Figure 2.

Missense variants and selections from the human glucagon receptor. All 250 glucagon receptor missense variants in 185 positions have been selected from the gnomAD cohort spanning 135,743 individuals or the literature depicted on a 2D snake-plot (34). We then selected variants in the binding interface (≤5 Å) of glucagon (n = 18, dark blue) by investigating all three glucagon-bound receptor structures (Protein Data Bank: 6LMK, 6LML, and 6WPW (16, 44)) and additional variants in the extracellular domain or from previous literature characterizations (n = 20, light blue). Structural mapping of the selected variants on the cryo-EM structure of the human glucagon receptor bound glucagon and Gα_s (6LMK) with a modeled AlphaFold2 disordered N terminus to illustrate two variants located outside the refined structure in the extracellular domain (84).