Phenylketonuria: genes and variants
Phenylketonuria is linked to 2 analyzed proteins (PAH and COL1A1). 32 DNA variants are known to cause it; 8 more are uncertain, and 5 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Genes linked to Phenylketonuria
PAH: Phenylalanine-4-hydroxylase
It converts phenylalanine to tyrosine using tetrahydrobiopterin, preventing toxic phenylalanine accumulation. Biallelic loss-of-function variants cause phenylketonuria and related hyperphenylalaninemias, which can impair brain development without early treatment.
31 disease-causing and 8 uncertain variants in PAH are linked to Phenylketonuria.
COL1A1: Collagen alpha-1(I) chain
The alpha-1 chain of type I collagen, the main fibrillar collagen in connective tissue, bone, and skin. Together with its partner chain, it forms strong extracellular fibers, and COL1A1 variants are associated with osteogenesis imperfecta and several Ehlers-Danlos syndromes.
1 disease-causing and 0 uncertain variants in COL1A1 are linked to Phenylketonuria.
Known disease-causing variants in Phenylketonuria
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| PAH A202T | 202 | Disease-causing (★★★) | |
| PAH A300V | 300 | Disease-causing (★★★) | |
| PAH A345T | 345 | Disease-causing (★★★) | |
| PAH A373D | 373 | Disease-causing (★★★) | |
| PAH A156P | 156 | Disease-causing (★★★) | |
| PAH A165D | 165 | Disease-causing (★★★) | |
| PAH A165T | 165 | Disease-causing (★★★) | |
| PAH A300G | 300 | Disease-causing (★★★) | |
| PAH A300S | 300 | Disease-causing (★★★) | |
| PAH A309V | 309 | Disease-causing (★★★) | |
| PAH A313V | 313 | Disease-causing (★★★) | |
| PAH A345S | 345 | Disease-causing (★★★) | |
| PAH A132V | 132 | Disease-causing (★★★) | |
| PAH A246V | 246 | Disease-causing (★★★) | |
| PAH A104V | 104 | ACT | Disease-causing (★★★) |
| PAH A202V | 202 | Disease-causing (★★★) | |
| PAH A309T | 309 | Disease-causing (★★★) | |
| PAH A322G | 322 | Disease-causing (★★★) | |
| PAH A322T | 322 | Disease-causing (★★★) | |
| PAH A373T | 373 | Disease-causing (★★★) | |
| PAH A104D | 104 | ACT | Disease-causing (★★★) |
| PAH A259T | 259 | Disease-causing (★★) | |
| PAH A309D | 309 | Disease-causing (★★) | |
| PAH A259V | 259 | Disease-causing (★★) | |
| PAH A342P | 342 | Disease-causing (★★) | |
| PAH A342T | 342 | Disease-causing (★★) | |
| PAH A309S | 309 | Disease-causing (★) | |
| PAH A313E | 313 | Disease-causing (★) | |
| PAH A156V | 156 | Disease-causing (★) | |
| PAH A156G | 156 | Disease-causing (★) | |
| COL1A1 G626D | 626 | Triple-helical region | Disease-causing (★) |
| PAH A342E | 342 | Disease-causing |
Uncertain variants in Phenylketonuria that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| PAH A313T | 313 | Conflicting reports | +7: 2 other pathogenic changes within 3 positions; A313E at the same position is pathogenic; seen in 6.6e-06 of gnomAD DNA copies; REVEL 0.934 | |
| PAH A165P | 165 | Uncertain (★★★) | +7: 2 other pathogenic changes within 3 positions; A165D at the same position is pathogenic; seen in 1.4e-06 of gnomAD DNA copies; REVEL 0.956 | |
| PAH A246D | 246 | Uncertain (★★★) | +7: in a 3D region that tolerates change poorly (1R); A246V at the same position is pathogenic; seen in 2.7e-06 of gnomAD DNA copies; REVEL 0.926 | |
| PAH A132T | 132 | Uncertain (★) | +7: in a 3D region that tolerates change poorly (1R); A132V at the same position is pathogenic; seen in 6.8e-07 of gnomAD DNA copies; REVEL 0.854 | |
| PAH A259G | 259 | Uncertain (★) | +6: 2 other pathogenic changes within 3 positions; A259V at the same position is pathogenic; not seen in the gnomAD population database; AlphaMissense 0.98 |
Which prediction tools work for Phenylketonuria
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- MetaLR: 100 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- REVEL: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CATVariant: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- AlphaMissense: 90 out of 100
- phyloP: 80 out of 100
- CADD: 80 out of 100
- PolyPhen-2: 80 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- SIFT: 77 out of 100
Same protein, different disease
- Osteogenesis imperfecta is also caused by COL1A1 variants; they fall mostly in different places as the Phenylketonuria variants (239 disease-causing).
- Osteogenesis imperfecta, perinatal lethal is also caused by COL1A1 variants; they fall mostly in different places as the Phenylketonuria variants (52 disease-causing).
- Osteogenesis imperfecta with normal sclerae, dominant form is also caused by COL1A1 variants; they fall mostly in different places as the Phenylketonuria variants (34 disease-causing).
- Infantile cortical hyperostosis is also caused by COL1A1 variants; they fall mostly in different places as the Phenylketonuria variants (15 disease-causing).
- Ehlers-Danlos syndrome, arthrochalasia type is also caused by COL1A1 variants; they fall mostly in different places as the Phenylketonuria variants (10 disease-causing).
Diseases related to Phenylketonuria
- Osteogenesis imperfecta, also linked to COL1A1
- Ehlers-Danlos syndrome, classic type, 1, also linked to COL1A1
- Ehlers-Danlos syndrome, also linked to COL1A1
- Osteogenesis imperfecta, perinatal lethal, also linked to COL1A1
- Osteogenesis imperfecta with normal sclerae, dominant form, also linked to COL1A1
- Connective tissue disorder, also linked to COL1A1
- Ehlers-Danlos syndrome, arthrochalasia type, also linked to COL1A1
- Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2, also linked to COL1A1
- Infantile cortical hyperostosis, also linked to COL1A1
- Fetal anomalies with a likely genetic cause, also linked to COL1A1
- Osteoporosis, also linked to COL1A1
- Postmenopausal osteoporosis, also linked to COL1A1
Frequently asked questions
Which genes are linked to Phenylketonuria?
In CATVariant, Phenylketonuria is linked to 2 analyzed proteins: PAH (Phenylalanine-4-hydroxylase) and COL1A1 (Collagen alpha-1(I) chain).
How many genetic variants are linked to Phenylketonuria?
261 variants: 32 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 8 are of uncertain significance or have conflicting reports.
Which uncertain variants in Phenylketonuria look disease-causing?
5 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example PAH A313T, PAH A165P, PAH A246D, PAH A132T and PAH A259G. These are leads for expert review, not diagnoses.
Which variant effect predictor works best for Phenylketonuria?
Among tools not trained on clinical labels, AlphaMissense separates this disease's known disease-causing variants from harmless ones best (AUROC 0.90, based on 19 disease-causing and 85 harmless variants).
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.
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