PAH p.Asp129Val
c.386A>T · rs199475623 · VCV102662
ClinGen expert panel — Phenylketonuria VCEP
Uncertain Significance for phenylketonuria. Applied ACMG criteria (verbatim):
PM2 PP3 PM5
Curation rationale (ClinGen, verbatim)
The c.386A>T (p.Asp129Val) variant in PAH has not been reported in the literature to our knowledge. This variant is absent from 1000G, ESP, ExAC and gnomAD (PM2). A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.986 (PM3). The (p.Asp129Gly) variant is likely pathogenic by 1 submitter and PAH VCEP (PM5). In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM5, PP3.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9943 | likely pathogenic · top 2% in PAH |
|---|---|---|
| REVEL | 0.986 | strongly pathogenic-leaning |
| SaProt | LLR -17.55 | 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 7.8 | GERP 2.1, phastCons 1 |
| Regional constraint | o/e 1.07 | unconstrained · MANE · 78 kb · p 0.12 · regional, not allelic |
| Overall | ||
| CADD | 30.0 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification
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.Asp129Val
- Coding
- c.386A>T
- MANE Select
- NM_000277
- dbSNP
- rs199475623
- Type
- single nucleotide variant
- Location
- chr12:102877517 (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 129
- 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.Asp129Gly Likely pathogenic ★★★ same residue
- PAH p.Asp129Tyr Pathogenic ★★ same residue
- PAH p.Asp129Ala Uncertain significance ★ ⚠ same residue
- PAH p.Asp129Glu Likely pathogenic ★ same residue
- PAH p.Asp129His 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
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-asp129val (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown