ALAS1
protein-coding5'-aminolevulinate synthase 1
Gene summary
This gene encodes the mitochondrial enzyme which is catalyzes the rate-limiting step in heme (iron-protoporphyrin) biosynthesis. The enzyme encoded by this gene is the housekeeping enzyme; a separate gene encodes a form of the enzyme that is specific for erythroid tissue. The level of the mature encoded protein is regulated by heme: high levels of heme down-regulate the mature enzyme in mitochondria while low heme levels up-regulate. A pseudogene of this gene is located on chromosome 12. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2015]
- ALAS3
- ALAS
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~16.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ALAS1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000688.6. 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 | 1 | 1 | ||||
| missense | 75 | 2 | 1 | 78 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 3 | 3 | ||||
| Total | 0 | 0 | 80 | 2 | 1 | 83 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000679.1 | 10 | MANE Select | |
| Ensembl | ENSP00000418779.1 | 10 | MANE Select | |
| RefSeq | NP_001291372.1 | 10 | Standard | |
| RefSeq | NP_001291373.1 | 11 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Glycine, serine and threonine metabolism - Homo sapiens (human)
- Porphyrin and chlorophyll metabolism - Homo sapiens (human)
- 3-Phosphoglycerate dehydrogenase deficiency
- Non Ketotic Hyperglycinemia
- Glycine and Serine Metabolism
Biological Process
- protoporphyrinogen IX biosynthetic process
- heme biosynthetic process
- mitochondrion organization
- regulation of lipid metabolic process
Molecular Function
- 5-aminolevulinate synthase activity
- protein binding
- pyridoxal phosphate binding
- identical protein binding
Cellular Component
- nucleoplasm
- mitochondrion
- mitochondrial matrix
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000394965
- Coding exons
- 10
- Length
- 16242
- Individuals with no LoFs
- 125684
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 64
- Defined
- 125748
- p
- 0.000255
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.19 | 310 | 375 | 0.828 | 0.0000213 | 4201 |
| Missense (PolyPhen) | 128 | 186.23 | 0.68732 | 2007 | ||
| Synonymous | -0.889 | 151 | 138 | 1.10 | 0.00000728 | 1281 |
| Loss of Function | 3.55 | 7 | 26.8 | 0.261 | 0.00000150 | 302 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.00038 | 0.00038 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00055 | 0.00054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00030 | 0.00029 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
Recessive Scores
- pRec
- 0.449
Intolerance Scores
- LoFtool
- 0.0429
- RVIS EVS
- -0.11
- RVIS percentile EVS
- 45.49
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.908
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |