ALAS2

Summary

ALAS2 (5’-aminolevulinate synthase 2, HGNC:397) is a protein-coding gene on chromosome Xp11.21, encoding 5-aminolevulinate synthase, erythroid-specific, mitochondrial (P22557). Catalyzes the pyridoxal 5’-phosphate (PLP)-dependent condensation of succinyl-CoA and glycine to form aminolevulinic acid (ALA), with CoA and CO2 as by-products.

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.

Source: NCBI Gene 212 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked erythropoietic protoporphyria (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 7
• Clinical variants (ClinVar): 414 total — 37 pathogenic, 18 likely-pathogenic
• Phenotypes (HPO): 23
• MANE Select transcript: NM_000032

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:397
Approved symbol	ALAS2
Name	5’-aminolevulinate synthase 2
Location	Xp11.21
Locus type	gene with protein product
Status	Approved
Aliases	ALAS-E
Ensembl gene	ENSG00000158578
Ensembl biotype	protein_coding
OMIM	301300
Entrez	212

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 9 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000335854, ENST00000396198, ENST00000455688, ENST00000463868, ENST00000477869, ENST00000493869, ENST00000498636, ENST00000644983, ENST00000650242, ENST00000886484

RefSeq mRNA: 3 — MANE Select: NM_000032 NM_000032, NM_001037967, NM_001037968

CCDS: CCDS14366, CCDS35303, CCDS43960

Canonical transcript exons

ENST00000650242 — 11 exons

Exon	Start	End
ENSE00001138097	55023757	55023867
ENSE00001700658	55013486	55013648
ENSE00001899039	55009055	55009343
ENSE00003460964	55020320	55020504
ENSE00003469529	55017486	55017665
ENSE00003472872	55015578	55015742
ENSE00003474411	55025820	55026015
ENSE00003493273	55030942	55030977
ENSE00003508089	55014747	55015015
ENSE00003611789	55021052	55021274
ENSE00003676814	55024718	55024840

Expression profiles

Bgee: expression breadth ubiquitous, 172 present calls, max score 99.23.

FANTOM5 (CAGE): breadth broad, TPM avg 29.8065 / max 9757.0964, expressed in 273 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199409	29.8065	273

Top tissues by expression

284 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
trabecular bone tissue	UBERON:0002483	99.23	gold quality
bone marrow	UBERON:0002371	98.20	gold quality
bone marrow cell	CL:0002092	98.08	gold quality
blood	UBERON:0000178	97.61	gold quality
mononuclear cell	CL:0000842	96.55	gold quality
monocyte	CL:0000576	96.53	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	93.46	gold quality
leukocyte	CL:0000738	92.56	gold quality
adrenal tissue	UBERON:0018303	85.69	gold quality
placenta	UBERON:0001987	77.02	gold quality
ganglionic eminence	UBERON:0004023	76.44	gold quality
embryo	UBERON:0000922	75.19	gold quality
spleen	UBERON:0002106	73.68	gold quality
colonic epithelium	UBERON:0000397	71.50	gold quality
apex of heart	UBERON:0002098	71.31	gold quality
amniotic fluid	UBERON:0000173	69.85	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	69.53	gold quality
triceps brachii	UBERON:0001509	68.67	gold quality
decidua	UBERON:0002450	68.23	silver quality
periodontal ligament	UBERON:0008266	67.74	silver quality
diaphragm	UBERON:0001103	67.66	gold quality
gluteal muscle	UBERON:0002000	67.56	gold quality
ventricular zone	UBERON:0003053	67.44	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	66.68	gold quality
germinal epithelium of ovary	UBERON:0001304	66.00	silver quality
hindlimb stylopod muscle	UBERON:0004252	65.12	gold quality
cortical plate	UBERON:0005343	64.99	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	64.89	gold quality
right lung	UBERON:0002167	64.67	gold quality
right lobe of liver	UBERON:0001114	62.77	gold quality

Single-cell (SCXA)

Detected in 18 experiment(s), a significant marker in 17.

Experiment	Marker?	Max mean expression
E-GEOD-150728	yes	6512.68
E-CURD-122	yes	4016.50
E-MTAB-9388	yes	2910.39
E-GEOD-130473	yes	2610.61
E-GEOD-149689	yes	1996.75
E-MTAB-9221	yes	1974.90
E-MTAB-8205	yes	1622.76
E-MTAB-9067	yes	1604.79
E-CURD-112	yes	1321.29
E-HCAD-15	yes	1315.66
E-HCAD-9	yes	1140.70
E-MTAB-9467	yes	1113.52
E-HCAD-4	yes	1112.88
E-HCAD-10	yes	718.21
E-ANND-5	yes	695.34

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CREB1, FOS, FOXA2, FOXC1, FOXM1, GATA1, HIF1A, JUN, JUND, KAT7, NFE2, NRF1, RFX2, SP1

miRNA regulators (miRDB)

7 targeting ALAS2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-711	96.60	65.75	528
HSA-MIR-7706	95.96	63.68	172

Literature-anchored findings (GeneRIF, showing 40)

• A novel mutation in exon 5 of the ALAS2 gene results in X-linked sideroblastic anemia. (PMID:12031592)
• A C to G transversion at nucleotide -206 from the transcription start site was found in the proximal promoter region of ALAS2 in X-linked sideroblastic anemia. The region of the mutation may bind a novel and important erythroid regulatory element. (PMID:12663458)
• the major splice isoform of ALAS2 is functional in vivo and could significantly contribute to erythroid heme biosynthesis and hemoglobin formation (PMID:14643893)
• there is nucleotide variation at Msn and Alas2 on the X chromosome (PMID:15166166)
• sequence identity of ALAS from Rhodobacter capsulatus and human eALAS is 49% (PMID:16121195)
• ALAS2 mutations might contribute to more severe iron loading in persons with primary hemochromatosis. (PMID:16446107)
• upon the NaBu stimulation, binding of Sp1 protein to ALAS2 promoter increased significantly, with concurrent increases in acetylation level of histone H3 and dimethylation level of H3-Lysine4 at ALAS2 promoter (PMID:18555711)
• An impact of ALAD2 on blood lead levels or hemoglobin was not seen in Romanian women from a lead-contaminated region. (PMID:18569569)
• gain-of-function mutations in ALAS2 cause a previously unrecognized form of porphyria, X-linked dominant protoporphyria, characterized biochemically by a high proportion of zinc-protoporphyrin in erythrocytes (PMID:18760763)
• Multi-organ iron overload in an African-American man with ALAS2 R452S and SLC40A1 R561G. (PMID:19066423)
• Hypoxia induces erythroid-specific 5-aminolevulinate synthase expression in human erythroid cells through transforming growth factor-beta signaling. (PMID:19187226)
• Seven ALAS2 mutations were detected in eight sporadic CSA cases, two being novel: V301A in a male patient and R517G in a female patient (PMID:19731322)
• About 4% of unrelated EPP patients have X-linked dominant protoporphyria (MIM 300752) caused by gain-of-function mutations in the ALAS2 gene leading to an increased erythroid heme biosynthesis & protoporphyrin accumulation. Review. (PMID:20850938)
• HIF1-mediated ALAS2 upregulation promotes erythropoiesis to satisfy the needs of an organism under hypoxic conditions. (PMID:21207956)
• We found the previously published R452H and R452C ALAS2 mutations in 3 patients with X-linked sideroblastic anemia (PMID:21252495)
• Thirteen different ALAS2 mutations were identified in 16 out of 29 probands with sideroblastic anemia. (PMID:21309041)
• Data suggest that ALAS2 gene mutations should be considered not only as causative of X-linked sideroblastic anemia (XLSA) and XLDPP but may also modulate gene function in other erythropoietic disorders. (PMID:21653323)
• identification of five probands with sideroblastic anemia and ALAS2 R452S (due to SNP); all were African-American males; all presented with moderate anemia; the four adults presented with iron overload [a multi-case report from the United States] (PMID:21800356)
• the C-terminal region of ALAS2 protein may function as an intrinsic modifier that suppresses catalytic activity and increases the degradation of its protein, each function of which is enhanced by the Met567Ile mutation and Val562Ala mutation, respectively (PMID:22269113)
• X-linked sideroblastic anemia due to carboxyl-terminal ALAS2 mutations that cause loss of binding to the beta-subunit of succinyl-CoA synthetase (SUCLA2). (PMID:22740690)
• Late-onset photosensitivity was caused by ALAS2 mutation in a family with dominant protoporphyria. (PMID:23223129)
• A large gain-of-function domain within the C-terminus of ALAS2 is associated with X-linked dominant protoporphyria. (PMID:23263862)
• ALAS2 gain-of-function mutations increas the specific activity (DeltaAT, DeltaAGTG and p.Q548X) or stability (DeltaG) of the enzyme, thereby leading to the increased erythroid protoporphyrin accumulation causing X-linked protoporphyria. (PMID:23348515)
• Loss-of-function FECH and gain-of-function erythroid-specific ALAS2 mutations causing erythropoietic protoporphyria and x-linked protoporphyria in North American patients reveal novel mutations and a high prevalence of X-linked protoporphyria. (PMID:23364466)
• the 130-base pair enhancer region located in the first intron of the ALAS2 gene should be examined in patients with congenital sideroblastic anemia in whom the gene responsible is unknown. (PMID:23935018)
• 5 families with X-linked sideroblastic anemia had mutations in a GATA transcription factor binding site located in a transcriptional enhancer element in intron 1 of the ALAS2 gene. (PMID:24166784)
• In this article we add a novel mutation to the previously described 61 different ALAS2 mutations identified in X-linked sideroblastic anaemia patients. (PMID:24829177)
• the primary deficiency in ferrochelatase leads to a secondary increase in ALAS2 expression. (PMID:25179834)
• The ALAS2 Y365C mutation impairs pyridoxal 5’-phosphate binding to ALAS2, destabilizing the enzyme. X inactivation was not highly skewed in WBC from affected women. This X-linked dominant mutation perturbs erythropoiesis via cell-nonautonomous effects. (PMID:25705881)
• data indicate that the X-linked protoporphyria variants possess enhanced ALAS activity and ALA dissociation rates, as well as distinct structural properties from those of wild-type hALAS (PMID:26300302)
• From pH jump experiments, comparable rates for the denaturation of the tertiary structure and PLP-microenvironment were discerned, indicating that the catalytic active site geometry strongly depends on the stable tertiary structural organization. Lastly, we demonstrate that partially folded ALAS tends to self-associate into higher oligomeric species at moderate GuHCl concentrations. (PMID:27751851)
• int-1-GATA site should be examined in patients with XLSA in clinical settings when no known mutation is found in ALAS2 exons. (PMID:28123038)
• A novel ALAS2 missense mutation in exon 9 affects the enzymatic activity of ALAS2 by affecting its interaction with the cofactor pyridoxal 5’-phosphate in X-linked sideroblastic anemia. (PMID:28667034)
• a case of X-linked sideroblastic anemia caused by a novel homozygous deletional mutation in exon 10 of ALAS2 gene is presented (PMID:28731922)
• report confirms the considerable variability in manifestations among patients with ALAS2 or SLC25A38 mutations and draws attention to differences in the assessment and the monitoring of iron overload and its complications (PMID:28772256)
• we report that the dynamics of ALAS2 active site loop is anti-correlated with the dynamics of the C-terminal tail and that this anti-correlation can represent a molecular basis for the functional and dynamic asymmetry of the ALAS2 homodimer. (PMID:29958424)
• Patients with porphyrias should always be assessed for the presence of the ALAS2 gain-of-function modifier variants identified here. A key region of the ALAS2 carboxyterminal region is identified by the truncation mutations, and the correlation of increased thermolability with activity suggests that increased molecular flexibility/active site openness is the mechanism of enhanced function of mutations in this region. (PMID:30678654)
• In erythropoietic protoporphyria, ALAS2 mRNA was increased both in absolute terms and in relation to deficiency in ferrochelatase mRNA as shown in this study. (PMID:31076252)
• A novel mutation, c.1108G > A (p.A370T, NM_000032), was found in the ALAS2 gene located in exon 8. A mother with X-linked sideroblastic anemia and her so-far asymptomatic daughter were heterozygous for this mutation. (PMID:31848684)
• Novel mutations in the ALAS2 gene from patients with X-linked sideroblastic anemia. (PMID:32297424)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	alas2	ENSDARG00000038643
mus_musculus	Alas2	ENSMUSG00000025270
rattus_norvegicus	Alas2	ENSRNOG00000000167
drosophila_melanogaster	Alas	FBGN0020764

Paralogs (5): ALAS1 (ENSG00000023330), SPTLC1 (ENSG00000090054), GCAT (ENSG00000100116), SPTLC2 (ENSG00000100596), SPTLC3 (ENSG00000172296)

Protein

Protein identifiers

5-aminolevulinate synthase, erythroid-specific, mitochondrial — P22557 (reviewed: P22557)

Alternative names: 5-aminolevulinic acid synthase 2, Delta-ALA synthase 2, Delta-aminolevulinate synthase 2

All UniProt accessions (6): A0A2R8Y6N3, A0A2R8Y6R4, A0A2R8Y782, A0A2R8Y836, P22557, H0Y6R3

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the pyridoxal 5’-phosphate (PLP)-dependent condensation of succinyl-CoA and glycine to form aminolevulinic acid (ALA), with CoA and CO2 as by-products. Contributes significantly to heme formation during erythropoiesis. Catalyzes the pyridoxal 5’-phosphate (PLP)-dependent condensation of succinyl-CoA and glycine to form aminolevulinic acid (ALA), with CoA and CO2 as by-products. Catalytic activity is 75-85% of isoform 1 activity. Catalyzes the pyridoxal 5’-phosphate (PLP)-dependent condensation of succinyl-CoA and glycine to form aminolevulinic acid (ALA), with CoA and CO2 as by-products. Catalytic activity is 65-75% of isoform 1 activity.

Subunit / interactions. Homodimer. Interacts with SUCLA2. Interacts with SUCLA2.

Subcellular location. Mitochondrion inner membrane Mitochondrion inner membrane.

Tissue specificity. Erythroid-specific. Erythroid-specific. Erythroid-specific. Erythroid-specific.

Disease relevance. Anemia, sideroblastic, 1 (SIDBA1) [MIM:300751] A form of sideroblastic anemia that shows a variable hematologic response to pharmacologic doses of pyridoxine. Sideroblastic anemia is characterized by anemia of varying severity, hypochromic peripheral erythrocytes, systemic iron overload secondary to chronic ineffective erythropoiesis, and the presence of bone marrow ringed sideroblasts. Sideroblasts are characterized by iron-loaded mitochondria clustered around the nucleus. The disease is caused by variants affecting the gene represented in this entry. 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. The disease is caused by variants 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.

Activity regulation. Down-regulated by itaconyl-CoA which acts as a competitive inhibitor of succinyl-CoA substrate.

Domain organisation. C-terminus is a mobile self-inhibitory loop which interferes directly with active site.

Pathway. Porphyrin-containing compound metabolism; protoporphyrin-IX biosynthesis; 5-aminolevulinate from glycine: step 1/1.

Similarity. Belongs to the class-II pyridoxal-phosphate-dependent aminotransferase family.

Isoforms (4)

UniProt ID	Names	Canonical?
P22557-1	1	yes
P22557-2	2, Delta4
P22557-3	3, F143M
P22557-4	4

RefSeq proteins (3): NP_000023, NP_001033056, NP_001033057 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001917	Aminotrans_II_pyridoxalP_BS	Binding_site
IPR004839	Aminotransferase_I/II_large	Domain
IPR010961	4pyrrol_synth_NH2levulA_synth	Domain
IPR015118	5aminolev_synth_preseq	Domain
IPR015421	PyrdxlP-dep_Trfase_major	Homologous_superfamily
IPR015422	PyrdxlP-dep_Trfase_small	Homologous_superfamily
IPR015424	PyrdxlP-dep_Trfase	Homologous_superfamily
IPR050087	AON_synthase_class-II	Family

Pfam: PF00155, PF09029

Enzyme classification (BRENDA):

• EC 2.3.1.37 — 5-aminolevulinate synthase (BRENDA: 31 organisms, 63 substrates, 127 inhibitors, 243 Km, 111 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GLYCINE	0.0003–400	125
SUCCINYL-COA	0.0006–52.4	77
BUTYRYL-COA	0.15–1.4	10
2-HYDROXYBUTANOYL-COA	0.0055–0.0742	4
BUTANOYL-COA	0.0005–0.0093	4
OCTANOYL-COA	0.0018–0.0172	4
GLUTARYL-COA	0.0075–0.0301	3
PYRIDOXAL 5’-PHOSPHATE	0.0008–0.015	3

Catalyzed reactions (Rhea), 1 shown:

• succinyl-CoA + glycine + H(+) = 5-aminolevulinate + CO2 + CoA (RHEA:12921)

UniProt features (85 total): sequence variant 26, helix 18, strand 15, binding site 11, splice variant 4, turn 4, sequence conflict 2, transit peptide 1, chain 1, modified residue 1, active site 1, mutagenesis site 1

Structure

Experimental structures (PDB)

27 structures.

PDB	Method	Resolution (Å)
5QR1	X-RAY DIFFRACTION	1.44
5QQR	X-RAY DIFFRACTION	1.46
5QQY	X-RAY DIFFRACTION	1.49
5QR5	X-RAY DIFFRACTION	1.49
5QQX	X-RAY DIFFRACTION	1.5
5QQV	X-RAY DIFFRACTION	1.52
5QR6	X-RAY DIFFRACTION	1.52
5QQU	X-RAY DIFFRACTION	1.55
5QQZ	X-RAY DIFFRACTION	1.55
5QQW	X-RAY DIFFRACTION	1.56
5QR4	X-RAY DIFFRACTION	1.57
5QR9	X-RAY DIFFRACTION	1.62
5QR0	X-RAY DIFFRACTION	1.65
5QR2	X-RAY DIFFRACTION	1.66
5QQT	X-RAY DIFFRACTION	1.67
5QRE	X-RAY DIFFRACTION	1.67
5QR3	X-RAY DIFFRACTION	1.71
5QRA	X-RAY DIFFRACTION	1.72
5QRB	X-RAY DIFFRACTION	1.72
5QR7	X-RAY DIFFRACTION	1.74
5QRD	X-RAY DIFFRACTION	1.76
5QRC	X-RAY DIFFRACTION	1.82
5QQS	X-RAY DIFFRACTION	1.85
5QR8	X-RAY DIFFRACTION	1.85
5QQQ	X-RAY DIFFRACTION	1.93
5QT3	X-RAY DIFFRACTION	1.95
6HRH	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P22557-F1	82.76	0.71

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 391

Ligand- & substrate-binding residues (11): 388 (in other chain); 420; 421; 508; 163; 258 (in other chain); 259 (in other chain); 280; 299; 332 (in other chain); 360 (in other chain)

Post-translational modifications (1): 391

Mutagenesis-validated functional residues (1):

Position	Phenotype
511	2-fold increased enzyme activity with a lower specificity for glycine and higher for succinyl-coa.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-189451	Heme biosynthesis

MSigDB gene sets: 205 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_HEMOGLOBIN_METABOLIC_PROCESS, GOBP_MYELOID_CELL_HOMEOSTASIS, REACTOME_METABOLISM_OF_PORPHYRINS, MODULE_45, GOBP_ERYTHROCYTE_HOMEOSTASIS, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_TETRAPYRROLE_BIOSYNTHETIC_PROCESS, MODULE_16, GOLDRATH_ANTIGEN_RESPONSE, GNF2_ANK1, GOBP_PORPHYRIN_CONTAINING_COMPOUND_METABOLIC_PROCESS, RHEIN_ALL_GLUCOCORTICOID_THERAPY_UP

GO Biological Process (12): response to hypoxia (GO:0001666), obsolete protoporphyrinogen IX biosynthetic process (GO:0006782), heme biosynthetic process (GO:0006783), heme B biosynthetic process (GO:0006785), intracellular iron ion homeostasis (GO:0006879), erythrocyte differentiation (GO:0030218), intracellular oxygen homeostasis (GO:0032364), hemoglobin biosynthetic process (GO:0042541), erythrocyte development (GO:0048821), porphyrin-containing compound metabolic process (GO:0006778), biosynthetic process (GO:0009058), tetrapyrrole biosynthetic process (GO:0033014)

GO Molecular Function (5): 5-aminolevulinate synthase activity (GO:0003870), pyridoxal phosphate binding (GO:0030170), protein binding (GO:0005515), transferase activity (GO:0016740), acyltransferase activity (GO:0016746)

GO Cellular Component (4): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial matrix (GO:0005759), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of porphyrins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
tetrapyrrole metabolic process	2
response to stress	1
response to decreased oxygen levels	1
porphyrin-containing compound biosynthetic process	1
heme metabolic process	1
pigment biosynthetic process	1
heme biosynthetic process	1
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
myeloid cell differentiation	1
erythrocyte homeostasis	1
intracellular chemical homeostasis	1
macromolecule biosynthetic process	1
hemoglobin metabolic process	1
erythrocyte differentiation	1
myeloid cell development	1
metabolic process	1
biosynthetic process	1
N-succinyltransferase activity	1
anion binding	1
vitamin B6 binding	1
binding	1
catalytic activity	1
transferase activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrion	1
intracellular organelle lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2024 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALAS2	FECH	P22830	979
ALAS2	ABCB7	O75027	902
ALAS2	GATA1	P15976	889
ALAS2	GLRX5	Q86SX6	884
ALAS2	HMBS	P08396	881
ALAS2	SLC25A38	Q96DW6	877
ALAS2	ACO1	P21399	841
ALAS2	PPOX	P50336	828
ALAS2	UROS	P10746	796
ALAS2	GYPB	P06028	778
ALAS2	IREB2	P48200	775
ALAS2	ALAD	P13716	770
ALAS2	CPOX	P36551	769
ALAS2	UROD	P06132	742
ALAS2	BLVRB	P30043	731

IntAct

5 interactions, top by confidence:

A	B	Type	Score
ALAS2	BANP	psi-mi:“MI:0915”(physical association)	0.560
BANP	ALAS2	psi-mi:“MI:0915”(physical association)	0.560
ALAS2	GRB2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (8): BANP (Two-hybrid), BANP (Two-hybrid), BANP (Two-hybrid), SUCLA2 (Affinity Capture-Western), ALAS2 (Negative Genetic), HNRNPD (Cross-Linking-MS (XL-MS)), ALAS2 (Affinity Capture-MS), ALAS2 (Two-hybrid)

ESM2 similar proteins: A0A0U2WCB2, A6NK44, A6QLI6, A8XX92, A9NNH7, B9FK36, O42764, P05165, P07997, P08680, P0DTA4, P13196, P13446, P14882, P16635, P22557, P43090, P54889, Q19842, Q28CR0, Q2KIZ3, Q2QMG2, Q42523, Q42777, Q4KLB0, Q4WHU1, Q502D1, Q553V2, Q5I0C3, Q5R557, Q5R7K1, Q5R9R9, Q612F5, Q63147, Q6CDR5, Q6JQN1, Q759G5, Q872T7, Q8K370, Q91ZA3

Diamond homologs: A0RIB9, A1AQT1, A1WVM6, A3DBD5, A5G6I9, A6LMP4, A6QLI6, A6TU88, A7GSE1, A7HMM1, A7LXM2, A7Z4X1, A7Z5B4, A8MEX7, A9BGL0, A9VG56, B0K590, B0KC20, B1I4F9, B1YMC6, B3EAE0, B3PI88, B4UCB1, B5EEV8, B5Y9Z4, B7HAZ0, B7HNN4, B7ID58, B7IWN1, B7JLX2, B8J637, B9IWY0, B9M8U3, O14092, O31777, O66875, O75600, O88986, O94069, P07997

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
HIF1A	“up-regulates quantity by expression”	ALAS2	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

414 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	37
Likely pathogenic	18
Uncertain significance	141
Likely benign	107
Benign	31

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
10468	NM_000032.5(ALAS2):c.1427T>A (p.Ile476Asn)	Pathogenic
10469	NM_000032.5(ALAS2):c.1163C>G (p.Thr388Ser)	Pathogenic
10470	NM_000032.5(ALAS2):c.495C>A (p.Phe165Leu)	Pathogenic
10471	NM_000032.5(ALAS2):c.871G>A (p.Gly291Ser)	Pathogenic
10472	NM_000032.5(ALAS2):c.895A>C (p.Lys299Gln)	Pathogenic
10474	NM_000032.5(ALAS2):c.569A>T (p.Asp190Val)	Pathogenic
10475	NM_000032.5(ALAS2):c.1231C>T (p.Arg411Cys)	Pathogenic
10476	NM_000032.5(ALAS2):c.1702A>G (p.Ser568Gly)	Pathogenic
10477	NM_000032.5(ALAS2):c.1184G>A (p.Cys395Tyr)	Pathogenic
10478	NM_000032.5(ALAS2):c.475G>T (p.Asp159Tyr)	Pathogenic
10479	NM_000032.5(ALAS2):c.475G>A (p.Asp159Asn)	Pathogenic
10481	NM_000032.5(ALAS2):c.1570C>G (p.His524Asp)	Pathogenic
10483	NM_000032.5(ALAS2):c.1699_1700del (p.Met567fs)	Pathogenic
10484	NM_000032.5(ALAS2):c.595T>C (p.Tyr199His)	Pathogenic
10485	NM_000032.5(ALAS2):c.1354C>T (p.Arg452Cys)	Pathogenic
1180551	GRCh37/hg19 Xp22.33-q28(chrX:60000-155234966)x1	Pathogenic
1340693	GRCh37/hg19 Xp11.22-11.21(chrX:52901458-55684871)x2	Pathogenic
146617	GRCh38/hg38 Xp11.22-11.21(chrX:53764152-58014767)x2	Pathogenic
148338	GRCh38/hg38 Xp11.22-q11.1(chrX:53750365-63089185)x2	Pathogenic
153755	GRCh38/hg38 Xp11.22-11.1(chrX:51654792-58469500)x1	Pathogenic
2138581	NM_000032.5(ALAS2):c.1354C>A (p.Arg452Ser)	Pathogenic
214095	NM_000032.5(ALAS2):c.606G>A (p.Met202Ile)	Pathogenic
214099	NM_000032.5(ALAS2):c.1355G>A (p.Arg452His)	Pathogenic
214104	NM_000032.5(ALAS2):c.1699A>G (p.Met567Val)	Pathogenic
253410	GRCh37/hg19 Xp11.22-11.21(chrX:53220822-58066465)x3	Pathogenic
253446	GRCh37/hg19 Xp11.22-q12(chrX:53085607-67176333)x2	Pathogenic
2737236	NM_000032.5(ALAS2):c.1499A>G (p.Tyr500Cys)	Pathogenic
3724241	NM_000032.5(ALAS2):c.902T>C (p.Val301Ala)	Pathogenic
3893296	NM_000032.5(ALAS2):c.224C>A (p.Ser75Ter)	Pathogenic
440879	NM_000032.5(ALAS2):c.508C>A (p.Arg170Ser)	Pathogenic

