Recent articles in JMG exemplify a broader shift from cataloguing gene-disease associations to estimating clinically calibrated variant effects. Large sequencing cohorts are coupled with deep clinical characterisation to (1) delineate how inherited variants contribute to fetal structural anomalies and adult disease risk, (2) expand and refine genotype-phenotype relationships for rare neurodevelopmental and syndromic conditions, and (3) reassess penetrance, including possible null effects, for proposed cancer and cardiovascular risk alleles. (see https://jmg.bmj.com/content/early/recent )