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GeneE
10 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
β“˜GeneE is for informational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment.
ALDH4A1
aldehyde dehydrogenase 4 family member A1
Chromosome 1 Β· 1p36.13
NCBI Gene: 8659Ensembl: ENSG00000159423.18HGNC: HGNC:406UniProt: A0A024RAC7
54PubMed Papers
21Diseases
0Drugs
25Pathogenic Variants
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
L-glutamate gamma-semialdehyde dehydrogenase activityaldehyde dehydrogenase (NAD+) activityprotein bindingidentical protein bindinghyperprolinemia type 2Intellectual disabilityhyperprolinemiaspermatocele
✦AI Summary

ALDH4A1 (aldehyde dehydrogenase 4 family member A1) is a mitochondrial enzyme that catalyzes the irreversible conversion of delta-1-pyrroline-5-carboxylate (P5C) to glutamate, serving as a critical link between proline metabolism and the tricarboxylic acid cycle 1. Recent discoveries have revealed that ALDH4A1 functions beyond its enzymatic role as an essential structural component of the mitochondrial pyruvate carrier (MPC) complex, forming a trimeric complex with MPC1-MPC2 to maintain pyruvate mitochondrial import independently of its catalytic activity 2. The enzyme is highly conserved across species and exhibits tumor suppressor functions through its role in maintaining MPC complex integrity 2. ALDH4A1 has emerged as a significant biomarker in cardiovascular disease, where it serves as an autoantigen targeted by protective antibodies that can delay atherosclerotic plaque formation 3. Elevated circulating ALDH4A1 levels are associated with atherosclerosis and specifically correlate with plaque erosion phenotypes in ST-segment elevation myocardial infarction patients 4. Additionally, genetic variants in ALDH4A1 are linked to age-related muscle function decline, positioning it as a predictive biomarker for muscle health across species 5. These findings establish ALDH4A1 as a multifunctional protein with roles in metabolism, cardiovascular pathology, and aging.

Sources cited
1
ALDH4A1 catalyzes conversion of P5C to glutamate linking proline metabolism to TCA cycle
PMID: 28990412
2
ALDH4A1 functions as structural component of MPC complex maintaining pyruvate import and has tumor suppressor functions
PMID: 40355545
3
ALDH4A1 serves as atherosclerosis autoantigen targeted by protective antibodies
PMID: 33268892
4
Elevated ALDH4A1 levels correlate with plaque erosion in STEMI patients
PMID: 38109905
5
ALDH4A1 genetic variants are linked to age-related muscle function and serve as biomarker for muscle health
PMID: 35470798
Disease Associationsβ“˜21
hyperprolinemia type 2Open Targets
0.79Strong
Intellectual disabilityOpen Targets
0.50Moderate
hyperprolinemiaOpen Targets
0.41Moderate
spermatoceleOpen Targets
0.30Weak
SeizureOpen Targets
0.15Weak
Immunodeficiency by defective expression of HLA class 2Open Targets
0.12Weak
MHC class II deficiencyOpen Targets
0.12Weak
chronic lung diseaseOpen Targets
0.08Suggestive
HepatomegalyOpen Targets
0.07Suggestive
breast carcinomaOpen Targets
0.03Suggestive
schizophreniaOpen Targets
0.03Suggestive
Escherichia coli InfectionsOpen Targets
0.03Suggestive
clear cell renal carcinomaOpen Targets
0.03Suggestive
Abnormality of the integumentOpen Targets
0.02Suggestive
luminal A breast carcinomaOpen Targets
0.02Suggestive
atherosclerosisOpen Targets
0.02Suggestive
male reproductive organ cancerOpen Targets
0.02Suggestive
Meniere diseaseOpen Targets
0.02Suggestive
bipolar disorderOpen Targets
0.02Suggestive
neoplasmOpen Targets
0.01Suggestive
Hyperprolinemia 2UniProt
Pathogenic Variants25
NM_003748.4(ALDH4A1):c.21del (p.Leu8fs)Likely pathogenic
