ALDH6A1
protein-codingaldehyde dehydrogenase 6 family member A1, the group of Aldehyde dehydrogenases
Gene summary
This gene encodes a member of the aldehyde dehydrogenase protein family. The encoded protein is a mitochondrial methylmalonate semialdehyde dehydrogenase that plays a role in the valine and pyrimidine catabolic pathways. This protein catalyzes the irreversible oxidative decarboxylation of malonate and methylmalonate semialdehydes to acetyl- and propionyl-CoA. Methylmalonate semialdehyde dehydrogenase deficiency is characterized by elevated beta-alanine, 3-hydroxypropionic acid, and both isomers of 3-amino and 3-hydroxyisobutyric acids in urine organic acids. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jun 2013]
- MMSDH
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~27.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013579
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0013579
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0013579
Submitter: ClinGen
ALDH6A1 was first reported in relation to autosomal recessive methylmalonate semialdehyde dehydrogenase deficiency in 2000 (Chambliss et al., PMID: 10947204). At least six unique missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes both case-level data and experimental data. Variants in this gene have been reported in at least 5 probands in 4 publications (PMIDs: 10947204, 21863277, 23835272, 32151545). No supporting segregation information is available. The disease mechanism appears to be biallelic loss-of-function, with a deficiency in the MMSDH protein leading to an increase in valine metabolites such as 3-hydroxyisobutyric acid and potentially the phenotypes seen in conjunction with the biochemical abnormality. This gene-disease relationship is supported by the biochemical function of methylmalonate semialdehyde dehydrogenase, which is consistent with the finding of persistently elevated 3-hydroxypropionate, 3-hydroxyisobutyrate, and β-aminoisobutyrate levels in patients with this condition (PMIDs: 3939535, 10971205, 32151545) In summary, there is limited evidence to support this gene-disease relationship. There is the question of whether the additional symptoms of some individuals are related to this disorder, although that is unrelated to the biochemical abnormality and the response to modified diet seems to indicate a connection. Although more evidence, genetic and experimental, is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Aminoacidopathy Working Group on 09/27/2019 (SOP Version 7). It was reevaluated on 10/14/2022 and 12/16/2025 with no new evidence found. As a result of these reevaluations, the classification remained Limited.
Inheritance Pattern: AR
Disease ID:MONDO:0013579
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013579
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Biochemical
Intervention: Biochemical
Rationale: Dietary management (eg, with low-protein, valine restricted diet) has been reported as beneficial
Comments: Some individuals have been reported as asymptomatic
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ALDH6A1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005589.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 3 | 26 | 1 | 30 | ||
| missense | 6 | 68 | 6 | 1 | 81 | |
| nonsense | 2 | 1 | 3 | |||
| start loss | 1 | 1 | ||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 4 | 4 | ||||
| Total | 6 | 3 | 77 | 32 | 2 | 120 |
Highest pathogenic variant AF is 0.000046047793
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005580.1 | 12 | MANE Select | |
| Ensembl | ENSP00000450436.1 | 12 | MANE Select | |
| RefSeq | NP_001265522.1 | 12 | Standard | |
| RefSeq | NP_001265523.1 | 7 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Inositol phosphate metabolism - Homo sapiens (human)
- beta-Alanine metabolism - Homo sapiens (human)
- Propanoate metabolism - Homo sapiens (human)
- Valine, leucine and isoleucine degradation - Homo sapiens (human)
- Carnosinuria, carnosinemia
Biological Process
- thymine catabolic process
- valine metabolic process
- valine catabolic process
- branched-chain amino acid catabolic process
- thymine metabolic process
Molecular Function
- fatty-acyl-CoA binding
- RNA binding
- methylmalonate-semialdehyde dehydrogenase (acylating) activity
- malonate-semialdehyde dehydrogenase (acetylating) activity
Cellular Component
- nucleoplasm
- mitochondrion
- mitochondrial matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000553458
- Coding exons
- 12
- Length
- 27644
- Individuals with no LoFs
- 125688
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 59
- Defined
- 125747
- p
- 0.000235
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.04 | 242 | 292 | 0.828 | 0.0000149 | 3474 |
| Missense (PolyPhen) | 114 | 142.76 | 0.79856 | 1698 | ||
| Synonymous | 1.28 | 87 | 104 | 0.839 | 0.00000505 | 1080 |
| Loss of Function | 1.79 | 19 | 29.5 | 0.644 | 0.00000184 | 315 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00031 | 0.00031 | rare |
| Latino/Admixed American | 0.00023 | 0.00023 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00060 | 0.00060 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00019 | 0.00018 | rare |
| South Asian | 0.00033 | 0.00033 | rare |
| Other | 0.00065 | 0.00065 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Plays a role in valine and pyrimidine metabolism. Binds fatty acyl-CoA.;
- Disease
- DISEASE: Methylmalonate semialdehyde dehydrogenase deficiency (MMSDHD) [MIM:614105]: A metabolic disorder characterized by elevated beta-alanine, 3-hydroxypropionic acid, and both isomers of 3-amino and 3-hydroxyisobutyric acids in urine organic acids. {ECO:0000269|PubMed:10947204}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.217
Intolerance Scores
- LoFtool
- 0.494
- RVIS EVS
- -0.4
- RVIS percentile EVS
- 26.73
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.915
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |