PAH p.Ala90fs
c.266dup · rs62506950 · VCV102642
ClinGen expert panel — Phenylketonuria VCEP
Pathogenic for phenylketonuria. Applied ACMG criteria (verbatim):
PM2 PVS1 PP4_Moderate PM3
Curation rationale (ClinGen, verbatim)
Variant classified as Pathogenic using the following criteria: PVS1; PM2; PM3; PP4_Moderate. PVS1: frameshift variant in exon 2 of 13, predicted to result in PTC with removal of >10% of the protein and NMD; PM2: absent from ExAC, gnomAD, 1000G, ESP. PP4_Moderate; PM3: c.266_267insC seen on 2 PKU alleles, with BH4 deficiency ruled out (PMID: 21147011). Detected with pathogenic variants IVS12+1G>A and p.I65T (PMID: 9452062); and p.Pro281Leu (Likely Pathogenic per ClinGen PAH VCEP, PMID: 26666653).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | frameshift | predicted loss-of-function |
|---|---|---|
| NMD | predicted | premature termination codon in exon 3 of 13 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP -0.22 | GERP -2.9 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.00133% | 75,024 |
| European (non-Finnish) | 8.48e-05% | 1,179,894 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- PAH
- Protein
- p.Ala90fs
- Coding
- c.266dup
- MANE Select
- NM_000277
- dbSNP
- rs62506950
- Type
- Duplication
- Location
- chr12:102894820 (GRCh38)
- Gene constraint
- LOEUF 1.265 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 89.04 · 21 PDB
- Residue 90
- the act domain; an α-helix
Disease context
phenylketonuria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsFor Phenylketonuria (Orphanet):
- Inheritance
- Autosomal recessive
- Onset
- Infancy
- Prevalence
- 1-9 / 100 000 (France)
Similar variants
- PAH p.Arg155fs Pathogenic ★★★ same condition
- PAH p.Asn393Ter Pathogenic ★★★ same condition
- PAH p.Asp17Ter Pathogenic ★★★ same condition
- PAH p.Asp229fs Pathogenic ★★★ same condition
- PAH p.Cys203fs Pathogenic ★★★ same condition
- PAH p.Gln226fs Pathogenic ★★★ same condition
- PAH p.Ile38fs Pathogenic ★★★ same condition
- PAH p.Leu367fs Pathogenic ★★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pah-p-ala90fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown