COX15

Chr 10AR

cytochrome c oxidase assembly homolog COX15

NCBI Gene: 1355ENSG00000014919UniProt: Q7KZN9

Catalyzes the second reaction in the biosynthesis of heme A, a prosthetic group of mitochondrial cytochrome c oxidase (CcO) (PubMed:12474143). Heme A is synthesized from heme B by two sequential enzymatic reactions catalyzed by heme O synthase (HOS) and heme A synthase (HAS). HAS catalyzes the conversion of heme O to heme A by two successive hydroxylations of the methyl group at C8, in a reaction that involves matrix ferredoxin and ferredoxin reductase. The first hydroxylation forms heme I, the second hydroxylation results in an unstable dihydroxymethyl group, which spontaneously dehydrates, resulting in the formyl group of heme A (By similarity)

Primary Disease Associations & Inheritance

Mitochondrial complex IV deficiency, nuclear type 6MIM #615119
AR
578
ClinVar variants
49
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— COX15
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
49 Pathogenic / Likely Pathogenic· 143 VUS of 578 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.26Z-score
OE missense 0.95 (0.85–1.07)
208 obs / 218.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.92 (0.65–1.33)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.95 (0.85–1.07)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.02
0≤1.21.6
LoF obs/exp: 21 / 22.8Missense obs/exp: 208 / 218.9Syn Z: -0.18

ClinVar Variant Classifications

578 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25
Likely Pathogenic24
VUS143
Likely Benign181
Benign11
Conflicting6
25
Pathogenic
24
Likely Pathogenic
143
VUS
181
Likely Benign
11
Benign
6
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
8
0
17
0
25
Likely Pathogenic
17
2
5
0
24
VUS
2
129
9
3
143
Likely Benign
3
6
78
94
181
Benign
0
0
11
0
11
Conflicting
—6
Total3013712097390

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

View in ClinVar →

Protein Context — Lollipop Plot

COX15 · protein map & ClinVar variants

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

Gene2Phenotype Curations

COX15-related Leigh syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Mitochondrial complex IV deficiency, nuclear type 6

MIM #615119

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
COX15 deficiency causes oocyte ferroptosis.
Zhang Z et al.·Proc Natl Acad Sci U S A
2024
A novel variant in the COX15 gene causing a fatal infantile cardioencephalomyopathy: A case report with clinical and molecular review.
Galvão de Oliveira M et al.·Eur J Med Genet
2021Review
Infantile cardioencephalopathy due to a COX15 gene defect: report and review.
Alfadhel M et al.·Am J Med Genet A
2011Review
Analysis of Oligomerization Properties of Heme a Synthase Provides Insights into Its Function in Eukaryotes.
Swenson S et al.·J Biol Chem
2016
Novel missense variants in COX15 cause oocyte degeneration and female infertility.
Yu R et al.·J Assist Reprod Genet
2026
Leigh syndrome associated with a novel mutation in the COX15 gene.
Miryounesi M et al.·J Pediatr Endocrinol Metab
2016Case report
Defects in the biosynthesis of mitochondrial heme c and heme a in yeast and mammals.
Moraes CT et al.·Biochim Biophys Acta
2004Review
Novel mutations in COX15 in a long surviving Leigh syndrome patient with cytochrome c oxidase deficiency.
Bugiani M et al.·J Med Genet
2005Case report
Mutation screening in patients with isolated cytochrome c oxidase deficiency.
Sacconi S et al.·Pediatr Res
2003Cohort
Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region.
Jordahl KM et al.·Cancer Epidemiol Biomarkers Prev
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools