BackgroundHigh-throughput sequencing (HTS) offers unprecedented opportunities for the discovery of causative gene variants in multiple human disorders including cancers, and has revolutionized clinical diagnostics. However, despite more than a decade of use of HTS-based assays, extracting relevant functional information from whole-exome sequencing (WES) data remains challenging, especially for non-specialists lacking in-depth bioinformatic skills.ResultsTo address this limitation, we developed Var∣Decrypt, a web-based tool designed to greatly facilitate WES data browsing and analysis. Var∣Decrypt offers a wide range of gene and variant filtering possibilities, clustering and enrichment tools, providing an efficient way to derive patient-specific functional information and to prioritize gene variants for functional analyses. We applied Var∣Decrypt on WES datasets of 10 acute erythroid leukemia patients, a rare and aggressive form of leukemia, and recovered known disease oncogenes in addition to novel putative drivers. We additionally validated the performance of Var∣Decrypt using an independent dataset of ~ 90 multiple myeloma WES, recapitulating the identified deregulated genes and pathways, showing the general applicability and versatility of Var∣Decrypt for WES analysis.ConclusionDespite years of use of WES in human health for diagnosis and discovery of disease drivers, WES data analysis still remains a complex task requiring advanced bioinformatic skills. In that context, there is a need for user-friendly all-in-one dedicated tools for data analysis, to allow biologists and clinicians to extract relevant biological information from patient datasets. Here, we provide Var∣Decrypt (trial version accessible here:https://vardecrypt.com/app/vardecrypt), a simple and intuitive Rshiny application created to fill this gap. Source code and detailed user tutorial are available athttps://gitlab.com/mohammadsalma/vardecrypt.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13072-023-00497-4.