PAH p.Lys115fs
c.344_347del · rs199475648 · VCV102652
ClinGen expert panel — Phenylketonuria VCEP
Pathogenic for phenylketonuria. Applied ACMG criteria (verbatim):
PM2 PVS1 PM3_Supporting PP4
Curation rationale (ClinGen, verbatim)
This c.344_347del (p.Lys115fs) variant in PAH was detected with the c.1315+1G>A pathogenic variant and the c.1066-14C>G likely pathogenic variant in multiple patients with PKU, phasing was not available (PMID: 11207989, 28676969, 25551302). This variant was absent in population databases. This is a frameshift variant in exon 3 of 13 coding exons with termination at position 194 predicted to undergo nonsense mediated decay. In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PVS1, PM2, PM3_Supporting, PP4.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | frameshift | predicted loss-of-function |
|---|---|---|
| NMD | predicted | premature termination codon in exon 3 of 13 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 2.9 | GERP -0.49, phastCons 1 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 0.00668% | 14,961 |
| Finnishnot grpmax-eligible | 0.00313% | 31,996 |
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.Lys115fs
- Coding
- c.344_347del
- MANE Select
- NM_000277
- dbSNP
- rs199475648
- Type
- Microsatellite
- Location
- chr12:102894740 (GRCh38)
- Gene constraint
- LOEUF 1.265 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
- Structure
- AlphaFold pLDDT 89.04 · 21 PDB
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.Lys115del Uncertain significance same residue
- PAH p.Asp17fs Pathogenic ★★★ same condition
- PAH p.Glu183del Likely pathogenic ★★★ same condition
- PAH p.Glu44del Likely pathogenic ★★★ same condition
- PAH p.Glu57_Asn58insTer Pathogenic ★★★ same condition
- PAH p.Ile95del Pathogenic ★★★ same condition
- PAH p.Leu15_Ser16insTer Pathogenic ★★★ same condition
- PAH p.Leu194fs 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-lys115fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown