We identified 983 different single-base substitution missense variants (Table 2 and Supplementary Table 3 online). The 26 in-frame deletions/insertions found are listed in Supplementary Table 4 online and described further in the Supplementary Note. As appears to be the case for truncating variants, missense variants may include a subset that causes mental retardation, with the remainder representing background population variation. However, the prevalence of missense variants in normal individuals is much higher than that of truncating variants, and the disruption of protein function they entail is generally more modest. Therefore, disease-causing missense variants are likely to represent a relatively small fraction of the total and distinguishing them from rare polymorphisms is problematic. We applied two analytic approaches to identify potential mental retardation–causing missense variants.
