NM_000314.8:c.388C>G (p.Arg130Gly) in PTEN is classified as Likely Pathogenic per the ClinGen PTEN Expert Panel Specifications Version 3.2.0, based on three moderate and three supporting criteria.¹ The variant is located in the PTEN catalytic P-loop (Arg130, residues 123–130), a critical functional domain defined by the VCEP as a mutational hotspot and catalytic motif (PM1).² PTEN phosphatase activity assay via saturation mutagenesis (Mighell et al. 2018) yields Cum_score = -2.14 (High_conf = True), meeting the VCEP PS3_Moderate threshold of ≤ -1.11. Functional studies demonstrate that R130G produces fully inactive PTEN protein with complete loss of PIP3 phosphatase activity in yeast (PMID:21828076) and abrogated tumor suppressive function in glioma cells (PMID:11948419).³ Other missense changes at Arg130 (R130Q, R130L, R130P) are established as pathogenic/likely pathogenic in ClinVar in association with Cowden syndrome/PHTS, and the BLOSUM62 score of R130G (-2) is less than or equal to these comparators, satisfying PM5.⁴ The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the VCEP PM2_Supporting threshold of <0.001% allele frequency.⁵ PP2 applies as PTEN has a low rate of benign missense variation and missense variants are a common disease mechanism. PP3 applies with a REVEL score of 0.962 (>0.7 threshold).⁶ The variant has been reported in ClinVar as Pathogenic by the Clingen PTEN Variant Curation Expert Panel (expert panel review) and as Pathogenic by four clinical laboratories. It is also reported in COSMIC (259 somatic observations) and classified as Oncogenic (loss-of-function) by OncoKB.⁷ Applying the PTEN VCEP classification combining rules: ≥3 moderate criteria (PS3_Moderate, PM1, PM5) satisfies Rule13 for Likely Pathogenic. The ClinVar expert panel classification of Pathogenic suggests additional proband-level evidence (PS4) may be available to elevate this to Pathogenic.⁸