COA8

Chr 14AR

cytochrome c oxidase assembly factor 8

Also known as: APOP, APOP1, APOPT1, C14orf153, MC4DN17

NCBI Gene: 84334 ENSG00000256053 UniProt: Q96IL0 OMIM: 616003

COA8 encodes a mitochondrial protein required for cytochrome c oxidase (complex IV) assembly and function, protecting the assembly process from oxidation-induced degradation. Biallelic mutations cause autosomal recessive mitochondrial complex IV deficiency, which typically presents as a multi-system disorder affecting energy metabolism. The gene shows minimal constraint against loss-of-function variants (pLI 0.0002, LOEUF 1.25), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein that localizes to the mitochondria, where it stimulates the release of cytochrome c, thereby promoting programmed cell death. Mutations in this gene have been found in individuals with mitochondrial complex IV deficiency. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2014]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Mitochondrial complex IV deficiency, nuclear type 17MIM #619061

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · mitochondrial disease · AR · ClinGen 2023

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

1.25

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.25LOEUF

pLI 0.000

Z-score 1.00

OE 0.67 (0.38–1.25)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.50Z-score

OE missense 1.14 (0.98–1.33)

114 obs / 100.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.67 (0.38–1.25)

0≤0.351.4

Missense OE?1.14 (0.98–1.33)

0≤0.61.4

Synonymous OE?1.25

0≤1.21.6

LoF obs/exp: 7 / 10.5Missense obs/exp: 114 / 100.0Syn Z: -1.16

Background carrier burden — how many people carry a rare variant somewhere in COA8?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 78

381 rare PASS variants

Rare truncating (LoF)

1 in 1,300

95 rare PASS variants

Rare synonymous (reference)

1 in 370

108 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for COA8. 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 130	1 in 1,600
South Asian	~43k	1 in 59	1 in 390
Remaining (unassigned)	~30k	1 in 92	1 in 1,100
European (Finnish)	~27k	1 in 250	1 in 2,200
Admixed American	~22k	1 in 87	≈ 1 in 4,900
African / African American	~21k	1 in 92	1 in 730
East Asian	~20k	1 in 210	1 in 750
Ashkenazi Jewish	~13k	1 in 420	1 in 1,000
Middle Eastern	~2,884	1 in 77	≈ 1 in 1,200

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 5 coding exons well covered in gnomAD exomes. Genomes: 4 of 5 (exon 3 below).? see exons ↓