Figure 2. Frequency, density, and position of CUBN variants along the cubilin protein.

Cubilin protein structure summarized with the 8 EGF-like (light blue) and 27 CUB domains (darker blue). The red dots correspond to the theoretical Ca²⁺-binding sites, and the arrows on top indicate the variants found in the 3 cohorts of this study (the green arrows represent the filtered CUBN variants, and the red arrows indicate the 4 GWAS missense variants A1690V, N2157D, A2914V, and I2984V). Gaussian kernel density curves (with a 0.2 width parameter) as well as the position of HGMD variants (red), the variants from this study (green), and PTVs from the in-house (yellow) and gnomAD (blue) databases are shown as curves and vertical lines, respectively. The minor allele frequencies (MAFs) of the HGMD and gnomAD variants are shown as red and blue dots, respectively.