Is PAH p.Ser67Pro (c.199T>C) pathogenic?

PAH p.Ser67Pro (c.199T>C) is classified Pathogenic in PAH (ClinVar, Expert panel, 6 submitters; last evaluated 2023-03-16). AlphaMissense: likely pathogenic (0.9952); Very rare (popmax 0.000254%, nfe); Associated with phenylketonuria.

What condition is associated with PAH p.Ser67Pro (c.199T>C)?

PAH p.Ser67Pro (c.199T>C) is associated with phenylketonuria (ClinVar).

How common is PAH p.Ser67Pro (c.199T>C) in the general population?

PAH p.Ser67Pro (c.199T>C) is very rare (popmax 0.000254%, 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.Ser67Pro (c.199T>C)?

AlphaMissense predicts likely pathogenic (score 0.9952) — an in-silico prediction, not a clinical call.

PAH p.Ser67Pro

c.199T>C · rs5030842 · VCV102625

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.9952 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

phenylketonuria

ClinGen expert panel — Phenylketonuria VCEP

Pathogenic for phenylketonuria. Applied ACMG criteria (verbatim):

PM2 PP4_Moderate PM3_VeryStrong PP3

Curation rationale (ClinGen, verbatim)

The c.199T>C (p.Ser67Pro) variant in PAH has been reported in multiple individuals with PKU (BH4 deficiency excluded). (PP4_Moderate; 8533759; 26351554). This variant has an extremely low allele frequency in ExAC (MAF=0.00002, PM2). This variant was detected in trans with L48S (PMID: 8592329), IVS10-11G>A, R408Q (P), R261Q, R252W (P/LP) PMID: 26351554 (PM3_VS). Multiple lines of computational evidence support a deleterious effect (SIFT, PolyPhen-2, MutationTaster, REVEL=0.954) (PP3). In summary, this variant meets criteria to be classified as pathogenic for PAH. PAH-specific ACMG/AMP criteria applied: PM3_VS, PM2, PP4_Moderate, PP3.

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

Computational evidence

Protein change
AlphaMissense	0.9952	likely pathogenic ✓ concordant with ClinVar · top 2% in PAH
REVEL	0.954	strongly pathogenic-leaning
SaProt	LLR -15.08	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 11	GERP 2.3, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 78 kb · p 0.12 · regional, not allelic
Overall
CADD	29.2	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 0.000254% European (non-Finnish) · 3/1,179,866 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,636 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.Ser67Pro
Coding: c.199T>C
MANE Select: NM_000277
dbSNP: rs5030842
Type: single nucleotide variant
Location: chr12:102894888 (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 67: the act domain; a β-strand; 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.Ser67Ala Pathogenic ★ same residue
PAH p.Ser67Tyr Likely pathogenic ★ same residue
PAH p.Ser67Cys Uncertain significance ★ ⚠ same residue
PAH p.Ser67= 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-ser67pro (accessed [today's date]).

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