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GeneE
10 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
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ALAS2
5'-aminolevulinate synthase 2
Chromosome X Β· Xp11.21
NCBI Gene: 212Ensembl: ENSG00000158578.22HGNC: HGNC:397UniProt: P22557
77PubMed Papers
22Diseases
0Drugs
50Pathogenic Variants
FUNCTIONAL ROLE
Highly Constrained
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
protein bindingheme B biosynthetic processmitochondrial inner membranemitochondrionX-linked sideroblastic anemia 1X-linked erythropoietic protoporphyriagenetic disorderdiabetes mellitus
✦AI Summary

ALAS2 (5'-aminolevulinate synthase 2) is the erythroid-specific isoform of aminolevulinic acid synthase that catalyzes the first and rate-limiting step of heme biosynthesis in red blood cells. The enzyme performs pyridoxal 5'-phosphate (PLP)-dependent condensation of succinyl-CoA and glycine to form aminolevulinic acid (ALA), producing CoA and CO2 as by-products 1. ALAS2 exhibits 65-75% of the catalytic activity compared to the housekeeping ALAS1 isoform and localizes to the mitochondrial matrix 1. The enzyme plays a critical role in erythropoiesis and hemoglobin biosynthesis, making it essential for red blood cell development and maturation 2. ALAS2 dysfunction leads to two distinct X-linked blood disorders: loss-of-function mutations cause X-linked sideroblastic anemia characterized by ring sideroblast formation and impaired heme synthesis 34, while gain-of-function mutations result in X-linked dominant erythropoietic protoporphyria due to excess protoporphyrin accumulation 35. The gene serves as a biomarker for blood identification in forensic applications and shows upregulation during high-altitude acclimatization, reflecting increased erythropoiesis in hypoxic conditions 62. Clinical management focuses on monitoring hematological parameters and preventing disease progression.

Sources cited
1
ALAS2 catalyzes PLP-dependent condensation of succinyl-CoA and glycine to form ALA with 65-75% activity of ALAS1
PMID: 38888931
2
ALAS2 mutations cause X-linked sideroblastic anemia and gain-of-function mutations cause X-linked dominant EPP
PMID: 31326287
3
X-linked sideroblastic anemia is the predominant type of congenital SA caused by ALAS2 mutations
PMID: 39358290
4
Gain-of-function ALAS2 mutations cause X-linked dominant protoporphyria in about 2% of EPP patients
PMID: 19744342
5
ALAS2 serves as an erythroid-specific gene for blood identification in forensic applications
PMID: 17868268
6
ALAS2 is a key gene upregulated during high-altitude acclimatization and plays critical role in heme biosynthesis
PMID: 39202434
Disease Associationsβ“˜22
X-linked sideroblastic anemia 1Open Targets
0.83Strong
X-linked erythropoietic protoporphyriaOpen Targets
0.76Strong
genetic disorderOpen Targets
0.19Weak
diabetes mellitusOpen Targets
0.14Weak
androgenetic alopeciaOpen Targets
0.06Suggestive
Blackfan-Diamond anemiaOpen Targets
0.06Suggestive
Adult-onset autosomal recessive sideroblastic anemiaOpen Targets
0.06Suggestive
necrotizing enterocolitisOpen Targets
0.06Suggestive
acute erythroleukemiaOpen Targets
0.05Suggestive
severe congenital hypochromic anemia with ringed sideroblastsOpen Targets
0.05Suggestive
IRIDA syndromeOpen Targets
0.05Suggestive
Hemolytic anemia due to red cell pyruvate kinase deficiencyOpen Targets
0.05Suggestive
myelodysplastic syndrome associated with isolated del(5q)Open Targets
0.05Suggestive
microcytic anemia with liver iron overloadOpen Targets
0.05Suggestive
hemoglobin D diseaseOpen Targets
0.05Suggestive
FTH1-related iron overloadOpen Targets
0.05Suggestive
hemochromatosis type 5Open Targets
0.05Suggestive
refractory anemia with ringed sideroblastsOpen Targets
0.04Suggestive
autosomal dominant sideroblastic anemiaOpen Targets
0.04Suggestive
