ApoA-1Milano is a variant of the apolipoprotein A-I protein that was discovered by the University of Milan when sequencing the genome of those native to the village Limone sul Garda. The mutation has been shown to dramatically reduce the occurrence of cardiovascular disease for those who carry it. There has been much research invested into developing a means of delivering a synthetic version of this protein to the tissues of people already suffering from cardiovascular disease.
Typically with protein variants as high profile as this one there'd be some consensus or theory as to why the variant performs in the way that it does. For instance, the G171V mutation in the LRP5 gene results in a variant LRP5 protein receptor that reduces the ability of the DKK1 inhibitor to bind to it, resulting in greater LRP5-induced canonical Wnt signaling, which augments load-induced bone formation, which increases bone mass/density.
So a known mutation with a known protein variant as a consequence, the exact structural difference of which is known, and the exact intermolecular consequence of this difference is known, and finally the resulting phenotype is also known.
But in the case of ApoA-1Milano I can't find any literature regarding what the specific intermolecular consequence of this variant is that confers the reduced risk of cardiovascular disease phenotype. Big pharma has gone so far as to inject the variant protein into living human beings since the beneficial nature of it is so definitive but there doesn't seem to be any consensus as to how this variant is beneficial?
