Is PAH p.Pro416fs (c.1247del) pathogenic?

PAH p.Pro416fs (c.1247del) is classified Pathogenic in PAH (ClinVar, Single submitter, 1 submitter). Associated with phenylketonuria.

What condition is associated with PAH p.Pro416fs (c.1247del)?

PAH p.Pro416fs (c.1247del) is associated with phenylketonuria (ClinVar).

How is Phenylketonuria inherited?

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

PAH p.Pro416fs

c.1247del · VCV3382860

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

phenylketonuria

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 12 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -4.4	GERP -4.4

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: PAH
Protein: p.Pro416fs
Coding: c.1247del
MANE Select: NM_000277
Type: Deletion
Location: chr12:102840468 (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 416: 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.Pro416Gln Likely pathogenic ★★★ same residue
PAH p.Pro416Thr Likely pathogenic ★★★ ⚠ same residue
PAH p.Pro416Leu Pathogenic ★ same residue
PAH p.Pro416= Likely benign ★ same residue
PAH c.1200-1delG Likely pathogenic ★★★ same condition
PAH c.1314_1315+4del Pathogenic ★★★ same condition
PAH c.169_171del Likely pathogenic ★★★ same condition
PAH c.442-1377_509+226del 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-pro416fs (accessed [today's date]).

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