P028: Population-specific structural variation linked to metabolic diseases in people of Pacific ancestry

B4GALNT3 were associated with increased ALP levels.These findings demonstrate that rare, high-impact variants in genes other than ALPL can bi-directionally influence ALP levels.Conclusion: Our UK Biobank analyses reinforce the strong association of pathogenic ALPL variants and persistently low ALP levels.However, the HPP penetrance of heterozygous hypomorphic ALPL variants, particularly c.571G>A, may be lower than previously reported.This observed lower penetrance may explain why the highly prevalent c.571G>A heterozygous genotype has low frequency in HPP patient cohorts, such as the Global HPP Registry (4.4% of participants).Our rare variant analyses identified additional genetic contributors to ALP levels, expanding on prior common variant analyses, and underscore the polygenic nature of ALP regulation.Future studies should aim to refine HPP penetrance estimates for pathogenic ALPL variants, and to elucidate the contributions of non-ALPL variants to persistently low ALP and HPP.