MT-CO3

Chr MTAR

cytochrome c oxidase subunit III

Also known as: COIII, MTCO3

NCBI Gene: 4514 ENSG00000198938 OMIM: 516050

This gene encodes cytochrome c oxidase subunit III, a core component of Complex IV in the mitochondrial respiratory chain that catalyzes the final step of electron transport. Mutations cause Complex IV deficiency presenting as Leigh syndrome, MELAS-like episodes, or recurrent myoglobinuria. Inheritance is maternal through mitochondrial DNA, with clinical severity depending on the degree of heteroplasmy in affected tissues.

GeneReviews OMIM ResearchSummary from Curated mito context

Predicted to contribute to cytochrome-c oxidase activity. Involved in respiratory chain complex IV assembly. Located in mitochondrial membrane. Part of respiratory chain complex IV. Implicated in MELAS syndrome. [provided by Alliance of Genome Resources, Apr 2025]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAR2 OMIM phenotypes

Clinical Summary— MT-CO3

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Gene-Disease Validity (ClinGen)

Leigh syndrome · MTLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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ClinVar Variants

9 unique Pathogenic / Likely Pathogenic· 82 VUS of 171 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MT-CO3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD

Constraint data not available from gnomAD.

This gene — mechanism propensity

0.88top 5%

GOF

0.84top 5%

LOF

0.04100th %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

171 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic5

VUS82

Likely Benign39

Benign39

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	—	—	—	—	4
Likely Pathogenic	—	—	—	—	5
VUS	—	—	—	—	82
Likely Benign	—	—	—	—	39
Benign	—	—	—	—	39
Conflicting	—				1
Total	—				170

Counts from ClinVar esearch · Updated hourly

View in ClinVar →

17 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap MT-CO3 — 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-CO3 · protein map & ClinVar variants

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

MITOMAP Disease Variants — MT-CO3

MITOMAP ↗

Variant	AA	Disease	Status	GenBank
m.9237G>A	V11M	Mitochondrial Respiratory Chain Disorder	Reported [VUS]	0.000%
m.9247G>C	S14T	MELAS	Reported	0.000%
m.9266G>T	G20G	Possible association with sepsis	Reported	0.150%
m.9267G>C	A21P	MIDD	Reported	0.000%
m.9331T>C	L42P	Failure to thrive with metabolic acidosis, cognitive impairment, optic atrophy	Reported	0.150%
m.9379G>A	W58Term	MM w lactic acidosis	Reported [VUS]	0.000%
m.9387G>A	V61M	Asthenozoospermia	Reported	0.000%
m.9399A>G	S65G	Patient with epilepsy, myopathy, hypoacusis, psychiatric disorders	Reported	0.150%
m.9403C>A	T66K	Possible association with sepsis	Reported	0.000%
m.9415A>G	H70R	Possible association with sepsis	Reported	0.000%
m.9438G>A	G78S	LHON / gout	Conflicting reports	123.300%
m.9444C>T	R80W	Possible LHON helper mutation	Reported	0.150%
m.9478T>C	V91A	Leigh Disease	Reported [VUS]	3.370%
m.9480TTTTTCTTCGCAGGA>-	FFFAG-del	Myoglobinuria	Cfrm [LP], alt locus at 9487del15	0.000%
m.9487TCGCAGGATTTTTCT>-	FFAGFF-del	Myoglobinuria	alt loc to 9480del15 [LP]	0.000%
m.9490C>T	A95V	Gout	Reported	3.830%
m.9537C>CC	frameshift	Leigh Disease	Cfrm [LP]	0.000%
m.9544G>A	G113E	Sporadic bilateral optic neuropathy / rhabdomyolysis	Reported	0.000%
m.9553G>A	W116Term	Adult-onset MELAS	Reported	0.000%
m.9559C>-	frameshift	Rhabdomyolysis	Reported	0.000%
m.9660A>C	M152L	LHON	Reported	0.000%
m.9738G>A	A178T	Marfan Syndrome patients	Reported	35.380%
m.9738G>T	A178S	LHON	Reported	0.000%
m.9789T>C	S195P	Myopathy	Reported	0.000%
m.9804G>A	A200T	LHON / MS	Reported [VUS]	29.560%
m.9856T>C	I217T	LVNC cardiomyopathy / gout	Reported	3.220%
m.9861T>C	F219L	AD	Reported	20.830%
m.9907G>A	G234D	Cavitating leukodystrophy	Reported	0.000%
m.9921G>A	A239T	Possible LHON helper mutation	Reported	10.420%
m.9952G>A	W249Term	Mitochondrial Encephalopathy	Cfrm [LP]	0.000%
m.9957T>C	F251L	PEM / MELAS / NAION / HCM / gout	Reported	7.660%
m.9966G>A	V254I	LHON possible helper variant	Reported	65.400%
m.9972A>C	I256L	EXIT & APS2 - possible link	Reported	0.310%
m.9984G>A	G260Term	Suspected mito disease	Reported	0.000%