In addition, as genome-interpretation approaches are becoming increasingly informed by diverse noncoding genome annotation,24–26 genome and transcriptome analysis within a single large family provides unique insight into the predictive power of diverse noncoding annotation for rare variants. In our study, we demonstrated that the combination of variant location, epigenomic information, and evolutionary constraint is considerably more informative for predicting the impact of rare noncoding variants than for predicting the impact of common variants. Likewise, we observed equivalent increases in predictive strength for rare splicing variants. This suggests that many rare noncoding variants are likely to be interpretable via existing noncoding annotation and supports their more routine integration in rare-variant association studies.