MT-ND5

Chr MT

NADH dehydrogenase subunit 5

Also known as: MTND5

NCBI Gene: 4540 ENSG00000198786 OMIM: 516005

This gene encodes a core subunit of NADH:ubiquinone oxidoreductase (Complex I) in the mitochondrial respiratory chain. Mutations cause mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS), Leber hereditary optic neuropathy (LHON), Leigh syndrome, and isolated Complex I deficiency. Inheritance is maternal, and clinical 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; Leigh disease; and MELAS syndrome. [provided by Alliance of Genome Resources, Jul 2025]

GeneReviews OMIM ResearchGenerating clinical summary…

Multiplemechanism

Clinical Summary— MT-ND5

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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

12 unique Pathogenic / Likely Pathogenic· 136 VUS of 332 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MT-ND5

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD

Constraint data not available from gnomAD.

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongMT-ND5-related Leber hereditary optic neuropathyOTHERmitochondrial

This gene — mechanism propensity

0.88top 5%

GOF

0.6541th %ile

LOF

0.2775th %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

332 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic8

VUS136

Likely Benign85

Benign96

Conflicting1

Pathogenic

Likely Pathogenic

136

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	—	—	—	—	4
Likely Pathogenic	—	—	—	—	8
VUS	—	—	—	—	136
Likely Benign	—	—	—	—	85
Benign	—	—	—	—	96
Conflicting	—				1
Total	—				330

Counts from ClinVar esearch · Updated hourly

View in ClinVar →

20 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap MT-ND5 — 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-ND5 · protein map & ClinVar variants

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

MITOMAP Disease Variants — MT-ND5

MITOMAP ↗

Variant	AA	Disease	Status	GenBank
m.12338T>C	M1T	DEAF1555 increased penetrance / LHON / MIDD	Conflicting reports	34.770%
m.12350C>A	T5N	SNHL + neurodevelopmental delay	Reported	0.000%
m.12361A>G	T9A	Non-alcoholic fatty liver disease	Reported	66.630%
m.12372G>A	L12L	Altered brain pH / sCJD patients; AD risk in certain haplogroups	Reported [B]	1348.370%
m.12397A>G	T21A	PD, early onset	Reported	60.350%
m.12414T>-	frameshift	EXIT	Reported	0.000%
m.12425A>-	frameshift	Mitochondrial myopathy & renal failure	Cfrm [LP]	0.310%
m.12477T>C	S47S	Possible HCM susceptibility / PCOS patients	Reported	54.990%
m.12622G>A	V96I	Leigh Disease	Conflicting reports	1.530%
m.12631T>A	S99T	found in 2 sCJD patients	Reported	0.000%
m.12634A>G	I100V	Thyroid Cancer Cell Line	Reported	37.990%
m.12635T>C	I100T	Suspected Leigh Disease	Reported	0.310%
m.12662A>G	N109S	Recurrent pregnancy loss	Reported	13.170%
m.12686T>A	F117Y	Dilated Cardiomyopathy	Reported	0.000%
m.12705C>T	I123I	Possible protective factor for normal tension glaucoma	Reported	4033.020%
m.12706T>C	F124L	Leigh Disease	Cfrm [LP]	0.000%
m.12770A>G	E145G	MELAS	Reported [VUS]	0.150%
m.12778G>C	G148R	Dilated Cardiomyopathy	Reported	0.000%
m.12782T>G	I149S	LHON	Reported	0.000%
m.12811T>C	Y159H	Possible LHON factor	Reported [B]	113.500%
m.12814G>T	A160S	LHON	Reported	0.460%
m.12848C>T	A171V	LHON	Reported [VUS]	0.000%
m.12858C>A	Y174Term	Unspecified suspected mitochondrial disorder	Reported	0.000%
m.12923G>A	W196Term	LHON/MELAS/LS	Reported	0.000%
m.12955A>G	N207D	EXIT and developmental delay	Reported	0.000%
m.13042G>A	A236T	Optic neuropathy/ retinopathy/ LD	Cfrm [LP]	0.310%
m.13045A>C	M237L	MELAS / LHON / Leigh overlap syndrome	Reported [VUS]	0.150%
m.13045A>G	M237V	MELAS	Reported	0.000%
m.13046T>C	M237T	LHON/MELAS overlap syndrome	Cfrm [LP]	0.000%
m.13051G>A	G239S	LHON	Cfrm [VUS*]	0.000%
m.13063G>A	V243I	Adult-onset Encephalopathy / Ataxia	Reported [VUS]	0.310%
m.13084A>T	S250C	MELAS / Leigh Disease	Reported [VUS]	0.000%
m.13091T>C	M252T	MELAS+Migraine	Reported	0.000%
m.13094T>C	V253A	Ataxia+PEO / MELAS, LD, LHON, myoclonus, fatigue	Cfrm [P]	0.150%
m.13112T>C	L259S	Leigh Disease	Reported	0.000%
m.13135G>A	A267T	Possible HCM susceptibility / PCOS patients	Reported	100.940%
m.13138G>A	E268K	Possible LHON modulator	Reported	0.000%
m.13204G>A	V290I	Peripheral neuropathy of T2 diabetes	Reported	7.050%
m.13268G>A	G311E	Possible ROS inducer-triggered lung cancer cell death	Reported	0.000%
m.13271T>C	L312P	Exercise intolerance (EXIT)	Reported	0.150%
m.13276A>G	M314V	MIDD+retinopathy	Conflicting reports	262.540%
m.13289G>A	G318D	MELAS	Reported	0.000%
m.13340T>C	F335S	LHON	Reported	0.150%
m.13345G>A	A337T	LHON	Reported	0.000%
m.13376T>C	I347T	MELAS w medial temporal lobe atrophy	Reported	0.150%
m.13379A>C	H348P	LHON	Reported [VUS]	0.000%
m.13379A>G	H348R	LHON	Cfrm [VUS*]	0.000%
m.13511A>T	K392M	Leigh-like syndrome	Reported	0.000%
m.13513G>A	D393N	Leigh Disease / MELAS / LHON-MELAS Overlap Syndrome / negative association w Carotid Atherosclerosis	Cfrm [P]	0.150%
m.13514A>G	D393G	Leigh Disease / MELAS / Ca2+ downregulation	Cfrm [LP]	0.000%
m.13528A>G	T398A	LHON-like, LHON, MELAS	Reported [LB]	11.640%
m.13565C>T	S410F	Found in MELAS patient	Reported	11.790%
m.13580C>G	A415G	Thyroid Cancer	Reported	0.000%
m.13590G>A	L418L	Possible protective factor for high altitude sickness / PCOS patient	Reported	550.650%
m.13615A>G	I427V	LHON	Reported	1.530%
m.13637A>G	Q434R	Possible LHON factor	Reported	93.590%
m.13702C>G	R456G	Possible LHON helper (one 14484 patient)	Reported	3.060%
m.13708G>A	A458T	LHON / Increased MS risk / higher freq in PD-ADS / PCOS patient	Conflicting reports	734.150%
m.13712C>T	A459V	Possible LHON helper (one 11778 patient)	Reported	1.680%
m.13730G>A	G465E	LHON	Reported [VUS]	0.000%
m.13759G>A	A475T	Possible LHON factor	Reported	341.420%
m.13831C>A	L499M	Thyroid Cancer Cell Line	Reported	0.460%
m.13849A>C	N505H	MELAS	Reported - possibly secondary	0.310%
m.13966A>G	T544A	Greater risk with hg X of end-stage kidney disease	Reported	135.710%
m.13967C>T	T544M	Possible LHON factor	Reported	30.790%
m.14002A>G	T556A	High altitude pulmonary edema susceptibility	Reported	22.520%
m.14063T>C	I576T	Potentially functional variant cosegregating with LHON3635A	Reported	3.980%
m.14091A>T	K585N	Developmental delay, seizure, hearing loss, diabetes	Reported	0.000%