PVS1
This variant is a missense substitution, p.(Ala438Asp), and does not fall within the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants.
PS1
No evidence was identified showing that this nucleotide change results in the same amino acid substitution as a previously established pathogenic variant.
PS2
No confirmed de novo occurrence with parental confirmation was identified for this variant.
PS3
No published functional study directly testing p.(Ala438Asp) was identified, so available evidence does not support a well-established damaging functional effect for this specific variant.
PS4
No case series, odds ratio, or count of independent affected individuals was identified for this variant, so enrichment in affected individuals has not been established.
PM1
This variant was not identified in a statistically significant hotspot, and no validated critical functional domain without benign variation was established at residue Ala438 from the available evidence.
PM3
No evidence was identified showing this variant in trans with a pathogenic variant in an affected individual.
PM4
This variant is a single amino acid substitution and does not change protein length or create an in-frame insertion or deletion.
PM5
No evidence was identified showing a different pathogenic missense substitution at the same residue, Ala438.
PM6
No presumed de novo occurrence without full parental confirmation was identified for this variant.
PP1
No segregation data were identified for this variant in affected family members.
PP2
Available evidence does not establish that pathogenic missense variation is a sufficiently predominant disease mechanism across SETBP1 to apply PP2 to this non-hotspot missense change.
PP3
Available computational evidence does not support a damaging effect.
PP4
No phenotype information was provided that is sufficiently specific for a single genetic etiology to support PP4.
PP5
No reputable source classification supporting pathogenicity was identified for this variant.
