The intolerant domain analysis did not improve over the gene-based analysis for SOD1 or TBK1 (Fig. 2; Fig. 3) but doubled the odds ratio and significantly lowered the p-value obtained for TARDBP. The improvement of the intolerant domain model (Fig. 1C, 1D) stemmed from a significant drop (one-tailed z-score p = 0.031) in the number of qualifying variants found in controls dispersed across tolerant regions, while highlighting qualifying variants in ALS cases predominantly in the intolerant C-terminal region. The gene discussed is SOD1; the disease is amyotrophic lateral sclerosis.