PAH p.Val262=
c.786C>T · rs776860902 · VCV883189
ClinGen expert panel — Phenylketonuria VCEP
Uncertain Significance for phenylketonuria. Applied ACMG criteria (verbatim):
PM2_Supporting
Curation rationale (ClinGen, verbatim)
The NM_000277.3:c.786C>T in PAH is a synonymous (silent) variant (p.Val262=) that is not predicted to impact splicing. To our knowledge, this variant has not been reported in the literature and results of functional studies are unavailable. This variant is absent in gnomAD v2.1.1 (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 883189, 1 star review status) with two submitters classifying the variant as a variant of uncertain significance and one submitter classifying the variant as likely benign. In summary, this variant meets the criteria to be classified as a variant of uncertain significance for PAH deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen PAH Variant Curation Expert Panel (Specifications Version 2.0): PM2_Supporting.
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 2.5 | GERP -0.8, phastCons 1 |
| Overall | ||
| CADD | 7.897 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,482 |
| European (non-Finnish)grpmax | 0.000254% | 393,335 |
Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
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.Val262=
- Coding
- c.786C>T
- MANE Select
- NM_000277
- dbSNP
- rs776860902
- Type
- single nucleotide variant
- Location
- chr12:102852871 (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 262
- a β-strand
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.Val262Gly Likely 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
- PAH c.1066-1G>A Pathogenic ★★★ same condition
- PAH c.1066-1G>C 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-val262 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown