ANGPT2

Summary

ANGPT2 (angiopoietin 2, HGNC:485) is a protein-coding gene on chromosome 8p23.1, encoding Angiopoietin-2 (O15123). Binds to TEK/TIE2, competing for the ANGPT1 binding site, and modulating ANGPT1 signaling.

This gene belongs to the angiopoietin family of growth factors. The protein encoded by this gene is an antagonist of angiopoietin 1, and both angiopoietin 1 and angiopoietin 2 are ligands for the endothelial TEK receptor tyrosine kinase. Angiopoietin 2 is upregulated in multiple inflammatory diseases and is implicated in the direct control of inflammation-related signaling pathways. The encoded protein affects angiogenesis during embryogenesis and tumorigenesis, disrupts the vascular remodeling ability of angiopoietin 1, and may induce endothelial cell apoptosis. This gene serves a prognostic biomarker for acute respiratory distress syndrome.

Source: NCBI Gene 285 — RefSeq curated summary.

At a glance

• Gene–disease (curated): lymphatic malformation 10 (Strong, GenCC)
• GWAS associations: 9
• Clinical variants (ClinVar): 197 total — 9 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 4
• Druggable target: yes
• MANE Select transcript: NM_001118887

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:485
Approved symbol	ANGPT2
Name	angiopoietin 2
Location	8p23.1
Locus type	gene with protein product
Status	Approved
Aliases	Ang2
Ensembl gene	ENSG00000091879
Ensembl biotype	protein_coding
OMIM	601922
Entrez	285

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000325203, ENST00000338312, ENST00000523120, ENST00000629816, ENST00000897269

RefSeq mRNA: 6 — MANE Select: NM_001118887 NM_001118887, NM_001118888, NM_001147, NM_001386335, NM_001386336, NM_001386337

CCDS: CCDS47761, CCDS47762, CCDS5958

Canonical transcript exons

ENST00000629816 — 9 exons

Exon	Start	End
ENSE00000924724	6532332	6532487
ENSE00000924725	6527555	6527676
ENSE00000924726	6521178	6521410
ENSE00000979541	6514677	6514778
ENSE00000979543	6508932	6509062
ENSE00001121499	6513678	6513844
ENSE00001733243	6519864	6519991
ENSE00003770034	6499632	6503261
ENSE00003899000	6562647	6563245

Expression profiles

Bgee: expression breadth ubiquitous, 219 present calls, max score 86.37.

FANTOM5 (CAGE): breadth broad, TPM avg 5.1599 / max 532.5154, expressed in 490 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
91694	3.5453	382
91696	0.6731	186
91692	0.3640	175
91698	0.2100	114
91697	0.1563	73
91695	0.1245	59
91693	0.0867	39

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	86.37	silver quality
popliteal artery	UBERON:0002250	85.22	gold quality
tibial artery	UBERON:0007610	85.19	gold quality
placenta	UBERON:0001987	84.16	gold quality
islet of Langerhans	UBERON:0000006	81.38	gold quality
visceral pleura	UBERON:0002401	81.05	gold quality
tendon	UBERON:0000043	80.80	gold quality
omental fat pad	UBERON:0010414	80.51	gold quality
subcutaneous adipose tissue	UBERON:0002190	80.47	gold quality
pericardium	UBERON:0002407	80.46	gold quality
aorta	UBERON:0000947	80.44	gold quality
peritoneum	UBERON:0002358	80.44	gold quality
medial globus pallidus	UBERON:0002477	79.54	gold quality
buccal mucosa cell	CL:0002336	79.36	gold quality
adipose tissue of abdominal region	UBERON:0007808	79.32	gold quality
calcaneal tendon	UBERON:0003701	79.01	gold quality
tibia	UBERON:0000979	78.49	gold quality
endothelial cell	CL:0000115	78.14	gold quality
blood vessel layer	UBERON:0004797	77.23	gold quality
decidua	UBERON:0002450	76.28	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.24	gold quality
colonic epithelium	UBERON:0000397	76.22	gold quality
lymph node	UBERON:0000029	76.05	gold quality
descending thoracic aorta	UBERON:0002345	75.98	gold quality
right lobe of thyroid gland	UBERON:0001119	75.84	gold quality
adipose tissue	UBERON:0001013	75.61	gold quality
left lobe of thyroid gland	UBERON:0001120	75.34	gold quality
pleura	UBERON:0000977	75.29	gold quality
thyroid gland	UBERON:0002046	75.26	gold quality
cartilage tissue	UBERON:0002418	75.23	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	666.67
E-MTAB-8142	yes	118.30
E-HCAD-10	yes	46.29
E-HCAD-11	yes	20.56
E-MTAB-6701	yes	19.06
E-CURD-46	yes	10.63
E-CURD-112	yes	7.39
E-MTAB-5061	no	3.39
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, ELF1, ELF2, ETS1, ETS2, FLCN, FOXC2, FOXO1, FOXO3, GATA2, HIF1A, HOXB5, HOXD8, LMO2, LYL1, MECOM, NR5A1, PBX1, SP3, TAL1, TXK, VHL, ZBTB16

