L-2-hydroxyglutaric aciduria

Summary

L-2-hydroxyglutaric aciduria (MONDO:0009370) is a disease caused by L2HGDH (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: L2HGDH (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 259
• Phenotypes (HPO): 12

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		140	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0001250	Seizure	Very frequent (80-99%)
HP:0002383	Infectious encephalitis	Very frequent (80-99%)
HP:0006887	Intellectual disability, progressive	Very frequent (80-99%)
HP:0010864	Intellectual disability, severe	Very frequent (80-99%)
HP:0000256	Macrocephaly	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001285	Spastic tetraparesis	Frequent (30-79%)
HP:0002071	Abnormality of extrapyramidal motor function	Frequent (30-79%)
HP:0004375	Neoplasm of the nervous system	Frequent (30-79%)
HP:0007360	Aplasia/Hypoplasia of the cerebellum	Frequent (30-79%)
HP:0002381	Aphasia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	L-2-hydroxyglutaric aciduria
Mondo ID	MONDO:0009370
OMIM	236792
Orphanet	79314
DOID	DOID:0050574
ICD-11	562958433
SNOMED CT	237961001
UMLS	C1855995
MedGen	341029
GARD	0010472
Is cancer (heuristic)	no

Also known as: L-2-HGA · L-2-hydroxyglutaric acidemia · L-2-hydroxyglutaric aciduria · L2HGA

Data availability: 259 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 › L-2-hydroxyglutaric aciduria

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

259 retrieved; paginated sample, class counts are floors:

98 uncertain significance, 77 likely benign, 34 pathogenic, 17 conflicting classifications of pathogenicity, 10 likely pathogenic, 10 benign/likely benign, 8 benign, 5 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1342871	NM_024884.3(L2HGDH):c.1A>G (p.Met1Val)	DMAC2L	Pathogenic	criteria provided, multiple submitters, no conflicts
1028352	NM_024884.3(L2HGDH):c.903T>G (p.Tyr301Ter)	L2HGDH	Pathogenic	criteria provided, multiple submitters, no conflicts
1070154	NC_000014.8:g.(?50778709)(50778888_?)del	L2HGDH	Pathogenic	criteria provided, single submitter
1299481	NM_024884.3(L2HGDH):c.959del (p.Asp320fs)	L2HGDH	Pathogenic	criteria provided, multiple submitters, no conflicts
1339478	NM_024884.3(L2HGDH):c.140+726del	L2HGDH	Pathogenic	no assertion criteria provided
1429237	NM_024884.3(L2HGDH):c.418G>C (p.Ala140Pro)	L2HGDH	Pathogenic	criteria provided, single submitter
1448939	NM_024884.3(L2HGDH):c.853del (p.Tyr285fs)	L2HGDH	Pathogenic	criteria provided, single submitter
1607	NM_024884.3(L2HGDH):c.905C>T (p.Pro302Leu)	L2HGDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1608	NM_024884.3(L2HGDH):c.1115del (p.Met372fs)	L2HGDH	Pathogenic	criteria provided, multiple submitters, no conflicts
1609	NM_024884.3(L2HGDH):c.906+1G>T	L2HGDH	Pathogenic	no assertion criteria provided
1610	NM_024884.3(L2HGDH):c.164G>A (p.Gly55Asp)	L2HGDH	Pathogenic	criteria provided, single submitter
1612	NM_024884.3(L2HGDH):c.293A>G (p.His98Arg)	L2HGDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2026101	NM_024884.3(L2HGDH):c.944del (p.Phe315fs)	L2HGDH	Pathogenic	criteria provided, single submitter
2086204	NM_024884.3(L2HGDH):c.256+2T>A	L2HGDH	Pathogenic	criteria provided, single submitter
211348	NM_024884.3(L2HGDH):c.465del (p.Gly156fs)	L2HGDH	Pathogenic	criteria provided, single submitter
2137582	NM_024884.3(L2HGDH):c.751C>T (p.Arg251Ter)	L2HGDH	Pathogenic	criteria provided, multiple submitters, no conflicts
2137583	NM_024884.3(L2HGDH):c.241A>G (p.Lys81Glu)	L2HGDH	Pathogenic	criteria provided, single submitter
2152204	NM_024884.3(L2HGDH):c.178G>A (p.Gly60Arg)	L2HGDH	Pathogenic	criteria provided, single submitter
2426898	NC_000014.8:g.(?50750569)(50750771_?)del	L2HGDH	Pathogenic	criteria provided, single submitter
2426899	NC_000014.8:g.(?50760813)(50768906_?)del	L2HGDH	Pathogenic	criteria provided, single submitter
2430996	NM_024884.3(L2HGDH):c.530_533delinsATT (p.Pro177fs)	L2HGDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2637446	NM_024884.3(L2HGDH):c.1081del (p.Ala361fs)	L2HGDH	Pathogenic	criteria provided, single submitter
30793	NM_024884.3(L2HGDH):c.1003C>T (p.Arg335Ter)	L2HGDH	Pathogenic	criteria provided, multiple submitters, no conflicts
3238838	NM_024884.3(L2HGDH):c.169G>A (p.Gly57Arg)	L2HGDH	Pathogenic	criteria provided, single submitter
3243997	NC_000014.8:g.(?50734451)(50734648_?)del	L2HGDH	Pathogenic	criteria provided, single submitter
3243998	NC_000014.8:g.(?50732056)(50732227_?)del	L2HGDH	Pathogenic	criteria provided, single submitter
3689720	NM_024884.3(L2HGDH):c.427C>T (p.Gln143Ter)	L2HGDH	Pathogenic	criteria provided, single submitter
3721504	NM_024884.3(L2HGDH):c.802G>T (p.Glu268Ter)	L2HGDH	Pathogenic	criteria provided, single submitter
379781	NM_024884.3(L2HGDH):c.256+1G>A	L2HGDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
435701	NM_024884.3(L2HGDH):c.1015del (p.Arg339fs)	L2HGDH	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
L2HGDH	Definitive	Autosomal recessive	L-2-hydroxyglutaric aciduria	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
L2HGDH	Orphanet:79314	L-2-hydroxyglutaric aciduria

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
L2HGDH	HGNC:20499	ENSG00000087299	Q9H9P8	L-2-hydroxyglutarate dehydrogenase, mitochondrial	gencc,clinvar
DMAC2L	HGNC:18799	ENSG00000125375	Q99766	ATP synthase subunit s, mitochondrial	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DMAC2L	ATP synthase subunit s, mitochondrial	Involved in regulation of mitochondrial membrane ATP synthase.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
L2HGDH	Enzyme (other)	yes	1.1.99.2	FAD-dep_OxRdtase, FAD/NAD-bd_sf
DMAC2L	Other/Unknown	no		LRR_dom_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
muscle of leg	1
primordial germ cell in gonad	1
male germ cell	1
right uterine tube	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
L2HGDH	209	ubiquitous	marker	primordial germ cell in gonad, muscle of leg, gastrocnemius
DMAC2L	294	ubiquitous	marker	sperm, right uterine tube, male germ cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
L2HGDH	1,778
DMAC2L	1,077

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DMAC2L	Q99766	91.27
L2HGDH	Q9H9P8	88.26

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 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
Aerobic respiration and respiratory electron transport	2	88.5×	9e-04	L2HGDH, DMAC2L
Interconversion of 2-oxoglutarate and 2-hydroxyglutarate	1	1903.3×	0.002	L2HGDH
Formation of ATP by chemiosmotic coupling	1	285.5×	0.008	DMAC2L
Cristae formation	1	173.0×	0.010	DMAC2L
Metabolism	2	11.6×	0.010	L2HGDH, DMAC2L
Mitochondrial biogenesis	1	84.0×	0.014	DMAC2L
Organelle biogenesis and maintenance	1	33.0×	0.030	DMAC2L

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
small molecule metabolic process	1	8426.0×	5e-04	L2HGDH
ATP biosynthetic process	1	495.6×	0.003	DMAC2L
2-oxoglutarate metabolic process	1	468.1×	0.003	L2HGDH
proton transmembrane transport	1	156.0×	0.006	DMAC2L

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 2 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
L2HGDH	0	0
DMAC2L	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
L2HGDH	1.1.99.2	L-2-hydroxyglutarate dehydrogenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	1	L2HGDH
E	Difficult family or no structure, no drug	1	DMAC2L

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)
L2HGDH	0	—
DMAC2L	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.