Is PAH p.Pro147= (c.441T>C) pathogenic?

PAH p.Pro147= (c.441T>C) is classified Uncertain significance in PAH (ClinVar, Expert panel, 1 submitter; last evaluated 2020-10-16). Very rare (popmax 0.00167%, amr); Associated with phenylketonuria.

What condition is associated with PAH p.Pro147= (c.441T>C)?

PAH p.Pro147= (c.441T>C) is associated with phenylketonuria (ClinVar).

How common is PAH p.Pro147= (c.441T>C) in the general population?

PAH p.Pro147= (c.441T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Phenylketonuria inherited?

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

PAH p.Pro147=

c.441T>C · rs1386014129 · VCV987766

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

phenylketonuria

ClinGen expert panel — Phenylketonuria VCEP

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

PM2 PP4

Curation rationale (ClinGen, verbatim)

The c.441T>C (p.Pro147=) PAH variant has been reported in 1 Chinese patient with mild hyperphenylalaninemia (PMID: 30459323) detected with the PAH variant of uncertain significance p.Arg53His. A defect in BH4 metabolism was not excluded. This variant is absent from population databases. It is a synonymous variant with conflicting predictions by splicing prediction algorithms. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4.

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 -8.2	GERP -4.2
Overall
CADD	0.066	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,002 alleles

Overall 0.000657% 1/152,168 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.Pro147=
Coding: c.441T>C
MANE Select: NM_000277
dbSNP: rs1386014129
Type: single nucleotide variant
Location: chr12:102877462 (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 147: a turn

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.Pro147Leu Likely pathogenic ★★★ same residue
PAH p.Pro147Ser Likely pathogenic ★★★ same residue
PAH p.Pro147fs 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

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-pro147 (accessed [today's date]).

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