Genetics is rapidly deepening our understanding of human health and disease by investigating common and rare genetic variants and their influence on gene expression1,2. Alternative splicing is a molecular mechanism enabling a single gene to produce multiple protein isoforms with distinct biological functions3. However, while protein isoforms are ubiquitous in humans, we here show that they are rarely considered when investigating common or rare genetic variants. To address this gap, we systematically assessed the impact of isoform-level analysis across more than 100 Quantitative Trait Loci (QTL) datasets and 76 million human genetic variants. Using strict colocalization, we find that ~45% of genes associated with human phenotypes via Genome-Wide Association Study (GWAS) exhibit isoform-specific effects. Similarly, we find that 72% of rare pathogenic variants alter their interpretation depending on the isoform expressed in relevant tissues or cell types. These findings establish isoform-level analysis as an essential approach for genetic research. Furthermore, they underscore the necessity of (re)analyzing genetic data at isoform resolution, thereby unlocking deeper insights into human biology and expanding clinical applications.

The authors have declared no competing interest.

This research was funded by a generous grant from the Lundbeck Foundation to KVS: R413‑2022‑878.

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