Constitutional sideroblastic anemiaOpen Targets
0.04Suggestive
Anemia, sideroblastic, 1UniProt
Erythropoietic protoporphyria, X-linked dominantUniProt
Pathogenic Variants50
NM_000032.5(ALAS2):c.1354C>T (p.Arg452Cys)Pathogenic
X-linked sideroblastic anemia 1|not provided|ALAS2-related disorder
β˜…β˜…β˜†β˜†2026β†’ Residue 452
NM_000032.5(ALAS2):c.1706_1709del (p.Glu569fs)Pathogenic
X-linked erythropoietic protoporphyria|not provided|See cases
β˜…β˜…β˜†β˜†2026β†’ Residue 569
NM_000032.5(ALAS2):c.1354C>A (p.Arg452Ser)Pathogenic
not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 452
NM_000032.5(ALAS2):c.-15-2187T>CPathogenic
X-linked sideroblastic anemia 1|not provided
β˜…β˜…β˜†β˜†2025
NM_000032.5(ALAS2):c.1355G>A (p.Arg452His)Pathogenic
not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 452
NM_000032.5(ALAS2):c.508C>T (p.Arg170Cys)Pathogenic
not provided
β˜…β˜…β˜†β˜†2024β†’ Residue 170
NM_000032.5(ALAS2):c.1231C>T (p.Arg411Cys)Pathogenic
X-linked sideroblastic anemia 1|not provided
β˜…β˜…β˜†β˜†2024β†’ Residue 411
NM_000032.5(ALAS2):c.1342C>G (p.Arg448Gly)Likely pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 448
NM_000032.5(ALAS2):c.1123C>T (p.Arg375Cys)Pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 375
NM_000032.5(ALAS2):c.1618_1630del (p.Trp540fs)Likely pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 540
NM_000032.5(ALAS2):c.611G>A (p.Arg204Gln)Pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 204
NM_000032.5(ALAS2):c.509G>T (p.Arg170Leu)Pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 170
NM_000032.5(ALAS2):c.1513A>G (p.Asn505Asp)Likely pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 505
NM_000032.5(ALAS2):c.1584del (p.Met528fs)Likely pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 528
NM_000032.5(ALAS2):c.1762T>C (p.Ter588Arg)Likely pathogenic
X-linked sideroblastic anemia 1
β˜…β˜†β˜†β˜†2024β†’ Residue 588
NM_000032.5(ALAS2):c.1115T>C (p.Ile372Thr)Likely pathogenic
X-linked sideroblastic anemia 1
β˜…β˜†β˜†β˜†2024β†’ Residue 372
NM_000032.5(ALAS2):c.1343G>A (p.Arg448Gln)Likely pathogenic
not provided
β˜…β˜†β˜†β˜†2024β†’ Residue 448
NM_000032.5(ALAS2):c.902T>C (p.Val301Ala)Pathogenic
not provided
β˜…β˜†β˜†β˜†2024β†’ Residue 301
NM_000032.5(ALAS2):c.606G>A (p.Met202Ile)Pathogenic
not provided
β˜…β˜†β˜†β˜†2023β†’ Residue 202
NM_000032.5(ALAS2):c.304+2T>ALikely pathogenic
X-linked sideroblastic anemia 1
β˜…β˜†β˜†β˜†2023
View on ClinVar β†—
Related Genes
GYPAProtein interaction100%GATA1Protein interaction100%GYPBProtein interaction100%HBDProtein interaction99%GLDCProtein interaction97%SARDHProtein interaction97%
Tissue Expression6 tissues
Bone Marrow
100%
Lung
1%
Liver
0%
Brain
0%
Ovary
0%
Heart
0%
Gene Interaction Network
Click a node to explore
ALAS2GYPAGATA1GYPBHBDGLDCSARDH
PROTEIN STRUCTURE
Preparing viewer…
PDB5QR1 Β· 1.44 Γ… Β· X-ray
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
0.23Highly Constrained
pLIβ“˜
1.00Intolerant
Observed/Expected LoF0.09 [0.04–0.23]
RankingsWhere ALAS2 stands among ~20K protein-coding genes
  • #6,131of 20,598
    Most Researched77
  • #1,338of 5,498
    Most Pathogenic Variants50 Β· top quartile
  • #639of 17,882
    Most Constrained (LOEUF)0.23 Β· top 5%
Genes detectedALAS2
Sources retrieved10 papers
Response timeβ€”
πŸ“„ Sources
10β–Ό
1
Heme biosynthesis and the porphyrias.
PMID: 31326287
Mol Genet Metab Β· 2019
1.00
2
mRNA profiling for body fluid identification by multiplex quantitative RT-PCR.
PMID: 17868268
J Forensic Sci Β· 2007
0.90
3
Erythropoietic protoporphyria.
PMID: 19744342
Orphanet J Rare Dis Β· 2009
0.80
4
Exploring the mechanistic link between SF3B1 mutation and ring sideroblast formation in myelodysplastic syndrome.
PMID: 36028755
Sci Rep Β· 2022
0.70
5
Noncanonical role of ALAS1 as a heme-independent inhibitor of small RNA-mediated silencing.
PMID: 39700288
Science Β· 2024
0.60