SpliceAI

1411 predictions. Top by Δscore:

Variant	Effect	Δscore
X:55009353:G:C	acceptor_gain	1.0000
X:55013484:AC:A	donor_gain	1.0000
X:55013485:CC:C	donor_gain	1.0000
X:55013485:CCCA:C	donor_gain	1.0000
X:55015572:ACTT:A	donor_loss	1.0000
X:55015573:CTTA:C	donor_loss	1.0000
X:55015574:TTAC:T	donor_loss	1.0000
X:55015575:TACC:T	donor_loss	1.0000
X:55015576:A:AC	donor_gain	1.0000
X:55015576:ACC:A	donor_loss	1.0000
X:55015577:C:CC	donor_gain	1.0000
X:55015577:CCAA:C	donor_gain	1.0000
X:55020315:CTTA:C	donor_loss	1.0000
X:55020317:TACC:T	donor_loss	1.0000
X:55020318:A:C	donor_loss	1.0000
X:55020319:C:A	donor_loss	1.0000
X:55020319:CCTGG:C	donor_gain	1.0000
X:55020510:C:CT	acceptor_gain	1.0000
X:55020511:A:T	acceptor_gain	1.0000
X:55020520:C:CT	acceptor_gain	1.0000
X:55020521:A:T	acceptor_gain	1.0000
X:55021121:T:TA	donor_gain	1.0000
X:55024741:T:TA	donor_gain	1.0000
X:55009342:CT:C	acceptor_gain	0.9900
X:55009350:G:C	acceptor_gain	0.9900
X:55009350:G:GC	acceptor_gain	0.9900
X:55009353:G:GC	acceptor_gain	0.9900
X:55013480:ACTT:A	donor_loss	0.9900
X:55013481:CTTA:C	donor_loss	0.9900
X:55013482:TTA:T	donor_loss	0.9900

AlphaMissense

3861 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:55014927:A:C	F419L	1.000
X:55014927:A:T	F419L	1.000
X:55014929:A:G	F419L	1.000
X:55017636:G:C	H285D	1.000
X:55020459:G:C	N228K	1.000
X:55020459:G:T	N228K	1.000
X:55013560:A:T	V509D	0.999
X:55013571:G:C	N505K	0.999
X:55013571:G:T	N505K	0.999
X:55014765:G:C	S473R	0.999
X:55014765:G:T	S473R	0.999
X:55014767:T:G	S473R	0.999
X:55014929:A:T	F419I	0.999
X:55015634:C:T	G371E	0.999
X:55015649:C:T	G366E	0.999
X:55015658:C:T	G363E	0.999
X:55015665:C:G	A361P	0.999
X:55015667:T:C	H360R	0.999
X:55015668:G:C	H360D	0.999
X:55015676:T:A	D357V	0.999
X:55015676:T:G	D357A	0.999
X:55015677:C:G	D357H	0.999
X:55015742:C:T	G335D	0.999
X:55017500:A:T	V330D	0.999
X:55017506:T:A	E328V	0.999
X:55017617:C:T	G291D	0.999
X:55017618:C:G	G291R	0.999
X:55017629:G:A	S287F	0.999
X:55017629:G:T	S287Y	0.999
X:55017630:A:G	S287P	0.999

dbSNP variants (sampled 300 via entrez): RS1000062079 (X:55013806 T>C), RS1000315701 (X:55017862 A>G), RS1000470371 (X:55008593 A>G), RS1000584823 (X:55015600 A>G), RS1000616095 (X:55015969 G>A,C), RS1000791230 (X:55010917 A>G), RS1001496350 (X:55020110 T>C), RS1001592312 (X:55029563 A>G), RS1001828660 (X:55029024 A>C), RS1001875456 (X:55010645 C>T), RS1001947933 (X:55023642 T>A), RS1002177303 (X:55011273 A>G,T), RS1002348948 (X:55011474 T>C), RS1002536544 (X:55026796 T>G), RS1002790538 (X:55012088 G>T)

