We have benchmarked QIAGEN® Bioinformatics’ CLC Genomics Server (GxS) with GATK 4.0 (Broad Institute, MA) (1), with and without the use of Apache Spark™ in different computing environments, and compared runtime and performance when analyzing 100X coverage of human whole-exome data. We also compared the sensitivity, precision and overall accuracy of variant calling performed by a workflow developed with CLC to both GATK and Strelka2 (2). When comparing runtime, CLC GxS performs competitively to GATK with Apache Spark on a 40-core server and Intel®-Optane™ SSD technology (60 versus 58 minutes, respectively). The CLC Genomics Server performs better overall than GATK without Apache Spark. In terms of sensitivity, the CLC GxS outperforms the other platforms in both SNP and INDEL calling (99.6% and 91.9%, respectively, on PASS variants). GATK, however, scores highest for SNP calling precision (99.9% versus 99.1% by CLC) and Strelka2 performs higher for INDELs precision (95.2% versus 92.3% by CLC). In terms of accuracy, CLC GxS performs best with SNPs (99.4% versus 97.4% and 97.3% by GATK and Strelka2, respectively), while Strelka2 performs best for INDELs (93.3% versus 92.3% by CLC).