Observation of a genomic variant at higher frequency in cases with disease compared to population controls can be compelling evidence towards the variant being pathogenic. We present the PS4-Likelihood Ratio Calculator, a tool with which the user defines the odds ratio (representing anticipated underlying strength of disease association for a gene).  A likelihood ratio towards pathogenicity (or benignity) is then generated based on the observed case and control variant frequencies.  We demonstrate various use-cases, such as a breast cancer susceptibility gene, a rare paediatric disease gene and a variant of suspected reduced penetrance.  We anticipate the tool’s more flexible quantitative evaluation of case-control data will prove valuable applied to the forthcoming ‘points-based’ ACMG/AMP framework update. (By Professor Clare Turnbull, https://jmg.bmj.com/content/early/2024/09/03/jmg-2024-110034 )