COX10

Chr 17AR

cytochrome c oxidase assembly factor heme A:farnesyltransferase COX10

Also known as: MC4DN3

NCBI Gene: 1352 ENSG00000006695 UniProt: Q12887 OMIM: 602125

The protein encodes heme A:farnesyltransferase, which is essential for the maturation of the heme A prosthetic group required for functional cytochrome c oxidase (complex IV) assembly. Biallelic mutations cause mitochondrial complex IV deficiency, nuclear type 3, inherited in an autosomal recessive pattern. The disease predominantly results from loss-of-function mutations that impair the enzyme's ability to process heme A, leading to defective complex IV assembly and mitochondrial respiratory chain dysfunction.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Cytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. This component is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may function in the regulation and assembly of the complex. This nuclear gene encodes heme A:farnesyltransferase, which is not a structural subunit but required for the expression of functional COX and functions in the maturation of the heme A prosthetic group of COX. This protein is predicted to contain 7-9 transmembrane domains localized in the mitochondrial inner membrane. A gene mutation, which results in the substitution of a lysine for an asparagine (N204K), is identified to be responsible for cytochrome c oxidase deficiency. In addition, this gene is disrupted in patients with CMT1A (Charcot-Marie-Tooth type 1A) duplication and with HNPP (hereditary neuropathy with liability to pressure palsies) deletion. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.611 OMIM phenotype

Clinical Summary— COX10

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.29) despite low pLI — interpret in context.

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ClinVar Variants

15 unique Pathogenic / Likely Pathogenic· 174 VUS of 370 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — COX10

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.61LOEUF

pLI 0.084

Z-score 2.73

OE 0.29 (0.15–0.61)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.18Z-score

OE missense 1.03 (0.93–1.14)

266 obs / 257.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.29 (0.15–0.61)

0≤0.351.4

Missense OE?1.03 (0.93–1.14)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 5 / 17.2Missense obs/exp: 266 / 257.9Syn Z: -1.02

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCOX10-related Leigh syndromeOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.74top 25%

GOF

0.5856th %ile

LOF

0.3161th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

370 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic11

VUS174

Likely Benign99

Benign41

Conflicting28

Pathogenic

Likely Pathogenic

174

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	4	0	0	4
Likely Pathogenic	8	3	0	0	11
VUS	1	137	33	3	174
Likely Benign	0	6	43	50	99
Benign	0	1	38	2	41
Conflicting	—				28
Total	9	151	114	55	357

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

111 pathogenic / likely-pathogenic (of 122) ClinVar copy-number / structural variants overlap COX10 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →