ETFA

Chr 15AR

electron transfer flavoprotein subunit alpha

Also known as: EMA, GA2, MADD

NCBI Gene: 2108ENSG00000140374UniProt: P13804

ETFA participates in catalyzing the initial step of the mitochondrial fatty acid beta-oxidation. It shuttles electrons between primary flavoprotein dehydrogenases and the membrane-bound electron transfer flavoprotein ubiquinone oxidoreductase. Defects in electron-transfer-flavoprotein have been implicated in type II glutaricaciduria in which multiple acyl-CoA dehydrogenase deficiencies result in large excretion of glutaric, lactic, ethylmalonic, butyric, isobutyric, 2-methyl-butyric, and isovaleric acids. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Glutaric acidemia IIAMIM #231680
AR
UniProtGlutaric aciduria 2A
526
ClinVar variants
84
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ETFA
🧬
Gene-Disease Validity (ClinGen)
multiple acyl-CoA dehydrogenase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
84 Pathogenic / Likely Pathogenic· 119 VUS of 526 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.
0.68LOEUF
pLI 0.003
Z-score 2.66
OE 0.38 (0.22–0.68)
Tolerant

Typical tolerance to LoF variation

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.
1.06Z-score
OE missense 0.78 (0.68–0.89)
139 obs / 179.0 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.0.38 (0.22–0.68)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.78 (0.68–0.89)
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.0.86
0≤1.21.6
LoF obs/exp: 8 / 21.2Missense obs/exp: 139 / 179.0Syn Z: 0.89

ClinVar Variant Classifications

526 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic33
Likely Pathogenic51
VUS119
Likely Benign283
Benign28
Conflicting12
33
Pathogenic
51
Likely Pathogenic
119
VUS
283
Likely Benign
28
Benign
12
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
12
2
19
0
33
Likely Pathogenic
38
4
9
0
51
VUS
1
91
23
4
119
Likely Benign
0
2
166
115
283
Benign
0
0
28
0
28
Conflicting
—12
Total5199245119526

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

View in ClinVar →

Protein Context — Lollipop Plot

ETFA · protein map & ClinVar variants

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

Gene2Phenotype Curations

ETFA-related glutaric aciduria

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Glutaric acidemia IIA

MIM #231680

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — ETFA
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
A novel deleterious ETFA promoter variant causative of multiple acyl-CoA dehydrogenase deficiency.
Prasun P et al.·Am J Med Genet A
2023Case report
Deep Intronic ETFDH Variants Represent a Recurrent Pathogenic Event in Multiple Acyl-CoA Dehydrogenase Deficiency.
Martino S et al.·Int J Mol Sci
2024Case report
Riboflavin in Neurological Diseases: A Narrative Review.
Plantone D et al.·Clin Drug Investig
2021Review
Update on clinical aspects and treatment of selected vitamin-responsive disorders II (riboflavin and CoQ 10).
Horvath R·J Inherit Metab Dis
2012Review
Potential Risk Factors and Therapeutic Targets for Dilated Cardiomyopathy Identified Through Mendelian Randomization Analysis.
Wang H et al.·J Am Heart Assoc
2026
Disorders of flavin adenine dinucleotide metabolism: MADD and related deficiencies.
Mereis M et al.·Int J Biochem Cell Biol
2021Review
Characterization of 31 Patients with Riboflavin-Responsive Multiple acyl-CoA Dehydrogenase Deficiency.
Zhang J et al.·Balkan Med J
2022Cohort
Platelet Microparticle-Derived MiR-320b Inhibits Hypertension with Atherosclerosis Development by Targeting ETFA.
He Y et al.·Int Heart J
2024
Prenatal diagnosis and outcome of fetal hyperechogenic kidneys in the era of antenatal next-generationsequencing.
Deng L et al.·Clin Chim Acta
2022
First report of neonatal-onset glutaric aciduria type II in the Iranian population caused by a novel deleterious ETFA variant.
Parvini F et al.·Orphanet J Rare Dis
2025
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