ALAS2
protein-coding5'-aminolevulinate synthase 2
Gene summary
The product of this gene specifies an erythroid-specific mitochondrially located enzyme. The encoded protein catalyzes the first step in the heme biosynthetic pathway. Defects in this gene cause X-linked pyridoxine-responsive sideroblastic anemia. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]
- ASB
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~21.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0020721
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0020721
Submitter: Genomics England PanelApp
Inheritance Pattern: XL
Disease ID:MONDO:0020721
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010420
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010420
Submitter: Genomics England PanelApp
Inheritance Pattern: XL
Disease ID:MONDO:0010420
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0010420
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0020721
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010420
Submitter: ClinGen
The *ALAS2* gene was first reported in relation to X-linked erythropoietic protoporphyria in 2008, with the publication of eight affected families of diverse ancestries (PMID: 18760763). Affected individuals frequently present in early childhood with severe cutaneous photosensitivity and accumulation of protoporphyrin within erythrocytes, often with an elevated proportion of zinc-protoporphyrin. Decreased iron stores and abnormal transferrin saturation are observed in some patients, as are hyperbilirubinemia, elevated liver enzymes, and other signs of liver disease. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, the molecular mechanism (gain-of-function) and mode of inheritance (X-linked dominant) were found to be distinct from patients with X-linked sideroblastic anemia 1, who instead harbor loss-of-function variants in *ALAS2* and exhibit a stronger male predominance among affected patients. The phenotypic differences between the two groups of cases appear to represent separate disease entities rather than a spectrum of disease. Therefore, cases caused by inherited *ALAS2* variants have been split into two separately-curated disease entities, referred to as X-linked erythropoietic protoporphyria (MONDO:0010420, MIM #300752), and X-linked sideroblastic anemia 1 (MONDO:0020721, MIM #300751). Five suspected pathogenic variants have been scored as part of this curation (three frameshift and two nonsense), which have been collectively reported in thirteen probands in three publications (PMID: 18760763, PMID: 23263862, PMID: 23364466). All thirteen probands were heterozygous for their respective variants. Segregation evidence was available in one of these publications (PMID: 18760763) and has contributed to the scoring of the gene-disease relationship. This gene-disease relationship has not been studied in case-control studies at the single variant level or aggregate variant level. The mechanism of pathogenicity appears to be monoallelic gain-of-function, caused by frameshift or nonsense variants in the final exon (11) of *ALAS2* that trigger disruption of the C-terminal autoinhibitory loop (PMID: 23263862). All probands in this curation harbored one variant allele within the *ALAS2* locus. This gene-disease association is also supported by experimental evidence, as *ALAS2* encodes an enzyme responsible for synthesis of 5-aminolevulinic acid, a critical step in the protoporphyrin biosynthesis, heme biosynthesis, and cellular iron homeostasis pathways (PMID: 2347585, PMID: 26300302). *ALAS2* expression is highly restricted to blood cells (PMID: 23715323) and erythrocytes specifically (PMID: 2347585). Elevated *ALAS2* expression also occurs in the erythrocytes of patients with protoporphyria caused by loss-of-function variants in the *FECH* gene (PMID: 25179834). Finally, transgenic mice overexpressing Alas2 show related symptoms characterized as porphyria (PMID: 33785075). In summary, *ALAS2* is definitively associated with X-linked erythropoietic protoporphyria. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a Definitive classification. This classification was approved by the ClinGen General Inborn Errors of Metabolism Gene Curation Expert Panel on March 11th, 2022 (SOP Version 8).
Clinical Genomic Database (CGD)
Manifestation: Dermatologic; Gastrointestinal; Hematologic
Intervention: Dermatologic; Gastrointestinal; Hematologic
Rationale: In X-linked sideroblastic anemia, phlebotomy can be effective to prevent the development of complications such as cardiovascular and liver damage, as well as diabetes, and is typically most effective in individuals who are pyridoxine-responsive; In Erythropoietic protoporphyria, sunlight protection (and possibly beta-carotene and alpha-melanocyte treatments, as well as more specific molecular modalities) may be beneficial, as well as medical treatment of hepatic manifestations (eg, with cholestyramine, plasmapharesis and IV hemin), though liver transplantations may be necessary, while BMT has been reported as effective
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ALAS2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000032.5. 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 | 13 | 65 | 6 | 84 | ||
| missense | 24 | 17 | 132 | 36 | 209 | |
| nonsense | 2 | 1 | 2 | 5 | ||
| start loss | 0 | |||||
| frameshift | 2 | 5 | 2 | 9 | ||
| splice donor/acceptor (+/-2bp) | 3 | 7 | 10 | |||
| Total | 28 | 26 | 156 | 101 | 6 | 317 |
Highest pathogenic variant AF is 0.000010930126
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000023.2 | 10 | MANE Select | |
| Ensembl | ENSP00000497236.1 | 10 | MANE Select | |
| RefSeq | NP_001033056.1 | 9 | Standard | |
| RefSeq | NP_001033057.1 | 10 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| alas2 | Danio rerio | Structure: nucleate erythrocyte Quality: decreased amount abnormal |
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)
- Heme Biosynthesis
- hemoglobins chaperone
- Heme biosynthesis
Biological Process
- response to hypoxia
- protoporphyrinogen IX biosynthetic process
- heme biosynthetic process
- cellular iron ion homeostasis
- erythrocyte differentiation
Molecular Function
- 5-aminolevulinate synthase activity
- protein binding
- glycine binding
- pyridoxal phosphate binding
- coenzyme binding
Cellular Component
- mitochondrion
- mitochondrial inner membrane
- mitochondrial matrix
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000330807
- Coding exons
- 10
- Length
- 22010
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.37 | 131 | 233 | 0.563 | 0.0000182 | 3841 |
| Missense (PolyPhen) | 28 | 98.899 | 0.28312 | 1577 | ||
| Synonymous | -0.815 | 94 | 84.5 | 1.11 | 0.00000603 | 1175 |
| Loss of Function | 3.73 | 0 | 16.2 | 0.00 | 0.00000116 | 277 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Disease
- DISEASE: Erythropoietic protoporphyria, X-linked dominant (XLDPT) [MIM:300752]: A form of porphyria. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. XLDPT is characterized biochemically by a high proportion of zinc-protoporphyrin in erythrocytes, in which a mismatch between protoporphyrin production and the heme requirement of differentiating erythroid cells leads to overproduction of protoporphyrin in amounts sufficient to cause photosensitivity and liver disease. {ECO:0000269|PubMed:18760763}. Note=The disease is caused by mutations affecting the gene represented in this entry. Gain of function mutations in ALS2 are responsible for XLDPT, but they can also be a possible aggravating factor in congenital erythropoietic porphyria and other erythropoietic disorders caused by mutations in other genes (PubMed:21309041). {ECO:0000269|PubMed:21309041}.;
Recessive Scores
- pRec
- 0.453
Intolerance Scores
- RVIS EVS
- 0.13
- RVIS percentile EVS
- 63.36
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.666
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |