COX18

Chr 4AR

cytochrome c oxidase assembly factor COX18

Also known as: CMT2MM, COX18HS, MC4DN25, OXA1L2

NCBI Gene: 285521ENSG00000163626UniProt: Q8N8Q8

This gene encodes a cytochrome c oxidase assembly protein. The encoded protein is essential for integral membrane protein insertion into the mitochondrial inner membrane. It is also required for cytochrome c oxidase assembly and activity. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

Primary Disease Associations & Inheritance

?Mitochondrial complex IV deficiency, nuclear type 25MIM #621487
AR
Charcot-Marie-Tooth disease, axonal, type 2MMMIM #621488
AR
95
ClinVar variants
26
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— COX18
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
26 Pathogenic / Likely Pathogenic· 62 VUS of 95 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.
1.70LOEUF
pLI 0.000
Z-score -0.70
OE 1.18 (0.83–1.70)
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.
0.13Z-score
OE missense 0.97 (0.86–1.10)
184 obs / 189.1 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.1.18 (0.83–1.70)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.97 (0.86–1.10)
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.0.96
0≤1.21.6
LoF obs/exp: 20 / 16.9Missense obs/exp: 184 / 189.1Syn Z: 0.24

ClinVar Variant Classifications

95 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic25
Likely Pathogenic1
VUS62
Likely Benign6
Benign1
25
Pathogenic
1
Likely Pathogenic
62
VUS
6
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
23
0
25
Likely Pathogenic
0
0
1
0
1
VUS
0
56
6
0
62
Likely Benign
0
4
1
1
6
Benign
0
0
1
0
1
Total06232195

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

View in ClinVar →

Protein Context — Lollipop Plot

COX18 · protein map & ClinVar variants

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

Gene2Phenotype Curations

COX18-related peripheral neuropathy

limited
ARLoss Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantregulatory region variant

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Mitochondrial complex IV deficiency, nuclear type 25

MIM #621487

Molecular basis of disorder known

Autosomal recessive

Charcot-Marie-Tooth disease, axonal, type 2MM

MIM #621488

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy.
Armirola-Ricaurte C et al.·Brain
2026
Pharmacogenetics of Bronchodilator Response: Future Directions.
Sordillo JE et al.·Curr Allergy Asthma Rep
2021Review
A biallelic variant in COX18 cause isolated Complex IV deficiency associated with neonatal encephalo-cardio-myopathy and axonal sensory neuropathy.
Ronchi D et al.·Eur J Hum Genet
2023Case report
Hydrochlorothiazide-induced hyperuricaemia in the pharmacogenomic evaluation of antihypertensive responses study.
Vandell AG et al.·J Intern Med
2014
Mutation analysis of COX18 in 29 patients with isolated cytochrome c oxidase deficiency.
Sacconi S et al.·J Hum Genet
2009Cohort
Sex-Specific Genetic Determinants of Asthma-COPD Phenotype and COPD in Middle-Aged and Older Canadian Adults: An Analysis of CLSA Data.
Odimba U et al.·COPD
2023
A splice-altering homozygous variant in COX18 causes severe sensory-motor neuropathy with oculofacial apraxia.
Mavillard F et al.·Biochim Biophys Acta Mol Basis Dis
2024Case report
Praziquantel inhibits Caenorhabditis elegans development and species-wide differences might be cct-8-dependent.
Wit J et al.·PLoS One
2023
Whole-Genome Sequencing of Pharmacogenetic Drug Response in Racially Diverse Children with Asthma.
Mak ACY et al.·Am J Respir Crit Care Med
2018
A case report of familial 4q13.3 microdeletion in three individuals with syndromic intellectual disability.
Maldžienė Ž et al.·BMC Med Genomics
2020Case report
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