D2HGDH

Chr 2AR

D-2-hydroxyglutarate dehydrogenase

Also known as: D2HGD

NCBI Gene: 728294ENSG00000180902UniProt: Q8N465

This gene encodes D-2hydroxyglutarate dehydrogenase, a mitochondrial enzyme belonging to the FAD-binding oxidoreductase/transferase type 4 family. This enzyme, which is most active in liver and kidney but also active in heart and brain, converts D-2-hydroxyglutarate to 2-ketoglutarate. Mutations in this gene are present in D-2-hydroxyglutaric aciduria, a rare recessive neurometabolic disorder causing developmental delay, epilepsy, hypotonia, and dysmorphic features. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

D-2-hydroxyglutaric aciduriaMIM #600721
AR
577
ClinVar variants
135
Pathogenic / LP
0.05
pLI score
0
Active trials
Clinical Summary— D2HGDH
🧬
Gene-Disease Validity (ClinGen)
mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.
📋
ClinVar Variants
135 Pathogenic / Likely Pathogenic· 220 VUS of 577 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.58LOEUF
pLI 0.054
Z-score 2.95
OE 0.29 (0.16–0.58)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.72Z-score
OE missense 0.89 (0.81–0.98)
300 obs / 337.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.29 (0.16–0.58)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.89 (0.81–0.98)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.05
0≤1.21.6
LoF obs/exp: 6 / 20.4Missense obs/exp: 300 / 337.1Syn Z: -0.54

ClinVar Variant Classifications

577 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic109
Likely Pathogenic26
VUS220
Likely Benign140
Benign46
Conflicting36
109
Pathogenic
26
Likely Pathogenic
220
VUS
140
Likely Benign
46
Benign
36
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
3
98
0
109
Likely Pathogenic
4
9
13
0
26
VUS
1
140
76
3
220
Likely Benign
0
12
36
92
140
Benign
0
0
42
4
46
Conflicting
—36
Total1316426599577

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

D2HGDH · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

D2HGDH-related D-2-hydroxyglutaric aciduria

limited
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

D-2-hydroxyglutaric aciduria

MIM #600721

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Oxidation of α-hydroxy acids by D-2-hydroxyglutarate dehydrogenase enzymes.
Quaye JA et al.·Arch Biochem Biophys
2025Review
D2HGDH-mediated D2HG catabolism enhances the anti-tumor activities of CAR-T cells in an immunosuppressive microenvironment.
Yang Q et al.·Mol Ther
2022
Adult diffuse glioma GWAS by molecular subtype identifies variants in D2HGDH and FAM20C.
Eckel-Passow JE et al.·Neuro Oncol
2020
Novel genetic associations with childhood adipocytokines in Indian adolescents.
Nair JM et al.·Cytokine
2025
D-2-hydroxyglutaric aciduria Type I: Functional analysis of D2HGDH missense variants.
Pop A et al.·Hum Mutat
2019Functional
Computational approach to unravel the impact of missense mutations of proteins (D2HGDH and IDH2) causing D-2-hydroxyglutaric aciduria 2.
Thirumal Kumar D et al.·Metab Brain Dis
2018
Trio Exome Sequencing Reveal Paternal Transmission Bias and Novel Gene Loci in Recurrent Spontaneous Abortion.
Duan H et al.·FASEB J
2025
Recurrent cis-SAGe chimeric RNA, D2HGDH-GAL3ST2, in prostate cancer.
Qin F et al.·Cancer Lett
2016
Widespread and debilitating hemangiomas in a patient with enchondromatosis and D-2-hydroxyglutaric aciduria.
Yeetong P et al.·Skeletal Radiol
2018Case report
[Analysis of L2HGDH gene mutation in a patient with 2-hydroxyglutaric aciduria].
Deng Y et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2016
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools