Contextual variant effects across the MAPK pathway

This atlas maps how 186,676 variants in 17 proteins of the RAS–MAPK pathway, the signaling pathway most often mutated in cancer, change each protein's abundance and the activity of the pathway in human cells. We also measured variants in altered cellular contexts: with the chaperone HSP90 inhibited, which showed that the abundance of most missense variants depends on HSP90; with RAS switched on from upstream; and with LZTR1, which marks RAS for degradation, knocked out. Finally, we used the variant effects to test hundreds of protein–protein interactions seen in experimental and predicted structures. For nearly all of them, mutations in the contact surface disrupted protein abundance or pathway activity more than mutations elsewhere on the protein's surface, pinpointing the contacts the pathway relies on.

• 17proteins
• 503,099variant effects
• 14,412dominant negative variants
• 67%missense HSP90-dependent
• 1,088interfaces scored
• 353 / 395supported interactors