NDUFS6

Chr 5AR

NADH:ubiquinone oxidoreductase subunit S6

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

NCBI Gene: 4726ENSG00000145494UniProt: O75380

This gene encodes a subunit of the NADH:ubiquinone oxidoreductase (complex I), which is the first enzyme complex in the electron transport chain of mitochondria. This complex functions in the transfer of electrons from NADH to the respiratory chain. The subunit encoded by this gene is one of seven subunits in the iron-sulfur protein fraction. Mutations in this gene cause mitochondrial complex I deficiency, a disease that causes a wide variety of clinical disorders, including neonatal disease and adult-onset neurodegenerative disorders.[provided by RefSeq, Oct 2009]

Primary Disease Associations & Inheritance

Mitochondrial complex I deficiency, nuclear type 9MIM #618232
AR
399
ClinVar variants
171
Pathogenic / LP
0.10
pLI score
0
Active trials
Clinical Summary— NDUFS6
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.10) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
171 Pathogenic / Likely Pathogenic· 75 VUS of 399 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.
1.30LOEUF
pLI 0.096
Z-score 1.18
OE 0.42 (0.17–1.30)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?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.
-0.22Z-score
OE missense 1.07 (0.89–1.29)
82 obs / 76.6 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.0.42 (0.17–1.30)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.07 (0.89–1.29)
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.1.70
0≤1.21.6
LoF obs/exp: 2 / 4.8Missense obs/exp: 82 / 76.6Syn Z: -3.17

ClinVar Variant Classifications

399 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic143
Likely Pathogenic28
VUS75
Likely Benign112
Benign19
Conflicting13
143
Pathogenic
28
Likely Pathogenic
75
VUS
112
Likely Benign
19
Benign
13
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
1
135
0
143
Likely Pathogenic
19
3
6
0
28
VUS
1
47
24
3
75
Likely Benign
0
0
42
70
112
Benign
0
0
18
1
19
Conflicting
—13
Total275122574390

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.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Mitochondrial complex I deficiency, nuclear type 9

MIM #618232

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
New perspective in diagnostics of mitochondrial disorders: two years' experience with whole-exome sequencing at a national paediatric centre.
Pronicka E et al.·J Transl Med
2016
NDUFS6 related Leigh syndrome: a case report and review of the literature.
Rouzier C et al.·J Hum Genet
2019Review
Variants in mitochondrial disease genes are common causes of inherited peripheral neuropathies.
Ferreira T et al.·J Neurol
2024
A Homozygous NDUFS6 Variant Associated with Neuropathy and Optic Atrophy.
Gangfuß A et al.·J Neuromuscul Dis
2024Case report
Alternative splicing expands the clinical spectrum of NDUFS6-related mitochondrial disorders.
Armirola-Ricaurte C et al.·Genet Med
2024
Case report: novel mutations of NDUFS6 and NHLRC2 genes potentially cause the quick postnatal death of a Chinese Hani minority neonate with mitochondrial complex I deficiency and FINCA syndrome.
Li Y et al.·Medicine (Baltimore)
2022Case report
Expanding the Phenotypic Spectrum of NDUFS6-Related Disease: From Neonatal Mitochondrial Encephalopathy to Childhood-Onset Axonal Neuropathy.
Baris S et al.·Int J Mol Sci
2026Case report
Mutated NDUFS6 is the cause of fatal neonatal lactic acidemia in Caucasus Jews.
Spiegel R et al.·Eur J Hum Genet
2009Case report
A protein microarray-based serum proteomic investigation reveals distinct autoantibody signature in colorectal cancer.
Barpanda A et al.·Proteomics Clin Appl
2023
The utility of next-generation sequencing technologies in diagnosis of Mendelian mitochondrial diseases and reflections on clinical spectrum.
Kose M et al.·J Pediatr Endocrinol Metab
2021
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