PAH p.Phe39del
c.113TCT[1] · rs199475565 · VCV188933
ClinGen expert panel — Phenylketonuria VCEP
Pathogenic for phenylketonuria. Applied ACMG criteria (verbatim):
PP4_Moderate PM2_Supporting PS3_Supporting PM3_Strong PM4
Curation rationale (ClinGen, verbatim)
This c.113_115TCTdel (p.Phe39del) variant is also known as c.115_117delTTC (p.Phe39del) in the literature. This variant in PAH was reported in 3 Chinese patients with PAH deficiency (PMID: 26503515). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia. This variant was documented in 5 patients with PAH deficiency with a pathogenic or likely pathogenic variant in trans (PMID: 16256386, 23500595, 26542770, 29102225, 12655550). This variant is present in European (non-Finnish) populations at a frequency of 0.000035 (gnomAD), and in European (non-Finnish) populations at a frequency of 0.000045 (ExAC). This variant changes the protein length from an in-frame deletion in a non-repetitive region. Functional analysis of this variant found that it is associated with approximately 20% residual enzyme activity (PMID: 11161839; 17935162). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM2_supporting, PP4_moderate, PM4, PS3-supporting, PM3_strong.
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. | ||
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 1.6, phastCons 1 |
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.Phe39del
- Coding
- c.113TCT[1]
- MANE Select
- NM_000277
- dbSNP
- rs199475565
- Type
- Microsatellite
- Location
- chr12:102912841 (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 39
- the act domain; a β-strand; a UniProt-annotated variant site (in pah deficiency); 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.Phe39Leu Pathogenic ★★★ same residue
- PAH p.Phe39Ter Pathogenic ★ 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
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-phe39del (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown