PS1
Not met: the same amino-acid change p.Asn412Ser is an established Benign/Likely benign allele in ClinVar, not a previously established pathogenic variant.
PS2
Not assessed: the sole reported carrier had no family history, but zero parental genotypes were reported, so confirmed de novo status is undetermined.
PS3
Not met: no assay shows a damaging effect; the only exact-variant experiment found no splicing alteration.
PS4
Not met: the variant showed no significant case-control enrichment (1/25 cases vs 4/275 controls, OR ~2.8, Fisher p=0.355; p<=0.05? no).
PM1
Not met: residue 412 lies outside AXIN2's RGS (81-200) and DIX (761-843) domains, is not a hot spot, and gnomAD v4.1 0.79% with 165 homozygotes shows benign variation there.
PM2
Not met: allele frequency 0.79% (gnomAD v4.1) is about 79-fold above the 0.0001 PM2 supporting threshold, with 165 homozygotes observed.
PM3
Not met: no pathogenic AXIN2 variant in trans with c.1235A>G has been reported, and its only co-inherited allele (c.1530G>A) is a non-pathogenic silent change.
PM5
Not met: no pathogenic variant exists at residue Asn412; the only comparators are p.Asn412His (VUS), p.Asn412Thr and p.Asn412Ile (both conflicting).
PM6
Not assessed: no source documents an apparently de novo occurrence for this variant, and zero parental genotypes exist to support even unconfirmed de novo status.
PP1
Not assessed: zero informative meioses or genotyped affected relatives are reported for this variant, so co-segregation cannot be evaluated.
PP2
Not met: AXIN2 shows no missense constraint (gnomAD o/e missense 1.03, mis_z -0.42) and its pathogenic variants are truncating, not missense.
PP3
Not met: missense REVEL score 0.119 falls below the 0.644 supporting PP3 threshold.
PP4
Not assessed: no proband phenotype or family history is recorded anywhere in this case, so PP4's single required input is unavailable.
PP5
Not met: ClinVar variation 136477 has zero expert-panel submissions (0 of 20; all is_expert_panel=false), so no expert-panel pathogenic assertion exists.
