NM_001330437.1:c.417G>C (p.Glu139Asp) is a missense variant in PTPN11 that has been classified as Pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (ClinVar variation ID 40513).¹ The variant has been observed as de novo with confirmed maternity and paternity in multiple unrelated probands with Noonan syndrome, meeting PS2 at Very_Strong level under the VCEP point-based scoring system (4 points).² Functional studies in two independent publications (Martinelli et al. 2008, PMID:18372317; Mueller et al. 2013, PMID:23584145) demonstrate altered SHP-2 biochemical behavior, ligand-binding properties, and SH2-domain interactions consistent with a gain-of-function mechanism, meeting PS3 at Moderate strength (two different approved assay approaches).³ The variant is significantly enriched in affected individuals compared to population controls. It is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (1/1,613,776 alleles; AF=6.2e-7), meeting PS4_Supporting and PM2_Supporting.⁴ In silico predictions support a deleterious effect: the REVEL score is 0.769, meeting the VCEP PP3 threshold of ≥0.7. PTPN11 also has a high missense constraint z-score (>3.09), meeting PP2.⁵ Applying the ClinGen RASopathy VCEP v2.3.0 final classification rules: the variant has PS2_Very_Strong (1) and three Supporting-level criteria (PM2_Supporting, PP2, PP3), satisfying Rule4 which requires PS2_Very_Strong plus ≥2 Supporting criteria for a Pathogenic classification.⁶ The overall classification is Pathogenic for Noonan syndrome and related RASopathies, consistent with the ClinGen RASopathy VCEP expert panel determination.⁷