PAH p.Leu348Pro
c.1043T>C · rs1874733519 · VCV932253
ClinGen expert panel — Phenylketonuria VCEP
Likely Pathogenic for phenylketonuria. Applied ACMG criteria (verbatim):
PM2 PP4_Moderate PP3 PM5
Curation rationale (ClinGen, verbatim)
The c.1043T>C (p.Leu348Pro) variant in PAH has been reported in a Chinese patient with PAH deficiency (BH4 deficiency excluded) (PMID: 23932990) This variant is absent from population databases. A deleterious effect is predicted in SIFT, Polyphen-2, MutationTaster, and REVEL=0.981. Another missense change at the same amino acid is pathogenic: p.Leu348Val Pathogenic by 7 submitters. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM5, PP3.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9912 | likely pathogenic ✓ concordant with ClinVar · top 4% in PAH |
|---|---|---|
| REVEL | 0.981 | strongly pathogenic-leaning |
| SaProt | LLR -15.21 | 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 11 | GERP 2.1, phastCons 1 |
| Regional constraint | o/e 1.07 | unconstrained · MANE · 78 kb · p 0.12 · regional, not allelic |
| Overall | ||
| CADD | 29.6 | 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.Leu348Pro
- Coding
- c.1043T>C
- MANE Select
- NM_000277
- dbSNP
- rs1874733519
- Type
- single nucleotide variant
- Location
- chr12:102844358 (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 348
- a UniProt-annotated variant site (in pah deficiency; mild); 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.Leu348Val Pathogenic ★★ same residue
- PAH p.Leu348= Uncertain significance same residue
- PAH p.Leu348fs 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
- PAH c.1066-14C>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-leu348pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown