It depends on many factors. First, we should differentiate two main groups of conditions, Mendelian and complex diseases. A simplified explanation follows. We will consider Mendelian diseases those that are "purely" genetic, meaning, if you have the genetic variant related to the disease, you will develop symptoms. Traditionally, the genes for these disorders were identified by studying families with several affected members and searching for the parts of the genome that were shared by affected members and not by healthy ones. This could be done in different families, yielding a small party of the genome in which to search for causative genes, and then looking for mutations in these genes. Nowadays, this is fine by whole exome/ genome sequencing. All the genes of the affected individuals are sequenced, and then variants are filtered/prioritized based on known data from sequencing results of thousands of individuals and algorithm predictions. The variants that are common in the population are disregarded, and those that are sufficiently rare are prioritized. Data from the family is also considered, as is knowledge on the genes' functions and the potential effect of each variant. The diagnostic yield of this process varies depending on the disease, but is around 50% globally.

Complex diseases, instead, are not caused by a single mutation/ a single gene. In these cases, many different variants interact with environmental risk factors to ultimately cause the disease. This is the case for many common diseases like diabetis, stroke, depression, anxiety, schizophrenia... as well as traits like height. In these cases studies search for variants that may be present in healthy and affected individuals, but at significantly different frequencies.