PDK3

Chr XXLD

pyruvate dehydrogenase kinase 3

Also known as: CMTX6, GS1-358P8.4

NCBI Gene: 5165 ENSG00000067992 UniProt: Q15120 OMIM: 300906

PDK3 encodes pyruvate dehydrogenase kinase 3, which inhibits the pyruvate dehydrogenase complex by phosphorylating its E1 subunit, thereby regulating the conversion of pyruvate to acetyl-CoA and controlling glucose metabolism. Mutations cause X-linked dominant Charcot-Marie-Tooth disease type 6, a peripheral neuropathy. The gene is predominantly expressed in heart and skeletal muscle and shows moderate constraint against loss-of-function variants (LOEUF 0.546).

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The pyruvate dehydrogenase (PDH) complex is a nuclear-encoded mitochondrial multienzyme complex that catalyzes the overall conversion of pyruvate to acetyl-CoA and CO(2). It provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle, and thus is one of the major enzymes responsible for the regulation of glucose metabolism. The enzymatic activity of PDH is regulated by a phosphorylation/dephosphorylation cycle, and phosphorylation results in inactivation of PDH. The protein encoded by this gene is one of the three pyruvate dehydrogenase kinases that inhibits the PDH complex by phosphorylation of the E1 alpha subunit. This gene is predominantly expressed in the heart and skeletal muscles. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismXLDLOEUF 0.551 OMIM phenotype

Clinical Summary— PDK3

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Gene-Disease Validity (ClinGen)

Charcot-Marie-Tooth disease X-linked dominant 6 · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

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

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 112 VUS of 313 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — PDK3

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

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?

LoF OE?0.21 (0.10–0.55)

0≤0.351.4

Missense OE?0.46 (0.38–0.56)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 3 / 14.2Missense obs/exp: 67 / 145.8Syn Z: 0.77

This gene — mechanism propensity

0.6357th %ile

GOF

0.6150th %ile

LOF

0.3939th %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

313 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS112

Likely Benign86

Benign39

Conflicting9

Pathogenic

112

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	1	0	1
Likely Pathogenic	0	0	0	0	0
VUS	11	73	26	2	112
Likely Benign	2	3	42	39	86
Benign	0	3	31	5	39
Conflicting	—				9
Total	13	79	100	46	247

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

View in ClinVar →

77 pathogenic / likely-pathogenic (of 87) ClinVar copy-number / structural variants overlap PDK3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →