COX4I2

Chr 20AR

cytochrome c oxidase subunit 4I2

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

NCBI Gene: 84701ENSG00000131055UniProt: Q96KJ9

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.

Summary from RefSeq, OMIM, UniProt, Mechanism
Research Assistant →

Primary Disease Associations & Inheritance

Exocrine pancreatic insufficiency, dyserythropoietic anemia, and calvarial hyperostosisMIM #612714
AR
0
Active trials
9
Pubs (1 yr)
16
P/LP submissions
0%
P/LP missense
1.34
LOEUF
DN
Mechanism· predicted
Clinical Summary— COX4I2
🧬
Gene-Disease Validity (ClinGen)
mitochondrial disease · ARLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
16 unique Pathogenic / Likely Pathogenic· 57 VUS of 115 total submissions
Explore recent and relevant literature in Research Assistant →

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 OE0.72 (0.41–1.34)
0≤0.351.4
Missense OE1.02 (0.87–1.20)
0≤0.61.4
Synonymous OE1.08
0≤1.21.6
LoF obs/exp: 7 / 9.8Missense obs/exp: 105 / 103.1Syn Z: -0.40
DN
0.74top 25%
GOF
0.4480th %ile
LOF
0.2190th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

115 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10
Likely Pathogenic6
VUS57
Likely Benign25
Benign14
Conflicting2
10
Pathogenic
6
Likely Pathogenic
57
VUS
25
Likely Benign
14
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
10
0
10
Likely Pathogenic
0
0
6
0
6
VUS
2
43
11
1
57
Likely Benign
0
3
11
11
25
Benign
0
1
13
0
14
Conflicting
—2
Total2475112114

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

COX4I2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients