Frequencies of germline variants and the associated likelihood for developing a phenotype. Graph depicting the frequencies of germline gene mutations in the general population (x-axis) and the likelihood that they will promote the manifestation of MPN or MPN-like disease (y-axis). The highest penetrance (close to 100%) is observed in rare families with erythrocytosis or thrombocytosis caused by mutations in a single gene that are most frequently inherited as a Mendelian trait with autosomal dominant transmission (EPOR, EPO, THPO, and MPL, etc), or autosomal recessive transmission (Chuvash polycythemia due to mutations in VHL). Rare familial cases with inherited predisposition to MPN require the acquisition of somatic disease driver mutations for disease manifestation, most frequently JAK2-p.V617F, or mutations in CALR or MPL. The predisposing germline mutations are inherited as autosomal dominant traits with reduced penetrance, in most cases ∼20% to 40%. Inherited predisposition to MPN due duplication of chr.14q32 is an exception, reaching higher penetrance around 80%. Finally, common polymorphisms found at high frequencies in the general populations located in, for example, the JAK2, MECOM, and TERT genes, are associated with a much weaker predisposing effect and also require the acquisition of somatic disease driver mutations for MPN.