PDK4

Chr 7

pyruvate dehydrogenase kinase 4

NCBI Gene: 5166ENSG00000004799UniProt: Q16654

This gene is a member of the PDK/BCKDK protein kinase family and encodes a mitochondrial protein with a histidine kinase domain. This protein is located in the matrix of the mitrochondria and inhibits the pyruvate dehydrogenase complex by phosphorylating one of its subunits, thereby contributing to the regulation of glucose metabolism. Expression of this gene is regulated by glucocorticoids, retinoic acid and insulin. [provided by RefSeq, Jul 2008]

79
ClinVar variants
17
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— PDK4
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
17 Pathogenic / Likely Pathogenic· 59 VUS of 79 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
1.24LOEUF
pLI 0.000
Z-score 0.68
OE 0.85 (0.59–1.24)
Tolerant

Highly tolerant — LoF variants common in population

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.
0.35Z-score
OE missense 0.93 (0.83–1.05)
208 obs / 222.8 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.0.85 (0.59–1.24)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.93 (0.83–1.05)
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.1.18
0≤1.21.6
LoF obs/exp: 19 / 22.5Missense obs/exp: 208 / 222.8Syn Z: -1.27

ClinVar Variant Classifications

79 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
VUS59
Likely Benign2
Benign1
17
Pathogenic
59
VUS
2
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
17
0
17
Likely Pathogenic
0
0
0
0
0
VUS
0
55
4
0
59
Likely Benign
0
1
1
0
2
Benign
0
1
0
0
1
Total05722079

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

View in ClinVar →

Protein Context — Lollipop Plot

PDK4 · 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
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Ketogenic diet but not free-sugar restriction alters glucose tolerance, lipid metabolism, peripheral tissue phenotype, and gut microbiome: RCT.
Hengist A et al.·Cell Rep Med
2024
N(6)-methyladenosine regulates glycolysis of cancer cells through PDK4.
Li Z et al.·Nat Commun
2020
METTL16 promotes glycolytic metabolism reprogramming and colorectal cancer progression.
Wei W et al.·J Exp Clin Cancer Res
2023
Pyruvate dehydrogenase kinase regulates vascular inflammation in atherosclerosis and increases cardiovascular risk.
Forteza MJ et al.·Cardiovasc Res
2023
Identification of cell death-related biomarkers and immune infiltration in ischemic stroke between male and female patients.
Chen W et al.·Front Immunol
2023Cohort
Cardiac PDK4 promotes neutrophilic PFKL methylation and drives the innate immune response in diabetic myocardial infarction.
Yang S et al.·Pharmacol Res
2025
Targeting PDK4 to mitigate osimertinib-induced cardiotoxicity: Insights into mitochondria-endoplasmic reticulum crosstalk and necroptosis.
Deng J et al.·Free Radic Biol Med
2025
Mitochondrial-related genes as prognostic and metastatic markers in breast cancer: insights from comprehensive analysis and clinical models.
Fang Y et al.·Front Immunol
2024Functional
Restoring Muribaculum intestinale-Derived Butyrate Mitigates Skeletal Muscle Loss in Cancer Cachexia.
Li L et al.·J Cachexia Sarcopenia Muscle
2025
Metabolic changes in bladder cancer.
Woolbright BL et al.·Urol Oncol
2018Review
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