COA4

Chr 11

cytochrome c oxidase assembly factor 4 homolog

Also known as: CHCHD8, CMC3, E2IG2

NCBI Gene: 51287 ENSG00000181924 UniProt: Q9NYJ1 OMIM: 608016

COA4 encodes a putative assembly factor for cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain. Mutations cause mitochondrial complex IV deficiency, presenting as a severe multisystem disorder affecting the brain, heart, and other energy-demanding organs. The condition follows autosomal recessive inheritance.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to be involved in mitochondrial respiratory chain complex IV assembly. Located in mitochondrion. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Clinical highlights

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

1.48

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.48LOEUF

pLI 0.213

Z-score 1.05

OE 0.34 (0.12–1.48)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.29Z-score

OE missense 0.89 (0.70–1.13)

48 obs / 54.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.34 (0.12–1.48)

0≤0.351.4

Missense OE?0.89 (0.70–1.13)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 1 / 2.9Missense obs/exp: 48 / 54.1Syn Z: 0.60

Background carrier burden — how many people carry a rare variant somewhere in COA4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 450

113 rare PASS variants

Rare truncating (LoF)

1 in 9,500

25 rare PASS variants

Rare synonymous (reference)

1 in 790

52 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for COA4. 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 770	1 in 7,900
South Asian	~43k	1 in 370	1 in 8,600
Remaining (unassigned)	~30k	1 in 340	≈ 1 in 30,000
European (Finnish)	~27k	1 in 510	none seen
Admixed American	~22k	1 in 270	≈ 1 in 7,500
African / African American	~21k	1 in 210	≈ 1 in 17,000
East Asian	~20k	1 in 710	≈ 1 in 9,900
Ashkenazi Jewish	~13k	1 in 1,200	≈ 1 in 13,000
Middle Eastern	~2,884	≈ 1 in 720	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): All 1 coding exons well covered in gnomAD exomes and genomes.? see exons ↓