Evolutionary sequence conservation and predicted functional effects of missense sequence variations in PCSK9. Conservation for each variation found in the low-LDL subjects only (green), the high-LDL subjects only (yellow), or both groups (gray) of the DHS sample and in patients with autosomal dominant hypercholesterolemia (red) (Abifadel et al. ; Leren ; Timms et al. ) is highlighted. An asterisk (*) indicates a SNP significantly associated with plasma LDL-C level. Sequences are shown for Homo sapiens, Pan troglodytes, Rhesus macaque, Mus musculus, Rattus norvegicus, Gallus gallus, Xenopus tropicalis, Xenopus laevis, Danio rerio, Fugu rubripes, Tetraodon nigroviridis, and Oryzias latipes. The predicted effect of each amino acid sequence variation on protein function is indicated (right columns). A v.2: − = tolerated; + = deleterious (low-confidence prediction); ++ = deleterious. B v.5.0: − = unlikely functional effect; + = possible deleterious functional effect; ++ = high probability of deleterious functional effect; NA = not modeled by the hidden Markov model (family sequence alignment absent or poor). C: − = benign; + = possibly damaging; ++ = probably damaging (Sunyaev et al. ; Ng and Henikoff ; Thomas et al. ).