NDUFS6

Chr 5AR

NADH:ubiquinone oxidoreductase subunit S6

Also known as: CI-13kA, CI-13kD-A, CI13KDA, MC1DN9

NCBI Gene: 4726ENSG00000145494UniProt: O75380OMIM: 603848

This gene encodes a subunit of mitochondrial complex I (NADH:ubiquinone oxidoreductase) that functions in electron transfer from NADH to the respiratory chain as part of the iron-sulfur protein fraction. Mutations cause autosomal recessive mitochondrial complex I deficiency, presenting with a spectrum of clinical disorders ranging from severe neonatal disease to adult-onset neurodegenerative conditions. The pathogenic mechanism involves dominant-negative effects from the mutant protein.

OMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
DNmechanismARLOEUF 1.301 OMIM phenotype
Clinical Summary— NDUFS6
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Gene-Disease Validity (ClinGen)
mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)
Low constraint (pLI 0.10) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
72 unique Pathogenic / Likely Pathogenic· 59 VUS of 204 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.30LOEUF
pLI 0.096
Z-score 1.18
OE 0.42 (0.17–1.30)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-0.22Z-score
OE missense 1.07 (0.89–1.29)
82 obs / 76.6 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.42 (0.17–1.30)
0≤0.351.4
Missense OE1.07 (0.89–1.29)
0≤0.61.4
Synonymous OE1.70
0≤1.21.6
LoF obs/exp: 2 / 4.8Missense obs/exp: 82 / 76.6Syn Z: -3.17
DN
0.6452th %ile
GOF
0.4185th %ile
LOF
0.3067th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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

204 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic43
Likely Pathogenic29
VUS59
Likely Benign58
Benign5
Conflicting1
43
Pathogenic
29
Likely Pathogenic
59
VUS
58
Likely Benign
5
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
0
37
0
43
Likely Pathogenic
26
3
0
0
29
VUS
0
40
16
3
59
Likely Benign
0
0
24
34
58
Benign
0
0
5
0
5
Conflicting
—1
Total32438237195

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

View in ClinVar →

Protein Context — Lollipop Plot

NDUFS6 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Exploring the role of mitochondrial metabolism and immune infiltration in myocardial infarction: novel insights from bioinformatics and experimental validation
Hou J et al.·Front Immunol
2025
Estimation of the proteome affecting changes in tenderness of yak meat during storage by label-free mass spectrometry
Li S et al.·Vet Med Sci
2022
Integrative machine learning-driven prognosis and immunotherapy stratification via lactylation-associated gene in ovarian cancer
Li X et al.·NPJ Precis Oncol
2025
Eleven Crucial Pesticides Appear to Regulate Key Genes That Link MPTP Mechanism to Cause Parkinson's Disease through the Selective Degeneration of Dopamine Neurons
Anirudhan A et al.·Brain Sci
2023Functional
PRMT1 methylation of WTAP promotes multiple myeloma tumorigenesis by activating oxidative phosphorylation via m6A modification of NDUFS6
Jia Y et al.·Cell Death Dis
2023
Top 5 full-text resultsSearch PubTator3 ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients