CADD-ThresholdApp: an interactive web application for calibrating CADD scores using ClinVar

The Combined Annotation Dependent Depletion (CADD) score is one of the most widely used genome-wide variant deleteriousness scores. In practice, however, the distribution of CADD scores differs across genes and gene sets and may also vary between genome builds and CADD releases, complicating the choice of a single threshold for prioritizing potentially pathogenic variants in routine diagnostics.

We present CADD-ThresholdApp, an interactive web application that supports threshold selection by visualizing CADD-score distributions of clinically classified variants from ClinVar and by reporting threshold-dependent performance metrics. The app enables comparisons across genome releases (GRCh37/GRCh38) and CADD versions (v1.6/v1.7), supports user-defined genes and gene lists, as well as curated gene panels from PanelApp. CADD-ThresholdApp is implemented in a modular, extensible framework and can be adapted to additional variant resources and deleteriousness scores. The app is available as a hosted web application at https://cadd-threshold.kircherlab.bihealth.org/ and can be installed locally via container, PyPI, Bioconda, or from source.

Overall, CADD-ThresholdApp provides a practical and transparent framework for context-specific threshold calibration to support more informed variant interpretation in research and diagnostics.