Finally, we investigated how these constraint metrics would stratify mutational classes according to their frequency spectrum, corrected for mutability as in the previous section (Figure 3f). The effect was most dramatic when considering nonsense variants in the LoF-intolerant set of genes. For missense variants, the missense Z score offers information additional to Polyphen2 and CADD classifications, indicating that gene-level measures of constraint offer additional information to variant-level metrics in assessing potential pathogenicity.
