NDUFS2

Chr 1AR

NADH:ubiquinone oxidoreductase core subunit S2

Also known as: CI-49, LHONAR2, MC1DN6

NCBI Gene: 4720ENSG00000158864UniProt: O75306

The protein encoded by this gene is a core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (complex I). Mammalian mitochondrial complex I is composed of at least 43 different subunits, 7 of which are encoded by the mitochondrial genome, and the rest are the products of nuclear genes. The iron-sulfur protein fraction of complex I is made up of 7 subunits, including this gene product. Complex I catalyzes the NADH oxidation with concomitant ubiquinone reduction and proton ejection out of the mitochondria. Mutations in this gene are associated with mitochondrial complex I deficiency. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Oct 2009]

Primary Disease Associations & Inheritance

?Leber-like hereditary optic neuropathy, autosomal recessive 2MIM #620569
AR
Mitochondrial complex I deficiency, nuclear type 6MIM #618228
AR
341
ClinVar variants
24
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— NDUFS2
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.
📋
ClinVar Variants
24 Pathogenic / Likely Pathogenic· 164 VUS of 341 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.56LOEUF
pLI 0.001
Z-score 3.50
OE 0.34 (0.21–0.56)
Moderately constrained

More LoF-intolerant than ~75% of genes

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.
1.47Z-score
OE missense 0.74 (0.66–0.84)
192 obs / 258.8 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.0.34 (0.21–0.56)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.74 (0.66–0.84)
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.1.16
0≤1.21.6
LoF obs/exp: 11 / 32.5Missense obs/exp: 192 / 258.8Syn Z: -1.18

ClinVar Variant Classifications

341 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15
Likely Pathogenic9
VUS164
Likely Benign91
Benign17
Conflicting28
15
Pathogenic
9
Likely Pathogenic
164
VUS
91
Likely Benign
17
Benign
28
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
3
11
0
15
Likely Pathogenic
3
2
4
0
9
VUS
1
125
32
6
164
Likely Benign
1
7
47
36
91
Benign
0
1
15
1
17
Conflicting
—28
Total613810943324

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

View in ClinVar →

Protein Context — Lollipop Plot

NDUFS2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

NDUFS2-related mitochondrial complex I deficiency

definitive
ARLoss Of FunctionAbsent Gene Product
Eye
G2P ↗

NDUFS2-related non-syndromic hereditary optic neuropathy

strong
ARLoss Of FunctionDecreased Gene Product Level
Eye
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Leber-like hereditary optic neuropathy, autosomal recessive 2

MIM #620569

Molecular basis of disorder known

Autosomal recessive

Mitochondrial complex I deficiency, nuclear type 6

MIM #618228

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Target oxidative stress-induced disulfidptosis: novel therapeutic avenues in Parkinson's disease.
Zhang J et al.·Mol Brain
2025
Identification of Potential Causal Genes for Neurodegenerative Diseases by Mitochondria-Related Genome-Wide Mendelian Randomization.
Yin KF et al.·Mol Neurobiol
2025
Complex I protein NDUFS2 is vital for growth, ROS generation, membrane integrity, apoptosis, and mitochondrial energetics.
Bandara AB et al.·Mitochondrion
2021
Cortex Dictamni-induced hepatotoxicity by enhanced oxidative phosphorylation: Insights from integrative transcriptomics, proteomics, and metabolomics analyses.
Sun H et al.·Phytomedicine
2025
S100A4 alters metabolism and promotes invasion of lung cancer cells by up-regulating mitochondrial complex I protein NDUFS2.
Liu L et al.·J Biol Chem
2019
Recessive MECR pathogenic variants cause an LHON-like optic neuropathy.
Fiorini C et al.·J Med Genet
2023
NUDT21 interacts with NDUFS2 to activate the PI3K/AKT pathway and promotes pancreatic cancer pathogenesis.
Huang XD et al.·J Cancer Res Clin Oncol
2024
Autosomal recessive Leber hereditary optic neuropathy, a new neuro-ophthalmo-genetic paradigm.
Lenaers G et al.·Brain
2023
[Autosomal recessive optic neuropathies: genetic variants, clinical manifestations].
Murakhovskaya YK et al.·Vestn Oftalmol
2022Review
Leigh Syndrome: Spectrum of Molecular Defects and Clinical Features in Russia.
Kistol D et al.·Int J Mol Sci
2023
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