle	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
protein-containing complex	1

Protein interactions and networks

STRING

1460 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TELO2	TTI1	O43156	997
TELO2	TTI2	Q6NXR4	990
TELO2	DEPTOR	Q8TB45	947
TELO2	MLST8	Q9BVC4	930
TELO2	FAAP24	Q9BTP7	850
TELO2	COQ7	Q99807	818
TELO2	RPTOR	Q8N122	817
TELO2	ATM	Q13315	808
TELO2	FANCM	Q8IYD8	787
TELO2	CLK3	P49761	767
TELO2	MTOR	P42345	746
TELO2	AKT1S1	Q96B36	743
TELO2	SMG1	Q96Q15	720
TELO2	CHEK1	O14757	711
TELO2	TRRAP	Q9Y4A5	710

IntAct

170 interactions, top by confidence:

A	B	Type	Score
TTI1	TELO2	psi-mi:“MI:0915”(physical association)	0.760
TELO2	TTI1	psi-mi:“MI:0915”(physical association)	0.760
TELO2	TTI1	psi-mi:“MI:0914”(association)	0.760
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
TELO2	PIH1D1	psi-mi:“MI:0915”(physical association)	0.700
PIH1D1	TELO2	psi-mi:“MI:0407”(direct interaction)	0.700
TELO2	PIH1D1	psi-mi:“MI:0407”(direct interaction)	0.700
TTI2	TTI1	psi-mi:“MI:0914”(association)	0.690
ATM	TELO2	psi-mi:“MI:0407”(direct interaction)	0.680
FBXO9	TELO2	psi-mi:“MI:0915”(physical association)	0.610
FBXO9	TTI1	psi-mi:“MI:0914”(association)	0.610

BioGRID (211): TELO2 (Affinity Capture-Western), TELO2 (Affinity Capture-Western), TELO2 (Affinity Capture-MS), TELO2 (Affinity Capture-MS), TELO2 (Affinity Capture-MS), TELO2 (Two-hybrid), TELO2 (Affinity Capture-MS), TELO2 (Affinity Capture-MS), TELO2 (Affinity Capture-MS), TELO2 (Affinity Capture-MS), TELO2 (Affinity Capture-MS), TELO2 (Affinity Capture-MS), TELO2 (Affinity Capture-MS), TELO2 (Affinity Capture-MS), TELO2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5PJB7, A0A1L8HX76, A6QR40, O08764, O60294, O95382, P10938, P70218, P97452, Q12851, Q14137, Q15334, Q16586, Q28686, Q32P44, Q3TJ91, Q499N3, Q499U2, Q4KLI9, Q561R2, Q562C2, Q5RBH8, Q5RCX2, Q61161, Q6AY79, Q6F5E8, Q6P1M3, Q6V7V2, Q7SZE3, Q7TMC8, Q80Y17, Q8BYZ7, Q8C3I8, Q8C6B2, Q8CHW4, Q8K4K5, Q8MKF0, Q8N0W3, Q8VC03, Q91WI7

Diamond homologs: Q08CY4, Q6GPP1, Q7T006, Q9DC40, Q9Y4R8

SIGNOR signaling

8 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

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	11
Likely pathogenic	13
Uncertain significance	250
Likely benign	285
Benign	47

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
1686256	NM_016111.4(TELO2):c.1825C>T (p.Arg609Cys)	Pathogenic
2015550	NM_016111.4(TELO2):c.2121dup (p.Asp708Ter)	Pathogenic
2103874	NM_016111.4(TELO2):c.460dup (p.Glu154fs)	Pathogenic
2426267	NC_000016.9:g.(?1550077)(1553023_?)del	Pathogenic
2446177	NM_016111.4(TELO2):c.1652del (p.Glu551fs)	Pathogenic
2783244	NM_016111.4(TELO2):c.418C>T (p.Gln140Ter)	Pathogenic
2980637	NM_016111.4(TELO2):c.569_570del (p.Glu190fs)	Pathogenic
3339339	NM_016111.4(TELO2):c.1612_1621dup (p.Leu541delinsProTer)	Pathogenic
3661655	NM_016111.4(TELO2):c.1922dup (p.Asn641fs)	Pathogenic
3907641	NM_016111.4(TELO2):c.434del (p.Thr145fs)	Pathogenic
4532811	NM_016111.4(TELO2):c.800_801del (p.Val267fs)	Pathogenic
1319744	NM_016111.4(TELO2):c.1110del (p.Gln370fs)	Likely pathogenic
1325187	NM_016111.4(TELO2):c.682+1G>A	Likely pathogenic
2072846	NM_016111.4(TELO2):c.2291+1G>C	Likely pathogenic
2831679	NM_016111.4(TELO2):c.742_830+600del	Likely pathogenic
3339225	NM_016111.4(TELO2):c.2226+1G>C	Likely pathogenic
3367131	NM_016111.4(TELO2):c.946C>T (p.Gln316Ter)	Likely pathogenic
3689592	NM_016111.4(TELO2):c.2227-1G>A	Likely pathogenic
3766160	NM_016111.4(TELO2):c.2299C>T (p.Arg767Cys)	Likely pathogenic
3766166	NM_016111.4(TELO2):c.1A>T (p.Met1Leu)	Likely pathogenic
4086194	NM_016111.4(TELO2):c.2034+2T>C	Likely pathogenic
452017	NM_016111.4(TELO2):c.561del (p.Leu188fs)	Likely pathogenic
4716134	NM_016111.4(TELO2):c.1282-1G>T	Likely pathogenic
4725492	NM_016111.4(TELO2):c.335+1G>C	Likely pathogenic

SpliceAI

3875 predictions. Top by Δscore:

Variant	Effect	Δscore
16:1493592:G:GT	donor_gain	1.0000
16:1494612:GCGGG:G	donor_gain	1.0000
16:1494614:GGG:G	donor_gain	1.0000
16:1494615:GGG:G	donor_gain	1.0000
16:1495581:G:GT	donor_gain	1.0000
16:1495621:AAGGT:A	donor_loss	1.0000
16:1495623:GGTGA:G	donor_loss	1.0000
16:1495624:G:GA	donor_loss	1.0000
16:1495624:G:GG	donor_gain	1.0000
16:1495625:T:A	donor_loss	1.0000
16:1496303:G:GT	donor_gain	1.0000
16:1497359:A:AG	acceptor_gain	1.0000
16:1497360:G:GG	acceptor_gain	1.0000
16:1497360:GAGGA:G	acceptor_gain	1.0000
16:1497505:TGGGG:T	donor_loss	1.0000
16:1497506:GGG:G	donor_gain	1.0000
16:1497506:GGGGT:G	donor_loss	1.0000
16:1497507:GG:G	donor_gain	1.0000
16:1497507:GGG:G	donor_gain	1.0000
16:1497508:GG:G	donor_gain	1.0000
16:1497508:GGT:G	donor_loss	1.0000
16:1497509:G:GG	donor_gain	1.0000
16:1497509:GTAAG:G	donor_loss	1.0000
16:1497510:T:TC	donor_loss	1.0000
16:1500161:GCAG:G	donor_gain	1.0000
16:1500163:AGGTA:A	donor_loss	1.0000
16:1500164:GGTA:G	donor_loss	1.0000
16:1500165:GT:G	donor_loss	1.0000
16:1500166:T:A	donor_loss	1.0000
16:1500342:TGCA:T	acceptor_loss	1.0000

AlphaMissense

5338 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:1500694:T:C	F426L	0.993
16:1500696:C:A	F426L	0.993
16:1500696:C:G	F426L	0.993
16:1500371:T:A	W343R	0.989
16:1500371:T:C	W343R	0.989
16:1502985:C:A	R609S	0.989
16:1500425:A:C	S361R	0.988
16:1500427:C:A	S361R	0.988
16:1500427:C:G	S361R	0.988
16:1502986:G:C	R609P	0.988
16:1505426:C:A	A620D	0.987
16:1500695:T:C	F426S	0.984
16:1500634:G:C	G406R	0.983
16:1502944:T:C	L595P	0.980
16:1500658:A:C	S414R	0.979
16:1500660:T:A	S414R	0.979
16:1500660:T:G	S414R	0.979
16:1500695:T:G	F426C	0.977
16:1507321:G:C	G748R	0.977
16:1500646:G:C	A410P	0.976
16:1507707:T:A	W800R	0.976
16:1507707:T:C	W800R	0.976
16:1500373:G:C	W343C	0.974
16:1500373:G:T	W343C	0.974
16:1495389:T:C	F127L	0.972
16:1495391:C:A	F127L	0.972
16:1495391:C:G	F127L	0.972
16:1502705:T:C	F572L	0.972
16:1502707:T:A	F572L	0.972
16:1502707:T:G	F572L	0.972

dbSNP variants (sampled 300 via entrez): RS1000047065 (16:1494011 C>A,T), RS1000137124 (16:1501840 G>T), RS1000496764 (16:1499143 C>A,T), RS1000499131 (16:1510060 G>A), RS1000615715 (16:1495087 C>T), RS1000646950 (16:1495335 C>A,G,T), RS1000772014 (16:1498696 A>C,G,T), RS1001014364 (16:1510470 T>G), RS1001045418 (16:1510788 G>A,T), RS1001064432 (16:1492295 C>A), RS1001204369 (16:1498973 A>C,G), RS1001233363 (16:1502062 C>A,T), RS1001304747 (16:1498222 C>T), RS1001396496 (16:1506149 C>A,T), RS1001436714 (16:1498775 C>T)

Disease associations

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

GenCC curated gene-disease

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

ClinGen Gene-Disease Validity (1)

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

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

Mondo (2): TELO2-related intellectual disability-neurodevelopmental disorder (MONDO:0014848), microcephaly (MONDO:0001149)

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

HPO phenotypes

68 total (30 of 68 shown, 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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST007843_25	Rheumatoid arthritis	2.000000e-08

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066377 (SINGLE PROTEIN)

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

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)

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

Trial	Phase	Status	Title
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.