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Huntington's disease (HD) is driven by somatic expansion of the HTT CAG repeat, with onset modified by genetic factors. One such modifier, 8AM1, maps to chromosome 8 near RRM2B, a gene not directly involved in the machinery that lengthens the repeat. To investigate this locus, we performed capture sequencing and identified variants at both the 5' and 3' ends of RRM2B with expected minor allele frequencies. A polymorphic frameshift variant (rs1037699) in an alternate exon 1 disrupts expression of a previously uncharacterized RRM2B isoform 2, but not isoform 1. Functional analyses in RRM2B knock-out cells and 8AM1 heterozygous LCLs suggest that isoform 2 may function at mitochondria. Several 3' variants, including a 21 bp 3'UTR deletion (rs200678743) and peak tag-SNV (rs79136984), act as cis expression quantitative trait loci. Analysis of HD onset data (n = 12,982) revealed that 5' and 3' variants contribute independently to the 8AM1 modifier effect, with full impact observed only in the absence of the frameshift variant. Knockdown of both isoforms increased neurodegeneration in HD neurons derived from pre-symptomatic patient fibroblasts, supporting an intersection of RRM2B biology and HD pathogenesis. We conclude that the 8AM1 haplotype, present in ~ 14% of Europeans, modifies RRM2B expression in a cell- and context-dependent manner, thereby accelerating HD onset in mutation carriers.