ANGPT2

Chr 8AD

angiopoietin 2

Also known as: AGPT2, ANG2, LMPHM10

NCBI Gene: 285 ENSG00000091879 UniProt: O15123 OMIM: 601922

The protein encoded by this gene is an angiopoietin that binds to the TEK/TIE2 receptor and competes with angiopoietin 1, regulating angiogenesis and lymphangiogenesis through modulation of endothelial cell migration, proliferation, and apoptosis. Mutations cause lymphatic malformation 10, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants (LOEUF 0.377), suggesting that complete protein loss is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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. [provided by RefSeq, Aug 2020]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.381 OMIM phenotype

Clinical Summary— ANGPT2

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.83) — some intolerance to loss-of-function variants.

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ClinVar Variants

10 unique Pathogenic / Likely Pathogenic· 93 VUS of 194 total submissions

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.38LOEUF

pLI 0.832

Z-score 4.02

OE 0.18 (0.09–0.38)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-0.53Z-score

OE missense 1.09 (0.99–1.20)

298 obs / 273.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.18 (0.09–0.38)

0≤0.351.4

Missense OE?1.09 (0.99–1.20)

0≤0.61.4

Synonymous OE?1.27

0≤1.21.6

LoF obs/exp: 5 / 27.9Missense obs/exp: 298 / 273.5Syn Z: -2.15

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedANGPT2-related non-immune hydrops fetalisLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6259th %ile

GOF

0.5857th %ile

LOF

0.4136th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

DNFunctional analyses revealed three missense mutations that resulted in decreased ANGPT2 secretion and inhibited the secretion of wild-type (WT)-ANGPT2, suggesting that they have a dominant-negative effect on ANGPT2 signaling.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 32908006 ↗

ClinVar Variant Classifications

194 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic2

VUS93

Likely Benign46

Benign20

Conflicting7

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	6	0	8
Likely Pathogenic	2	0	0	0	2
VUS	1	86	5	1	93
Likely Benign	0	6	20	20	46
Benign	0	4	6	10	20
Conflicting	—				7
Total	3	98	37	31	176

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

110 pathogenic / likely-pathogenic (of 136) ClinVar copy-number / structural variants overlap ANGPT2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →