MT-ND6

Chr MT

NADH dehydrogenase subunit 6

Also known as: MTND6

NCBI Gene: 4541 ENSG00000198695 UniProt: P03923 OMIM: 516006

This gene encodes a core subunit of NADH:ubiquinone oxidoreductase (Complex I) in the mitochondrial respiratory chain. Mutations cause Leber hereditary optic neuropathy (particularly the m.14484T>C variant), Leigh syndrome, dystonia, and Complex I deficiency. Inheritance is maternal through the mitochondrial genome, with clinical severity dependent on the degree of heteroplasmy.

GeneReviews OMIM ResearchSummary from Curated mito context

Enables NADH dehydrogenase (ubiquinone) activity. Involved in mitochondrial electron transport, NADH to ubiquinone and mitochondrial respiratory chain complex I assembly. Located in mitochondrial inner membrane. Implicated in Leber hereditary optic neuropathy; Leigh disease; and spinal muscular atrophy with lower extremity predominant 2B. [provided by Alliance of Genome Resources, Jul 2025]

GeneReviews OMIM ResearchGenerating clinical summary…

Multiplemechanism

Clinical Summary— MT-ND6

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Gene-Disease Validity (ClinGen)

mitochondrial disease · MTDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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ClinVar Variants

13 unique Pathogenic / Likely Pathogenic· 41 VUS of 116 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MT-ND6

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD

Constraint data not available from gnomAD.

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongMT-ND6-related Leber hereditary optic neuropathyOTHERmitochondrial

This gene — mechanism propensity

0.82top 10%

GOF

0.88top 5%

LOF

0.2288th %ile

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

GOFprediction above median

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

116 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic9

VUS41

Likely Benign29

Benign32

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories· variant type breakdown unavailable

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	—	—	—	—	4
Likely Pathogenic	—	—	—	—	9
VUS	—	—	—	—	41
Likely Benign	—	—	—	—	29
Benign	—	—	—	—	32
Total	—				115

Counts from ClinVar esearch · Updated hourly

View in ClinVar →

10 pathogenic / likely-pathogenic (of 10) ClinVar copy-number / structural variants overlap MT-ND6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

MT-ND6 · protein map & ClinVar variants

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

MITOMAP Disease Variants — MT-ND6

MITOMAP ↗

Variant	AA	Disease	Status	GenBank
m.14163C>T	A171T	Possible deafness factor	Conflicting reports	1.990%
m.14179A>G	Y165Y	Recurrent pregnancy loss	Reported	53.300%
m.14258G>A	P139L	LHON synergistic combo 10680A + 12033G + 14258A also combo 14258A + 14582G	Reported: individually neutral variants causing LHON in combination	5.970%
m.14263C>T	E137E	Recurrent pregnancy loss	Reported	1.070%
m.14279G>A	S132L	LHON	Reported	1.070%
m.14319T>C	N119D	PD, early onset	Reported	12.410%
m.14325T>C	N117D	LHON	Reported	9.340%
m.14340C>T	V112M	SNHL	Reported	3.680%
m.14342C>A	G111V	Possible association with sepsis	Reported	0.000%
m.14351T>C	E108G	SNHL + neurodevelopmental delay	Reported	0.310%
m.14430A>C	W82G	Leigh Syndrome	Reported	0.000%
m.14430A>G	W82R	Thyroid Cancer / Leigh Syndrome	Reported	0.000%
m.14439G>A	P79S	LS / Mitochondrial Respiratory Chain Disorder	Reported	0.000%
m.14441T>C	Y78C	Leigh-like phenotype	Reported	0.000%
m.14453G>A	A74V	MELAS / Leigh Disease	Cfrm [LP]	0.000%
m.14459G>A	A72V	LDYT / Leigh Disease / dystonia / carotid atherosclerosis risk	Cfrm [P]	0.460%
m.14465G>A	T70I	LHON / various supected mitochondrial disease	Cfrm [LP]	0.000%
m.14482C>A	M64I	LHON	Cfrm [LP]	0.310%
m.14482C>G	M64I	LHON	Cfrm [LP]	0.000%
m.14484T>C	M64V	LHON	Cfrm [P]	10.880%
m.14487T>C	M63V	Dystonia / Leigh Disease / ataxia / ptosis / epilepsy	Cfrm [P]	0.000%
m.14495A>G	L60S	LHON	Cfrm [LP]	0.310%
m.14498T>C	Y59C	LHON	Reported	0.000%
m.14502T>C	I58V	LHON	Reported - possibly synergistic	34.160%
m.14512TA>-	frameshift	EXIT w mild myopathy & hyperCKaemia	Cfrm [LP]	0.000%
m.14535C>CC	frameshift	DMDF	Reported	0.150%
m.14538A>G	F46L	LHON	Reported	0.000%
m.14568C>T	G36S	LHON	Cfrm [LP]	0.920%
m.14577T>C	I33V	MIDM	Reported	69.080%
m.14582A>G	V31A	LHON synergistic combo 14258A + 14582G	Reported: individually neutral variants causing LHON in combination	55.600%
m.14596A>T	I26M	LHON with hereditary spastic dystonia	Reported [VUS]	0.000%
m.14597A>G	I26T	LHON / LS	Cfrm [LP]	0.000%
m.14598T>C	I26V	PD / LS	Reported [VUS]	1.070%
m.14600G>A	P25L	Leigh Disease w/optic atrophy / mouse model	Reported	0.000%
m.14668C>T	M2M	Depressive disorder associated; reduced risk of esophageal cancer [D1-D2-D3-D4 marker]	Reported	385.380%