ENO2

Chr 12

enolase 2

Also known as: HEL-S-279, NSE

NCBI Gene: 2026 ENSG00000111674 UniProt: P09104

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.

ResearchSummary from RefSeq, UniProt

This gene encodes one of the three enolase isoenzymes found in mammals. This isoenzyme, a homodimer, is found in mature neurons and cells of neuronal origin. A switch from alpha enolase to gamma enolase occurs in neural tissue during development in rats and primates. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.47

Clinical Summary— ENO2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.

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ClinVar Variants

41 VUS of 54 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.47LOEUF

pLI 0.384

Z-score 3.40

OE 0.22 (0.12–0.47)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.81Z-score

OE missense 0.69 (0.61–0.78)

180 obs / 262.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.22 (0.12–0.47)

0≤0.351.4

Missense OE?0.69 (0.61–0.78)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 5 / 22.3Missense obs/exp: 180 / 262.5Syn Z: 0.43

This gene — mechanism propensity

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

54 submitted variants in ClinVar

ClinVar

Classification Summary

VUS41

Likely Benign2

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0	0
Likely Pathogenic	0	0	0	0	0
VUS	1	39	1	0	41
Likely Benign	0	0	0	2	2
Benign	0	0	1	0	1
Total	1	39	2	2	44

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

View in ClinVar →

47 pathogenic / likely-pathogenic (of 59) ClinVar copy-number / structural variants overlap ENO2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →