SPARC and open-angle glaucoma: If any kind of SPARC variations are associated with or causative for POAG, at least 5 possibilities should be considered: (1) promoter polymorphisms that affect the expression level of the gene; (2) missense variants with gain (or loss)-of-function; (3) nonsense mutations leading to loss-of-function; (4) variants at the exon-intron boundaries causing alternative splicing; and (5) copy number variants that may alter gene dosage.