MT-ND1

Chr MT

NADH dehydrogenase subunit 1

Also known as: MTND1

NCBI Gene: 4535 ENSG00000198888 UniProt: P03886

This gene encodes a core subunit of NADH:ubiquinone oxidoreductase (Complex I) in the mitochondrial respiratory chain, essential for cellular energy production through oxidative phosphorylation. Mutations cause MELAS, Leigh syndrome, Leber hereditary optic neuropathy (LHON), and isolated Complex I deficiency. Inheritance is maternal through the mitochondrial genome, and disease severity depends on the level of heteroplasmy in affected tissues.

GeneReviews 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. Part of respiratory chain complex I. Implicated in several diseases, including MELAS syndrome; neurodegenerative disease (multiple); optic nerve disease (multiple); toxic shock syndrome; and type 2 diabetes mellitus. Biomarker of Alzheimer's disease; Parkinson's disease; and multiple sclerosis. [provided by Alliance of Genome Resources, Jul 2025]

GeneReviews ResearchGenerating clinical summary…

Multiplemechanism

Clinical Summary— MT-ND1

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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

11 unique Pathogenic / Likely Pathogenic· 79 VUS of 189 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MT-ND1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD

Constraint data not available from gnomAD.

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMT-ND1-related Leber hereditary optic neuropathyOTHERmitochondrial

This gene — mechanism propensity

0.88top 5%

GOF

0.82top 10%

LOF

0.10100th %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

189 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic9

VUS79

Likely Benign49

Benign48

Conflicting2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

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

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	—	—	—	—	2
Likely Pathogenic	—	—	—	—	9
VUS	—	—	—	—	79
Likely Benign	—	—	—	—	49
Benign	—	—	—	—	48
Conflicting	—				2
Total	—				189

Counts from ClinVar esearch · Updated hourly

View in ClinVar →

3 pathogenic / likely-pathogenic (of 4) ClinVar copy-number / structural variants overlap MT-ND1 — 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-ND1 · protein map & ClinVar variants

