ENO2 encodes gamma-enolase, a glycolytic enzyme that catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate and has neurotrophic properties in central nervous system neurons. Mutations cause autosomal recessive glycolytic enzymopathy with hemolytic anemia, characterized by exercise intolerance, muscle weakness, and chronic hemolysis. The gene is moderately constrained against loss-of-function variants (LOEUF 0.471), reflecting its essential role in neuronal glucose metabolism.

OMIMResearchSummary from RefSeq, UniProt
MultiplemechanismLOEUF 0.47
Clinical SummaryENO2
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Moderate LoF intolerance
LoF Constraint
0.47LOEUF
pLI 0.384
Z-score 3.40
OE 0.22 (0.120.47)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
1.81Z-score
OE missense 0.69 (0.610.78)
180 obs / 262.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.22 (0.120.47)
00.351.4
Missense OE0.69 (0.610.78)
00.61.4
Synonymous OE0.95
01.21.6
LoF obs/exp: 5 / 22.3Missense obs/exp: 180 / 262.5Syn Z: 0.43
DN
0.7033th %ile
GOF
0.6540th %ile
LOF
0.3259th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
GOFprediction 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

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

ENO2 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold
Clinical Literature
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