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ALDH4A1

aldehyde dehydrogenase 4 family member A1

The ALDH4A1 gene provides instructions for an enzyme crucial in the breakdown of proline, an amino acid, and is associated with hyperprolinemia type II. ALDH4A1 encodes pyrroline-5-carboxylate dehydrogenase, an enzyme functioning within mitochondria to process the amino acid proline.

Chromosome 1p36.13 HGNC:406 Tier C
ALDH4A1 1p36.13 p arm q arm 1

ALDH4A1 is located on the short (p) arm of chromosome 1, at band 1p36.13. Arm ratio per GRCh38 - banding schematic.

Explore chromosome 1 in the library →

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Clinical tests that include this

Carrier Screening panel
ALDH4A1 is 1 of 1,008 genes on this panel
Expanded carrier screening for recessive and X-linked conditions

Overview

The ALDH4A1 gene, or aldehyde dehydrogenase 4 family member A1, is integral to the body's metabolic processes. It directs the production of an enzyme called pyrroline-5-carboxylate dehydrogenase, which is found in mitochondria across various tissues. This enzyme plays a key role in breaking down the amino acid proline, converting it into another amino acid, glutamate.

What the gene does

The ALDH4A1 gene encodes the enzyme pyrroline-5-carboxylate dehydrogenase. This enzyme is localised in the mitochondria, which are the energy-producing structures within cells. Its primary function is to catalyse the second step in the catabolism (breakdown) of the amino acid proline. Specifically, it converts pyrroline-5-carboxylate, an intermediate product, into glutamate. This conversion pathway from proline to glutamate is vital for maintaining appropriate amino acid supplies required for protein synthesis and for energy transfer processes within cells. Disruptions in this enzyme's function can lead to impaired proline metabolism.

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Chromosome location

The ALDH4A1 gene is situated on chromosome 1, specifically at position 1p36.13. This precise location specifies where the gene resides on the short arm of chromosome 1, a large chromosome that contains many genes essential for human health.

Protein structure

The ALDH4A1 gene produces a protein that is 563 amino acids in length. Domain architecture has not been experimentally characterised in detail for this protein.

Key variants

Genetic variations within the ALDH4A1 gene can alter the function or production of the pyrroline-5-carboxylate dehydrogenase enzyme. These variants range from single nucleotide changes to larger alterations that may impact the gene's ability to produce a functional protein. Such changes can lead to an accumulation of proline in the body.

The table below shows the top 8 pathogenic or likely-pathogenic variants currently classified in ClinVar for ALDH4A1.
View all on ClinVar →

Sample of pathogenic variants

8 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.

Variant (HGVS) Protein change Classification Evidence Associated condition
c.139C>T
single nucleotide variant
 p.Arg47Ter Pathogenic/Likely pathogenic ★★☆☆ Hyperprolinemia type 2
c.1560dup
Duplication
 p.Gly521fs Pathogenic/Likely pathogenic ★★☆☆ Hyperprolinemia type 2
c.866+1G>A
single nucleotide variant
 - Pathogenic/Likely pathogenic ★★☆☆ Hyperprolinemia type 2
g.(?_19199339)_(19201095_?)del
Deletion
 - Pathogenic ★☆☆☆ Hyperprolinemia type 2
c.200del
Deletion
 p.Val67fs Pathogenic ★☆☆☆ Hyperprolinemia type 2
c.451C>T
single nucleotide variant
 p.Gln151Ter Pathogenic ★☆☆☆ Hyperprolinemia type 2
c.72del
Deletion
 p.Arg23_Trp24insTer Pathogenic ★☆☆☆ Hyperprolinemia type 2
c.960_964del
Deletion
 p.His321fs Pathogenic ★☆☆☆ Hyperprolinemia type 2

Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.

Associated conditions

Variants in the ALDH4A1 gene are primarily associated with hyperprolinemia type II. This condition is characterised by elevated levels of proline in the blood, often leading to neurological symptoms such as seizures or intellectual disability. It is generally considered the more severe form of hyperprolinemia.

No disease links recorded for this gene in our reference set.

UK clinical status

ALDH4A1 is listed on several NHS Genomic Medicine Service national test directories, indicating its clinical relevance in the UK. It is included on the Developmental Disorders Gene Panel (DDG2P), Intellectual disability panel, Likely inborn error of metabolism panel (R98), and Undiagnosed metabolic disorders panel.

Green-listed
High evidence · clinically actionable in NHS testing
Included in NHS GMS signed-off panels
Likely inborn error of metabolism · R98 NHS GMS → DDG2P NHS GMS → Intellectual disability NHS GMS →
NHS Genomic Medicine Service Jeen carrier screening

Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory

Frequently asked questions

What is the main function of the ALDH4A1 gene?

The ALDH4A1 gene provides instructions for creating an enzyme called pyrroline-5-carboxylate dehydrogenase, which is responsible for breaking down the amino acid proline into glutamate within the mitochondria.

What condition is associated with ALDH4A1 gene variants?

Variants in the ALDH4A1 gene are linked to hyperprolinemia type II, a metabolic disorder characterised by excessive levels of proline in the blood, which can lead to neurological issues.

Where is the ALDH4A1 gene located?

The ALDH4A1 gene is located on chromosome 1, specifically at the position 1p36.13.

References

  1. Inagaki E, Ohshima N, Takahashi H. Crystal structure of Thermus thermophilus Delta1-pyrroline-5-carboxylate dehydrogenase. Journal of molecular biology. 2006. PMID: 16934832
  2. Sophos NA, Vasiliou V. Aldehyde dehydrogenase gene superfamily: the 2002 update. Chemico-biological interactions. 2003. PMID: 12604184
  3. Vasiliou V, Pappa A. Polymorphisms of human aldehyde dehydrogenases. Consequences for drug metabolism and disease. Pharmacology. 2000. PMID: 10971205
  4. Vasiliou V, Bairoch A, Tipton KF. Eukaryotic aldehyde dehydrogenase (ALDH) genes: human polymorphisms, and recommended nomenclature based on divergent evolution and chromosomal mapping. Pharmacogenetics. 1999. PMID: 10780262
  5. Yoshida A, Rzhetsky A, Hsu LC. Human aldehyde dehydrogenase gene family. European journal of biochemistry. 1998. PMID: 9490025
  6. Geraghty MT, Vaughn D, Nicholson AJ. Mutations in the Delta1-pyrroline 5-carboxylate dehydrogenase gene cause type II hyperprolinemia. Human molecular genetics. 1998. PMID: 9700195
  7. Hu CA, Lin WW, Valle D. Cloning, characterization, and expression of cDNAs encoding human delta 1-pyrroline-5-carboxylate dehydrogenase. The Journal of biological chemistry. 1996. PMID: 8621661
Educational content. This page is not medical or genetic advice, is not individually reviewed by a clinician for each reader, and should not replace a consultation with a qualified healthcare professional or genetic counsellor. If you are considering genetic testing or acting on a test result, book a consultation.
Data sources Last updated 30 August 2026. Content compiled from HGNC · MedlinePlus Genetics · ClinGen · Genomics England PanelApp · NHS National Genomic Test Directory · ClinVar · UniProt · AlphaFold .