X-linked sideroblastic anemia 1

Summary

X-linked sideroblastic anemia 1 (MONDO:0020721) is a disease caused by ALAS2 (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: ALAS2 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 73
• Phenotypes (HPO): 10

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		200	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0000980	Pallor	Very frequent (80-99%)
HP:0001324	Muscle weakness	Very frequent (80-99%)
HP:0001903	Anemia	Very frequent (80-99%)
HP:0011031	Abnormality of iron homeostasis	Very frequent (80-99%)
HP:0012378	Fatigue	Very frequent (80-99%)
HP:0000953	Hyperpigmentation of the skin	Occasional (5-29%)
HP:0001744	Splenomegaly	Occasional (5-29%)
HP:0001952	Glucose intolerance	Occasional (5-29%)
HP:0002094	Dyspnea	Occasional (5-29%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	X-linked sideroblastic anemia 1
Mondo ID	MONDO:0020721
MeSH	C536761
OMIM	300751
Orphanet	75563
DOID	DOID:0060063
SNOMED CT	62677000
UMLS	C4551511
MedGen	1638704
GARD	0009456
Is cancer (heuristic)	no

Also known as: anaemia hereditary sideroblastic · anaemia sex-linked hypochromic sideroblastic · anemia hereditary sideroblastic · anemia sex-linked hypochromic sideroblastic · anemia, sideroblastic, 1, X-linked recessive · anemia, sideroblastic, X-linked · ANH1 · erythroid 5-aminolevulinate synthase deficiency · hereditary iron-loading Anaemia · SIDBA1 · sideroblastic anaemia X-linked · sideroblastic anemia X-linked · sideroblastic anemia, X-linked · X chromosome-linked sideroblastic anaemia · X chromosome-linked sideroblastic anemia · X-linked sideroblastic anemia · XLSA

Data availability: 73 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › X-linked disease › X-linked sideroblastic anemia 1

Related subtypes (49): X-linked Opitz G/BBB syndrome, X-linked immunoneurologic disorder, X-linked adrenal hypoplasia congenita, X-linked lissencephaly with abnormal genitalia, X-linked severe congenital neutropenia, X-linked distal spinal muscular atrophy type 3, epilepsy, X-linked 1, with variable learning disabilities and behavior disorders, Aland island eye disease, X-linked erythropoietic protoporphyria, X-linked central congenital hypothyroidism with late-onset testicular enlargement, X-linked colobomatous microphthalmia-microcephaly-intellectual disability-short stature syndrome, X-linked acrogigantism due to Xq26 microduplication, Wiskott-Aldrich syndrome, X-linked Alport syndrome, X-linked mandibulofacial dysostosis, X-linked chondrodysplasia punctata, choroideremia, cone dystrophy, X-linked, with tapetal-like sheen, diabetes insipidus, nephrogenic, X-linked, Dyggve-Melchior-Clausen syndrome, X-linked, dyskeratosis congenita, X-linked, X-linked hypohidrotic ectodermal dysplasia, X-linked Ehlers-Danlos syndrome, epidermodysplasia verruciformis, X-linked, exudative vitreoretinopathy 2, X-linked, Aarskog-Scott syndrome, X-linked, hemophilia A, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius, hyper-IgM syndrome type 1, X-linked lymphoproliferative syndrome, macular dystrophy, X-linked, X-linked Emery-Dreifuss muscular dystrophy, X-linked myotubular myopathy, X-linked lethal multiple pterygium syndrome, X-linked retinoschisis, spondyloepiphyseal dysplasia tarda, X-linked, X-linked cerebellar ataxia, adrenoleukodystrophy, Charcot-Marie-Tooth disease type X, X-linked dominant disease, X-linked recessive disease, X-linked hypophosphatemic rickets, X-linked deafness, X-linked cone-rod dystrophy, X-linked congenital stationary night blindness, X-linked congenital hemolytic anemia, X-linked complex neurodevelopmental disorder, X-linked intellectual disability, leukemia, acute, X-linked

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

73 retrieved; paginated sample, class counts are floors:

20 conflicting classifications of pathogenicity, 17 pathogenic, 14 uncertain significance, 8 benign, 7 benign/likely benign, 7 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
10468	NM_000032.5(ALAS2):c.1427T>A (p.Ile476Asn)	ALAS2	Pathogenic	no assertion criteria provided
10469	NM_000032.5(ALAS2):c.1163C>G (p.Thr388Ser)	ALAS2	Pathogenic	no assertion criteria provided
10470	NM_000032.5(ALAS2):c.495C>A (p.Phe165Leu)	ALAS2	Pathogenic	criteria provided, single submitter
10471	NM_000032.5(ALAS2):c.871G>A (p.Gly291Ser)	ALAS2	Pathogenic	no assertion criteria provided
10474	NM_000032.5(ALAS2):c.569A>T (p.Asp190Val)	ALAS2	Pathogenic	no assertion criteria provided
10475	NM_000032.5(ALAS2):c.1231C>T (p.Arg411Cys)	ALAS2	Pathogenic	criteria provided, multiple submitters, no conflicts
10476	NM_000032.5(ALAS2):c.1702A>G (p.Ser568Gly)	ALAS2	Pathogenic	no assertion criteria provided
10477	NM_000032.5(ALAS2):c.1184G>A (p.Cys395Tyr)	ALAS2	Pathogenic	no assertion criteria provided
10478	NM_000032.5(ALAS2):c.475G>T (p.Asp159Tyr)	ALAS2	Pathogenic	no assertion criteria provided
10479	NM_000032.5(ALAS2):c.475G>A (p.Asp159Asn)	ALAS2	Pathogenic	no assertion criteria provided
10481	NM_000032.5(ALAS2):c.1570C>G (p.His524Asp)	ALAS2	Pathogenic	no assertion criteria provided
10484	NM_000032.5(ALAS2):c.595T>C (p.Tyr199His)	ALAS2	Pathogenic	no assertion criteria provided
10485	NM_000032.5(ALAS2):c.1354C>T (p.Arg452Cys)	ALAS2	Pathogenic	criteria provided, multiple submitters, no conflicts
3893296	NM_000032.5(ALAS2):c.224C>A (p.Ser75Ter)	ALAS2	Pathogenic	no assertion criteria provided
440879	NM_000032.5(ALAS2):c.508C>A (p.Arg170Ser)	ALAS2	Pathogenic	no assertion criteria provided
3377333	NM_000032.5(ALAS2):c.-15-2187T>C	PAGE2B	Pathogenic	criteria provided, multiple submitters, no conflicts
4278442	NM_001167.4(XIAP):c.449C>G (p.Ser150Ter)	XIAP	Pathogenic	criteria provided, single submitter
3602606	NM_000032.5(ALAS2):c.1115T>C (p.Ile372Thr)	ALAS2	Likely pathogenic	criteria provided, single submitter
3731274	NM_000032.5(ALAS2):c.1762T>C (p.Ter588Arg)	ALAS2	Likely pathogenic	criteria provided, single submitter
4683078	NM_000032.5(ALAS2):c.905T>C (p.Phe302Ser)	ALAS2	Likely pathogenic	no assertion criteria provided
978811	NM_000032.5(ALAS2):c.1382T>A (p.Leu461His)	ALAS2	Likely pathogenic	criteria provided, single submitter
992940	NM_000032.5(ALAS2):c.1571A>G (p.His524Arg)	ALAS2	Likely pathogenic	criteria provided, single submitter
3075690	NM_000032.5(ALAS2):c.304+2T>A	LOC108663984	Likely pathogenic	criteria provided, single submitter
2500873	NM_000032.5(ALAS2):c.-15-2188A>G	PAGE2B	Likely pathogenic	criteria provided, single submitter
10473	NM_000032.5(ALAS2):c.514G>A (p.Ala172Thr)	ALAS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1065640	NM_000032.5(ALAS2):c.488G>A (p.Arg163His)	ALAS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1206683	NM_000032.5(ALAS2):c.653G>A (p.Arg218His)	ALAS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1702971	NM_000032.5(ALAS2):c.1244C>T (p.Ala415Val)	ALAS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214088	NM_000032.5(ALAS2):c.1559C>T (p.Pro520Leu)	ALAS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214089	NM_000032.5(ALAS2):c.1560C>A (p.Pro520=)	ALAS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ALAS2	Strong	X-linked	X-linked sideroblastic anemia 1	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALAS2	Orphanet:443197	X-linked erythropoietic protoporphyria
ALAS2	Orphanet:75563	X-linked sideroblastic anemia
XIAP	Orphanet:538934	X-linked lymphoproliferative disease due to XIAP deficiency

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ALAS2	HGNC:397	ENSG00000158578	P22557	5-aminolevulinate synthase, erythroid-specific, mitochondrial	gencc,clinvar
PAGE2B	HGNC:31805	ENSG00000238269	Q5JRK9	Putative G antigen family E member 3	clinvar
XIAP	HGNC:592	ENSG00000101966	P98170	E3 ubiquitin-protein ligase XIAP	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALAS2	5-aminolevulinate synthase, erythroid-specific, mitochondrial	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.
XIAP	E3 ubiquitin-protein ligase XIAP	Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	4.0×	0.482
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALAS2	Enzyme (other)	yes	2.3.1.37	Aminotrans_II_pyridoxalP_BS, Aminotransferase_I/II_large, 4pyrrol_synth_NH2levulA_synth
PAGE2B	Other/Unknown	no		GAGE_fam, GAGE
XIAP	Transcription factor	no		BIR_rpt, Znf_RING, DEATH-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
bone marrow	1
bone marrow cell	1
trabecular bone tissue	1
male germ line stem cell (sensu Vertebrata) in testis	1
right testis	1
testis	1
buccal mucosa cell	1
ileal mucosa	1
kidney epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALAS2	172	broad	marker	trabecular bone tissue, bone marrow, bone marrow cell
PAGE2B	122	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, right testis, testis
XIAP	256	ubiquitous	marker	kidney epithelium, ileal mucosa, buccal mucosa cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
XIAP	5,252
ALAS2	2,037
PAGE2B	211

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
XIAP	P98170	74
ALAS2	P22557	27

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PAGE2B	Q5JRK9	62.21

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 3 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Activation of caspases through apoptosome-mediated cleavage	1	951.7×	0.005	XIAP
SMAC (DIABLO) binds to IAPs	1	815.7×	0.005	XIAP
SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes	1	815.7×	0.005	XIAP
SMAC, XIAP-regulated apoptotic response	1	815.7×	0.005	XIAP
Regulation of PTEN localization	1	519.1×	0.005	XIAP
Regulation of the apoptosome activity	1	519.1×	0.005	XIAP
Heme biosynthesis	1	380.7×	0.006	ALAS2
RIPK1-mediated regulated necrosis	1	228.4×	0.007	XIAP
TNFR1-induced proapoptotic signaling	1	219.6×	0.007	XIAP
Regulation of necroptotic cell death	1	219.6×	0.007	XIAP
TNFR1-induced NF-kappa-B signaling pathway	1	167.9×	0.008	XIAP
Deactivation of the beta-catenin transactivating complex	1	116.5×	0.010	XIAP
Regulation of TNFR1 signaling	1	112.0×	0.010	XIAP
Regulation of PTEN stability and activity	1	92.1×	0.012	XIAP
Activation of STAT3 by cadherin engagement	1	81.6×	0.012	XIAP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of protein linear polyubiquitination	1	4213.0×	0.004	XIAP
regulation of apoptosis involved in tissue homeostasis	1	2808.7×	0.004	XIAP
copper ion homeostasis	1	2106.5×	0.004	XIAP
regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway	1	1685.2×	0.004	XIAP
nucleotide-binding oligomerization domain containing 1 signaling pathway	1	1685.2×	0.004	XIAP
hemoglobin biosynthetic process	1	1404.3×	0.004	ALAS2
obsolete protoporphyrinogen IX biosynthetic process	1	842.6×	0.004	ALAS2
heme B biosynthetic process	1	842.6×	0.004	ALAS2
quinolinate biosynthetic process	1	766.0×	0.004	XIAP
intracellular oxygen homeostasis	1	766.0×	0.004	ALAS2
nucleotide-binding oligomerization domain containing 2 signaling pathway	1	766.0×	0.004	XIAP
regulation of BMP signaling pathway	1	601.9×	0.005	XIAP
regulation of innate immune response	1	324.1×	0.008	XIAP
heme biosynthetic process	1	300.9×	0.008	ALAS2
erythrocyte development	1	263.3×	0.009	ALAS2
negative regulation of tumor necrosis factor-mediated signaling pathway	1	227.7×	0.009	XIAP
positive regulation of type I interferon production	1	210.7×	0.009	XIAP
erythrocyte differentiation	1	133.8×	0.013	ALAS2
protein K63-linked ubiquitination	1	133.8×	0.013	XIAP
intracellular iron ion homeostasis	1	122.1×	0.014	ALAS2
positive regulation of protein ubiquitination	1	106.7×	0.015	XIAP
neuron apoptotic process	1	92.6×	0.017	XIAP
regulation of inflammatory response	1	84.3×	0.017	XIAP
positive regulation of JNK cascade	1	81.8×	0.017	XIAP
positive regulation of canonical Wnt signaling pathway	1	77.3×	0.018	XIAP
response to lipopolysaccharide	1	62.4×	0.021	XIAP
defense response to bacterium	1	54.0×	0.023	XIAP
Wnt signaling pathway	1	49.9×	0.024	XIAP
response to hypoxia	1	47.9×	0.024	ALAS2
regulation of apoptotic process	1	41.7×	0.027	XIAP

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
XIAP	6	3
ALAS2	0	0
PAGE2B	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
XEVINAPANT	3	XIAP
PHENYLALANINE	3	XIAP
LCL-161	2	XIAP
BIRINAPANT	2	XIAP
GDC-0152	1	XIAP
ASTX-660	1	XIAP

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
XIAP	499	Binding:468, Functional:24, ADMET:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALAS2	2.3.1.37	5-aminolevulinate synthase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
XIAP	499

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

6 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
XEVINAPANT	3	XIAP
PHENYLALANINE	3	XIAP
LCL-161	2	XIAP
BIRINAPANT	2	XIAP
GDC-0152	1	XIAP
ASTX-660	1	XIAP

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	XIAP
C	Druggable family + PDB, no drug	1	ALAS2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PAGE2B

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ALAS2	0	—
PAGE2B	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.