Is PAH p.Val45Ala (c.134T>C) pathogenic?

PAH p.Val45Ala (c.134T>C) is classified Uncertain significance in PAH (ClinVar, Expert panel, 1 submitter; last evaluated 2019-04-04). AlphaMissense: likely benign (0.1785); Very rare (popmax 0.00017%, nfe); Associated with phenylketonuria.

What condition is associated with PAH p.Val45Ala (c.134T>C)?

PAH p.Val45Ala (c.134T>C) is associated with phenylketonuria (ClinVar).

How common is PAH p.Val45Ala (c.134T>C) in the general population?

PAH p.Val45Ala (c.134T>C) 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.Val45Ala (c.134T>C)?

AlphaMissense predicts likely benign (score 0.1785) — an in-silico prediction, not a clinical call.

PAH p.Val45Ala

c.134T>C · rs1592988883 · VCV805809

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1785 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

phenylketonuria

ClinGen expert panel — Phenylketonuria VCEP

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

PM2 PP4

Curation rationale (ClinGen, verbatim)

The c.134T>C (p.Val45Ala) PAH variant has been reported in a patient with mild hyperphenylalaninemia (PMID: 22513348). This variant is absent from 1000G, ESP, and gnomAD databases. It is a missense variant with conflicting predictions of pathogenicity: SIFT: Tolerated, PolyPhen: Benign, MutationTaster: Disease causing, REVEL=0.697. In summary, this variant meets criteria to be classified as uncertain significance for PAH. PAH-specific ACMG/AMP criteria applied: PM2, PP4.

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

Computational evidence

Protein change
AlphaMissense	0.1785	likely benign
REVEL	0.697	pathogenic-leaning
SaProt	LLR -7.63	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 78 kb · p 0.12 · regional, not allelic
Overall
CADD	24.4	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) · 2/1,179,540 alleles

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

Overall 0.000137% 2/1,461,270 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.Val45Ala
Coding: c.134T>C
MANE Select: NM_000277
dbSNP: rs1592988883
Type: single nucleotide variant
Location: chr12:102912825 (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 45: the act domain; a UniProt-annotated variant site (in pah deficiency; severe; uncertain significance)

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.Val45Phe Pathogenic ★ ⚠ same residue
PAH p.Val45= 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
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-val45ala (accessed [today's date]).

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