miRNA regulators (miRDB)

150 targeting ANGPT2, 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-340-5P	100.00	72.50	4437
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-3162-3P	100.00	65.37	363
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AS-5P	99.94	71.22	3482

Literature-anchored findings (GeneRIF, showing 40)

• Genomic structures of the human angiopoietins show polymorphism in angiopoietin-2 (PMID:11856872)
• ang-2 is expressed in areas undergoing vascular remodeling and is involved in neovascularization. (PMID:11861279)
• results indicate that there is a difference in the Ang/Tie2 gene expression between physiological and pathological angiogenesis in the ovary. (PMID:12138242)
• angiopoietin-2 is selectively induced in cultured human umbilical vein endothelial cells by hyperbaric oxygen treatment (PMID:12176040)
• may play important roles in placental biology and chorionic villus vascular development and remodeling in an autocrine/paracrine manner (PMID:12213874)
• In focal nodular hyperplasia, Ang-1 was significantly up-regulated, Ang-2 was down-regulated, and the Ang-1/Ang-2 ratio was highly and specifically increased. (PMID:12612904)
• an increased expression of Ang-2/1 in the presence of VEGF may play a critical role in promoting tumor angiogenesis and progression in human hepatocellular carcinoma (PMID:12717391)
• Tumor-derived VEGF significantly up-regulated the expression of Ang-2 in host stroma endothelial cells, resulting in markedly increased Ang-2/Tie-2 mRNA copy number ratio in vivo. (PMID:12810677)
• plays a critical role in inducing tumor cell infiltration, and this invasive phenotype is caused by activation of MMP-2 (PMID:12861074)
• High-level expression of angiopoietin-2 and VEGF receptors observed in endothelium of verruga peruana. Infection of cultured endothelium with B. bacilliformis also resulted in induction of angiopoetin-2 in vitro. (PMID:14507641)
• No association between mutant allele and the occurrence of idiopathic recurrent miscarriage. No statistically significant differences with respect to allele frequencies were observed. (PMID:14556828)
• Ang2, PIGF and VEGF-C play a role in promote endothelial survival and vascular remodeling by human cytotrophoblast. (PMID:14568550)
• hypoxia-induced Ang2 expression is regulated by COX-2-dependent prostanoids (PMID:14702352)
• Angiopoietin 2 induced STAT5 activation and p21waf expression and increased the fraction of endothelial cells in G1. (PMID:14726409)
• angiopoietin-2 and VEGF at the deepest invasive tumor site may have roles in tumor angiogenesis (PMID:14767538)
• increase in ANG2 RNA from peripheral tumor to the intermediate portion, and decrease in recruitment of periendothelial supporting cells around the vascular endothelial, suggests that Ang-2 may play a role in the immaturity of vessels in liver neoplasm (PMID:14768007)
• Ang-2 is a stored, rapidly available molecule in endothelial cells suggesting that the angiopoietin/Tie-2 system during angiogenesis likely to be involved in rapid vascular homeostatic reactions such as inflammation and coagulation. (PMID:14976056)
• The autocrine/paracrine signaling of the Ang/Tie2 system is important for the up-regulated angiogenesis in the RA synovium, as well as for synoviocyte behavior, by regulating chemotactic cell movement. (PMID:14991531)
