PAH p.Ala156Pro
c.466G>C · rs199475686 · VCV102688
ClinGen expert panel — Phenylketonuria VCEP
Pathogenic for phenylketonuria. Applied ACMG criteria (verbatim):
PP4_Moderate PM2_Supporting PM3_VeryStrong PS3_Supporting
Curation rationale (ClinGen, verbatim)
The c.466G>C (p.Ala156Pro) variant in PAH has been reported in multiple individuals with PAH deficiency (BH4 deficiency excluded). (PMID: 26322415). This variant is absent in population databases. This variant was detected in trans with multiple pathogenic variants: p.H220P (PMID 26322415); c.611A>G (aka EX6-96A>G, PMID: 26600521); p.V5Sfs*33, p.R158W, p.R241C (2 patients), p.R261Q, p.R400T, p.T418P (PMID: 30050108). Functional studies show the PAH A156P mutant produces reduced protein (8.7% of wild type), with a residual enzyme activity of 10.4% (PMID 24327145). Computational evidence is conflicting. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_very-strong, PM2_supporting, PP4_Moderate, PS3_supporting.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.8851 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.832 | moderately pathogenic-leaning |
| SaProt | LLR -12.46 | 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 1.8 | GERP -0.92, phastCons 0.091 |
| Regional constraint | o/e 1.07 | unconstrained · MANE · 78 kb · p 0.12 · regional, not allelic |
| Overall | ||
| CADD | 21.0 | 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.Ala156Pro
- Coding
- c.466G>C
- MANE Select
- NM_000277
- dbSNP
- rs199475686
- Type
- single nucleotide variant
- Location
- chr12:102866639 (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 156
- an α-helix
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.Ala156Gly Likely pathogenic ★ ⚠ same residue
- PAH p.Ala156Val Likely pathogenic ★ ⚠ same residue
- PAH p.Ala156fs Likely pathogenic ★ same residue
- PAH p.Ala156Glu 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-ala156pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown