ClinGen expert panel — Phenylketonuria VCEP
Benign for phenylketonuria. Applied ACMG criteria (verbatim):
BS2 BP4 BA1
Curation rationale (ClinGen, verbatim)
The c.735G>A (p.Val245=) variant in PAH has a MAF of 0.29058 in ExAC (BA1; http://exac.broadinstitute.org) with 6,524 homozygotes (BS2). This is a synonymous variant, predicted tolerated and benign in SIFT, Polyphen. MutationTaster predicted polymorphism with no abrogation of splice sites (BP4). In summary, this variant meets criteria to be classified as benign.
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 · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 0.38 | GERP -0.91, phastCons 0.98 |
| Overall | ||
| CADD | 7.753 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 75.8% | 1 |
| South Asian | 36.9% | 3 |
| Finnishnot grpmax-eligible | 30.6% | 3 |
| Middle Eastern | 30.3% | 3 |
| Ashkenazi Jewishnot grpmax-eligible | 28.8% | 3 |
| Remaining individualsnot grpmax-eligible | 27.1% | 4 |
| Amishnot grpmax-eligible | 26.8% | 4 |
| European (non-Finnish) | 23.9% | 4 |
| Admixed American | 20.3% | 5 |
| African / African-American | 4.45% | 22 |
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.Val245=
- Coding
- c.735G>A
- MANE Select
- NM_000277
- dbSNP
- rs1042503
- Type
- single nucleotide variant
- Location
- chr12:102852922 (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 245
- 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.Val245Leu Pathogenic ★★★ same residue
- PAH p.Val245Met Pathogenic ★★★ same residue
- PAH p.Val245Glu 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-val245 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown