DHODH

Chr 16AR

dihydroorotate dehydrogenase (quinone)

Also known as: DHOdehase, POADS, URA1

NCBI Gene: 1723ENSG00000102967UniProt: Q02127

This mitochondrial enzyme catalyzes the conversion of dihydroorotate to orotate in the de novo pyrimidine biosynthesis pathway, which is required for UMP production. Autosomal recessive mutations cause Miller syndrome, a rare disorder characterized by severe micrognathia, cleft lip/palate, cup-shaped ears, eyelid colobomas, and postaxial limb defects. The pathogenic mechanism involves dominant-negative effects that disrupt pyrimidine metabolism.

Summary from RefSeq, OMIM, UniProt, Mechanism

Primary Disease Associations & Inheritance

Miller syndromeMIM #263750
AR
UniProtPostaxial acrofacial dysostosis
1
Active trials
146
Pubs (1 yr)
52
P/LP submissions
15%
P/LP missense
0.78
LOEUF
LOF*
Mechanism· G2P
Clinical Summary— DHODH
🧬
Gene-Disease Validity (ClinGen)
postaxial acrofacial dysostosis · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
39 unique Pathogenic / Likely Pathogenic· 115 VUS of 256 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.78LOEUF
pLI 0.003
Z-score 2.23
OE 0.41 (0.23–0.78)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
-0.34Z-score
OE missense 1.06 (0.96–1.18)
254 obs / 239.3 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.41 (0.23–0.78)
0≤0.351.4
Missense OE1.06 (0.96–1.18)
0≤0.61.4
Synonymous OE1.18
0≤1.21.6
LoF obs/exp: 7 / 16.9Missense obs/exp: 254 / 239.3Syn Z: -1.41
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveDHODH-related postaxial acrofacial dysostosisLOFAR
DN
0.7228th %ile
GOF
0.4677th %ile
LOF
0.2873th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

256 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic32
Likely Pathogenic7
VUS115
Likely Benign47
Benign31
Conflicting13
32
Pathogenic
7
Likely Pathogenic
115
VUS
47
Likely Benign
31
Benign
13
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
3
26
0
32
Likely Pathogenic
0
3
4
0
7
VUS
1
79
31
4
115
Likely Benign
0
5
18
24
47
Benign
0
3
28
0
31
Conflicting
—13
Total49310728245

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

View in ClinVar →

Protein Context — Lollipop Plot

DHODH · protein map & ClinVar variants

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

Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Exploiting metabolic dependencies in acute myeloid leukemia: DHODH inhibition meets lipid and cholesterol metabolism.
Cruz-Rodriguez N.·Haematologica
2026
Targeting the NSUN2-DHODH axis reverses ferroptosis resistance and oxaliplatin resistance in colorectal cancer.
Zhang J et al.·Front Pharmacol
2026Open Access
Development of DHODH inhibitors incorporating virtual screening, pharmacophore modeling, fragment-based optimization methods, ADMET, molecular docking, molecular dynamics, PCA analysis, and free energy landscape.
Wang Q et al.·PLoS One
2026Open AccessFunctional
Ectopic expression of cytosolic DHODH uncouples de novo pyrimidine biosynthesis from mitochondrial electron transport.
Curtabbi A et al.·Nat Metab
2026Open Access
Co-disruption of GPX4 and DHODH Ferroptosis Defense Systems via Excipient-Free Self-Assembled Nanoassemblies for Enhanced Ferroptosis Therapy in Triple-Negative Breast Cancer.
Xia T et al.·ACS Appl Mater Interfaces
2026
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients