Towards Increasing the Clinical Relevance of In Silico Methods to Predict Pathogenic Missense Variants

As genetic sequencing throughput continues to accelerate, so does the accumulation of variants of unknown clinical significance. The great majority of these variants cause amino acid substitutions (cSNVs) in protein sequence. The need to interpret these variants continues to motivate development of better in silico bioinformatic methods. Despite the development of dozens of such methods over the past 15 years, clinically relevant prediction accuracy remains elusive.