Is PAH p.Arg86Pro (c.257G>C) pathogenic?

PAH p.Arg86Pro (c.257G>C) is classified Likely pathogenic in PAH (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.2744); Absent from gnomAD v4.1; Associated with phenylketonuria.

What condition is associated with PAH p.Arg86Pro (c.257G>C)?

PAH p.Arg86Pro (c.257G>C) is associated with phenylketonuria (ClinVar).

How common is PAH p.Arg86Pro (c.257G>C) in the general population?

PAH p.Arg86Pro (c.257G>C) is absent from gnomAD v4.1 (gnomAD).

How is Phenylketonuria inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PAH p.Arg86Pro (c.257G>C)?

AlphaMissense predicts likely benign (score 0.2744) — an in-silico prediction, not a clinical call.

PAH p.Arg86Pro

c.257G>C · VCV3382859

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2744 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

phenylketonuria

Computational evidence

Protein change
AlphaMissense	0.2744	likely benign ⚠ discordant with ClinVar
REVEL	0.587	indeterminate
SaProt	LLR -8.52	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.11	GERP -1.1
Regional constraint	o/e 1.07	unconstrained · MANE · 78 kb · p 0.12 · regional, not allelic
Overall
CADD	13.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PAH
Protein: p.Arg86Pro
Coding: c.257G>C
MANE Select: NM_000277
Type: single nucleotide variant
Location: chr12:102894830 (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 86: the act domain; an α-helix

Full PAH gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

phenylketonuria — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Phenylketonuria (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy
Prevalence: 1-9 / 100 000 (France)

Similar variants

PAH p.Arg86His Uncertain significance ★★ ⚠ same residue
PAH p.Arg86fs 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

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-arg86pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown