Fig. 2

Map of glucokinase variant activity. A Heatmap showing the GCK activity score for each substitution (x-axis) at every position (y-axis) based on the multiplexed functional complementation assay. A score of one (white) corresponds to the activity of wild-type-like synonymous variants, a score of zero (red) corresponds to total loss-of-function (nonsense) variants and a score above one (blue) corresponds to activity above synonymous variants. The median (MED) activity score at each position is included. Yellow indicates the wild-type amino acid and variants with missing data ('missing variants') are shown in grey. The secondary structure of GCK is shown next to the activity map with β-sheets shown as arrows and α-helices shown as waves. A map where missing variants have been imputed can be found in Additional file 1: Fig. S3. B Distributions of activity scores for synonymous variants (green), nonsense variants (red) and missense variants (grey). The activity score of the hyperactive variant p.W99R (blue) and the median activity score of the catalytic residue p.D205 (red) are shown. C The median activity score at each position was mapped onto the closed glucose-bound conformation of GCK (PDB 1V4S). The color scheme is the same as in panel A