NDUFAF3

Chr 3AR

NADH:ubiquinone oxidoreductase complex assembly factor 3

Also known as: 2P1, C3orf60, E3-3, MC1DN18

NCBI Gene: 25915ENSG00000178057UniProt: Q9BU61

This gene encodes a mitochondrial complex I assembly protein that interacts with complex I subunits. Mutations in this gene cause mitochondrial complex I deficiency, a fatal neonatal disorder of the oxidative phosphorylation system. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2009]

Primary Disease Associations & Inheritance

Mitochondrial complex I deficiency, nuclear type 18MIM #618240
AR
146
ClinVar variants
21
Pathogenic / LP
0.01
pLI score
0
Active trials
Clinical Summary— NDUFAF3
🧬
Gene-Disease Validity (ClinGen)
mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
21 Pathogenic / Likely Pathogenic· 69 VUS of 146 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.
1.07LOEUF
pLI 0.005
Z-score 1.43
OE 0.51 (0.26–1.07)
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.
-0.49Z-score
OE missense 1.14 (0.98–1.32)
120 obs / 105.7 exp
Tolerant

Tolerant to missense variation

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.0.51 (0.26–1.07)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.14 (0.98–1.32)
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.1.09
0≤1.21.6
LoF obs/exp: 5 / 9.8Missense obs/exp: 120 / 105.7Syn Z: -0.47

ClinVar Variant Classifications

146 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16
Likely Pathogenic5
VUS69
Likely Benign39
Benign2
Conflicting15
16
Pathogenic
5
Likely Pathogenic
69
VUS
39
Likely Benign
2
Benign
15
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
4
11
0
16
Likely Pathogenic
1
1
3
0
5
VUS
0
45
22
2
69
Likely Benign
0
1
22
16
39
Benign
0
0
1
1
2
Conflicting
—15
Total2515919146

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

View in ClinVar →

Protein Context — Lollipop Plot

NDUFAF3 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Mitochondrial complex I deficiency, nuclear type 18

MIM #618240

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Expanding the phenotypic and biochemical spectrum of NDUFAF3-related mitochondrial disease.
van der Ven AT et al.·Mol Genet Metab
2023Case report
Mutations in mitochondrial complex I assembly factor NDUFAF3 cause Leigh syndrome.
Baertling F et al.·Mol Genet Metab
2017Case report
NDUFAF3 variants that disrupt mitochondrial complex I assembly may associate with cavitating leukoencephalopathy.
Ishiyama A et al.·Clin Genet
2018Case report
Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease.
Saada A et al.·Am J Hum Genet
2009Case report
Early complex I assembly defects result in rapid turnover of the ND1 subunit.
Zurita Rendón O et al.·Hum Mol Genet
2012
Immunomodulatory Mechanisms of Rehmanniae Radix Praeparata-Achyranthes Root-Chinese Angelica Root Combination in Nontraumatic Osteonecrosis of the Femoral Head: A Comprehensive Network Pharmacology and Molecular Docking Study Focusing on Immunological Pathways.
Li X et al.·Mediators Inflamm
2025Functional
Spectrum of Inherited Childhood-Onset Dystonia: Case Series of 19 Families With Genotype and Phenotype Characterization Highlighting the Treatable Causes.
Adarsha N et al.·Clin Genet
2025Cohort
Defective Expression of the Mitochondrial-tRNA Modifying Enzyme GTPBP3 Triggers AMPK-Mediated Adaptive Responses Involving Complex I Assembly Factors, Uncoupling Protein 2, and the Mitochondrial Pyruvate Carrier.
Martínez-Zamora A et al.·PLoS One
2015
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