Is PAH p.Pro407Ser (c.1219C>T) pathogenic?

PAH p.Pro407Ser (c.1219C>T) is classified Pathogenic in PAH (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-09-30). AlphaMissense: ambiguous (0.3831); Very rare (popmax 0.00446%, eas); Associated with phenylketonuria.

What condition is associated with PAH p.Pro407Ser (c.1219C>T)?

PAH p.Pro407Ser (c.1219C>T) is associated with phenylketonuria (ClinVar).

How common is PAH p.Pro407Ser (c.1219C>T) in the general population?

PAH p.Pro407Ser (c.1219C>T) is very rare (popmax 0.00446%, eas) (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.Pro407Ser (c.1219C>T)?

AlphaMissense predicts ambiguous (score 0.3831) — an in-silico prediction, not a clinical call.

PAH p.Pro407Ser

c.1219C>T · rs62644465 · VCV102568

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3831 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

phenylketonuria

Computational evidence

Protein change
AlphaMissense	0.3831	ambiguous
REVEL	0.884	moderately pathogenic-leaning
SaProt	LLR -11.18	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.3, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 78 kb · p 0.12 · regional, not allelic
Overall
CADD	27.1	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 0.00446% East Asian · 2/44,876 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000137% 2/1,461,450 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.Pro407Ser
Coding: c.1219C>T
MANE Select: NM_000277
dbSNP: rs62644465
Type: single nucleotide variant
Location: chr12:102840496 (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 407: 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.Pro407Leu Likely pathogenic ★★★ same residue
PAH p.Pro407Thr Likely pathogenic ★ ⚠ same residue
PAH p.Pro407= 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-pro407ser (accessed [today's date]).

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