Rare variants in the complement factor H (CFH) gene are associated with age-related macular degeneration (AMD). In fact, the highly penetrant rare variant CFH p.Arg1210Cys (R1210C) is the strongest genetic risk factor for AMD identified to date.1 Carriers of this mutation have about a 20-fold higher risk of developing the disease compared with noncarriers.1 A large targeted sequencing study of samples from 1665 AMD cases and 752 control individuals found an increased burden of CFH rare variants: 65 missense, nonsense, or splice-site mutations with a minor allele frequency of 1% or less were enriched in advanced AMD cases. The magnitude of the effect was found to correlate with the disruptive nature of the variant and location in a functional site, and a stronger association was seen for variants with lower minor allele frequency.2 Numerous rare genetic variants in the coding regions of CFH also explain the high risk of disease in some families.3,4