Forty-six mutations in the human APOA1 gene are listed in the Human Gene Mutation Database. Eighteen mutations cause a Low-HDL phenotype associated with an extremely variable atherosclerosis burden and coronary risk, illustrating that the plasma HDL level per se does not necessarily reflect the atheroprotective potential of these lipoproteins, and highlighting the need for novel tools for cardiovascular risk prediction in individuals with low-HDL. Eleven amyloidogenic APOA1 gene mutations cause rare forms of hereditary amyloidosis, characterized by the generation of amyloid fibrils comprising a truncated form of apoA-I corresponding to its 90-100 N-terminal residues. An accelerated catabolism and/or an impaired secretion are intrinsic properties of amyloidogenic apoA-I mutants. However, how this altered metabolism is linked to the susceptibility of the protein to proteolytic remodeling and to its progressive deposition in tissues as amyloid fibrils remains a largely unknown feature of the disease.