COX15

Chr 10AR

cytochrome c oxidase assembly factor COX15

Also known as: CEMCOX2, HAS, MC4DN6

NCBI Gene: 1355 ENSG00000014919 UniProt: Q7KZN9 OMIM: 603646

The protein functions in the biogenesis of cytochrome c oxidase (complex IV) and is involved in the hydroxylation of heme O, which is essential for proper assembly of this terminal component of the mitochondrial respiratory chain. Mutations cause mitochondrial complex IV deficiency through an autosomal recessive inheritance pattern, resulting in impaired cellular respiration. The pathogenic mechanism involves loss of function leading to defective complex IV assembly and subsequent mitochondrial dysfunction.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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 a protein which is not a structural subunit, but may be essential for the biogenesis of COX formation and may function in the hydroxylation of heme O, according to the yeast mutant studies. This protein is predicted to contain 5 transmembrane domains localized in the mitochondrial inner membrane. Alternative splicing of this gene generates two transcript variants diverging in the 3' region. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.331 OMIM phenotype

Clinical Summary— COX15

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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)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

46 unique Pathogenic / Likely Pathogenic· 242 VUS of 559 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — COX15

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?

1.33LOEUF

pLI 0.000

Z-score 0.35

OE 0.92 (0.65–1.33)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.26Z-score

OE missense 0.95 (0.85–1.07)

208 obs / 218.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.92 (0.65–1.33)

0≤0.351.4

Missense OE?0.95 (0.85–1.07)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 21 / 22.8Missense obs/exp: 208 / 218.9Syn Z: -0.18

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCOX15-related Leigh syndromeLOFAR

This gene — mechanism propensity

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

0.6647th %ile

GOF

0.5170th %ile

LOF

0.4136th %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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

559 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20

Likely Pathogenic26

VUS242

Likely Benign211

Benign25

Conflicting25

Pathogenic

Likely Pathogenic

242

VUS

211

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	16	1	3	0	20
Likely Pathogenic	24	2	0	0	26
VUS	4	149	85	4	242
Likely Benign	4	11	91	105	211
Benign	0	1	23	1	25
Conflicting	—				25
Total	48	164	202	110	549

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

View in ClinVar →

16 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap COX15 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →