COX8A

Chr 11AR

cytochrome c oxidase subunit 8A

Also known as: COX, COX8, COX8-2, COX8L, MC4DN15, VIII, VIII-L

NCBI Gene: 1351 ENSG00000176340 UniProt: P10176 OMIM: 123870

The protein is a nuclear-encoded subunit of cytochrome c oxidase (complex IV), the terminal enzyme of the mitochondrial respiratory chain that transfers electrons from cytochrome c to molecular oxygen while generating a proton gradient across the inner mitochondrial membrane. Mutations cause mitochondrial complex IV deficiency, nuclear type 15, inherited in an autosomal recessive pattern. The pathogenic mechanism appears to involve loss of function, leading to impaired mitochondrial respiratory chain activity.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The protein encoded by this gene is the terminal enzyme of the respiratory chain, coupling the transfer of electrons from cytochrome c to molecular oxygen, with the concomitant production of a proton electrochemical gradient across the inner mitochondrial membrane. In addition to 3 mitochondrially encoded subunits, which perform the catalytic function, the eukaryotic enzyme contains nuclear-encoded smaller subunits, ranging in number from 4 in some organisms to 10 in mammals. It has been proposed that nuclear-encoded subunits may be involved in the modulation of the catalytic function. This gene encodes one of the nuclear-encoded subunits. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

?Mitochondrial complex IV deficiency, nuclear type 15MIM #619059

Clinical highlights

Gene–disease validity (ClinGen)

not for standalone diagnostic reporting

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.84

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — COX8A

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?

1.84LOEUF

pLI 0.116

Z-score 0.37

OE 0.67 (0.21–1.84)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.15Z-score

OE missense 0.93 (0.71–1.23)

35 obs / 37.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.67 (0.21–1.84)

0≤0.351.4

Missense OE?0.93 (0.71–1.23)

0≤0.61.4

Synonymous OE?0.75

0≤1.21.6

LoF obs/exp: 1 / 1.5Missense obs/exp: 35 / 37.7Syn Z: 0.86

Background carrier burden — how many people carry a rare variant somewhere in COX8A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 700

79 rare PASS variants

Rare truncating (LoF)

1 in 15,000

17 rare PASS variants

Rare synonymous (reference)

1 in 1,200

55 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for COX8A. 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 1,200	1 in 20,000
South Asian	~43k	1 in 1,300	≈ 1 in 43,000
Remaining (unassigned)	~30k	1 in 2,200	≈ 1 in 30,000
European (Finnish)	~27k	1 in 2,700	≈ 1 in 8,800
Admixed American	~22k	1 in 1,600	≈ 1 in 22,000
African / African American	~21k	1 in 1,100	≈ 1 in 10,000
East Asian	~20k	1 in 2,200	≈ 1 in 20,000
Ashkenazi Jewish	~13k	≈ 1 in 13,000	none seen
Middle Eastern	~2,884	≈ 1 in 960	≈ 1 in 1,400

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): All 2 coding exons well covered in gnomAD exomes and genomes.? see exons ↓