PS1 (Strong): p.Ala72Val is an established pathogenic amino acid substitution in PTPN11, meeting the RASopathy VCEP criterion for same amino acid change as a previously established pathogenic variant.

PM1 (Moderate): Residue 72 lies within the N-SH2/PTPN domain interaction interface (amino acids 69-77), a critical functional domain defined by the RASopathy VCEP as a known mutational hotspot.

PM2 (Supporting): The variant is absent from gnomAD population controls (v2.1 and v4.1), meeting the VCEP threshold for absence from controls.

PP2 (Supporting): PTPN11 has a low rate of benign missense variation with a gnomAD missense Z-score >3.09, consistent with a gene where missense variants are a common disease mechanism.

PP3 (Supporting): In silico prediction with a REVEL score of 0.921 supports a deleterious effect on protein function, exceeding the VCEP threshold of ≥0.7.

PS3_Supporting: Functional studies demonstrate gain-of-function activity of the p.Ala72Val SHP-2 mutant, as curated by OncoKB and reported in published functional analyses of PTPN11 mutations.

PS4_Supporting: The variant has been observed in multiple individuals with Noonan syndrome/RASopathy phenotypes, meeting the VCEP threshold of ≥1 point for PS4 at Supporting strength.

Final classification: Pathogenic per RASopathy VCEP v2.3.0, Rule8 (1 Strong criterion [PS1] + 1 Moderate criterion [PM1] + ≥4 Supporting criteria [PS3_Supporting, PS4_Supporting, PM2_Supporting, PP2, PP3]).