Recent rise in the number and therapeutic potential of genome engineering technologies has generated excitement for their application in cardiovascular therapeutics. One significant barrier to their implementation is costly and time-consuming reagent development for novel variants. We have previously shown that disease-associated variants cluster in functional protein domains where variants are found in the general population at lower frequency.1,2 These findings may provide an opportunity to pre-emptively target multiple pathogenic variant clusters (“pathogenic hotspots”) that address a majority of pathogenic and likely pathogenic (P/LP) variants for a given disease with a small number of pre-designed reagents. Prime editing, a search-and-replace editing technology, can overwrite genomic sequences with a reverse transcriptase guided by a Cas9 nickase and prime editing guide (peg)RNA.3 We hypothesized that most cardiovascular disease-relevant genes in ClinVar would display regional variant clustering, and that multiple variants within a regional hotspot could be targeted with a limited number of prime editing reagents.