Retention or loss of function in cellular assays predicts function in vivo. Variants were classified as having reduced function if they exhibited uptake values <60% of control. (A) Allele frequency distributions between variants that retained function vs. those that exhibited loss of function in cellular assays. The resulting curves were significantly different (Log-Rank test, P = 9.3 × 10-3), with a skew toward lower population allele frequencies for reduced-function variants. (B) Allele frequency distributions between variants at evolutionarily conserved (EC) positions that retained function vs. variants at evolutionarily unconserved (EU) positions that retained function. EC variants showed a significant shift toward lower allele frequencies (Log-Rank test, P = 0.02), even for variants that retained function in cellular assays.
