NDUFS6

Chr 5AR

NADH:ubiquinone oxidoreductase subunit S6

Also known as: CI-13kA, CI-13kD-A, CI13KDA, MC1DN9

NCBI Gene: 4726 ENSG00000145494 UniProt: O75380 OMIM: 603848

This gene encodes a subunit of mitochondrial complex I (NADH:ubiquinone oxidoreductase) that functions in electron transfer from NADH to the respiratory chain as part of the iron-sulfur protein fraction. Mutations cause autosomal recessive mitochondrial complex I deficiency, presenting with a spectrum of clinical disorders ranging from severe neonatal disease to adult-onset neurodegenerative conditions. The pathogenic mechanism involves dominant-negative effects from the mutant protein.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a subunit of the NADH:ubiquinone oxidoreductase (complex I), which is the first enzyme complex in the electron transport chain of mitochondria. This complex functions in the transfer of electrons from NADH to the respiratory chain. The subunit encoded by this gene is one of seven subunits in the iron-sulfur protein fraction. Mutations in this gene cause mitochondrial complex I deficiency, a disease that causes a wide variety of clinical disorders, including neonatal disease and adult-onset neurodegenerative disorders.[provided by RefSeq, Oct 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 1.301 OMIM phenotype

Clinical Summary— NDUFS6

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.10) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

43 unique Pathogenic / Likely Pathogenic· 64 VUS of 259 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — NDUFS6

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.30LOEUF

pLI 0.096

Z-score 1.18

OE 0.42 (0.17–1.30)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.22Z-score

OE missense 1.07 (0.89–1.29)

82 obs / 76.6 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.42 (0.17–1.30)

0≤0.351.4

Missense OE?1.07 (0.89–1.29)

0≤0.61.4

Synonymous OE?1.70

0≤1.21.6

LoF obs/exp: 2 / 4.8Missense obs/exp: 82 / 76.6Syn Z: -3.17

This gene — mechanism propensity

0.6452th %ile

GOF

0.4185th %ile

LOF

0.3067th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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

259 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11

Likely Pathogenic32

VUS64

Likely Benign111

Benign19

Conflicting13

Pathogenic

Likely Pathogenic

VUS

111

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	6	0	5	0	11
Likely Pathogenic	26	5	1	0	32
VUS	1	48	12	3	64
Likely Benign	0	0	41	70	111
Benign	0	0	18	1	19
Conflicting	—				13
Total	33	53	77	74	250

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

View in ClinVar →

134 pathogenic / likely-pathogenic (of 147) ClinVar copy-number / structural variants overlap NDUFS6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →