Our study demonstrates that distinguishing disruptive from non-disruptive missense alleles in a well-described disease gene (LDLR) through systematic functional characterization in vitro can further our understanding how rare, potentially damaging genetic variation contributes to common, complex (hypercholesterolemia; MI) as well as Mendelian disease (FH). The gene discussed is LDLR; the disease is Hypercholesterolemia.