Comprehensive and accurate detection of variants from whole-genome sequencing (WGS) is a strong prerequisite for translational genomic medicine; however, low concordance between analytic pipelines is an outstanding challenge. We processed a European and an African WGS samples with 70 analytic pipelines comprising the combination of 7 short-read aligners and 10 variant calling algorithms (VCAs), and observed remarkable differences in the number of variants called by different pipelines (max/min ratio: 1.3~3.4). The similarity between variant call sets was more closely determined by VCAs rather than by short-read aligners. Remarkably, reported minor allele frequency had a substantial effect on concordance between pipelines (concordance rate ratio: 0.11~0.92; Wald tests, P < 0.001), entailing more discordant results for rare and novel variants. We compared the performance of analytic pipelines and pipeline ensembles using gold-standard variant call sets and the catalog of variants from the 1000 Genomes Project. Notably, a single pipeline using BWA-MEM and GATK-HaplotypeCaller performed comparable to the pipeline ensembles for 'callable' regions (~97%) of the human reference genome. While a single pipeline is capable of analyzing common variants in most genomic regions, our findings demonstrated the limitations and challenges in analyzing rare or novel variants, especially for non-European genomes.