We compare the known retinitis pigmentosa (RP) mutations in rhodopsin with mutational data obtained for the complement factor 5a receptor (C5aR), a member of the rhodopsin-like family of G protein-coupled receptors (GPCRs). We have performed genetic analyses that define residues that are required for C5aR folding and function. The cognate residues in rhodopsin are not preferentially mutated in RP, suggesting that the predominant molecular defect in RP involves more than simple misfolding or inactivation. Energy calculations are performed to elucidate the structural effects of the RP mutations. Many of these mutations specifically disrupt the environment of the retinal prosthetic group of rhodopsin, and these do not correspond to essential residues in C5aR. This may be because a retinal group is present in rhodopsin but not in C5aR. Another subset of RP mutations is more generally important for receptor structure, and these mutations correlate with essential residues of C5aR.