It is now well recognized that there are many examples of human sequence variants that had been considered pathogenic or likely pathogenic that have subsequently been reclassified. A large proportion of these have been reclassified as benign or likely benign. 1, 2 There are multiple reasons for reclassification and downgrading of variants, but the most powerful tool has been the cataloging of population variants with significant minor allele frequency in certain subsets of the human population, owing to efforts such as the Exome Aggregation Consortium (ExAC) and now the Genome Aggregation Database (gnomAD). We have an ethical imperative in medical genetics not to overclassify the pathogenicity of variants because this has significant potential to cause downstream harm to patients. Otherwise, we run the risk of genomic sequencing being perceived as a flawed technique with limited clinical utility. In interpreting the results of genomic sequencing analysis, sequence variants should therefore be considered “uncertain until proven guilty.” While I applaud the recent efforts in correction of variant classification, it would be better if false calls of pathogenicity were not made in the first place. It is better to be uncertain than to be wrong. Similar caution should be applied in reporting novel genes associated with genetic disease in individual patients. Bigger is not always better when it comes to selection of which genes to interrogate. A tiered approach to clinical genomic analysis, targeting initial analysis on genes well known to be associated with a particular phenotype, will improve the positive predictive value of genomic sequencing and reduce the likelihood of false ascertainment. There are several types of uncertainty inherent to diagnostic genomic sequencing not limited to variants, including gene evidence and phenotypic spectrum. Uncertainty at any level should be appropriately conveyed when reporting results.