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

MITOMAP Disease Variants — MT-ND1

MITOMAP ↗

Variant	AA	Disease	Status	GenBank
m.3308T>C	M1T	MELAS / DEAF enhancer / hypertension / LVNC / putative LHON	Reported - possibly synergistic; hg L1b and A2i marker	72.760%
m.3308T>G	M1Term	Sudden Infant Death	Reported	0.920%
m.3310C>T	P2S	Diabetes / HCM	Reported	1.990%
m.3316G>A	A4T	Diabetes / LHON / PEO / vascular dementia	Reported; hg D1 D2 M33 R30 marker	96.350%
m.3335T>C	I10T	LHON	Reported	10.260%
m.3336T>C	I10I	Carotid atherosclerosis risk	Reported	36.760%
m.3337G>A	V11M	Cardiomyopathy	Reported - possibly synergistic	17.000%
m.3340C>T	P12S	Encephaloneuromyopathy	Reported	0.460%
m.3365T>C	L20P	EXIT	Reported	0.000%
m.3376G>A	E24K	LHON MELAS overlap	Cfrm [VUS*]	0.000%
m.3380G>A	R25Q	MELAS	Reported [VUS]	0.310%
m.3388C>A	L28M	Materally Inherited Nonsyndromic Deafness	Reported	4.600%
m.3391G>A	G29S	LHON	Reported	8.580%
m.3394T>C	Y30H	LHON / Diabetes / CPTdeficiency / high altitude adaptation	Reported [VUS] -population dependent; hg M9 marker	131.120%
m.3395A>G	Y30C	LHON / HCM with hearing loss	Reported	4.440%
m.3396T>C	Y30Y	NSHL / MIDD	Reported / Unclear	83.170%
m.3397A>G	M31V	ADPD / possibly LVNC-cardiomyopathy associated / resistance to high altitude pulmonary edema	Reported	27.110%
m.3398T>C	M31T	DMDF+HCM / GDM / possibly LVNC cardiomyopathy-associated	Reported	48.250%
m.3399A>T	M31I	Gestational Diabetes (GDM)	Reported	8.420%
m.3407G>A	R34H	HCM / Muscle involvement	Conflicting reports	0.150%
m.3418A>G	N38D	AMegL	Reported	0.150%
m.3421G>A	V39I	MIDD	Reported	13.330%
m.3437G>A	G44E	Mitochondrial myopathy, EXIT	Reported	0.000%
m.3457G>A	D51N	LS+HCM	Reported	0.000%
m.3460G>A	A52T	LHON	Cfrm [P]	4.750%
m.3461C>T	A52V	LHON	Reported	0.000%
m.3472T>C	F56L	LHON	Reported	0.770%
m.3481G>A	E59K	MELAS / Progressive Encephalomyopathy	Cfrm [LP]	0.000%
m.3482A>G	E59G	MELAS/LS overlap	Reported	0.000%
m.3488T>C	L61P	LHON	Reported	0.150%
m.3496G>T	A64S	LHON	Reported / Secondary	1.680%
m.3497C>T	A64V	LHON	Reported / Secondary	33.390%
m.3502T>C	S66P	MELAS / MM w reversible COX deficiency	Reported [VUS]	0.000%
m.3548T>C	I81T	Possible LHON helper (one 14484 patient)	Reported	5.670%
m.3551C>T	A82V	LHON	Reported	0.000%
m.3552T>A	A82A	Resistance to high altitude pulmonary edema (HAPE) / matrilineal hypertension	Reported; hg C marker	334.990%
m.3571C>T	L89F	Possible LHON helper mut / idiopathic epilepsy	Reported	21.750%
m.3571C>-	frameshift	Mitochondrial myopathy with reversible cytochrome C oxidase deficiency	Cfrm [LP]	0.000%
m.3632C>T	S109F	LHON	Reported	0.000%
m.3634A>G	S110G	LHON	Reported	0.000%
m.3635G>A	S110N	LHON	Cfrm [LP]	1.380%
m.3644T>C	V113A	BD-associated	Reported	36.000%
m.3667T>G	W121G	Peripheral neuropathy of T2 diabetes	Reported	0.000%
m.3685T>C	Y127H	Leigh Syndrome	Reported [VUS]	0.000%
m.3688G>A	A128T	Leigh Syndrome	Cfrm [LP]	0.150%
m.3697G>A	G131S	MELAS / Leigh Syndrome / LDYT / BSN	Cfrm [LP]	0.000%
m.3700G>A	A132T	LHON	Cfrm [VUS*]	0.460%
m.3713T>C	V136A	LHON	Reported	0.000%
m.3733G>C	E143Q	LHON	Reported	0.000%
m.3733G>A	E143K	LHON	Cfrm [VUS*]	0.310%
m.3734A>G	E143G	LHON	Reported [VUS]	0.150%
m.3736G>A	V144I	LHON	Reported	17.310%
m.3745G>A	A147T	LHON / high altitude variant	Reported / Population-dependent	19.150%
m.3761C>A	S152Term	Deafness w relapsing/remitting neurological symptoms	Reported [VUS]	0.000%
m.3769C>G	L155V	LHON	Reported	0.000%
m.3781T>C	S159P	LHON	Reported	0.000%
m.3796A>G	T164A	Adult-Onset Dystonia	Reported	45.800%
m.3833T>A	L176Q	PEG	Reported	0.000%
m.3861A>C	W185C	SNHL + neurodevelopmental delay	Reported	0.000%
m.3866T>C	I187T	LHON + limb claudication	Reported / possibly synergistic	32.630%
m.3890G>A	R195Q	Progressive Encephalomyopathy / Leigh Syndrome / Optic Atrophy	Cfrm [LP]	0.150%
m.3902ACCTTGC>GCAAGGT	DLA-GKV	EXIT+myalgia / severe LA+cardiac / 3-MGA aciduria / nephropathy+deafness+diabetes	Cfrm [LP]	0.000%
m.3911A>G	E202G	Multisystemic disorder with SNHL and neurodevelopmental delay	Reported	0.000%
m.3919T>C	S205P	LHON	Reported	0.000%
m.3945C>A	I213M	Leigh-like phenotype	Reported	0.000%
m.3946G>A	E214K	MELAS	Cfrm [LP]	0.150%
m.3949T>C	Y215H	MELAS	Reported [VUS]	0.150%
m.3955G>A	A217T	Leigh Syndrome	Reported	0.000%
m.3958G>A	G218S	LHON	Reported	0.000%
m.3959G>A	G218D	MELAS	Reported	0.000%
m.3995A>G	N230S	MELAS	Reported	3.220%
m.4081T>C	F259L	LHON	Reported	0.150%
m.4115T>C	F270S	Possible LHON helper (one 11778 patient)	Reported	0.000%
m.4123A>T	I273F	LHON	Reported	0.000%
m.4132G>A	A276T	NAION-associated	Reported [VUS]	1.380%
m.4135T>C	Y277H	LHON	Reported	4.140%
m.4136A>G	Y277C	LHON	Reported - possibly synergistic	11.950%
m.4142G>T	R279L	Leigh Syndrome	Reported	0.000%
m.4142G>A	R279Q	Developmental delay, seizure, hypotonia	Reported [VUS]	0.000%
m.4160T>C	L285P	LHON / LHON plus	Reported - possibly synergistic	0.150%
m.4163T>C	M286T	LHON	Reported	0.150%
m.4171C>A	L289M	LHON / Leigh-like phenotype	Cfrm [VUS*]	0.310%
m.4175G>A	W290Term	EXIT	Reported	0.000%
m.4216T>C	Y304H	LHON / Insulin Resistance /possible adaptive high altitude variant / miscarriage	Conflicting reports	1018.440%