NM_000021.3(PSEN1):c.1234G>A (p.Val412Ile) is extremely rare in population databases, with an allele frequency of 0.00107% in gnomAD v2.1 (3/280,740 alleles) and 0.00143% in gnomAD v4.1 (23/1,613,504 alleles), meeting PM2 at supporting level.¹ The variant co-segregates with early-onset frontotemporal dementia in 4 affected individuals across 2 generations in the FUS family (Bernardi et al. 2009, PMID:18314228), meeting PP1 at supporting level. However, incomplete penetrance is noted with 2 cognitively healthy carriers identified at ages 49 and 71 in follow-up (Bernardi et al. 2011, PMID:21297264).² No variant-specific functional data are available. The in vitro study of 138 PSEN1 pathogenic mutations by Sun et al. (PMID:27930341) did not include p.Val412Ile, as it is currently classified as a variant of uncertain significance.³ In silico predictors are mixed: REVEL score is 0.679, BayesDel is 0.305, and SpliceAI predicts no splicing impact (delta=0.00). The ClinVar submitter LabCorp notes 3 of 5 in silico tools predict a benign effect, precluding application of PP3.⁴ This variant is classified as Uncertain significance by 3 clinical laboratories in ClinVar (ID: 1318725). No submitter classifies it as pathogenic or likely pathogenic.⁵ Overall, the evidence for pathogenicity is limited to one supporting criterion (PM2) and one supporting criterion (PP1). With only 2 supporting criteria met and no moderate or strong pathogenic criteria, the variant does not reach the threshold for Likely Pathogenic (which requires 2 supporting + 1 moderate, or variants thereof). The classification remains Uncertain significance.⁶