Hyperprolinemia type 2|not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 8
NM_003748.4(ALDH4A1):c.139C>T (p.Arg47Ter)Pathogenic
Hyperprolinemia type 2
β˜…β˜…β˜†β˜†2025β†’ Residue 47
NM_003748.4(ALDH4A1):c.1560dup (p.Gly521fs)Pathogenic
Hyperprolinemia type 2|not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 521
NM_003748.4(ALDH4A1):c.866+1G>APathogenic
Hyperprolinemia type 2|not provided
β˜…β˜…β˜†β˜†2025
NM_003748.4(ALDH4A1):c.200del (p.Val67fs)Pathogenic
Hyperprolinemia type 2
β˜…β˜†β˜†β˜†2026β†’ Residue 67
NM_003748.4(ALDH4A1):c.1461-2A>GLikely pathogenic
Hyperprolinemia type 2
β˜…β˜†β˜†β˜†2025
NM_003748.4(ALDH4A1):c.960_964del (p.His321fs)Pathogenic
Hyperprolinemia type 2
β˜…β˜†β˜†β˜†2024β†’ Residue 321
NM_003748.4(ALDH4A1):c.1152dup (p.Gly385fs)Likely pathogenic
Hyperprolinemia type 2
β˜…β˜†β˜†β˜†2024β†’ Residue 385
NM_003748.4(ALDH4A1):c.689_696dup (p.Lys233fs)Likely pathogenic
Hyperprolinemia type 2
β˜…β˜†β˜†β˜†2024β†’ Residue 233
NM_003748.4(ALDH4A1):c.451C>T (p.Gln151Ter)Pathogenic
Hyperprolinemia type 2
β˜…β˜†β˜†β˜†2024β†’ Residue 151
NM_003748.4(ALDH4A1):c.19_34dup (p.Leu12fs)Likely pathogenic
Hyperprolinemia type 2
β˜…β˜†β˜†β˜†2024β†’ Residue 12
NM_003748.4(ALDH4A1):c.1137delC (p.Pro380fs)Likely pathogenic
Hyperprolinemia type 2
β˜…β˜†β˜†β˜†2024β†’ Residue 380
NM_003748.4(ALDH4A1):c.1333A>T (p.Lys445Ter)Likely pathogenic
Hyperprolinemia type 2
β˜…β˜†β˜†β˜†2024β†’ Residue 445
NM_003748.4(ALDH4A1):c.250-2A>GLikely pathogenic
Hyperprolinemia type 2
β˜…β˜†β˜†β˜†2024
NM_003748.4(ALDH4A1):c.1580-2A>GLikely pathogenic
Hyperprolinemia type 2
β˜…β˜†β˜†β˜†2024
NM_003748.4(ALDH4A1):c.1057dup (p.Arg353fs)Likely pathogenic
Hyperprolinemia type 2
β˜…β˜†β˜†β˜†2024β†’ Residue 353
NM_003748.4(ALDH4A1):c.356del (p.Lys119fs)Likely pathogenic
Hyperprolinemia type 2
β˜…β˜†β˜†β˜†2024β†’ Residue 119
NM_003748.4(ALDH4A1):c.551dup (p.Pro185fs)Likely pathogenic
Hyperprolinemia type 2
β˜…β˜†β˜†β˜†2024β†’ Residue 185
NM_003748.4(ALDH4A1):c.453+1G>ALikely pathogenic
Hyperprolinemia type 2
β˜…β˜†β˜†β˜†2024
NM_003748.4(ALDH4A1):c.240C>G (p.Tyr80Ter)Likely pathogenic
Hyperprolinemia type 2
β˜…β˜†β˜†β˜†2023β†’ Residue 80
View on ClinVar β†—
Related Genes
PYCR2Protein interaction98%OATProtein interaction97%PYCR1Protein interaction97%ALDH18A1Protein interaction97%PYCR3Protein interaction97%GOT1L1Protein interaction96%
Tissue Expression6 tissues
Liver
100%
Heart
7%
Brain
5%
Bone Marrow
3%
Ovary
2%
Lung
1%
Gene Interaction Network
Click a node to explore
ALDH4A1PYCR2OATPYCR1ALDH18A1PYCR3GOT1L1
PROTEIN STRUCTURE
Preparing viewer…
PDB8RKR Β· 1.20 Γ… Β· X-ray
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
0.90LoF Tolerant
pLIβ“˜
0.00Tolerant
Observed/Expected LoF0.71 [0.56–0.90]
RankingsWhere ALDH4A1 stands among ~20K protein-coding genes
  • #8,277of 20,598
    Most Researched54
  • #1,985of 5,498
    Most Pathogenic Variants25
  • #8,166of 17,882
    Most Constrained (LOEUF)0.90
Genes detectedALDH4A1
Sources retrieved10 papers
Response timeβ€”
πŸ“„ Sources
10β–Ό
1
ALDH4A1 is an atherosclerosis auto-antigen targeted by protective antibodies.
PMID: 33268892
Nature Β· 2021
1.00
2
ALDH Enzymes and Hematological Diseases: A Scoping Review of Literature.
PMID: 39726306
Discov Med Β· 2024
0.90
3
Aldehyde dehydrogenases and cell proliferation.
PMID: 22206977
Free Radic Biol Med Β· 2012
0.80
4
ALDH4A1 functions as an active component of the MPC complex maintaining mitochondrial pyruvate import for TCA cycle entry and tumour suppression.
PMID: 40355545
Nat Cell Biol Β· 2025
0.70
5
Sequences, phylogeny and evolution of mitochondrial delta-1-pyrroline-5-carboxylate dehydrogenases (ALDH4A1). Evidence for a second locus (ALDH4A2) in Drosophila.
PMID: 37597643
Chem Biol Interact Β· 2023
0.60