Sideroblastic anemia 3

Summary

Sideroblastic anemia 3 (MONDO:0014804) is a disease caused by GLRX5 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GLRX5 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 8

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	sideroblastic anemia 3
Mondo ID	MONDO:0014804
OMIM	616860
Orphanet	255132
DOID	DOID:0080343
SNOMED CT	720465002
UMLS	C4225155
MedGen	895975
GARD	0017235
Is cancer (heuristic)	no

Also known as: adult-onset autosomal recessive sideroblastic anaemia · adult-onset autosomal recessive sideroblastic anemia · anemia, sideroblastic, 3, pyridoxine-refractory · GLRX5-related sideroblastic anaemia · GLRX5-related sideroblastic anemia · SIDBA3

Data availability: 8 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial membrane transport disorder › mitochondrial substrate carrier disorder › sideroblastic anemia 3

Related subtypes (4): Sengers syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, developmental and epileptic encephalopathy, 39, combined oxidative phosphorylation deficiency 28

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

8 retrieved; paginated sample, class counts are floors:

5 pathogenic, 2 uncertain significance, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1606	NM_016417.3(GLRX5):c.294A>G (p.Gln98=)	GLRX5	Pathogenic	no assertion criteria provided
224510	NM_016417.3(GLRX5):c.301A>C (p.Lys101Gln)	GLRX5	Pathogenic	no assertion criteria provided
224511	NM_016417.3(GLRX5):c.443T>C (p.Leu148Ser)	GLRX5	Pathogenic	no assertion criteria provided
915891	NM_016417.3(GLRX5):c.200G>A (p.Cys67Tyr)	GLRX5	Pathogenic	no assertion criteria provided
915892	NM_016417.3(GLRX5):c.383T>A (p.Met128Lys)	GLRX5	Pathogenic	no assertion criteria provided
4691653	NM_016417.3(GLRX5):c.98_116dup (p.Gly40fs)	GLRX5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029602	NM_016417.3(GLRX5):c.314A>G (p.Asn105Ser)	GLRX5	Uncertain significance	criteria provided, multiple submitters, no conflicts
1029603	NM_016417.3(GLRX5):c.322A>G (p.Thr108Ala)	GLRX5	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 2 · 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
GLRX5	Strong	Autosomal recessive	sideroblastic anemia 3	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GLRX5	Orphanet:255132	Adult-onset autosomal recessive sideroblastic anemia
GLRX5	Orphanet:401866	Childhood-onset spasticity with hyperglycinemia

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GLRX5	HGNC:20134	ENSG00000182512	Q86SX6	Glutaredoxin-related protein 5, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GLRX5	Glutaredoxin-related protein 5, mitochondrial	Monothiol glutaredoxin involved in mitochondrial iron-sulfur (Fe/S) cluster transfer.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GLRX5	Other/Unknown	no		Glutaredoxin, Monothiol_GRX-rel, GRX_PICOT-like

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
diaphragm	1
trabecular bone tissue	1
triceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GLRX5	287	ubiquitous	marker	trabecular bone tissue, diaphragm, triceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GLRX5	1,460

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GLRX5	Q86SX6	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Mitochondrial iron-sulfur cluster biogenesis	1	815.7×	0.001	GLRX5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
[2Fe-2S] cluster assembly	1	1404.3×	0.004	GLRX5
iron-sulfur cluster assembly	1	601.9×	0.005	GLRX5
cell redox homeostasis	1	343.9×	0.005	GLRX5
hemopoiesis	1	267.5×	0.005	GLRX5
intracellular iron ion homeostasis	1	244.2×	0.005	GLRX5
protein maturation	1	163.6×	0.006	GLRX5

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GLRX5	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	GLRX5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GLRX5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.