Is PAH p.Pro225Ala (c.673C>G) pathogenic?

PAH p.Pro225Ala (c.673C>G) is classified Likely pathogenic in PAH (ClinVar, Expert panel, 3 submitters; last evaluated 2021-02-14). AlphaMissense: likely pathogenic (0.7436); Very rare (popmax 0.000339%, nfe); Associated with phenylketonuria.

What condition is associated with PAH p.Pro225Ala (c.673C>G)?

PAH p.Pro225Ala (c.673C>G) is associated with phenylketonuria (ClinVar).

How common is PAH p.Pro225Ala (c.673C>G) in the general population?

PAH p.Pro225Ala (c.673C>G) is very rare (popmax 0.000339%, nfe) (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.Pro225Ala (c.673C>G)?

AlphaMissense predicts likely pathogenic (score 0.7436) — an in-silico prediction, not a clinical call.

PAH p.Pro225Ala

c.673C>G · rs199475589 · VCV102780

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7436 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

phenylketonuria

ClinGen expert panel — Phenylketonuria VCEP

Likely Pathogenic for phenylketonuria. Applied ACMG criteria (verbatim):

PM2 PP4_Moderate PP3 PM5

Curation rationale (ClinGen, verbatim)

The c.673C>G (p.Pro225Ala) variant in PAH has been reported in 1 individual with classic PKU (BH4 deficiency excluded, PMID: 29499199). This variant is absent in population databases. Multiple lines of computational evidence support a deleterious effect. Another missense change at the same amino acid, p.Pro225Thr, is interpreted as pathogenic by multiple submitters in ClinVar (variation ID 102779). In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PP4_Moderate, PM2, PM5, PP3.

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

Computational evidence

Protein change
AlphaMissense	0.7436	likely pathogenic ✓ concordant with ClinVar
REVEL	0.986	strongly pathogenic-leaning
SaProt	LLR -14.06	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 78 kb · p 0.12 · regional, not allelic
Overall
CADD	28.2	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

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,974 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000274% 4/1,461,810 alleles · very rare

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.Pro225Ala
Coding: c.673C>G
MANE Select: NM_000277
dbSNP: rs199475589
Type: single nucleotide variant
Location: chr12:102855169 (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 225: an α-helix; a UniProt-annotated variant site (in pah deficiency; severe)

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.Pro225Leu Likely pathogenic ★★★ same residue
PAH p.Pro225Thr Pathogenic ★★ same residue
PAH p.Pro225= 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
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-pro225ala (accessed [today's date]).

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