• Protein kinase C and protein kinase A activators increased the mRNA levels of ANGPT-2 in human granulosa cells. Role of both PKA and PKC dependent signaling cascades in the regulation of ANGPT-2 mRNA. (PMID:15002056)
• Transcription factor Ets-1 has a role in transactivation of the angiopoietin 2 promotor. (PMID:15003510)
• increased expression of Angiopoietin-1 and Angiopoietin-2 play a critical role in the process of vascular development in HCC (PMID:15094228)
• Data show that angiopoietin-2, coordinated with VEGF, may play a role in regulating tumor angiogenesis in gastric cancer. (PMID:15112366)
• in granulosa cells the mRNA of various growth factors is detectable by RT-PCR and that VEGF-A and ANG2 is regulated by the gonadotropic hormone choriogonadotropin (PMID:15127326)
• Thrombin reduces expression of Ang-2 protein and mRNA expression in human endometrial stromal cells. (PMID:15161644)
• the angiopoietin/Tie-2 system may participate in the angiogenic response to hypoxia in renal tissues and in tumor angiogenesis in renal carcinoma. (PMID:15198927)
• angiopoietins -1 and 2 have roles in endothelial development (PMID:15213103)
• Under non-reducing conditions, angiopoietin 2 forms disulfide-linked dimers. (PMID:15284220)
• Overexpression of Ang-2 mRNA is associated with non-small cell lung cancer (PMID:15375511)
• Ang2 demonstrates proinflmmatory potential by inducing endothelial P-selectin translocation and neutrophil adhesion onto vascular endothelial cells. (PMID:15498854)
• systemic administration of ang2-selective inhibitors will suppress tumor angiogenesis, supporting the idea that Ang2 plays a proangiogenic role postnatally (PMID:15542434)
• Plasma levels in type 2 diabetes are selectively elevated in patients with diabetes and are associated with indexes of endothelial damage/dysfunction. (PMID:15562207)
• Expression and purification of recombinant ANGPT2 produced in CHO cells was studied. (PMID:15642468)
• Ang2 overexpression may play a key role in placental vascular remodelling. (PMID:15734895)
• up-regulation of Ang2, MMP-2, MT1-MMP, and LN 5 gamma 2 is associated with the invasiveness displayed by human gliomas (PMID:15743799)
• Ang-2 (but not Ang-1) was higher in patients with diabetes compared to controls (p<0.01), with no significant difference between patients with and without cardiovascular diseases (PMID:15823283)
• Tie-2 receptor is expressed by human neutrophils whose active site ligation with either angiopoietin-1 or angiopoietin-2 exerts migratory effects on the one hand and arrests VEGF-mediated chemotaxis on the other (PMID:16020388)
• We show for the first time that Ang2 causes a marked stimulation of EPC migration. (PMID:16129411)
• Measurement of serum Ang-2 concentration in pregnant women may serve as a useful marker in the diagnosis and potentially in predicting subsequent development of preeclampsia. (PMID:16182107)
• Expressions of Ang-1 and Ang-2 in advanced squamous cell carcinoma were higher than that of normal mucosal tissues. (PMID:16229183)
• A3 receptor stimulation activates p44/p42 and p38 mitogen-activated protein kinases, which are required for A3-induced increase of HIF-1alpha and Ang-2 (PMID:16242072)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	angpt2a	ENSDARG00000014946
mus_musculus	Angpt2	ENSMUSG00000031465
rattus_norvegicus	Angpt2	ENSRNOG00000016696

