PDK3

Chr XXLD

pyruvate dehydrogenase kinase 3

NCBI Gene: 5165ENSG00000067992UniProt: Q15120

Inhibits pyruvate dehydrogenase activity by phosphorylation of the E1 subunit PDHA1, and thereby regulates glucose metabolism and aerobic respiration. Can also phosphorylate PDHA2. Decreases glucose utilization and increases fat metabolism in response to prolonged fasting, and as adaptation to a high-fat diet. Plays a role in glucose homeostasis and in maintaining normal blood glucose levels in function of nutrient levels and under starvation. Plays a role in the generation of reactive oxygen species

Primary Disease Associations & Inheritance

?Charcot-Marie-Tooth disease, X-linked dominant, 6MIM #300905
XLD
0
ClinVar variants
0
Pathogenic / LP
0.45
pLI score
0
Active trials
Clinical Summary— PDK3
🧬
Gene-Disease Validity (ClinGen)
Charcot-Marie-Tooth disease X-linked dominant 6 · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.21) despite low pLI — interpret in context.

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.
0.55LOEUF
pLI 0.445
Z-score 2.75
OE 0.21 (0.10–0.55)
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.
2.32Z-score
OE missense 0.46 (0.38–0.56)
67 obs / 145.8 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.21 (0.10–0.55)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.46 (0.38–0.56)
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.0.87
0≤1.21.6
LoF obs/exp: 3 / 14.2Missense obs/exp: 67 / 145.8Syn Z: 0.77

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

PDK3 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Charcot-Marie-Tooth disease, X-linked dominant, 6

MIM #300905

Molecular basis of disorder known

X-linked dominant
📖
GeneReview available — PDK3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
NCAPD3 enhances Warburg effect through c-myc and E2F1 and promotes the occurrence and progression of colorectal cancer.
Jing Z et al.·J Exp Clin Cancer Res
2022
Synchronized long-read genome, methylome, epigenome and transcriptome profiling resolve a Mendelian condition.
Vollger MR et al.·Nat Genet
2025
Recent advances in Charcot-Marie-Tooth disease.
Baets J et al.·Curr Opin Neurol
2014Review
Exploring PDK3 inhibition in lung cancer through drug repurposing for potential therapeutic interventions.
Khan ZF et al.·Sci Rep
2024
Overexpression of PDK2 and PDK3 reflects poor prognosis in acute myeloid leukemia.
Cui L et al.·Cancer Gene Ther
2020
Melittin suppresses aerobic glycolysis by regulating HSF1/PDK3 to increase chemosensitivity of NSCLC.
Wang Y et al.·Eur J Pharmacol
2025
The Novel Role of Mitochondrial Citrate Synthase and Citrate in the Pathophysiology of Alzheimer's Disease.
Chhimpa N et al.·J Alzheimers Dis
2023Review
A Mitochondria-Related Signature in Diffuse Large B-Cell Lymphoma: Prognosis, Immune and Therapeutic Features.
Zhou ZZ et al.·Cancer Med
2025
Correlation of Glycolysis-immune-related Genes in the Follicular Microenvironment of Endometriosis Patients with ART Outcomes.
Guo S et al.·Reprod Sci
2024Cohort
The hypoxia-associated genes in immune infiltration and treatment options of lung adenocarcinoma.
Liu L et al.·PeerJ
2023
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