Rare functional variant
A rare functional variant is a genetic variant which alters gene function, and which occurs at low frequency in a population. Rare variants may play a significant role in complex disease, as well as some Mendelian conditions. Rare variants may be responsible for a portion of the missing heritability of complex diseases. The theoretical case for a significant role of rare variants is that alleles that strongly predispose an individual to disease will be kept at low frequencies in populations by purifying selection. Rare variants are increasingly being studied, as a consequence of whole exome and whole  genome sequencing efforts. While these variants are individually infrequent in populations, there are many in human populations, and they can be unique to specific populations. They are more likely to be deleterious than common variants, as a result of rapid population growth and weak purifying selection. They have been suspected of acting independently or along with common variants to cause disease states. Methods of discovery. Some methods, such as genetic burden tests, has been specifically developed to study in genetic association of rare variants. These methods aggregates rare variants over genetic regions, such as genes or whole pathways, and evaluate  cumulative effects of multiple genetic variants. These methods may increase power when multiple variants in the region are associated with a disease or a trait. In addition, compared to a genome-wide association study, a region or gene based test performs much fewer tests resulting in a less stringent multiple-hypothesis correction than the genome-wide significance. Some examples of these methods are SKAT, SKAT-O, ARIEL test, aSUM and STAAR. SNP annotations help to prioritize rare functional variants, and incorporating these annotations can effectively boost the power of genetic association of rare variants analysis of whole exome and whole  genome sequencing studies.