NM_002878.3:c.26G>C (p.Cys9Ser) is a missense variant in exon 1 of RAD51D. This variant is present in gnomAD at a low frequency: 0.0405% (113/278,930 alleles, 1 homozygote) in v2.1 and 0.0656% (1058/1,612,440 alleles, 1 homozygote) in v4.1, with a maximum population frequency of 0.083% in the European (non-Finnish) population (v4.1).¹ The variant has been reported in ClinVar (ID 127886) as Uncertain significance by 10 clinical laboratories and Likely benign by 9 clinical laboratories; no expert panel has reviewed this variant.² Multiple lines of computational evidence predict no significant impact on the gene product: REVEL score 0.218, BayesDel score 0.087, and SpliceAI maximum delta score 0.00.³ PM2 (supporting) is applied because the variant is present at very low frequency in population databases (<0.1% AF in all populations), though weakened by the observation of homozygotes.⁴ BP4 (supporting benign) is applied because multiple computational prediction algorithms (REVEL, BayesDel, SpliceAI) support no deleterious effect.⁵ BP1 (supporting benign) is applied because RAD51D-associated disease is primarily caused by truncating loss-of-function variants rather than missense changes.⁶ BS2 (supporting benign) is applied because one homozygous individual was observed in gnomAD v2.1 and one in gnomAD v4.1, suggesting this variant can be tolerated in at least some individuals.⁷ BP6 (supporting benign) is applied because nine independent clinical laboratories have classified this variant as Likely benign with criteria provided.⁸ PVS1 is not applicable as this is a missense variant, not a null variant.⁹ PS3 is not met because no experimental functional studies have been performed for this variant.¹⁰ PP3 is not met because the aggregate computational evidence supports a benign rather than pathogenic interpretation.¹¹ Using generic ACMG/AMP 2015 combination rules (PMID:25741868), the evidence profile includes: 1 supporting pathogenic criterion (PM2) and 4 supporting benign criteria (BP1, BP4, BS2, BP6). The net benign evidence outweighs the single pathogenic criterion, supporting a classification of Likely benign.¹²