PAH p.Pro69Ser
c.205C>T · rs199475678 · VCV102628
ClinGen expert panel — Phenylketonuria VCEP
Likely Pathogenic for phenylketonuria. Applied ACMG criteria (verbatim):
PM2 PP4_Moderate PM3
Curation rationale (ClinGen, verbatim)
The c.205C>T (p.Pro69Ser) variant in PAH has been reported in at least two individuals with PKU without specified Phe levels, including at least one for whom BH4 deficiency has been excluded (PMID: 15503242, PMID: 32668217, PMID: 26503515). p.Pro69Ser has been detected at least twice with p.Arg261Gln, which is classified pathogenic by PAH VCEP, but without documentation of parental testing to establish phase. In-vitro studies show reduced enzyme activity, but not below the PAH VCEP cutoff of 50% (PMID: 16253218). p.Pro69Ser is absent from population databases. Multiple lines of computational evidence yield inconsistent predictions regarding the impact of this substitution. In summary, this variant meets criteria to be classified as likely pathogenic. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM3.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.4755 | ambiguous |
|---|---|---|
| REVEL | 0.673 | pathogenic-leaning |
| SaProt | LLR -11.16 | damaging |
| ⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 2.3, phastCons 1 |
| Regional constraint | o/e 1.07 | unconstrained · MANE · 78 kb · p 0.12 · regional, not allelic |
| Overall | ||
| CADD | 24.8 | 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.Pro69Ser
- Coding
- c.205C>T
- MANE Select
- NM_000277
- dbSNP
- rs199475678
- Type
- single nucleotide variant
- Location
- chr12:102894882 (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 69
- the act domain; a β-strand
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.Pro69Leu Uncertain significance ★ ⚠ 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-pro69ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown