NDUFB9

Chr 8AR

NADH:ubiquinone oxidoreductase subunit B9

Also known as: B22, CI-B22, LYRM3, MC1DN24, UQOR22

NCBI Gene: 4715 ENSG00000147684 UniProt: Q9Y6M9 OMIM: 601445

The protein is an accessory subunit of mitochondrial complex I (NADH dehydrogenase) that functions in electron transfer from NADH to ubiquinone in the respiratory chain. Mutations cause mitochondrial complex I deficiency with autosomal recessive inheritance, though the specific clinical phenotype associated with NDUFB9 mutations remains uncertain. Complex I deficiencies typically present with variable manifestations including neonatal disease, cardiomyopathy, liver disease, and neurodegenerative disorders.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a subunit of the mitochondrial oxidative phosphorylation complex I (nicotinamide adenine dinucleotide: ubiquinone oxidoreductase). Complex I is localized to the inner mitochondrial membrane and functions to dehydrogenate nicotinamide adenine dinucleotide and to shuttle electrons to coenzyme Q. Complex I deficiency is the most common defect found in oxidative phosphorylation disorders and results in a range of conditions, including lethal neonatal disease, hypertrophic cardiomyopathy, liver disease, and adult-onset neurodegenerative disorders. Pseudogenes of this gene are found on chromosomes five, seven and eight. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2015]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.041 OMIM phenotype

Clinical Summary— NDUFB9

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 56 VUS of 128 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.04LOEUF

pLI 0.000

Z-score 1.45

OE 0.58 (0.34–1.04)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.00Z-score

OE missense 1.00 (0.85–1.18)

104 obs / 104.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.58 (0.34–1.04)

0≤0.351.4

Missense OE?1.00 (0.85–1.18)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 8 / 13.8Missense obs/exp: 104 / 104.0Syn Z: 0.10

This gene — mechanism propensity

0.7228th %ile

GOF

0.72top 25%

LOF

0.2190th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction 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

128 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS56

Likely Benign43

Benign16

Conflicting6

Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	0	0	0	0	0
VUS	5	48	3	0	56
Likely Benign	0	2	21	20	43
Benign	0	1	14	1	16
Conflicting	—				6
Total	5	52	38	21	122

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

View in ClinVar →

54 pathogenic / likely-pathogenic (of 60) ClinVar copy-number / structural variants overlap NDUFB9 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →