PAH p.Phe233Ile
c.697T>A · rs1565848061 · VCV619163
ClinGen expert panel — Phenylketonuria VCEP
Pathogenic for phenylketonuria. Applied ACMG criteria (verbatim):
PM2 PP4_Moderate PS3 PM3_Strong PP3
Curation rationale (ClinGen, verbatim)
The c.697T>A (p.Phe233Ile) variant in PAH has been reported in 2 unrelated patients with PKU (BH4 deficiency excluded) and was detected with known pathogenic variants p.R408W and p.V245A. (PP4_Moderate, PM3_Strong; PMID: 23764561). This variant is absent in population databases (PM2). This variant showed no specific activity in functional assay and no response to chaperone co-expression (PS3; PMID: 28653649). Computational prediction tools and conservation analysis suggest this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PS3, PM3_strong, PM2, PP3.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.8231 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.92 | moderately pathogenic-leaning |
| SaProt | LLR -13.25 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 11 | GERP 2.1, phastCons 1 |
| Regional constraint | o/e 1.07 | unconstrained · MANE · 78 kb · p 0.12 · regional, not allelic |
| Overall | ||
| CADD | 25.9 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- PAH
- Protein
- p.Phe233Ile
- Coding
- c.697T>A
- MANE Select
- NM_000277
- dbSNP
- rs1565848061
- Type
- single nucleotide variant
- Location
- chr12:102855145 (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 233
- 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.Phe233Leu Pathogenic ★★★ same residue
- PAH c.1065+1G>A Likely pathogenic ★★★ same condition
- PAH c.1065+1G>T Likely pathogenic ★★★ same condition
- PAH c.1065+3A>G Likely pathogenic ★★★ same condition
- PAH c.1066-11G>A Pathogenic ★★★ same condition
- PAH c.1066-14C>G Likely pathogenic ★★★ same condition
- PAH c.1066-1G>A Pathogenic ★★★ same condition
- PAH c.1066-1G>C 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-phe233ile (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown