D,L-2-hydroxyglutaric aciduria

Summary

D,L-2-hydroxyglutaric aciduria (MONDO:0014072) is a disease caused by SLC25A1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC25A1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 6

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		13	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	D,L-2-hydroxyglutaric aciduria
Mondo ID	MONDO:0014072
OMIM	615182
Orphanet	356978
DOID	DOID:0111619
SNOMED CT	713401006
UMLS	C5574940
MedGen	1802316
GARD	0017540
Is cancer (heuristic)	no

Also known as: combined D-2- and L-2-hydroxyglutaric aciduria · combined D-2-hydroxyglutaric acidemia and L-2-hydroxyglutaric acidemia · combined D-2-hydroxyglutaric aciduria and L-2-hydroxyglutaric aciduria · D,L-2-HGA · D,L-2-hydroxyglutaric acidemia · D,L-2-hydroxyglutaric aciduria · D2L2AD

Data availability: 6 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › 2-hydroxyglutaric aciduria › D,L-2-hydroxyglutaric aciduria

Related subtypes (2): L-2-hydroxyglutaric aciduria, D-2-hydroxyglutaric aciduria

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

6 retrieved; paginated sample, class counts are floors:

3 likely pathogenic, 2 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
42194	NM_005984.5(SLC25A1):c.844C>T (p.Arg282Cys)	SLC25A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
42198	NM_005984.5(SLC25A1):c.517_526del (p.Arg173fs)	SLC25A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
42193	NM_005984.5(SLC25A1):c.844C>G (p.Arg282Gly)	SLC25A1	Likely pathogenic	criteria provided, single submitter
42195	NM_005984.5(SLC25A1):c.845G>A (p.Arg282His)	SLC25A1	Likely pathogenic	criteria provided, single submitter
42197	NM_005984.5(SLC25A1):c.821C>T (p.Ala274Val)	SLC25A1	Likely pathogenic	criteria provided, single submitter
42196	NM_005984.5(SLC25A1):c.389G>A (p.Gly130Asp)	SLC25A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
SLC25A1	Definitive	Autosomal recessive	D,L-2-hydroxyglutaric aciduria	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC25A1	Orphanet:356978	D,L-2-hydroxyglutaric aciduria
SLC25A1	Orphanet:98914	Presynaptic congenital myasthenic syndromes

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
SLC25A1	HGNC:10979	ENSG00000100075	P53007	Tricarboxylate transport protein, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC25A1	Tricarboxylate transport protein, mitochondrial	Mitochondrial electroneutral antiporter that exports citrate from the mitochondria into the cytosol in exchange for malate.

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)
SLC25A1	Other/Unknown	no		MCP, MCP_transmembrane, MCP_dom_sf

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
endometrium epithelium	1
mucosa of transverse colon	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC25A1	284	ubiquitous	marker	endometrium epithelium, mucosa of transverse colon, right lobe of liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC25A1	2,949

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC25A1	P53007	75.09

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
Organic anion transport by SLC5/17/25 transporters	1	1427.5×	7e-04	SLC25A1

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
mitochondrial citrate transmembrane transport	1	8426.0×	4e-04	SLC25A1
negative regulation of ferroptosis	1	802.5×	0.002	SLC25A1
monoatomic ion transport	1	156.0×	0.006	SLC25A1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC25A1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC25A1	5	Binding:5

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	SLC25A1

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)
SLC25A1	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.