Rare genetic variants, characterized by their low frequency in a population, have emerged as essential components in the study of complex disease genetics. The biology of rare variants underscores their significance, as they can exert profound effects on phenotypic variation and disease susceptibility. Recent advancements in sequencing technologies have yielded the availability of large-scale sequencing data such as the UK Biobank whole-exome sequencing (WES) cohort empowered researchers to conduct rare variant association studies (RVASs). This review paper discusses the significance of rare variants, available methodologies, and applications. We provide an overview of RVASs, emphasizing their relevance in unraveling the genetic architecture of complex diseases with special focus on chronic pain and Arthritis. Additionally, we discuss the strengths and limitations of various rare variant association testing methods, outlining a typical pipeline for conducting rare variant association. This pipeline encompasses crucial steps such as quality control of WES data, rare variant annotation, and association testing. It serves as a comprehensive guide for researchers in the field of chronic pain diseases interested in rare variant association studies in large-scale sequencing datasets like the UK Biobank WES cohort. Lastly, we discuss how the identified variants can be further investigated through detailed experimental studies in animal models to elucidate their functional impact and underlying mechanisms.