The interpretation of genetic variants identified during clinical sequencing has come to rely heavily on reference population databases such as the Exome Aggregation Consortium (ExAC). Genuinely pathogenic variants, particularly in genes associated with severe autosomal dominant conditions, are assumed to be absent or extremely rare in these databases. Clinical exome sequencing of a six-year-old female patient with seizures, global developmental delay, dysmorphic features and failure to thrive identified an ASXL1 variant that was previously reported as causative of Bohring-Opitz syndrome (BOS). Surprisingly, the variant was observed seven times in the ExAC database, presumably in individuals without BOS. Although the BOS phenotype matched the presentation of the patient, the presence of the variant in reference population databases introduced ambiguity in result interpretation. Interrogation of the literature revealed that acquired somatic mosaicism of ASXL1 variants (including known pathogenic variants) during hematopoietic clonal expansion may be concomitant with aging in healthy individuals. We examined all high quality ASXL1 predicted truncating variant calls in the ExAC database and determined the majority could be attributed to this phenomenon. Failure to consider somatic mosaicism may lead to the inaccurate assumption that conditions like Bohring-Opitz syndrome have reduced penetrance, or the misclassification of potentially pathogenic variants.