Genetics provide a robust scientific platform for establishing a relationship between a cause, for example, a genetic variant, and an effect, such as a disease phenotype. Yet, causality in genetics is a probabilistic and rarely a deterministic certainty. The causal relationship between a genetic variant and a phenotype is provisional to the conditions and the environment, such as the genetic backgrounds, in which the causal variants and the phenotype operate. The degree of probabilistic causality is, in part, determined by the effect sizes of the genetic variants, which typically follow a gradient ranging from minimal to large. 1, 2 Genetic variants (single nucleotide variants, small insertion/deletions, and structural variations) with large effect sizes are highly penetrant, as exemplified by variants that are responsible for the single gene disorders with Mendelian patterns of inheritance. In such circumstances, the cause-and-effect relationship is best analyzed through cosegregation and linkage analyses, whereby a logarithm of odds score of≥ 3 is considered strong evidence of a genetic linkage but not necessarily a definitive indicator of causality. On the opposite end of the spectrum are the variants that exert modest effect sizes and, hence, are less penetrant. In such cases, establishing a cause-and-effect relationship is more challenging, because such low-penetrant variants typically do not show a clear cosegregation with the phenotype and are often found in the general population as well. Establishing the causal role of the variants is more challenging in small families, and even more so in a single individual. Further compounding the ascertainment of causality is the influence of the genetic backgrounds (modifier genetic variants) and the environmental factors, which are expected to exert greater influence when the effect sizes of the causal genetic variants are rather small. Hence, a genetic variant with a small or moderate effect size might be penetrant in certain genetic backgrounds but not in others. Notwithstanding the effect sizes of the causal genetic variants, the modifier variants and the environmental factors contribute to penetrance of the causal variants and phenotypic variability of the disease. In the background of these concepts, the author suggests categorization of genetic variants in the human genome, with regard to their pathogenic role in human diseases, into the following 5 groups2:

1. Disease-Causing Variants. This category encompasses genetic variants that benefit from the most robust evidence of causality, typically achieved through genetic linkage analysis in large families. The variants generally exhibit high penetrance, exert large effect sizes, and are typically responsible for the single-gene disorders with Mendelian patterns of inheritance. Hence, when present in an individual’s genome, they commonly lead to the linked disease, albeit the severity of the phenotype is also influenced by modifier variants, genomic factors, and other determinants. Functional and mechanistic data lend further support to the causal role of