NDUFB3

Chr 2AR

NADH:ubiquinone oxidoreductase subunit B3

Also known as: B12, CI-B12, MC1DN25

NCBI Gene: 4709ENSG00000119013UniProt: O43676

This gene encodes an accessory subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which is the first enzyme in the electron transport chain of mitochondria. This protein localizes to the inner membrane of the mitochondrion as a single-pass membrane protein. Mutations in this gene contribute to mitochondrial complex 1 deficiency. Alternative splicing results in multiple transcript variants encoding the same protein. Humans have multiple pseudogenes of this gene. [provided by RefSeq, Mar 2012]

Primary Disease Associations & Inheritance

Mitochondrial complex I deficiency, nuclear type 25MIM #618246
AR
83
ClinVar variants
38
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— NDUFB3
🧬
Gene-Disease Validity (ClinGen)
mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
38 Pathogenic / Likely Pathogenic· 28 VUS of 83 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.
1.94LOEUF
pLI 0.000
Z-score -1.10
OE 1.61 (0.79–1.94)
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.
0.32Z-score
OE missense 0.88 (0.69–1.12)
45 obs / 51.4 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.1.61 (0.79–1.94)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.88 (0.69–1.12)
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.0.70
0≤1.21.6
LoF obs/exp: 6 / 3.7Missense obs/exp: 45 / 51.4Syn Z: 0.98

ClinVar Variant Classifications

83 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic33
Likely Pathogenic5
VUS28
Likely Benign7
Benign8
Conflicting2
33
Pathogenic
5
Likely Pathogenic
28
VUS
7
Likely Benign
8
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
0
31
0
33
Likely Pathogenic
1
1
3
0
5
VUS
0
22
6
0
28
Likely Benign
0
0
4
3
7
Benign
0
0
8
0
8
Conflicting
—2
Total32352383

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

View in ClinVar →

Protein Context — Lollipop Plot

NDUFB3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

NDUFB3-related mitochondrial complex I deficiency

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 25

MIM #618246

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
A recurrent mitochondrial p.Trp22Arg NDUFB3 variant causes a distinctive facial appearance, short stature and a mild biochemical and clinical phenotype.
Alston CL et al.·J Med Genet
2016
Clinical manifestations and pathogenesis of mitochondrial dysfunction in short stature.
Jiang Y et al.·World J Pediatr
2025Review
Clinical Relevance and Tumor Growth Suppression of Mitochondrial ROS Regulators along NADH:Ubiquinone Oxidoreductase Subunit B3 in Thyroid Cancer.
Zhu J et al.·Oxid Med Cell Longev
2022
Investigation of Mitochondrial Related Variants in a Cerebral Small Vessel Disease Cohort.
Dunn PJ et al.·Mol Neurobiol
2022Cohort
Clinical utility of genomic analysis in adults with idiopathic liver disease.
Hakim A et al.·J Hepatol
2019
Unveiling shared therapeutic targets and pathological pathways between coronary artery disease and major depressive disorder through bioinformatics analysis.
Hu M et al.·Sci Rep
2024
Mitochondria-Related Candidate Genes and Diagnostic Model to Predict Late-Onset Alzheimer's Disease and Mild Cognitive Impairment.
Yan R et al.·J Alzheimers Dis
2024Functional
Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing.
Calvo SE et al.·Sci Transl Med
2012
Identification of hub genes in peripheral blood and construction of a diagnostic nomogram model in ulcerative colitis.
Li X et al.·PeerJ
2025Functional
Molecular diagnosis in mitochondrial complex I deficiency using exome sequencing.
Haack TB et al.·J Med Genet
2012
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Role of COX6C and NDUFB3 in septic shock and stroke.
Tian W et al.·Open Med (Wars)
2024🔓 Open Access
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