[civilized]

Forgive my ignorance - is that true even for non-synonymous mutations? They usually have a hard time disrupting the big structure?

[flobosg]

If non-synonymous mutations do not change the biophysical features of the amino acid residues, then the structure is usually kept. Alternatively, it can be the case that a disruptive mutation is compensated by another one that keeps the structure/function/phenotype. This is the basis for evolutionary coupling based structure prediction methods, such as Alphafold.