The pathway linking a mutation in a contractile protein, the smooth muscle–specific isoform of α-actin (SMA, encoded by ACTA2), and increased atherosclerosis is initiated by misfolding and retention of the SMA R149C monomer in the cytoplasmic complex that folds all actins, the chaperonin-containing t-complex polypeptide 1 (CCT) (12). Here, ACTA2 is linked to atherosclerosis.