Is PAH p.Asp59Val (c.176A>T) pathogenic?

PAH p.Asp59Val (c.176A>T) is classified Uncertain significance in PAH (ClinVar, Expert panel, 3 submitters; last evaluated 2018-12-10). AlphaMissense: likely benign (0.2166); Very rare (popmax 0.00017%, nfe); Associated with phenylketonuria.

What condition is associated with PAH p.Asp59Val (c.176A>T)?

PAH p.Asp59Val (c.176A>T) is associated with phenylketonuria (ClinVar).

How common is PAH p.Asp59Val (c.176A>T) in the general population?

PAH p.Asp59Val (c.176A>T) is very rare (popmax 0.00017%, 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.Asp59Val (c.176A>T)?

AlphaMissense predicts likely benign (score 0.2166) — an in-silico prediction, not a clinical call.

PAH p.Asp59Val

c.176A>T · rs199475672 · VCV619154

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2166 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

phenylketonuria

ClinGen expert panel — Phenylketonuria VCEP

Uncertain Significance for phenylketonuria. Applied ACMG criteria (verbatim):

PM2 PP4 PM3

Curation rationale (ClinGen, verbatim)

The c.176A>T (p.Asp59Val) variant in PAH has been reported in an Italian patient with mild PKU (BH4 deficiency not totally excluded) with pathogenic variant p.R261Q (PP4, PM3; PMID: 25003100) This variant is absent from 1000G, ESP, ExAC and gnomAD. computational evidence is conflicting. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PP4, PM2, PP3.

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

Computational evidence

Protein change
AlphaMissense	0.2166	likely benign
REVEL	0.747	pathogenic-leaning
SaProt	LLR -11.21	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.69	GERP -0.038, phastCons 0.32
Regional constraint	o/e 1.07	unconstrained · MANE · 78 kb · p 0.12 · regional, not allelic
Overall
CADD	20.5	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 0.00017% European (non-Finnish) · 2/1,179,180 alleles

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

Overall 0.000124% 2/1,612,596 alleles · very rare exomes 1/1,460,434 · genomes 1/152,162 · joint denominator

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.Asp59Val
Coding: c.176A>T
MANE Select: NM_000277
dbSNP: rs199475672
Type: single nucleotide variant
Location: chr12:102894911 (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 59: the act domain

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.Asp59Gly Uncertain significance ★★★ ⚠ same residue
PAH p.Asp59Tyr Uncertain significance ★★★ ⚠ 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
PAH c.1066-1G>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-asp59val (accessed [today's date]).

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