COX5A

Chr 15

cytochrome c oxidase subunit 5A

Also known as: COX, COX-VA, MC4DN20, VA

NCBI Gene: 9377 ENSG00000178741 UniProt: P20674

Cytochrome c oxidase (COX) is the terminal enzyme of the mitochondrial respiratory chain. It is a multi-subunit enzyme complex that couples the transfer of electrons from cytochrome c to molecular oxygen and contributes to a proton electrochemical gradient across the inner mitochondrial membrane. The complex consists of 13 mitochondrial- and nuclear-encoded subunits. The mitochondrially-encoded subunits perform the electron transfer of proton pumping activities. The functions of the nuclear-encoded subunits are unknown but they may play a role in the regulation and assembly of the complex. This gene encodes the nuclear-encoded subunit Va of the human mitochondrial respiratory chain enzyme. A pseudogene COX5AP1 has been found in chromosome 14q22. [provided by RefSeq, Jul 2008]

Research

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtMitochondrial complex IV deficiency, nuclear type 20

Clinical highlights

Gene–disease validity (ClinGen)

Moderate · mitochondrial disease · AR · ClinGen 2024

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.79

LOEUF

Mechanism· predicted

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?

0.79LOEUF

pLI 0.494

Z-score 1.89

OE 0.17 (0.06–0.79)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.25Z-score

OE missense 0.92 (0.75–1.13)

65 obs / 70.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.17 (0.06–0.79)

0≤0.351.4

Missense OE?0.92 (0.75–1.13)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 1 / 6.0Missense obs/exp: 65 / 70.8Syn Z: 0.07

Background carrier burden — how many people carry a rare variant somewhere in COX5A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 220

211 rare PASS variants

Rare truncating (LoF)

1 in 13,000

20 rare PASS variants

Rare synonymous (reference)

1 in 1,000

86 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for COX5A. 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 210	1 in 11,000
South Asian	~43k	1 in 130	none seen
Remaining (unassigned)	~30k	1 in 250	none seen
European (Finnish)	~27k	1 in 1,100	≈ 1 in 11,000
Admixed American	~22k	1 in 350	≈ 1 in 11,000
African / African American	~21k	1 in 180	≈ 1 in 5,700
East Asian	~20k	1 in 450	≈ 1 in 9,900
Ashkenazi Jewish	~13k	1 in 140	none seen
Middle Eastern	~2,884	1 in 370	none seen

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): 3 of 4 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 4.? see exons ↓