Humans detoxify As(III) by methylation. Rapid methylation results in rapid clearance of arsenic from the body, leading to lower risk of arsenic-related diseases. Paradoxically, the methylated products, MAs(III) and DMAs(III) are more toxic and potentially more carcinogenic than inorganic arsenic. When methylation is slow, body clearance is slower, and the risk of arsenic-related diseases increases. We demonstrate that human single nucleotide polymorphisms in the AS3MT coding region lead to less active enzymes that slow the rate of methylation. We predict that these SNPs lead to increased risk of arsenic-related diseases. To understand the relationship between slower methylation and AS3MT activity, we conducted a structure-function analysis of an AS3MT ortholog and identified the rate limiting step in the catalytic cycle as slow reorientation of the methyl group of enzyme-bound MAs(III).