PS1
Not met: no previously established pathogenic p.Pro725Ser change exists, and this exact variant is Benign or Likely benign across all ClinVar submitters.
PS2
Not met: no parental testing confirms a de novo origin, and the variant is present in gnomAD v2.1 at 252/282,872 alleles.
PS3
Not assessed: no validated functional assay of PTCH1 p.(Pro725Ser) was reported; PMID:28733979 performed no assay and in silico tools predicted a neutral effect.
PS4
Not met: no case-control enrichment exists, and the variant is carried in gnomAD v4.1 at AF 0.00088 with seven homozygotes.
PM1
Not met: PTCH1 has no mutational hotspot and residue 725 is not a VCEP-approved critical domain, while gnomAD v4.1 carries 1,420 alleles with 7 homozygotes there.
PM2
Not met: gnomAD frequency ~0.088% (v4.1 and v2.1) is about nine-fold above the 0.0001 PM2 threshold.
PM5
Not met: the only other residue-725 missense variants, p.Pro725Arg and p.Pro725His, are Uncertain significance or Benign in ClinVar, not established pathogenic.
PM6
Not met: no source assumes a de novo origin, and p.P725S recurs in gnomAD v4.1 with 1,420 alleles including 7 homozygotes.
PP1
Not assessed: zero informative meioses, because the only genotyped relatives in the reported cohort carried different, truncating PTCH1 variants.
PP2
Not met: PTCH1 disease variants are predominantly truncating (17 of 19 novel mutations; 87% of patients), so missense change is not the primary mechanism.
PP3
Not met: REVEL 0.299 for the p.(Pro725Ser) missense variant is below the PP3 supporting threshold of 0.644 under the ClinGen SVI calibration.
PP4
Not assessed: no proband phenotype or family history is available to test specificity for a single-gene disorder.
PP5
Not met: the exact variant's ClinVar record has no expert-panel submission (expert_panels empty; highest review status 2-star, benign).
