Low complexity domain sequences are often only conserved among mammals and specific residues have outsized importance such that even relatively conservative changes can disrupt normal function.41,43,44,51 In fact, several established disease-causing mutations in ANXA11 and other amyotrophic lateral sclerosis/frontotemporal dementia genes illustrate the limits of in silico modeling for mutations within low complexity domains (Fig. 2D). This evidence concerns the gene ANXA11 and amyotrophic lateral sclerosis.