ETFDH

Chr 4AR

electron transfer flavoprotein dehydrogenase

Also known as: ETFQO, MADD

NCBI Gene: 2110ENSG00000171503UniProt: Q16134

This gene encodes a component of the electron-transfer system in mitochondria and is essential for electron transfer from a number of mitochondrial flavin-containing dehydrogenases to the main respiratory chain. Mutations in this gene are associated with glutaric acidemia. Alternatively spliced transcript variants that encode distinct isoforms have been observed. [provided by RefSeq, Aug 2013]

Primary Disease Associations & Inheritance

Glutaric acidemia IICMIM #231680
AR
UniProtGlutaric aciduria 2C
1038
ClinVar variants
319
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ETFDH
🧬
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
319 Pathogenic / Likely Pathogenic· 237 VUS of 1038 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.
1.04LOEUF
pLI 0.000
Z-score 1.36
OE 0.74 (0.54–1.04)
Tolerant

Highly tolerant — LoF variants common in population

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.
0.39Z-score
OE missense 0.94 (0.86–1.03)
314 obs / 334.2 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.0.74 (0.54–1.04)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.94 (0.86–1.03)
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.1.02
0≤1.21.6
LoF obs/exp: 24 / 32.3Missense obs/exp: 314 / 334.2Syn Z: -0.16

ClinVar Variant Classifications

1038 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic138
Likely Pathogenic181
VUS237
Likely Benign399
Benign22
Conflicting61
138
Pathogenic
181
Likely Pathogenic
237
VUS
399
Likely Benign
22
Benign
61
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
46
21
71
0
138
Likely Pathogenic
76
72
33
0
181
VUS
2
205
26
4
237
Likely Benign
2
4
166
227
399
Benign
0
1
20
1
22
Conflicting
—61
Total1263033162321,038

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

View in ClinVar →

Protein Context — Lollipop Plot

ETFDH · protein map & ClinVar variants

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

Gene2Phenotype Curations

ETFDH-related glutaric aciduria

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Glutaric acidemia IIC

MIM #231680

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — ETFDH
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Value of genetic analysis for confirming inborn errors of metabolism detected through the Spanish neonatal screening program.
Navarrete R et al.·Eur J Hum Genet
2019
NGS-Based Genetic Analysis in a Cohort of Italian Patients with Suspected Inherited Myopathies and/or HyperCKemia.
Invernizzi F et al.·Genes (Basel)
2023Cohort
Effects of putative metformin targets on phenotypic age and leukocyte telomere length: a mendelian randomisation study using data from the UK Biobank.
Luo S et al.·Lancet Healthy Longev
2023
Variants in mitochondrial disease genes are common causes of inherited peripheral neuropathies.
Ferreira T et al.·J Neurol
2024
The difference of variation types between late-onset multiple acyl-CoA dehydrogenase deficiency patients carrying biallelic and single heterozygous variations in ETFDH: a systematic review and meta-analysis.
Zhang H et al.·Orphanet J Rare Dis
2025Meta-analysis
Human CoQ10 deficiencies.
Quinzii CM et al.·Biofactors
2008
A compound heterozygote case of glutaric aciduria type II in a patient carrying a novel candidate variant in ETFDH gene: A case report and literature review on compound heterozygote cases.
Seyedtaghia MR et al.·Mol Genet Genomic Med
2024Review
Identification of ETFDH gene c. 487 + 2 T > A pathogenic variant and mechanisms for polycystic kidney in neonatal onset MADD.
Zhang B et al.·Orphanet J Rare Dis
2025Functional
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
Genomic modifiers of neurological resilience in a Niemann-Pick C family.
Las Heras M et al.·FEBS Lett
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