lovezahra

I'm a student currently trying to do the ScienceBuddies Project "From Genes to Genetic Diseases: What Kinds of Mutations Matter?" (https://www.sciencebuddies.org/science- ... -mutations) and I'm struggling quite a bit. The thing I don't quite understand is why some mutations cause a disease while similar mutations don't. For example, Table 3 in the project site has recorded one amino acid change from Valine to Methionine, and this is listed as non-pathogenic (this particular mutation does not cause cystic fibrosis). However, when filling up the rest of Table 3 with other genetic mutations that ARE pathogenic, I noticed one in particular (this is taken from the NCBI website). Its variant ID is rs397508328 (CTFR gene, single nucleotide variant, pathogenic), and the amino acid change is from Methionine to Valine. Despite both amino acids being non polar and hydrophobic, Met > Val causes cystic fibrosis. Valine is also one the favorable amino acid substitutions for Methionine. I find this confusing, as I thought only the drastic amino acid changes (for example, Met > Lys) caused trouble. How do I better understand what variants during DNA replication really matter? I can't find any answers to this anywhere. Please answer if you know anything related to the question.