Mutations of the Gα-proteins GNAQ and GNA11 are found in 85-90% of uveal melanomas (UMs). We analyzed the association of GNAQ and GNA11 mutations with disease-specific survival, gene expression profiles, and cytogenetic alterations in 219 UMs. Our analysis showed a shorter disease-specific survival of GNA11 mutated cases as compared to those carrying a GNAQ mutation (median months: 26.97 [95% CI 25.02-37.08], vs not reached, p=0.058; HR=1.97 [95%CI 1.12-3.46], p=0.02). The GNA11 mutation was associated with expression alterations of the BRCA1-associated protein 1 (BAP1; p=0.0005), chr3 monosomy (p=0.0002), chr8q amplification (p=0.038), the combination of the latter two (p=0.0002), and, inversely, with chr6p amplification (p=0.003). We used tandem-affinity-purification and mass spectrometry to show that the two G-proteins have different protein interaction partners. The Tet Methylcytosine Dioxygenase 2, TET2, a protein that is involved in DNA-demethylation, physically interacts with GNAQ but not with GNA11 as confirmed by immunoprecipitation analyses. High risk UM shows a clearly different DNA-methylation pattern and different control of DNA-methylation by the two G-proteins might, at least in part, explain the different association with UM progression.