PAH p.Ser70Pro
c.208T>C · rs63048261 · VCV102631
ClinGen expert panel — Phenylketonuria VCEP
Likely Pathogenic for phenylketonuria. Applied ACMG criteria (verbatim):
PM2 PP4_Moderate PM3_Supporting PS3_Supporting PP3
Curation rationale (ClinGen, verbatim)
The c.208T>C (p.Ser70Pro) variant in PAH has been reported in at least four individuals with hyperphenylalanemia, including at least one for whom BH4 deficiency was excluded (PMID: 9860305, PMID: 21307867). Of these, two were siblings who also had p.Arg241His (PMID: 22330942), which is classified as pathogenic by PAH VCEP (Variation ID: 102804), without documentation of parental testing to establish phase. In-vitro studies show 20% enzyme activity (PMID: 9860305). This variant is absent from population databases. Multiple lines of computational evidence support a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP3, PP4, PM2, PM3_Supporting, PS3_supporting.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.8691 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.968 | strongly pathogenic-leaning |
| SaProt | LLR -7.51 | tolerated |
| ⇒ AlphaMissense and REVEL call this damaging; SaProt does not. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 11 | GERP 2.3, phastCons 1 |
| Regional constraint | o/e 1.07 | unconstrained · MANE · 78 kb · p 0.12 · regional, not allelic |
| Overall | ||
| CADD | 28.5 | 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.Ser70Pro
- Coding
- c.208T>C
- MANE Select
- NM_000277
- dbSNP
- rs63048261
- Type
- single nucleotide variant
- Location
- chr12:102894879 (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 70
- the act domain
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.Ser70Phe Likely pathogenic ★★★ ⚠ same residue
- PAH p.Ser70del Pathogenic ★★★ same residue
- PAH p.Ser70fs Pathogenic ★★★ same residue
- PAH p.Ser70_Arg71insProSer 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
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-ser70pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown