Is PAH p.Arg86fs (c.256del) pathogenic?

PAH p.Arg86fs (c.256del) is classified Likely pathogenic in PAH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-08). Absent from gnomAD; Associated with phenylketonuria.

What condition is associated with PAH p.Arg86fs (c.256del)?

PAH p.Arg86fs (c.256del) is associated with phenylketonuria (ClinVar).

How common is PAH p.Arg86fs (c.256del) in the general population?

PAH p.Arg86fs (c.256del) is absent from gnomAD (gnomAD).

How is Phenylketonuria inherited?

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

PAH p.Arg86fs

c.256del · rs2499521460 · VCV2677437

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

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 3 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.11	GERP -1.1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PAH
Protein: p.Arg86fs
Coding: c.256del
MANE Select: NM_000277
dbSNP: rs2499521460
Type: Deletion
Location: chr12:102894831 (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 86: the act domain; an α-helix

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.Arg86His Uncertain significance ★★ ⚠ same residue
PAH p.Arg86Pro Likely pathogenic ★ ⚠ 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
PAH c.442-4403_509+883del Pathogenic ★★★ same condition
PAH c.443_509+1del 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-arg86fs (accessed [today's date]).

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