Disease associations

OMIM: gene MIM:301300 | disease phenotypes: MIM:300751, MIM:300752, MIM:300884

GenCC curated gene-disease

Disease	Classification	Inheritance
X-linked sideroblastic anemia 1	Strong	X-linked
X-linked erythropoietic protoporphyria	Strong	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
X-linked erythropoietic protoporphyria	Definitive	XL

Mondo (3): X-linked sideroblastic anemia 1 (MONDO:0020721), X-linked erythropoietic protoporphyria (MONDO:0010420), developmental and epileptic encephalopathy, 36 (MONDO:0010472)

Orphanet (3): X-linked sideroblastic anemia (Orphanet:75563), X-linked erythropoietic protoporphyria (Orphanet:443197), ALG13-CDG (Orphanet:324422)

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000953	Hyperpigmentation of the skin
HP:0000980	Pallor
HP:0000992	Cutaneous photosensitivity
HP:0001017	Anemic pallor
HP:0001081	Cholelithiasis
HP:0001324	Muscle weakness
HP:0001419	X-linked recessive inheritance
HP:0001423	X-linked dominant inheritance
HP:0001744	Splenomegaly
HP:0001891	Iron deficiency anemia
HP:0001903	Anemia
HP:0001924	Sideroblastic anemia
HP:0001952	Glucose intolerance
HP:0001972	Macrocytic anemia
HP:0002094	Dyspnea
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0004840	Hypochromic microcytic anemia
HP:0010972	Anemia of inadequate production
HP:0011031	Abnormality of iron homeostasis
HP:0011463	Childhood onset
HP:0012187	Increased erythrocyte protoporphyrin concentration
HP:0012378	Fatigue
HP:0025406	Asthenia

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST90002390_290	Mean corpuscular hemoglobin	6.000000e-42
GCST90002390_291	Mean corpuscular hemoglobin	4.000000e-20
GCST90002391_181	Mean corpuscular hemoglobin concentration	1.000000e-11
GCST90002392_237	Mean corpuscular volume	4.000000e-37
GCST90002392_238	Mean corpuscular volume	4.000000e-25
GCST90002403_717	Red blood cell count	4.000000e-13
GCST90002404_420	Red cell distribution width	3.000000e-21

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004527	mean corpuscular hemoglobin
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0004305	erythrocyte count
EFO:0009188	Red cell distribution width

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C567464	Protoporphyria, Erythropoietic, X-Linked Dominant (supp.)
C536761	X-linked sideroblastic anemia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
catechol	affects cotreatment, increases expression, decreases reaction, increases reaction	3
Hemin	affects cotreatment, increases expression, decreases reaction, increases reaction	3
bisphenol A	decreases methylation	1
CGP 52608	affects binding, increases reaction	1
Irinotecan	increases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	increases methylation, decreases methylation	1
Carbamazepine	affects expression	1
Diclofenac	affects expression	1
S-Adenosylhomocysteine	affects cotreatment, decreases reaction, increases expression	1
S-Adenosylmethionine	affects cotreatment, decreases reaction, increases expression	1
T-2 Toxin	increases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	decreases expression	1
Phenol	decreases reaction, increases expression	1
Butyric Acid	increases expression	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

5 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04402489	PHASE3	COMPLETED	Study to Evaluate Efficacy, Safety, and Tolerability of MT-7117 in Subjects With Erythropoietic Protoporphyria or X-Linked Protoporphyria
NCT05005975	PHASE3	RECRUITING	Extension Study to Evaluate Safety and Tolerability of Oral Dersimelagon (MT-7117) in Subjects With Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP)
NCT01550705	Not specified	TERMINATED	Effect of Isoniazid on Protoporphyrin Levels in Erythropoietic Protoporphyria
NCT01688895	Not specified	COMPLETED	Erythropoietic Protoporphyrias: Studies of the Natural History, Genotype-Phenotype Correlations, and Psychosocial Impact
NCT02979249	Not specified	COMPLETED	Oral Iron for Erythropoietic Protoporphyrias