Shown are the domain organization of the protein backbone of K8 and K18 and the general distribution of different point mutations and deletions. K8 Y54H, G62C, R341H, and G434S variants are found in patients with liver disease, but show a strong ethnic distribution. The first described SEK variant was K18 H128L (74). In white individuals, the most common K8 variant is R341H, while the most common amino acid–altering variant in black individuals is G434S. The 2 human mutations, K8 G62C and G434S, inhibit the phosphorylation of the adjacent S74 and S432, respectively. Notably, transgenic mice that express K8 G62C phenocopy the marked predisposition to liver injury observed in mice that express the phosphomutant K8 S74A. Asterisks at the beginning and end of the rod domain highlight the helix initiation and helix termination motifs that include mutation hot spots for epidermal keratins, and for IFs in general, but not for the SEKs. The assignment of the specific location of the keratin subdomains was obtained from the Human Intermediate Filament Database (http://www.interfil.org/proteinsTypeInII.php) and includes the start methionine residue. Most individuals with keratin mutations that are at increased risk of liver disease are heterozygous for the mutations, with few patients harboring compound heterozygous mutations. K19 variants are not included in this schematic since they are newly identified (91) and have not been characterized in the detail that K8 and K18 variants have.