PDHA1

Chr X

pyruvate dehydrogenase E1 subunit alpha 1

Also known as: E1alpha, PDHA, PDHAD, PDHCE1A, PHE1A

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), and provides the primary link between glycolysis and the tricarboxylic acid (TCA) cycle. The PDH complex is composed of multiple copies of three enzymatic components: pyruvate dehydrogenase (E1), dihydrolipoamide acetyltransferase (E2) and lipoamide dehydrogenase (E3). The E1 enzyme is a heterotetramer of two alpha and two beta subunits. This gene encodes the E1 alpha 1 subunit containing the E1 active site, and plays a key role in the function of the PDH complex. Mutations in this gene are associated with pyruvate dehydrogenase E1-alpha deficiency and X-linked Leigh syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]

ResearchGenerating clinical summary…
LOFmechanismLOEUF 0.27
VCEP Guidelines: Mitochondrial DiseaseReleased
View SpecificationsClinGen Panel
Clinical SummaryPDHA1
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Gene-Disease Validity (ClinGen)
Leigh syndrome · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint?
0.27LOEUF
pLI 0.988
Z-score 3.70
OE 0.06 (0.020.27)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?
2.57Z-score
OE missense 0.45 (0.380.55)
79 obs / 174.7 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?
LoF OE?0.06 (0.020.27)
00.351.4
Missense OE?0.45 (0.380.55)
00.61.4
Synonymous OE?0.84
01.21.6
LoF obs/exp: 1 / 17.8Missense obs/exp: 79 / 174.7Syn Z: 1.04
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitivePDHA1-related intellectual disabilityLOFXLR
definitivePDHA1-related pyruvate dehydrogenase E1-alpha deficiencyLOFmonoallelic_X_heterozygous

This gene — mechanism propensity

DN
0.3892th %ile
GOF
0.3888th %ile
LOF
0.69top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.27 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

PDHA1 · protein map & ClinVar variants

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