PAH p.Ser231fs
c.690_691insG · rs1875354018 · VCV987779
ClinGen expert panel — Phenylketonuria VCEP
Pathogenic for phenylketonuria. Applied ACMG criteria (verbatim):
PM2 PVS1 PP4
Curation rationale (ClinGen, verbatim)
This c.690_691insG (p.Ser231ValfsTer?) variant in PAH was reported in one patient with Hyperphenylalaninemia (PMID: 28982351). This variant is absent from controls in population databases. This is a frameshift variant in exon 6 out of 13 coding exons. The variant is predicted to undergo nonsense mediated mRNA decay (NMD), as it is not located in the 3’-most exon or the 3’-most 50 bp of the penultimate exon. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, and PP4.
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 6 of 13 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 11 | GERP 2.1, phastCons 1 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.
Variant & gene context
- Gene
- PAH
- Protein
- p.Ser231fs
- Coding
- c.690_691insG
- MANE Select
- NM_000277
- dbSNP
- rs1875354018
- Type
- Insertion
- Location
- chr12:102855151 (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 231
- an α-helix; a UniProt-annotated variant site (in pah deficiency; severe)
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.Ser231Phe Pathogenic ★★ same residue
- PAH p.Ser231Pro Pathogenic ★★ same residue
- PAH p.Ser231= Likely benign ★ same residue
- PAH p.Asn393fs Likely pathogenic ★★★ same condition
- PAH p.Glu280fs Pathogenic ★★★ same condition
- PAH p.Leu15fs Pathogenic ★★★ same condition
- PAH p.Leu62fs Pathogenic ★★★ same condition
- PAH p.Lys320fs 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-ser231fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown