D-2-hydroxyglutaric aciduria 1

Summary

D-2-hydroxyglutaric aciduria 1 (MONDO:0024554) is a disease caused by D2HGDH (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: D2HGDH (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 353

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	D-2-hydroxyglutaric aciduria 1
Mondo ID	MONDO:0024554
OMIM	600721
DOID	DOID:0111351
UMLS	C3152055
MedGen	463405
GARD	0025429
Is cancer (heuristic)	no

Also known as: D-2-hydroxyglutaric aciduria · D-2-hydroxyglutaric aciduria 1 · D-2-hydroxyglutaric aciduria caused by mutation in D2HGDH · D2HGA1 · D2HGDH D-2-hydroxyglutaric aciduria

Data availability: 353 ClinVar variants · 3 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-2-hydroxyglutaric aciduria › D-2-hydroxyglutaric aciduria 1

Related subtypes (1): d-2-hydroxyglutaric aciduria 2

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

353 retrieved; paginated sample, class counts are floors:

133 uncertain significance, 110 likely benign, 37 conflicting classifications of pathogenicity, 30 benign, 17 benign/likely benign, 15 pathogenic, 7 likely pathogenic, 3 pathogenic/likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1411455	NC_000002.11:g.(?238233417)(242801596_?)del	ATG4B	Pathogenic	criteria provided, single submitter
1022469	NM_152783.5(D2HGDH):c.1393del (p.Thr465fs)	D2HGDH	Pathogenic	criteria provided, single submitter
1480964	NM_152783.5(D2HGDH):c.1306+1del	D2HGDH	Pathogenic	criteria provided, single submitter
1701413	NM_152783.5(D2HGDH):c.326C>G (p.Ser109Trp)	D2HGDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1805533	NM_152783.5(D2HGDH):c.71G>A (p.Trp24Ter)	D2HGDH	Pathogenic	criteria provided, single submitter
1852	NM_152783.5(D2HGDH):c.1331T>C (p.Val444Ala)	D2HGDH	Pathogenic	criteria provided, single submitter
1853	NM_152783.5(D2HGDH):c.440T>G (p.Ile147Ser)	D2HGDH	Pathogenic	no assertion criteria provided
1854	NM_152783.5(D2HGDH):c.293-23A>G	D2HGDH	Pathogenic	no assertion criteria provided
1855	NM_152783.5(D2HGDH):c.685-2A>G	D2HGDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1856	NM_152783.5(D2HGDH):c.1315A>G (p.Asn439Asp)	D2HGDH	Pathogenic	no assertion criteria provided
1857	NM_152783.5(D2HGDH):c.325_326dup (p.Glu110fs)	D2HGDH	Pathogenic	criteria provided, single submitter
1954804	NM_152783.5(D2HGDH):c.392dup (p.Asn132fs)	D2HGDH	Pathogenic	criteria provided, single submitter
2014046	NM_152783.5(D2HGDH):c.887_888insGG (p.Phe296fs)	D2HGDH	Pathogenic	criteria provided, single submitter
3247382	NC_000002.11:g.(?242690641)(242690823_?)del	D2HGDH	Pathogenic	criteria provided, single submitter
3902760	NM_152783.5(D2HGDH):c.505C>T (p.Gln169Ter)	D2HGDH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
572875	NM_152783.5(D2HGDH):c.642del (p.Arg215fs)	D2HGDH	Pathogenic	criteria provided, single submitter
579877	NM_152783.5(D2HGDH):c.1353del (p.Ser452fs)	D2HGDH	Pathogenic	criteria provided, single submitter
539292	NC_000002.12:g.(?241741010)(241767989_?)del	LOC129389016	Pathogenic	criteria provided, single submitter
3362676	NM_152783.5(D2HGDH):c.523G>T (p.Glu175Ter)	D2HGDH	Likely pathogenic	criteria provided, single submitter
3382850	NM_152783.5(D2HGDH):c.457A>G (p.Met153Val)	D2HGDH	Likely pathogenic	criteria provided, single submitter
4056413	NM_152783.5(D2HGDH):c.814T>C (p.Cys272Arg)	D2HGDH	Likely pathogenic	criteria provided, single submitter
4765381	NM_152783.5(D2HGDH):c.1421C>A (p.Ala474Glu)	D2HGDH	Likely pathogenic	criteria provided, single submitter
570363	NM_152783.5(D2HGDH):c.853+2T>C	D2HGDH	Likely pathogenic	criteria provided, single submitter
649282	NM_152783.5(D2HGDH):c.1370T>C (p.Leu457Pro)	D2HGDH	Likely pathogenic	criteria provided, single submitter
3065857	NM_152783.5(D2HGDH):c.10dup (p.Arg4fs)	LOC129936031	Likely pathogenic	criteria provided, single submitter
1480672	NM_152783.5(D2HGDH):c.1243G>A (p.Val415Met)	D2HGDH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
158408	NM_152783.5(D2HGDH):c.1184G>A (p.Arg395Gln)	D2HGDH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
158409	NM_152783.5(D2HGDH):c.1258G>A (p.Ala420Thr)	D2HGDH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
158422	NM_152783.5(D2HGDH):c.566C>T (p.Pro189Leu)	D2HGDH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1965886	NM_152783.5(D2HGDH):c.418G>A (p.Val140Ile)	D2HGDH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
D2HGDH	Strong	Autosomal recessive	D-2-hydroxyglutaric aciduria 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
D2HGDH	Orphanet:79315	D-2-hydroxyglutaric aciduria
AGXT	Orphanet:93598	Primary hyperoxaluria type 1

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
D2HGDH	HGNC:28358	ENSG00000180902	Q8N465	D-2-hydroxyglutarate dehydrogenase, mitochondrial	gencc,clinvar
ATG4B	HGNC:20790	ENSG00000168397	Q9Y4P1	Cysteine protease ATG4B	clinvar
AGXT	HGNC:341	ENSG00000172482	P21549	Alanine–glyoxylate aminotransferase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
D2HGDH	D-2-hydroxyglutarate dehydrogenase, mitochondrial	Catalyzes the oxidation of D-2-hydroxyglutarate (D-2-HG) to alpha-ketoglutarate.
ATG4B	Cysteine protease ATG4B	Cysteine protease that plays a key role in autophagy by mediating both proteolytic activation and delipidation of ATG8 family proteins.
AGXT	Alanine–glyoxylate aminotransferase	Peroxisomal aminotransferase that catalyzes the transamination of glyoxylate to glycine and contributes to the glyoxylate detoxification.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	2	8.0×	0.039
Protease	1	12.2×	0.080

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
D2HGDH	Enzyme (other)	yes	1.1.99.39	FAD-bd_oxidored_4_C, Oxid_FAD_bind_N, FAD-linked_Oxase-like_C
ATG4B	Protease	yes		Peptidase_C54, Papain-like_cys_pep_sf, Peptidase_C54_cat
AGXT	Enzyme (other)	yes	2.6.1.44	Aminotrans_V_dom, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase_small

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
pancreatic ductal cell	1
right uterine tube	1
tendon of biceps brachii	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
endometrium epithelium	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
D2HGDH	223	ubiquitous	marker	right uterine tube, pancreatic ductal cell, tendon of biceps brachii
ATG4B	289	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
AGXT	125	tissue_specific	marker	right lobe of liver, liver, endometrium epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AGXT	2,648
ATG4B	2,076
D2HGDH	1,885

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AGXT	P21549	17
ATG4B	Q9Y4P1	7
D2HGDH	Q8N465	6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Interconversion of 2-oxoglutarate and 2-hydroxyglutarate	1	1268.9×	0.006	D2HGDH
Glyoxylate metabolism and glycine degradation	1	253.8×	0.016	AGXT
Protein localization	1	63.4×	0.032	AGXT
Peroxisomal protein import	1	57.7×	0.032	AGXT
Autophagy	1	49.4×	0.032	ATG4B
Macroautophagy	1	38.5×	0.034	ATG4B
Metabolism of amino acids and derivatives	1	22.5×	0.050	AGXT
Metabolism	1	3.9×	0.237	AGXT

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
otolith mineralization completed early in development	1	5617.3×	0.003	ATG4B
tartrate metabolic process	1	5617.3×	0.003	D2HGDH
microautophagy	1	1872.4×	0.003	ATG4B
obsolete glycine biosynthetic process, by transamination of glyoxylate	1	1872.4×	0.003	AGXT
oxalic acid secretion	1	1872.4×	0.003	AGXT
glyoxylate catabolic process	1	1404.3×	0.003	AGXT
L-cysteine catabolic process	1	1404.3×	0.003	AGXT
L-alanine catabolic process	1	1404.3×	0.003	AGXT
protein delipidation	1	1123.5×	0.003	ATG4B
response to manganese ion	1	936.2×	0.003	D2HGDH
glyoxylate metabolic process	1	936.2×	0.003	AGXT
response to cobalt ion	1	802.5×	0.003	D2HGDH
lactate metabolic process	1	624.1×	0.003	D2HGDH
malate metabolic process	1	624.1×	0.003	D2HGDH
L-serine metabolic process	1	561.7×	0.003	AGXT
aggrephagy	1	561.7×	0.003	ATG4B
protein localization to phagophore assembly site	1	330.4×	0.005	ATG4B
2-oxoglutarate metabolic process	1	312.1×	0.005	D2HGDH
piecemeal microautophagy of the nucleus	1	312.1×	0.005	ATG4B
response to zinc ion	1	208.1×	0.007	D2HGDH
mitophagy	1	106.0×	0.013	ATG4B
protein destabilization	1	96.8×	0.014	D2HGDH
macroautophagy	1	80.2×	0.016	ATG4B
autophagosome assembly	1	74.9×	0.016	ATG4B
protein processing	1	56.7×	0.020	ATG4B
Notch signaling pathway	1	47.2×	0.023	AGXT
autophagy	1	36.7×	0.029	ATG4B
protein transport	1	14.6×	0.069	ATG4B
proteolysis	1	11.4×	0.085	ATG4B

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ATG4B	TIOCONAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATG4B	7	4
D2HGDH	0	0
AGXT	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TIOCONAZOLE	4	ATG4B
BIFONAZOLE	4	ATG4B
HYPERICIN	3	ATG4B
EBSELEN	3	ATG4B
TOLFENAMIC ACID	2	ATG4B
FENTICLOR	2	ATG4B
ELLAGIC ACID	2	ATG4B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ATG4B	63	Binding:61, Functional:2
AGXT	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
D2HGDH	1.1.99.39	D-2-hydroxyglutarate dehydrogenase
AGXT	2.6.1.44, 2.6.1.51	alanine-glyoxylate transaminase, serine-pyruvate transaminase

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

7 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)
TIOCONAZOLE	4	ATG4B
BIFONAZOLE	4	ATG4B
HYPERICIN	3	ATG4B
EBSELEN	3	ATG4B
TOLFENAMIC ACID	2	ATG4B
FENTICLOR	2	ATG4B
ELLAGIC ACID	2	ATG4B

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ATG4B
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	D2HGDH, AGXT
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
D2HGDH	0	—
AGXT	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.