Paralogs (25): TNC (ENSG00000041982), FCN1 (ENSG00000085265), ANGPT4 (ENSG00000101280), FGL1 (ENSG00000104760), FN1 (ENSG00000115414), TNR (ENSG00000116147), ANGPTL1 (ENSG00000116194), TNN (ENSG00000120332), FGL2 (ENSG00000127951), FIBCD1 (ENSG00000130720), ANGPTL6 (ENSG00000130812), ANGPTL3 (ENSG00000132855), ANGPTL2 (ENSG00000136859), FCN3 (ENSG00000142748), FNDC7 (ENSG00000143107), ANGPT1 (ENSG00000154188), FCN2 (ENSG00000160339), MFAP4 (ENSG00000166482), ANGPTL4 (ENSG00000167772), TNXB (ENSG00000168477), FGG (ENSG00000171557), FGA (ENSG00000171560), FGB (ENSG00000171564), ANGPTL7 (ENSG00000171819), ANGPTL5 (ENSG00000187151)

Protein

Protein identifiers

Angiopoietin-2 — O15123 (reviewed: O15123)

All UniProt accessions (2): O15123, E7EVQ3

UniProt curated annotations — full annotation on UniProt →

Function. Binds to TEK/TIE2, competing for the ANGPT1 binding site, and modulating ANGPT1 signaling. Can induce tyrosine phosphorylation of TEK/TIE2 in the absence of ANGPT1. In the absence of angiogenic inducers, such as VEGF, ANGPT2-mediated loosening of cell-matrix contacts may induce endothelial cell apoptosis with consequent vascular regression. In concert with VEGF, it may facilitate endothelial cell migration and proliferation, thus serving as a permissive angiogenic signal. Involved in the regulation of lymphangiogenesis.

Subunit / interactions. Interacts with TEK/TIE2, competing for the same binding site as ANGPT1. Interacts with ITGA5. Interacts with SVEP1/polydom. Interacts with THBD; this interaction significantly inhibits the generation of activated PC and TAFIa/CPB2 by the thrombin/thrombomodulin complex.

Subcellular location. Secreted.

Disease relevance. Lymphatic malformation 10 (LMPHM10) [MIM:619369] A form of primary lymphedema, a disease characterized by swelling of body parts due to developmental anomalies and functional defects of the lymphatic system. Patients with lymphedema may suffer from recurrent local infections. LMPHM10 is an autosomal dominant form characterized by the onset of swelling in the lower extremities within the first year of life. Lymphedema may also occur in the neck, upper extremities, and scrotum or labia majora. Gradual resorption generally occurs, although some patients may experience progression complicated by cellulitis. Incomplete penetrance has been observed in some families. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The Fibrinogen C-terminal domain mediates interaction with the TEK/TIE2 receptor.

Isoforms (3)

UniProt ID	Names	Canonical?
O15123-1	1	yes
O15123-2	3
O15123-3	2

RefSeq proteins (6): NP_001112359, NP_001112360, NP_001138, NP_001373264, NP_001373265, NP_001373266 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002181	Fibrinogen_a/b/g_C_dom	Domain
IPR014716	Fibrinogen_a/b/g_C_1	Homologous_superfamily
IPR020837	Fibrinogen_CS	Conserved_site
IPR036056	Fibrinogen-like_C	Homologous_superfamily
IPR037579	FIB_ANG-like	Family
IPR057439	ANG-1/2/4	Domain

Pfam: PF00147, PF25443

UniProt features (46 total): strand 14, helix 7, glycosylation site 6, sequence variant 5, binding site 4, disulfide bond 3, splice variant 2, signal peptide 1, chain 1, domain 1, coiled-coil region 1, turn 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
4JZC	X-RAY DIFFRACTION	1.9
1Z3U	X-RAY DIFFRACTION	2.25
4ZFG	X-RAY DIFFRACTION	2.27
1Z3S	X-RAY DIFFRACTION	2.35
8VGP	ELECTRON MICROSCOPY	2.7
9HMI	X-RAY DIFFRACTION	2.78
2GY7	X-RAY DIFFRACTION	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15123-F1	84.15	0.66

Antibody-complex structures (SAbDab): 2 — 4ZFG, 8VGP

Functional residue map

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

Ligand- & substrate-binding residues (4): 429; 431; 433; 435

Disulfide bonds (3): 284–313, 433–435, 437–450

Glycosylation sites (6): 133, 151, 240, 304, 89, 119

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-210993	Tie2 Signaling
R-HSA-109582	Hemostasis
R-HSA-202733	Cell surface interactions at the vascular wall

MSigDB gene sets: 276 (showing top): HORIUCHI_WTAP_TARGETS_DN, HARRIS_HYPOXIA, GOBP_REGULATION_OF_COAGULATION, GOBP_NEGATIVE_REGULATION_OF_BLOOD_VESSEL_ENDOTHELIAL_CELL_MIGRATION, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_COAGULATION, GOBP_REGENERATION, GOBP_REGULATION_OF_POSITIVE_CHEMOTAXIS, CLASPER_LYMPHATIC_VESSELS_DURING_METASTASIS_UP, REACTOME_TIE2_SIGNALING, NKX61_01, GOBP_NEGATIVE_REGULATION_OF_CELL_SUBSTRATE_ADHESION, GOBP_WOUND_HEALING, VART_KSHV_INFECTION_ANGIOGENIC_MARKERS_UP, GOBP_TAXIS

GO Biological Process (24): angiogenesis (GO:0001525), response to hypoxia (GO:0001666), signal transduction (GO:0007165), germ cell development (GO:0007281), blood coagulation (GO:0007596), response to mechanical stimulus (GO:0009612), response to glucose (GO:0009749), gene expression (GO:0010467), negative regulation of cell-substrate adhesion (GO:0010812), response to activity (GO:0014823), negative regulation of angiogenesis (GO:0016525), animal organ regeneration (GO:0031100), negative regulation of blood vessel endothelial cell migration (GO:0043537), positive regulation of angiogenesis (GO:0045766), Tie signaling pathway (GO:0048014), positive regulation of coagulation (GO:0050820), negative regulation of positive chemotaxis (GO:0050928), maternal process involved in female pregnancy (GO:0060135), cellular response to growth factor stimulus (GO:0071363), glomerulus vasculature development (GO:0072012), cell differentiation (GO:0030154), negative regulation of blood coagulation (GO:0030195), blood vessel morphogenesis (GO:0048514), positive regulation of multicellular organismal process (GO:0051240)

GO Molecular Function (5): signaling receptor binding (GO:0005102), receptor tyrosine kinase binding (GO:0030971), metal ion binding (GO:0046872), receptor ligand activity (GO:0048018), protein binding (GO:0005515)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Cell surface interactions at the vascular wall	1
Hemostasis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
coagulation	2
angiogenesis	2
regulation of angiogenesis	2
signaling receptor binding	2
cellular anatomical structure	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
response to stress	1
response to decreased oxygen levels	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
developmental process involved in reproduction	1
gamete generation	1
cellular process involved in reproduction in multicellular organism	1
cell development	1
hemostasis	1
wound healing	1
response to external stimulus	1
response to abiotic stimulus	1
response to hexose	1
macromolecule biosynthetic process	1
negative regulation of cell adhesion	1
regulation of cell-substrate adhesion	1
cell-substrate adhesion	1
response to stimulus	1
negative regulation of blood vessel morphogenesis	1
regeneration	1
animal organ development	1
negative regulation of endothelial cell migration	1
blood vessel endothelial cell migration	1
regulation of blood vessel endothelial cell migration	1
positive regulation of vasculature development	1
cell surface receptor protein tyrosine kinase signaling pathway	1
regulation of coagulation	1
positive regulation of multicellular organismal process	1
positive chemotaxis	1
negative regulation of chemotaxis	1

Protein interactions and networks

STRING

2020 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANGPT2	TEK	Q02763	999
ANGPT2	TIE1	P35590	992
ANGPT2	NTRK1	P04629	981
ANGPT2	KDR	P35968	955
ANGPT2	FLT4	P35916	938
ANGPT2	FLT1	P16057	936
ANGPT2	EDN1	P05305	891
ANGPT2	VWF	P04275	889
ANGPT2	CXCL8	P10145	868
ANGPT2	SELP	P16109	836
ANGPT2	FGF2	P09038	830
ANGPT2	PGF	P49763	822
ANGPT2	VEGFC	P49767	795
ANGPT2	EGF	P01133	749
ANGPT2	IL6	P05231	748

IntAct

20 interactions, top by confidence:

A	B	Type	Score
	ANGPT2	psi-mi:“MI:0407”(direct interaction)	0.650
ANGPT2		psi-mi:“MI:0407”(direct interaction)	0.650
	ANGPT2	psi-mi:“MI:0915”(physical association)	0.650
VEGFA		psi-mi:“MI:0915”(physical association)	0.650
TEK	ANGPT2	psi-mi:“MI:0407”(direct interaction)	0.620
ANGPT2	TEK	psi-mi:“MI:0407”(direct interaction)	0.620
ANGPT2	ZZEF1	psi-mi:“MI:0914”(association)	0.530
ANGPT2		psi-mi:“MI:0407”(direct interaction)	0.440
ANGPT2	VIM	psi-mi:“MI:0915”(physical association)	0.400
ANGPT2	ANXA7	psi-mi:“MI:0915”(physical association)	0.370
ANGPT2	CDKN1A	psi-mi:“MI:0915”(physical association)	0.370
ANGPT2	CSNK2B	psi-mi:“MI:0915”(physical association)	0.370
IQCB1	PCP4L1	psi-mi:“MI:0914”(association)	0.350
CDH5	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
CDH5	MYO1C	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (25): TEK (Reconstituted Complex), ITGB1 (Reconstituted Complex), ITGA5 (Reconstituted Complex), ITGB1 (Affinity Capture-Western), ITGA5 (Affinity Capture-Western), ITGAV (Affinity Capture-Western), ANGPT2 (Affinity Capture-Western), ZZEF1 (Affinity Capture-MS), FBXO28 (Affinity Capture-MS), HECTD3 (Affinity Capture-MS), VIM (Proximity Label-MS), ANGPT2 (Reconstituted Complex), ANGPT2 (Affinity Capture-Western), ANGPT2 (Affinity Capture-Western), ANGPT2 (Reconstituted Complex)

ESM2 similar proteins: A0A8J8, O08538, O15123, O18920, O35460, O35462, O35608, O43827, O77802, O95841, P02675, P02676, P02678, P02679, P02680, P04115, P12799, P12804, P14480, P17634, P21758, P30204, P86239, Q02020, Q08830, Q0P4P2, Q14314, Q15389, Q1RMR1, Q29RY7, Q3SZZ7, Q5EA66, Q5M8C6, Q5XK91, Q60FC1, Q640P2, Q6AX44, Q71KU9, Q86XS5, Q8K0E8

Diamond homologs: A0A8J8, A2AV25, D8VNS7, D8VNS8, D8VNS9, D8VNT0, E2IYB3, E9PV24, O00602, O08538, O15123, O18920, O35460, O35462, O35608, O43827, O70165, O70497, O75636, O77802, O93526, O95841, P02671, P02675, P02676, P02678, P02679, P02680, P04115, P06399, P10039, P12799, P12804, P14448, P14480, P17634, P19477, P21520, P22105, P24821

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
LMO2	“up-regulates quantity by expression”	ANGPT2	“transcriptional regulation”
LYL1	“up-regulates quantity by expression”	ANGPT2	“transcriptional regulation”
TAL1	“up-regulates quantity by expression”	ANGPT2	“transcriptional regulation”
ANGPT2	up-regulates	TEK	binding
MECOM	“up-regulates quantity by expression”	ANGPT2	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	2
Uncertain significance	101
Likely benign	45
Benign	19

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
1141561	NM_001118887.2(ANGPT2):c.893C>T (p.Thr298Met)	Pathogenic
1141562	NM_001118887.2(ANGPT2):c.1301G>C (p.Cys434Ser)	Pathogenic
1456804	NC_000008.10:g.(?6264189)(6420455_?)del	Pathogenic
150724	GRCh38/hg38 8p23.2-23.1(chr8:2605460-6605579)x3	Pathogenic
2426840	NC_000008.10:g.(?6264189)(6500570_?)del	Pathogenic
3245597	NC_000008.10:g.(?6264189)(6479232_?)del	Pathogenic
32742	GRCh38/hg38 8p23.3-23.1(chr8:241530-7022841)x1	Pathogenic
4688532	NC_000008.10:g.(6264211_6266799)_(6357451_6478974)del	Pathogenic
4688536	NC_000008.10:g.(?6264147)(6357451_6478974)del	Pathogenic
2431739	NM_024596.5(MCPH1):c.2214+1G>A	Likely pathogenic
3595813	NM_024596.5(MCPH1):c.2195_2196del (p.His732fs)	Likely pathogenic

