NDUFS8

Chr 11AR

NADH:ubiquinone oxidoreductase core subunit S8

Also known as: CI-23k, CI23KD, MC1DN2, TYKY

NCBI Gene: 4728ENSG00000110717UniProt: O00217

This gene encodes a subunit of mitochondrial NADH:ubiquinone oxidoreductase, or Complex I, a multimeric enzyme of the respiratory chain responsible for NADH oxidation, ubiquinone reduction, and the ejection of protons from mitochondria. The encoded protein is involved in the binding of two of the six to eight iron-sulfur clusters of Complex I and, as such, is required in the electron transfer process. Mutations in this gene have been associated with Leigh syndrome. [provided by RefSeq, Mar 2010]

Primary Disease Associations & Inheritance

Mitochondrial complex I deficiency, nuclear type 2MIM #618222
AR
176
ClinVar variants
29
Pathogenic / LP
0.17
pLI score
0
Active trials
Clinical Summary— NDUFS8
🧬
Gene-Disease Validity (ClinGen)
Leigh syndrome · ARModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.
📋
ClinVar Variants
29 Pathogenic / Likely Pathogenic· 72 VUS of 176 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

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.
0.74LOEUF
pLI 0.166
Z-score 2.15
OE 0.29 (0.13–0.74)
Tolerant

Typical tolerance to LoF variation

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.
0.74Z-score
OE missense 0.83 (0.71–0.96)
119 obs / 144.1 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.0.29 (0.13–0.74)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.83 (0.71–0.96)
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.1.10
0≤1.21.6
LoF obs/exp: 3 / 10.5Missense obs/exp: 119 / 144.1Syn Z: -0.59

ClinVar Variant Classifications

176 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11
Likely Pathogenic18
VUS72
Likely Benign48
Benign11
Conflicting16
11
Pathogenic
18
Likely Pathogenic
72
VUS
48
Likely Benign
11
Benign
16
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
4
7
0
11
Likely Pathogenic
3
9
6
0
18
VUS
1
62
9
0
72
Likely Benign
0
0
22
26
48
Benign
0
0
11
0
11
Conflicting
—16
Total4755526176

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

View in ClinVar →

Protein Context — Lollipop Plot

NDUFS8 · protein map & ClinVar variants

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

Gene2Phenotype Curations

NDUFS8-related mitochondrial respiratory chain complex I deficiency

definitive
ARLoss Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Mitochondrial complex I deficiency, nuclear type 2

MIM #618222

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — NDUFS8
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Emerging Roles of NDUFS8 Located in Mitochondrial Complex I in Different Diseases.
Wang S et al.·Molecules
2022Review
Systematic analysis of NDUFAF6 in complex I assembly and mitochondrial disease.
Sung AY et al.·Nat Metab
2024
Human umbilical mesenchymal stem cells ameliorate atrophic gastritis in aging mice by participating in mitochondrial autophagy through Ndufs8 signaling.
Rui Q et al.·Stem Cell Res Ther
2024
Targeting NDUFS8 in basal forebrain ameliorates cognitive decline related to chronic cerebral hypoperfusion.
Qu Y et al.·Theranostics
2026
Expanding the phenotype of DNAJC30-associated Leigh syndrome.
Zawadzka M et al.·Clin Genet
2022Case report
NDUFS8-Related Leigh Syndrome Mimicking a Leukodystrophy.
Hogue B et al.·J Child Neurol
2025Case report
Leigh Syndrome: Spectrum of Molecular Defects and Clinical Features in Russia.
Kistol D et al.·Int J Mol Sci
2023
Transcriptome-based molecular subgroup identification and prognosis stratification in pediatric AML.
Huang Y et al.·Ann Hematol
2025
Revealing the potential role of hub metabolism-related genes and their correlation with immune cells in acute ischemic stroke.
Zhang X et al.·IET Syst Biol
2024
Sequence analysis of nuclear genes encoding functionally important complex I subunits in children with encephalomyopathy.
Hinttala R et al.·J Mol Med (Berl)
2005Functional
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