COX18

Chr 4

cytochrome c oxidase assembly factor COX18

Also known as: CMT2MM, COX18HS, MC4DN25, OXA1L2

NCBI Gene: 285521 ENSG00000163626 UniProt: Q8N8Q8

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.

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]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 1.70

Clinical Summary— COX18

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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

3 unique Pathogenic / Likely Pathogenic· 56 VUS of 74 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedCOX18-related peripheral neuropathyLOFAR

This gene — mechanism propensity

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

0.6745th %ile

GOF

0.6930th %ile

LOF

0.3550th %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

74 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

VUS56

Likely Benign5

Pathogenic

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Total
Pathogenic	0	2	1	3
Likely Pathogenic	0	0	0	0
VUS	2	54	0	56
Likely Benign	1	4	0	5
Benign	0	0	0	0
Total	3	60	1	64

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

View in ClinVar →

24 pathogenic / likely-pathogenic (of 32) ClinVar copy-number / structural variants overlap COX18 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →