Recent findings suggest that rare variants play an important role in both monogenic and common diseases. Due to their rarity, however, it remains unclear how to appropriately analyze the association between such variants and disease. A common approach entails combining rare variants together based on a priori information and analyzing them as a single group. Here one must make some assumptions about what to aggregate. Instead, we propose two approaches to empirically determine the most efficient grouping of rare variants. The first considers multiple possible groupings using existing information. The second is an agnostic "step-up" approach that determines an optimal grouping of rare variants analytically and does not rely on prior information. To evaluate these approaches, we undertook a simulation study using sequence data from genes in the one-carbon folate metabolic pathway. Our results show that using prior information to group rare variants is advantageous only when information is quite accurate, but the step-up approach works well across a broad range of plausible scenarios. This agnostic approach allows one to efficiently analyze the association between rare variants and disease while avoiding assumptions required by other approaches for grouping such variants.