COX4I2

Chr 20AR

cytochrome c oxidase subunit 4I2

Also known as: COX4, COX4-2, COX4B, COX4L2, COXIV-2, dJ857M17.2

NCBI Gene: 84701 ENSG00000131055 UniProt: Q96KJ9 OMIM: 607976

COX4I2 encodes subunit IV isoform 2 of cytochrome c oxidase, the terminal enzyme of the mitochondrial respiratory chain that catalyzes electron transfer from reduced cytochrome c to oxygen. Biallelic mutations cause autosomal recessive exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosis through a predicted dominant-negative mechanism. This nuclear-encoded subunit plays a pivotal role in regulating the cytochrome c oxidase complex.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Cytochrome c oxidase (COX), the terminal enzyme of the mitochondrial respiratory chain, catalyzes the electron transfer from reduced cytochrome c to oxygen. It is a heteromeric complex consisting of 3 catalytic subunits encoded by mitochondrial genes and multiple structural subunits encoded by nuclear genes. The mitochondrially-encoded subunits function in electron transfer, and the nuclear-encoded subunits may be involved in the regulation and assembly of the complex. This nuclear gene encodes isoform 2 of subunit IV. Isoform 1 of subunit IV is encoded by a different gene, however, the two genes show a similar structural organization. Subunit IV is the largest nuclear encoded subunit which plays a pivotal role in COX regulation. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosisMIM #612714

Clinical highlights

Gene–disease validity (ClinGen)

Limited · mitochondrial disease · AR · ClinGen 2024

not for standalone diagnostic reporting

Active trials

—

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.34

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.34LOEUF

pLI 0.000

Z-score 0.82

OE 0.72 (0.41–1.34)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.07Z-score

OE missense 1.02 (0.87–1.20)

105 obs / 103.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.72 (0.41–1.34)

0≤0.351.4

Missense OE?1.02 (0.87–1.20)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 7 / 9.8Missense obs/exp: 105 / 103.1Syn Z: -0.40

Background carrier burden — how many people carry a rare variant somewhere in COX4I2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 210

237 rare PASS variants

Rare truncating (LoF)

1 in 1,600

53 rare PASS variants

Rare synonymous (reference)

1 in 750

84 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for COX4I2. 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 310	1 in 1,800
South Asian	~43k	1 in 120	1 in 3,300
Remaining (unassigned)	~30k	1 in 130	1 in 1,900
European (Finnish)	~27k	1 in 480	1 in 550
Admixed American	~22k	1 in 150	1 in 870
African / African American	~21k	1 in 180	1 in 2,900
East Asian	~20k	1 in 140	1 in 3,300
Ashkenazi Jewish	~13k	1 in 410	none seen
Middle Eastern	~2,884	1 in 190	≈ 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 4 coding exons well covered in gnomAD exomes and genomes.? see exons ↓