NDUFA9

Chr 12AR

NADH:ubiquinone oxidoreductase subunit A9

Also known as: CC6, CI-39k, CI39k, COQ11, MC1DN26, NDUFS2L, SDR22E1

NCBI Gene: 4704 ENSG00000139180 UniProt: Q16795 OMIM: 603834

The protein is a subunit of NADH:ubiquinone oxidoreductase (complex I), the first enzyme complex in the mitochondrial electron transport chain. Mutations cause mitochondrial complex I deficiency, nuclear type 26, inherited in an autosomal recessive pattern. The pathogenic mechanism appears to involve dominant-negative effects.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The encoded protein is a subunit of the hydrophobic protein fraction of the NADH:ubiquinone oxidoreductase (complex I), the first enzyme complex in the electron transport chain located in the inner mitochondrial membrane. A pseudogene has been identified on chromosome 12. [provided by RefSeq, May 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.641 OMIM phenotype

Clinical Summary— NDUFA9

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

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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

12 unique Pathogenic / Likely Pathogenic· 133 VUS of 286 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — NDUFA9

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.64LOEUF

pLI 0.005

Z-score 2.84

OE 0.35 (0.21–0.64)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.09Z-score

OE missense 0.98 (0.88–1.10)

226 obs / 229.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.35 (0.21–0.64)

0≤0.351.4

Missense OE?0.98 (0.88–1.10)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 8 / 22.6Missense obs/exp: 226 / 229.7Syn Z: -0.28

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedNDUFA9-related Leigh syndromeOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7131th %ile

GOF

0.5660th %ile

LOF

0.3357th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

286 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic5

VUS133

Likely Benign74

Benign41

Conflicting10

Pathogenic

Likely Pathogenic

133

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	5	0	0	7
Likely Pathogenic	4	1	0	0	5
VUS	4	120	8	1	133
Likely Benign	0	8	29	37	74
Benign	0	3	37	1	41
Conflicting	—				10
Total	10	137	74	39	270

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

View in ClinVar →

59 pathogenic / likely-pathogenic (of 66) ClinVar copy-number / structural variants overlap NDUFA9 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →