Is PAH p.Pro147Ser (c.439C>T) pathogenic?

PAH p.Pro147Ser (c.439C>T) is classified Likely pathogenic in PAH (ClinVar, Expert panel, 11 submitters; last evaluated 2020-10-15). AlphaMissense: likely pathogenic (0.9313); Very rare (popmax 0.00167%, amr); Associated with phenylketonuria.

What condition is associated with PAH p.Pro147Ser (c.439C>T)?

PAH p.Pro147Ser (c.439C>T) is associated with phenylketonuria (ClinVar).

How common is PAH p.Pro147Ser (c.439C>T) in the general population?

PAH p.Pro147Ser (c.439C>T) 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.

What do computational predictors say about PAH p.Pro147Ser (c.439C>T)?

AlphaMissense predicts likely pathogenic (score 0.9313) — an in-silico prediction, not a clinical call.

PAH p.Pro147Ser

c.439C>T · rs199475624 · VCV102669

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 11 submitters

AlphaMissense

likely pathogenic

0.9313 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

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 PM3_Strong PP3

Curation rationale (ClinGen, verbatim)

This c.439C>T (p.Pro147Ser) variant in PAH was reported in at least 5 patients with PAH deficiency, detected with pathogenic variants p.Arg243Gln (PMID: 27121329), p.S349P (PMID: 15589814), c.1045T>C, c.782G>A (PMID: 24941924) and p.A403V (PMID: 10234516). DHPR activity, biopterin and/or pteridine analysis was performed to rule out other causes of hyperphenylalaninemia (PMID: 27121329). This variant is present at an extremely low frequency in gnomAD (MAF=0.00003). Computational evidence for this missense variant supports a deleterious effect. In summary, this variant meets criteria to be classified as likely pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_strong, PM2, PP4_moderate, PP3.

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

Computational evidence

Protein change
AlphaMissense	0.9313	likely pathogenic ✓ concordant with ClinVar
REVEL	0.96	strongly pathogenic-leaning
SaProt	LLR -12.61	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	32.0	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 0.00167% Admixed American · 1/60,020 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000206% 3/1,459,846 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,020
European (non-Finnish)	0.00017%	589,081

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.Pro147Ser
Coding: c.439C>T
MANE Select: NM_000277
dbSNP: rs199475624
Type: single nucleotide variant
Location: chr12:102877464 (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.Pro147= Uncertain significance ★★★ 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-pro147ser (accessed [today's date]).

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