SpliceAI

1969 predictions. Top by Δscore:

Variant	Effect	Δscore
8:6499930:G:GG	donor_gain	1.0000
8:6508933:T:TA	donor_gain	1.0000
8:6514671:CCTTA:C	donor_loss	1.0000
8:6514672:CTTAC:C	donor_loss	1.0000
8:6514673:TTACC:T	donor_loss	1.0000
8:6514674:TA:T	donor_loss	1.0000
8:6514676:CCA:C	donor_gain	1.0000
8:6514779:CT:C	acceptor_loss	1.0000
8:6514780:T:G	acceptor_loss	1.0000
8:6519996:T:C	acceptor_gain	1.0000
8:6521171:AACTT:A	donor_loss	1.0000
8:6521172:ACTT:A	donor_loss	1.0000
8:6521173:CTTA:C	donor_loss	1.0000
8:6521174:TTA:T	donor_loss	1.0000
8:6521175:TAC:T	donor_loss	1.0000
8:6521176:A:AC	donor_gain	1.0000
8:6521176:A:T	donor_loss	1.0000
8:6521177:C:CT	donor_gain	1.0000
8:6521177:CA:C	donor_gain	1.0000
8:6521177:CAG:C	donor_gain	1.0000
8:6521177:CAGT:C	donor_gain	1.0000
8:6521177:CAGTT:C	donor_gain	1.0000
8:6521213:A:C	donor_gain	1.0000
8:6521411:C:CC	acceptor_gain	1.0000
8:6521412:T:C	acceptor_gain	1.0000
8:6521412:T:TC	acceptor_gain	1.0000
8:6532326:ACTT:A	donor_loss	1.0000
8:6532327:CTT:C	donor_loss	1.0000
8:6532328:TTAC:T	donor_loss	1.0000
8:6532329:TACT:T	donor_loss	1.0000

AlphaMissense

3316 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:6503243:C:T	C450Y	1.000
8:6508952:C:G	C437S	1.000
8:6508953:A:T	C437S	1.000
8:6503172:A:G	W474R	0.999
8:6503172:A:T	W474R	0.999
8:6503242:A:C	C450W	0.999
8:6503243:C:A	C450F	0.999
8:6503243:C:G	C450S	0.999
8:6503244:A:G	C450R	0.999
8:6503244:A:T	C450S	0.999
8:6503254:C:A	W446C	0.999
8:6503254:C:G	W446C	0.999
8:6503256:A:G	W446R	0.999
8:6503256:A:T	W446R	0.999
8:6503259:A:G	W445R	0.999
8:6503259:A:T	W445R	0.999
8:6508951:A:C	C437W	0.999
8:6508952:C:A	C437F	0.999
8:6508952:C:T	C437Y	0.999
8:6508953:A:G	C437R	0.999
8:6508958:C:G	C435S	0.999
8:6508958:C:T	C435Y	0.999
8:6508959:A:G	C435R	0.999
8:6508959:A:T	C435S	0.999
8:6508964:C:G	C433S	0.999
8:6508965:A:G	C433R	0.999
8:6508965:A:T	C433S	0.999
8:6508994:A:C	F423C	0.999
8:6503170:C:A	W474C	0.998
8:6503170:C:G	W474C	0.998

dbSNP variants (sampled 300 via entrez): RS1000039233 (8:6538027 G>C), RS1000166675 (8:6508625 C>A,G), RS1000225212 (8:6513976 A>G), RS1000227103 (8:6549277 T>C,G), RS1000230343 (8:6506941 A>G), RS1000290360 (8:6545059 T>C), RS1000299448 (8:6519719 C>A,G,T), RS1000372895 (8:6558749 T>C), RS1000383914 (8:6510157 T>C), RS1000390548 (8:6538169 C>G), RS1000423423 (8:6535448 T>A,G), RS1000439255 (8:6547212 C>T), RS1000463482 (8:6549521 T>A,C), RS1000467209 (8:6523399 T>G), RS1000524342 (8:6527177 A>C,G)

Disease associations

OMIM: gene MIM:601922 | disease phenotypes: MIM:619369, MIM:251200

GenCC curated gene-disease

Disease	Classification	Inheritance
lymphatic malformation 10	Strong	Semidominant

Mondo (4): lymphatic malformation 10 (MONDO:0023662), intellectual disability (MONDO:0001071), microcephaly 1, primary, autosomal recessive (MONDO:0009617), autosomal recessive primary microcephaly (MONDO:0016660)

Orphanet (3): Autosomal recessive primary microcephaly (Orphanet:2512), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), Premature chromosome condensation with microcephaly and intellectual disability (Orphanet:52183)

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000034	Hydrocele testis
HP:0001004	Lymphedema
HP:0003593	Infantile onset

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST002343_4	Response to cytidine analogues (gemcitabine)	1.000000e-06
GCST004860_74	Alcoholic chronic pancreatitis	3.000000e-06
GCST005580_120	Intraocular pressure	2.000000e-15
GCST006394_70	Intraocular pressure	5.000000e-12
GCST006412_73	Intraocular pressure	2.000000e-13
GCST006585_2702	Blood protein levels	7.000000e-06
GCST009269_9	Dental caries (decayed and filled deciduous teeth)	5.000000e-06
GCST009391_1402	Metabolite levels	3.000000e-06
GCST009391_1965	Metabolite levels	1.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004695	intraocular pressure measurement
EFO:0005132	5-HIAA measurement
EFO:0010541	trimethylamine-N-oxide measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C579935	Autosomal Recessive Primary Microcephaly (supp.)
C565384	Microcephaly, Primary Autosomal Recessive, 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3580489 (SINGLE PROTEIN)

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

PharmGKB variants

6 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11989215	ANGPT2, MCPH1		0.00	0
rs2515409	ANGPT2, MCPH1		0.00	0
rs10102851	ANGPT2, MCPH1		0.00	0
rs2515462	ANGPT2, MCPH1		0.00	0
rs13269021	ANGPT2, MCPH1		0.00	0
rs1375668	ANGPT2, MCPH1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tretinoin	increases expression, increases secretion	3
Valproic Acid	affects expression, increases expression, increases methylation	3
trichostatin A	affects cotreatment, increases expression	2
Arsenic Trioxide	increases expression	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Vehicle Emissions	decreases expression, increases abundance, increases expression	2
Calcitriol	increases expression, affects cotreatment	2
Estradiol	affects cotreatment, decreases expression	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Progesterone	affects cotreatment, decreases expression	2
Particulate Matter	increases expression, decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
2-methoxy-6-undecyl-1,4-benzoquinone	decreases expression	1
bisphenol F	decreases methylation	1
methylmercuric chloride	increases expression	1
bisphenol A	decreases methylation	1
tris(2-butoxyethyl) phosphate	affects expression	1
cobaltous chloride	decreases expression	1
tetrathiomolybdate	increases expression	1
norcantharidin	decreases expression	1
perfluorooctane sulfonic acid	decreases reaction, increases expression	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases expression, decreases reaction, increases expression	1
RTKI cpd	decreases reaction, increases expression	1
arachidonyl-2-chloroethylamide	decreases reaction, increases secretion	1
1,1-dimethylbutyl-1-deoxy-Delta(9)-THC	decreases reaction, increases secretion	1
lipopolysaccharide, Escherichia coli O111 B4	decreases reaction, increases secretion	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
belinostat	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8B9	Abcam HCT 116 ANGPT2 KO	Cancer cell line	Male
CVCL_B8SE	Abcam MCF-7 ANGPT2 KO	Cancer cell line	Female
CVCL_B9DC	Abcam A-549 ANGPT2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders