NDUFS4

Chr 5AR

NADH:ubiquinone oxidoreductase subunit S4

Also known as: AQDQ, CI-18, CI-18 kDa, CI-AQDQ, MC1DN1

NCBI Gene: 4724ENSG00000164258UniProt: O43181

This gene encodes an nuclear-encoded accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I, or NADH:ubiquinone oxidoreductase). Complex I removes electrons from NADH and passes them to the electron acceptor ubiquinone. Mutations in this gene can cause mitochondrial complex I deficiencies such as Leigh syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

Primary Disease Associations & Inheritance

Mitochondrial complex I deficiency, nuclear type 1MIM #252010
AR
259
ClinVar variants
60
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— NDUFS4
🧬
Gene-Disease Validity (ClinGen)
Leigh syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
60 Pathogenic / Likely Pathogenic· 68 VUS of 259 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.
1.16LOEUF
pLI 0.000
Z-score 1.20
OE 0.62 (0.35–1.16)
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.
-0.84Z-score
OE missense 1.25 (1.07–1.46)
114 obs / 91.3 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.0.62 (0.35–1.16)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.25 (1.07–1.46)
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.1.35
0≤1.21.6
LoF obs/exp: 7 / 11.4Missense obs/exp: 114 / 91.3Syn Z: -1.55

ClinVar Variant Classifications

259 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30
Likely Pathogenic30
VUS68
Likely Benign94
Benign28
Conflicting9
30
Pathogenic
30
Likely Pathogenic
68
VUS
94
Likely Benign
28
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
0
22
0
30
Likely Pathogenic
22
2
6
0
30
VUS
1
51
15
1
68
Likely Benign
0
4
47
43
94
Benign
0
0
25
3
28
Conflicting
—9
Total315711547259

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

View in ClinVar →

Protein Context — Lollipop Plot

NDUFS4 · protein map & ClinVar variants

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

Gene2Phenotype Curations

NDUFS4-related Leigh syndrome

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

Mitochondrial complex I deficiency, nuclear type 1

MIM #252010

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — NDUFS4
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Ndufs4 knockout mouse models of Leigh syndrome: pathophysiology and intervention.
van de Wal MAE et al.·Brain
2022Review
Lian Qiao Wen Dan Decoction attenuates gastric carcinogenesis by alleviating oxidative phosphorylation dysfunction.
Chi X et al.·Phytomedicine
2025
Defective function of α-ketoglutarate dehydrogenase exacerbates mitochondrial ATP deficits during complex I deficiency.
Piroli GG et al.·Redox Biol
2023
Ndufs4 related Leigh syndrome: A case report and review of the literature.
Ortigoza-Escobar JD et al.·Mitochondrion
2016Review
Immune mitochondrial complex I mediates vascular damage in toll-like receptor 7 (TLR7)-induced lupus.
Miñano S et al.·Pharmacol Res
2025
Microglial response promotes neurodegeneration in the Ndufs4 KO mouse model of Leigh syndrome.
Aguilar K et al.·Glia
2022Functional
Elevated serum levels of GPX4, NDUFS4, PRDX5, and TXNRD2 as predictive biomarkers for castration resistance in prostate cancer patients: an exploratory study.
Wang R et al.·Br J Cancer
2025Cohort
Ndufs4 KO mice: A model to study comorbid mood disorders associated with mitochondrial dysfunction.
van Rensburg DJ et al.·Pharmacol Biochem Behav
2024Functional
The immune system as a driver of mitochondrial disease pathogenesis: a review of evidence.
Hanaford A et al.·Orphanet J Rare Dis
2022Review
Evaluating the efficacy of vatiquinone in preclinical models of Leigh syndrome and GPX4 deficiency.
Kayser EB et al.·Orphanet J Rare Dis
2025Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Mitochondrial complex I subunit NDUFS4 overexpression drives glioma progression by regulating mitochondrial function and COX5B.
Wu J et al.·NPJ Precis Oncol
2026🔓 Open Access
NDUFS4, a mitochondrial complex I subunit, is essential for T-cell metabolic fitness and immune function.
Shamriz O et al.·Front Immunol
2025🔓 Open Access
Energy Metabolism Under Stress: Late-Stage Leigh Syndrome Reveals Profound Cardiometabolic Perturbations in Ndufs4 KO Mice.
Terburgh K et al.·J Inherit Metab Dis
2026🔓 Open Access
Hepatic bioenergetics and metabolism in mitochondrial disease: insights from the Ndufs4 KO mouse model.
Terburgh K et al.·Metabolomics
2025🔓 Open AccessFunctional
Disruption of adaptive immunity does not attenuate disease in the Ndufs4(-/-) model of Leigh syndrome.
Hanaford AR et al.·PLoS One
2025🔓 Open AccessFunctional
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