The most severe gain-of-function PCSK9 mutation, increasing LDLR-binding affinity 10-25-fold to cause extreme LDL elevation and early-onset coronary artery disease in carriers of this rare pathogenic variant

Intronic variant in ZFPM1 (FOG1), the master transcriptional co-regulator of megakaryopoiesis; the A allele is the strongest common GWAS signal for elevated platelet count (p=1×10⁻⁵⁰) and plateletcrit, with implications for thrombotic tendency and cardiovascular risk

Intronic variant in amelogenin X-linked gene affecting enamel mineralization and susceptibility to dental caries and developmental enamel defects

Missense variant in the linker region of XRCC1 that disrupts interaction with the OGG1 glycosylase, impairing base excision repair of oxidative DNA damage; effect direction varies by cancer type and ancestry

Promoter variant in the GRIN2B Sp1 binding site that reduces NR2B subunit expression, lowering NMDA receptor activity critical for learning and memory

ENPP1 K121Q variant that increases ENPP1 binding affinity to the insulin receptor by 2–3 fold, blunting insulin signaling and raising insulin resistance risk.

Synonymous variant in P-glycoprotein affecting drug efflux pump expression and hundreds of substrate drugs

Pathogenic missense variant abolishing 17α-hydroxylase/17,20-lyase activity, causing combined cortisol and sex steroid deficiency with mineralocorticoid excess

Phase I detoxification enzyme that activates polycyclic aromatic hydrocarbons and metabolizes estrogens; the Val variant increases catalytic activity, producing more reactive intermediates

Missense variant in alpha-dystrobrevin disrupting the EF-hand calcium-binding domain, associated with left ventricular noncompaction cardiomyopathy in a single Japanese family