Beyond Coding Variants: RNA-Level Mechanisms in Human Disease and Precision Therapeutics

RNA-level regulation provides a therapeutically actionable bridge between genomic variation and disease mechanism. Although clinical genomics has traditionally prioritised variants that alter protein-coding sequence, many pathogenic variants act by disrupting RNA processing, stability, localisation, translation, editing, or surveillance. These mechanisms determine whether a transcript is correctly spliced, degraded, translated, toxic, or therapeutically recoverable. This review examines RNA-level mechanisms in human disease with emphasis on their implications for precision therapeutics. Splicing defects, pseudoexon inclusion, untranslated-region variants, premature termination codons, stop-loss variants, RNA-binding protein dysfunction, non-coding RNA dysregulation, altered codon usage, ribosome stalling, and surveillance pathways such as nonsense-mediated decay, nonstop decay, and no-go decay all create distinct therapeutic opportunities. Importantly, treatment selection must be mechanism-matched: splice defects may require antisense-mediated correction or small-molecule splice modulation; toxic transcripts may require antisense oligonucleotides (ASOs) or siRNA-mediated silencing; haploinsufficiency may require mRNA replacement, gene replacement, or transcript rescue; premature termination codons may be considered for readthrough only when the transcript and protein context are favourable; and regulatory RNA defects require network-aware approaches. RNA sequencing, long-read transcriptomics, allele-specific expression analysis, and functional assays are therefore essential not only for diagnosis but also for therapeutic stratification. An RNA-centric framework moves variant interpretation beyond descriptive classification toward mechanism-based intervention and precision RNA medicine.