COX4I1

Chr 16AR

cytochrome c oxidase subunit 4I1

Also known as: COX IV-1, COX4, COX4-1, COXIV, COXIV-1, MC4DN16

NCBI Gene: 1327 ENSG00000131143 UniProt: P13073 OMIM: 123864

COX4I1 encodes subunit IV isoform 1 of cytochrome c oxidase (complex IV), the terminal enzyme of the mitochondrial electron transport chain that reduces oxygen to water and contributes to ATP production through oxidative phosphorylation. Mutations cause mitochondrial complex IV deficiency, nuclear type 16, which follows autosomal recessive inheritance. This gene has a relatively low constraint against loss-of-function variants (pLI 0.39, LOEUF 0.68), suggesting some tolerance to heterozygous loss of function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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 and 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 IV isoform 1 of the human mitochondrial respiratory chain enzyme. It is located at the 3' of the NOC4 (neighbor of COX4) gene in a head-to-head orientation, and shares a promoter with it. Pseudogenes related to this gene are located on chromosomes 13 and 14. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.681 OMIM phenotype

Clinical Summary— COX4I1

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Gene-Disease Validity (ClinGen)

Leigh syndrome · ARLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 30 VUS of 50 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — COX4I1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.68LOEUF

pLI 0.394

Z-score 2.21

OE 0.22 (0.09–0.68)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.17Z-score

OE missense 1.05 (0.90–1.23)

112 obs / 106.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.22 (0.09–0.68)

0≤0.351.4

Missense OE?1.05 (0.90–1.23)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 2 / 9.3Missense obs/exp: 112 / 106.9Syn Z: -0.54

This gene — mechanism propensity

0.6453th %ile

GOF

0.4282th %ile

LOF

0.3358th %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

50 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS30

Likely Benign4

Benign3

Conflicting1

Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	0	0	2
Likely Pathogenic	0	0	0	0	0
VUS	1	29	0	0	30
Likely Benign	0	2	0	2	4
Benign	0	2	0	1	3
Conflicting	—				1
Total	1	35	0	3	40

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

View in ClinVar →

45 pathogenic / likely-pathogenic (of 60) ClinVar copy-number / structural variants overlap COX4I1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →