TEK

Chr 9AD

TEK receptor tyrosine kinase

Also known as: CD202B, GLC3E, TIE-2, TIE2, VMCM, VMCM1

NCBI Gene: 7010 ENSG00000120156 UniProt: Q02763 OMIM: 600221

The TEK protein is a tyrosine kinase receptor that binds angiopoietins to regulate angiogenesis, endothelial cell functions, and vascular development during embryogenesis and throughout life. Mutations cause autosomal dominant venous malformations of the skin and mucous membranes, and primary congenital glaucoma. This gene is highly constrained against loss-of-function variants (pLI 0.999, LOEUF 0.179), reflecting its essential role in vascular development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.182 OMIM phenotypes

Clinical Summary— TEK

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Gene-Disease Validity (ClinGen)

TEK-related primary glaucoma · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

2 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

LoF intolerant — likely haploinsufficient

LoF Constraint

0.18LOEUF

pLI 1.000

Z-score 6.49

OE 0.09 (0.04–0.18)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

1.35Z-score

OE missense 0.84 (0.78–0.91)

501 obs / 593.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.09 (0.04–0.18)

0≤0.351.4

Missense OE0.84 (0.78–0.91)

0≤0.61.4

Synonymous OE1.28

0≤1.21.6

LoF obs/exp: 5 / 58.6Missense obs/exp: 501 / 593.5Syn Z: -3.20

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTEK-related venous malformations, multiple cutaneous and mucosalGOFAD

definitiveTEK-related primary congenital glaucomaLOFAD

0.4883th %ile

GOF

0.6540th %ile

LOF

0.55top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · LOEUF 0.18

GOFprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFFunctional characterization of an activating TEK mutation in acute myeloid leukemia: a cellular context-dependent activating mutation.PMID:19340004

LOFHerein, we identified rare TEK variants in 10 of 189 unrelated PCG families and demonstrated that each mutation results in haploinsufficiency due to protein loss of function.PMID:27270174

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