Is PAH p.Pro366Ala (c.1096C>G) pathogenic?

PAH p.Pro366Ala (c.1096C>G) is classified Uncertain significance in PAH (ClinVar, Expert panel, 1 submitter; last evaluated 2022-10-14). AlphaMissense: likely benign (0.1129); Absent from gnomAD v4.1; Associated with phenylketonuria.

What condition is associated with PAH p.Pro366Ala (c.1096C>G)?

PAH p.Pro366Ala (c.1096C>G) is associated with phenylketonuria (ClinVar).

How common is PAH p.Pro366Ala (c.1096C>G) in the general population?

PAH p.Pro366Ala (c.1096C>G) 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.Pro366Ala (c.1096C>G)?

AlphaMissense predicts likely benign (score 0.1129) — an in-silico prediction, not a clinical call.

PAH p.Pro366Ala

c.1096C>G · rs2136635839 · VCV1810389

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1129 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

phenylketonuria

ClinGen expert panel — Phenylketonuria VCEP

Uncertain Significance for phenylketonuria. Applied ACMG criteria (verbatim):

PM2 PP4 PM3

Curation rationale (ClinGen, verbatim)

This c.1096C>G (p.Pro366Ala) variant in PAH was seen in a patient with PKU in trans with the likely pathogenic variant p.Gly247Arg (PMID: 28982351). This variant was absent in population databases. Computational evidence is conflicting. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PM3, PP4.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.1129	likely benign
REVEL	0.608	indeterminate
SaProt	LLR -11.84	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.032, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 78 kb · p 0.12 · regional, not allelic
Overall
CADD	19.66	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.Pro366Ala
Coding: c.1096C>G
MANE Select: NM_000277
dbSNP: rs2136635839
Type: single nucleotide variant
Location: chr12:102843749 (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 366: a UniProt-annotated variant site (in pah deficiency; severe); a β-strand

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.Pro366His Likely pathogenic ★★★ ⚠ same residue
PAH p.Pro366Ser Likely pathogenic ★ ⚠ same residue
PAH p.Pro366Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
PAH p.Pro366= Likely benign ★ 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

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-pro366ala (accessed [today's date]).

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