Moore, N.; Sargeant, C. J.; Wakefield, M. J.; Popp, N. A.; Fowler, D. M.; Rubin, A. F.

Deep Mutational Scanning (DMS) experiments generate large volumes of sequencing data that must be processed through multi-step computational pipelines to yield interpretable variant scores. At least twelve dedicated tools have been published for this purpose, yet the diversity of experimental designs, scoring strategies, and software implementations has produced a fragmented landscape in which no single tool accommodates the full range of workflows encountered in practice. Here we present CountESS (Count-based Experiment Scoring and Statistics), an open-source pipeline tool that provides a modular, graphical interface for constructing flexible DMS analysis workflows. CountESS supports a wide range of input formats, barcode translation, HGVS variant calling, and user-defined scoring functions, enabling it to accommodate diverse experimental designs including selection assays, time-series experiments, and bin-based assays such as VAMP-seq. Implemented in Python with DuckDB as a computational backend, the software provides high-performance, memory-efficient processing suitable for large datasets. CountESS is freely available at https://github.com/CountESS-Project/CountESS under the 3-Clause BSD Licence. Supplementary data, including demonstration pipelines and example datasets, are available at https://github.com/CountESS-Project/countess-demo.