ALAS2

5'-aminolevulinate synthase 2

Basic information

Region (hg38): X:55009055-55030977

Previous symbols: [ "ASB" ]

Links

ENSG00000158578 ∙ NCBI:212 ∙ OMIM:301300 ∙ HGNC:397 ∙ Uniprot:P22557 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• X-linked erythropoietic protoporphyria (Strong), mode of inheritance: XL
• X-linked sideroblastic anemia 1 (Strong), mode of inheritance: XL
• X-linked sideroblastic anemia 1 (Supportive), mode of inheritance: XL
• X-linked erythropoietic protoporphyria (Supportive), mode of inheritance: XL
• X-linked sideroblastic anemia 1 (Strong), mode of inheritance: XL
• X-linked erythropoietic protoporphyria (Strong), mode of inheritance: XL
• X-linked erythropoietic protoporphyria (Definitive), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Anemia, sideroblastic 1; Protoporphyria, erythropoietic, X-linked	XL	Dermatologic; Gastrointestinal; Hematologic	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	Dermatologic; Gastrointestinal; Hematologic	14247476; 130377; 1570328; 7949148; 7560104; 10029606; 10886220; 12531813; 16315313; 16735131; 18760763; 19144952; 19656325; 21252495; 23016163; 23263862; 37043653

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ALAS2 gene.

• not provided (8 variants)
• X-linked sideroblastic anemia 1 (3 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ALAS2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			5	34	5	44
missense	8	9	70	11	1	99
nonsense		1	1			2
start loss						0
frameshift		2				2
inframe indel			1			1
splice donor/acceptor (+/-2bp)		2				2
splice region			2	10	2	14
non coding		1	4	32	24	61
Total	8	15	81	77	30

Highest pathogenic variant AF is 0.00000889

Variants in ALAS2

This is a list of pathogenic ClinVar variants found in the ALAS2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
X-55009056-G-A		X-linked sideroblastic anemia 1	Benign/Likely benign (Jul 31, 2018)
X-55009124-T-G		X-linked sideroblastic anemia 1	Benign (Jun 28, 2018)
X-55009187-T-A		X-linked sideroblastic anemia 1 • Developmental and epileptic encephalopathy, 36 • X-linked erythropoietic protoporphyria	Conflicting classifications of pathogenicity (Jun 27, 2024)
X-55009198-ATA-T			Uncertain significance (Feb 10, 2023)
X-55009202-T-C			Uncertain significance (Aug 10, 2023)
X-55009219-G-A			Likely benign (Mar 10, 2021)
X-55009226-G-A		X-linked sideroblastic anemia 1 • ALAS2-related disorder	Benign/Likely benign (Oct 23, 2023)
X-55009234-CCACT-C		X-linked erythropoietic protoporphyria • See cases	Pathogenic/Likely pathogenic (Mar 15, 2023)
X-55009242-T-C		X-linked sideroblastic anemia 1	Pathogenic (Jul 01, 1999)
X-55009243-CAT-C		X-linked erythropoietic protoporphyria	Pathogenic (Sep 01, 2008)
X-55009245-T-C			Pathogenic (Oct 03, 2014)
X-55009248-G-A		Inborn genetic diseases	Uncertain significance (Jun 29, 2023)
X-55009249-C-G		ALAS2-related disorder	Conflicting classifications of pathogenicity (May 15, 2023)
X-55009251-C-G			Uncertain significance (Feb 07, 2017)
X-55009259-A-G			Uncertain significance (Sep 05, 2023)
X-55009265-C-T			Uncertain significance (Aug 11, 2023)
X-55009266-G-A			Uncertain significance (Nov 06, 2022)
X-55009267-GCGACAGAAATTGCAGGCAGCCACAGA-G		X-linked erythropoietic protoporphyria	Pathogenic (Apr 01, 2013)
X-55009268-C-G			Likely pathogenic (Jan 08, 2013)
X-55009268-C-T		not specified • X-linked sideroblastic anemia 1 • ALAS2-related disorder	Benign/Likely benign (Jan 11, 2024)
X-55009279-G-GCAGGCAGCCACAGACACAT			Likely pathogenic (Mar 25, 2022)
X-55009297-A-G		not specified	Benign/Likely benign (Jan 25, 2024)
X-55009302-G-A		X-linked erythropoietic protoporphyria	Pathogenic (Apr 01, 2013)
X-55009306-G-C		X-linked sideroblastic anemia 1	Uncertain significance (Jan 12, 2018)
X-55009318-C-T		X-linked sideroblastic anemia 1 • ALAS2-related disorder	Benign (Jan 22, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ALAS2	protein_coding	protein_coding	ENST00000330807	10	22010

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.996	0.00414	0	0	0	0	0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.37	131	233	0.563	0.0000182	3841
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00	0.00
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• 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}.
• Pathway: Glycine, serine and threonine metabolism - Homo sapiens (human);Porphyrin and chlorophyll metabolism - Homo sapiens (human);Heme Biosynthesis;hemoglobins chaperone;Heme biosynthesis;Metabolism of porphyrins;Glycine Serine metabolism;Metabolism;Porphyrin metabolism;Glycine, serine, alanine and threonine metabolism;tetrapyrrole biosynthesis;heme biosynthesis (Consensus)

Recessive Scores

• pRec: 0.453

Intolerance Scores

• rvis_EVS: 0.13
• rvis_percentile_EVS: 63.36

Haploinsufficiency Scores

• pHI: 0.804
• hipred: Y
• hipred_score: 0.617
• ghis: 0.689

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.666

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Alas2
• Phenotype: mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; embryo phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); homeostasis/metabolism phenotype

Zebrafish Information Network

• Gene name: alas2
• Affected structure: nucleate erythrocyte
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: response to hypoxia;protoporphyrinogen IX biosynthetic process;heme biosynthetic process;cellular iron ion homeostasis;erythrocyte differentiation;oxygen homeostasis;hemoglobin biosynthetic process
• Cellular component: mitochondrion;mitochondrial inner membrane;mitochondrial matrix
• Molecular function: 5-aminolevulinate synthase activity;protein binding;glycine binding;pyridoxal phosphate binding;coenzyme binding