MT-ND4

Chr MT

NADH dehydrogenase subunit 4

Also known as: MTND4

NCBI Gene: 4538 ENSG00000198886 UniProt: P03905 OMIM: 516003

This gene encodes a subunit of NADH:ubiquinone oxidoreductase (Complex I) in the mitochondrial respiratory chain. Mutations cause MELAS, Leigh syndrome, and Leber hereditary optic neuropathy (LHON), with m.11778G>A being the most common LHON mutation. Inheritance is maternal through mitochondrial DNA, and disease severity depends on the degree of heteroplasmy in affected tissues.

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. Part of respiratory chain complex I. Implicated in Leber hereditary optic neuropathy; Parkinson's disease; macular degeneration; and schizophrenia. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Jul 2025]

GeneReviews OMIM ResearchGenerating clinical summary…

Multiplemechanism

Clinical Summary— MT-ND4

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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

2 unique Pathogenic / Likely Pathogenic· 63 VUS of 151 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MT-ND4

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD

Constraint data not available from gnomAD.

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMT-ND4-related Leber hereditary optic neuropathyOTHERmitochondrial

This gene — mechanism propensity

0.88top 5%

GOF

0.80top 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

151 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic1

VUS63

Likely Benign38

Benign47

Conflicting1

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	—	—	—	—	1
Likely Pathogenic	—	—	—	—	1
VUS	—	—	—	—	63
Likely Benign	—	—	—	—	38
Benign	—	—	—	—	47
Conflicting	—				1
Total	—				151

Counts from ClinVar esearch · Updated hourly

View in ClinVar →

22 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap MT-ND4 — 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-ND4 · protein map & ClinVar variants

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

MITOMAP Disease Variants — MT-ND4

MITOMAP ↗

Variant	AA	Disease	Status	GenBank
m.11042T>C	Y95H	Biliary atresia	Reported	0.000%
m.11048T>-	frameshift	Biliary atresia	Reported	0.000%
m.11084A>G	T109A	AD, PD MELAS	Conflicting reports	35.080%
m.11150G>A	A131T	Found in a Multiple Sclerosis patient	Reported	25.270%
m.11232T>C	L158P	CPEO	Reported	0.000%
m.11240C>T	L161F	Leigh Syndrome	Reported	0.000%
m.11251A>G	L164L	Reduced risk of PD	Reported	949.510%
m.11253T>C	I165T	LHON PD	Reported	51.470%
m.11365T>C	A202A	found in HCM patient	Reported	21.900%
m.11375A>C	K206Q	found in sCJD patient	Reported	0.000%
m.11406T>A	L216H	MELAS	Reported	0.000%
m.11467A>G	L236L	Altered brain pH / sCJD patients	Reported [B]	1249.580%
m.11470A>C	K237N	MELAS	Reported	0.000%
m.11519A>C	T254P	ND4 mutation set found in a Multiple Sclerosis patient	Reported	0.000%
m.11523A>C	K255T	ND4 mutation set found in a Multiple Sclerosis patient	Reported	0.000%
m.11527C>T	H256H	ND4 mutation set found in a Multiple Sclerosis patient	Reported	3.830%
m.11621TA>-	frameshift	CPEO, exercise intolerance	Reported [VUS]	0.000%
m.11696G>A	V313I	LHON / LDYT / DEAF / hypertension helper mut.	Reported / possibly synergistic	57.290%
m.11777C>A	R340S	Leigh Disease	Cfrm [LP]	0.000%
m.11778G>A	R340H	LHON / Progressive Dystonia	Cfrm [P]	29.260%
m.11832G>A	W358Term	EXIT / oncocytoma	Reported	0.000%
m.11874C>A	T372N	LHON	Reported	0.000%
m.11914G>A	T385T	Possible susceptibility to bullous pemphigoid	Reported	1039.120%
m.11919C>T	S387F	Thyroid Cancer Cell Line	Reported	0.150%
m.11984T>C	Y409H	Leigh Syndrome	Reported	9.960%
m.11994C>T	T412I	Oligoasthenoteratozoospermia (OAT)	Conflicting reports	0.000%
m.12015T>C	L419P	Atypical MELAS	Reported	0.460%
m.12026A>G	I423V	DM	Reported	42.740%
m.12027T>C	I423T	SZ-associated	Reported	0.310%
m.12033A>G	N425S	LHON synergistic combo 10680A + 12033G + 14258A	Reported: individually neutral variants causing LHON in combination	3.520%
m.12058A>C	E433D	Multisystemic disorder with SNHL and neurodevelopmental delay	Reported	0.000%
m.12063C>T	T435I	Recurrent pregnancy loss	Reported	6.890%