PAH Y414C - GET-Evidence



(PAH Tyr414Cys)

Short summary

This recessive variant has reduced PAH enzyme activity. It is associated with mild PKU (especially when compound heterozygous with more deleterious PAH mutations) and mild hyperphenylalaninemia.

Variant evidence
Computational 3

Other mutations in this gene cause the disease, BLOSUM100 score indicates disruptive amino acid change, Polyphen predicts damaging effect

Functional 2

Two different papers report reduced (but not absent) enzyme activity.

See Okano Y et al. 1991 (2044609), Cerone R et al. 2004 (14741196).

Case/Control 5

This is a well-established variant which lowers (but does not knock out) enzyme activity.

Familial -
Clinical importance
Severity 3
Treatability 5

See unpublished research (below).

Penetrance 5


High clinical importance, pathogenic

(The "high clinical importance, " qualifier is assigned automatically based on the above evidence and importance scores.)

Inheritance pattern


Summary of published research, and additional commentary

Used in Counsyl Diagnostic Carrier Screen

Allele frequency

  • C @ chr12:103234252: 0.0% (4/10758) in EVS
  • C @ chr12:101758381: 0.8% (1/128) in GET-Evidence
  • Frequency shown in summary reports: 0.0% (4/10758)


Okano Y, Eisensmith RC, Dasovich M, Wang T, Güttler F, Woo SL. A prevalent missense mutation in Northern Europe associated with hyperphenylalaninaemia. Eur J Pediatr. 1991 Mar;150(5):347-52. PubMed PMID: 2044609.

Identified in a Danish patient with hyperphenylalaninaemia. They report that this variant had “a significant amount of normal PAH enzyme activity”.

Nowacki PM, Byck S, Prevost L, Scriver CR. PAH Mutation Analysis Consortium Database: 1997. Prototype for relational locus-specific mutation databases. Nucleic Acids Res. 1998 Jan 1;26(1):220-5. PubMed PMID: 9399840; PubMed Central PMCID: PMC147234.

This variant is the most common cause mild recessive non-PKU Hyperphenylalaninemia in N. Europe, accounting for 5% of cases.

Guldberg P, Rey F, Zschocke J, Romano V, François B, Michiels L, Ullrich K, Hoffmann GF, Burgard P, Schmidt H, Meli C, Riva E, Dianzani I, Ponzone A, Rey J, Güttler F. A European multicenter study of phenylalanine hydroxylase deficiency: classification of 105 mutations and a general system for genotype-based prediction of metabolic phenotype. Am J Hum Genet. 1998 Jul;63(1):71-9. Erratum in: Am J Hum Genet 1998 Oct;63(4):1252-3. PubMed PMID: 9634518; PubMed Central PMCID: PMC1377241.

This variant is reported as having mild PKU severity — when in combination with more severe mutations, mild PKU is likely. When homozygous, the authors predict mild PKU or mild hyperphenylalaninemia.

Pey AL, Desviat LR, Gámez A, Ugarte M, Pérez B. Phenylketonuria: genotype-phenotype correlations based on expression analysis of structural and functional mutations in PAH. Hum Mutat. 2003 Apr;21(4):370-8. PubMed PMID: 12655546.

In contrast to Pey AL 2004, this study reports near normal activity (80%, std dev of 16%), but finds the variant forms more aggregates and less tetramers/dimers compared to wild-type (with chaperonin, Wild type is 27% vs 73%, Y414C was 41% vs. 59%) and a lower half-denaturation temperature (Tm 55C vs 59C).

Cerone R, Schiaffino MC, Fantasia AR, Perfumo M, Birk Moller L, Blau N. Long-term follow-up of a patient with mild tetrahydrobiopterin-responsive phenylketonuria. Mol Genet Metab. 2004 Feb;81(2):137-9. PubMed PMID: 14741196.

This authors report that, in a eukaryotic recombinant system, the Y414C mutant protein has 28% of the wild-type activity.

Pey AL, Pérez B, Desviat LR, Martínez MA, Aguado C, Erlandsen H, Gámez A, Stevens RC, Thórólfsson M, Ugarte M, Martínez A. Mechanisms underlying responsiveness to tetrahydrobiopterin in mild phenylketonuria mutations. Hum Mutat. 2004 Nov;24(5):388-99. PubMed PMID: 15459954.

They report the recombinant protein in E coli has 9% of wild-type activity and 18% after treatment with BH4.


Other external references

  • Score: 1.0 (probably damaging)

Other in silico analyses

  • NBLOSUM100 score = 6
  • GET-Evidence autoscore = 6

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Gene search

"GENE" or "GENE A123C":

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