COX18

Chr 4AR

cytochrome c oxidase assembly factor COX18

Also known as: CMT2MM, COX18HS, MC4DN25, OXA1L2

NCBI Gene: 285521 ENSG00000163626 UniProt: Q8N8Q8 OMIM: 610428

This gene encodes a mitochondrial membrane insertase that translocates cytochrome c oxidase subunit II across the mitochondrial inner membrane and is essential for respiratory chain complex IV assembly and stability. Mutations cause autosomal recessive mitochondrial complex IV deficiency and Charcot-Marie-Tooth disease type 2MM, an axonal peripheral neuropathy. The gene appears relatively tolerant to loss-of-function variants based on constraint metrics.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

?Mitochondrial complex IV deficiency, nuclear type 25MIM #621487

Charcot-Marie-Tooth disease, axonal, type 2MMMIM #621488

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Charcot-Marie-Tooth disease, axonal, type 2MM; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.70

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

0.13Z-score

OE missense 0.97 (0.86–1.10)

184 obs / 189.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.18 (0.83–1.70)

0≤0.351.4

Missense OE?0.97 (0.86–1.10)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 20 / 16.9Missense obs/exp: 184 / 189.1Syn Z: 0.24

Background carrier burden — how many people carry a rare variant somewhere in COX18?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 150

485 rare PASS variants

Rare truncating (LoF)

1 in 2,000

83 rare PASS variants

Rare synonymous (reference)

1 in 130

187 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for COX18. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 110	1 in 2,500
South Asian	~43k	1 in 78	1 in 830
Remaining (unassigned)	~30k	1 in 110	1 in 2,700
European (Finnish)	~27k	1 in 760	none seen
Admixed American	~22k	1 in 110	1 in 1,600
African / African American	~21k	1 in 87	1 in 370
East Asian	~20k	1 in 150	1 in 1,200
Ashkenazi Jewish	~13k	1 in 340	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 170	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 5 of 6 coding exons well covered in gnomAD exomes; exon 5 marginal. Genomes: 5 of 6 (exon 2 below).? see exons ↓