PAH p.Arg155Pro
c.464G>C · rs199475663 · VCV102687
ClinGen expert panel — Phenylketonuria VCEP
Likely Pathogenic for phenylketonuria. Applied ACMG criteria (verbatim):
PM2 PP4_Moderate PP3 PM3
Curation rationale (ClinGen, verbatim)
PAH-specific ACMG/AMP criteria applied: PM2: absent from ExAC, gnomAD, 1000G, ESP. PAGE MAF=0.00066; PP3: Deleterious effect predicted in SIFT, Polyphen-2, MutationTaster. REVEL=0.967; PP4_Moderate: Detected in a patient with classic PKU. Cofactor deficiency excluded. (PMID:10679941); PM3: Detected in trans with R408W (P) (PMID:10679941). In summary this variant meets criteria to be classified as likely pathogenic for phenylketonuria in an autosomal recessive manner based on the ACMG/AMP criteria applied as specified by the PAH Expert Panel: (PM2, PP3, PP4_Moderate, PM3).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9936 | likely pathogenic ✓ concordant with ClinVar · top 3% in PAH |
|---|---|---|
| REVEL | 0.967 | strongly pathogenic-leaning |
| SaProt | LLR -16.90 | 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 4.9 | GERP 2.1, phastCons 1 |
| Regional constraint | o/e 1.07 | unconstrained · MANE · 78 kb · p 0.12 · regional, not allelic |
| Overall | ||
| CADD | 28.4 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
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.Arg155Pro
- Coding
- c.464G>C
- MANE Select
- NM_000277
- dbSNP
- rs199475663
- Type
- single nucleotide variant
- Location
- chr12:102866641 (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 155
- 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.Arg155Cys Likely pathogenic ★★★ same residue
- PAH p.Arg155His Pathogenic ★★★ same residue
- PAH p.Arg155= Likely benign ★ same residue
- PAH p.Arg155fs 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
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-arg155pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown