TY  - JOUR
T1  - Rare Functional Variants Challenge Population-Based Rules for Precision Pharmacotherapy
A1  - David Osei
A1  - Akua Afriyie
A1  - Kofi Adu
JF  - International Journal of Pharmaceutical Research and Allied Sciences
JO  - Int J Pharm Res Allied Sci
SN  - 2277-3657
Y1  - 2024
VL  - 13
IS  - 3
DO  - 10.51847/8OJFIfwLuO
SP  - 77
EP  - 86
N2  - Pharmacogenomic implementation has largely been built around recurrent alleles whose population frequencies, functional effects, and clinical consequences are sufficiently characterized to support reproducible genotype-to-phenotype translation. Rare functional variants expose the limits of this architecture. Their clinical interpretation is difficult not simply because they are uncommon, but because variant detection, molecular function, pharmacological consequence, phenotype assignment, and prescribing actionability are separate inferential problems that often have unequal evidential support. Expanded sequencing can reveal variation omitted by targeted assays, yet additional detection frequently produces variants for which substrate-specific function, haplotype context, population distribution, or clinical consequence remains uncertain. High-throughput functional assays and computational annotation can narrow this gap, but assay readouts are not interchangeable and cannot automatically establish drug-specific clinical utility. Structural variation, reference-database imbalance, and ancestry-dependent discovery further complicate population-derived rules. This Current Opinion argues that rare-variant pharmacotherapy should therefore be organized around evidence transfer rather than population frequency alone. A proposed uncertainty-aware interpretation architecture distinguishes analytical detection, functional characterization, phenotype translation, and drug-decision evidence, while explicitly retaining discordance and unvalidated transitions. The central implication is that rarity should neither trigger automatic clinical action nor justify automatic dismissal. Precision pharmacotherapy instead requires variant-specific evidence interpreted within gene, substrate, drug, population, and decision-point boundaries.
UR  - https://ijpras.com/article/rare-functional-variants-challenge-population-based-rules-for-precision-pharmacotherapy-63jtbmnsldgih4k
ER  -