Fig. 1: 35-year timeline depicting major historical events in the development of in silico variant pathogenicity prediction tools (VPPTs).

Major historical events by timelines shaping VPPT development and defined as 1990-2000 (Genomic Era Begins), 2000ā2010 (First Generation of VPPTs), 2010ā2015 (Early Machine Learning) and 2015ācurrent (Contemporary Machine Learning).