The location of 2 common perforin polymorphisms and missense mutations identified in HLH. The putative domains of perforin are indicated as boxes, and the numerals indicate the approximate amino acid boundaries for each domain, designating the first residue of the leader as residue 1. The N-terminus is predicted to have lytic properties; 2 low-homology regions have no significant similarity to other mammalian protein domains; amphipathic α-helix is homologous to regions of the complement membrane attack complex components C5b to C9; the EGF-like domain is structurally similar to ubiquitous EGF domains, primarily due to highly conserved cysteine residues; the C2 domain is the calcium-binding region responsible for membrane binding of perforin. The asterisked residues A91V and N252S refer to suspected PRF1 polymorphisms.