NM_002775.4:c.333G>A (p.Val111=) is a synonymous variant in exon 1 of HTRA1, encoding HtrA serine peptidase 1. This variant is ultra-rare in population databases: absent from gnomAD v2.1 and present in gnomAD v4.1 at an allele frequency of 6.56e-7 (1/1,524,404 alleles), satisfying PM2 at supporting strength.¹ Computational evidence supports a benign interpretation: REVEL score is 0.041 (well below the 0.5 pathogenic threshold), and SpliceAI predicts no splicing alteration (max delta = 0.00), meeting BP4 at supporting benign strength.² As a synonymous variant with no predicted splicing impact (SpliceAI max delta = 0.00) and low nucleotide conservation (REVEL = 0.041), this variant meets BP7 at supporting benign strength.³ No functional studies, segregation data, de novo observations, case-control analyses, ClinVar classifications, or variant-specific publications are available for this variant. All other ACMG/AMP criteria are either not met or not applicable. The evidence profile is conflicting: PM2_Supporting on the pathogenic side versus BP4_Supporting and BP7_Supporting on the benign side. Per the generic ACMG/AMP 2015 final classification rules (PMID:25741868), this constellation of conflicting supporting-level evidence is insufficient to reach a Likely Benign or Likely Pathogenic classification. The variant is classified as a Variant of Uncertain Significance (VUS).⁴