COX16
protein-codingcytochrome c oxidase assembly factor COX16, the group of Mitochondrial respiratory chain complex assembly factors
Gene summary
Involved in mitochondrial respiratory chain complex IV assembly. Located in mitochondrial inner membrane. Implicated in mitochondrial complex IV deficiency nuclear type 22. [provided by Alliance of Genome Resources, Jun 2026]
- C14orf112
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~91.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0044970
Submitter: ClinGen
The relationship between *COX16* and *COX16*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 11, 2025. The *COX16* gene encodes a complex IV (cytochrome c oxidase, COX) assembly factor. Defects of this protein lead to complex IV deficiency. The first and only reports of *COX16* in relation to autosomal recessive *COX16*-related primary mitochondrial disease was in 2020 (PMID: 33169484). *COX16* has been associated with a single disease entity to date; mitochondrial complex IV deficiency, nuclear type 22 [OMIM# 619355]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *COX16*-related primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one homozygous nonsense variant predicted to escape nonsense mediated decay seen in two unrelated cases from one publication (PMID: 33169484). Both cases had neonatal lactic acidosis. Additional clinical features seen in these cases include hypotonia, areflexia, failure to thrive, liver failure, coagulopathy, cardiomyopathy, and sensorineural hearing loss. Muscle and skin fibroblasts showed complex IV deficiency. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416), functional alteration studies and rescue in patient cells (PMID: 33169484), functional alternation in non-patient cells (PMID: 29355485), and *C. elegans* model system (PMID: 29355485). In summary, there is moderate evidence to support the relationship between *COX16* and autosomal recessive *COX16*-related primary mitochondrial disease. Although the gene curation point total is in the Definitive range, there have not yet been two independent scored publications documenting human genetic evidence over at least 3 years. Therefore, the classification comes to Moderate. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 11, 2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0859160
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0859160
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Biochemical; Gastrointestinal; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to COX16 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_016468.7. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 3 | 3 | ||||
| missense | 13 | 13 | ||||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 1 | 1 | 13 | 3 | 0 | 18 |
Highest pathogenic variant AF is 0.00007954264
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_057552.1 | 4 | MANE Select | |
| Ensembl | ENSP00000374562.5 | 4 | MANE Select | |
| RefSeq | NP_001191019.1 | 3 | Standard | |
| Ensembl | ENSP00000480746.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Thermogenesis - Homo sapiens (human)
- Gene expression (Transcription)
- Generic Transcription Pathway
- RNA Polymerase II Transcription
- Respiratory electron transport
Biological Process
- mitochondrial respiratory chain complex IV assembly
Molecular Function
- molecular_function
- protein binding
Cellular Component
- integral component of mitochondrial inner membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000389912
- Coding exons
- 4
- Length
- 34651
- Individuals with no LoFs
- 125703
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 42
- Defined
- 125745
- p
- 0.000167
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.254 | 48 | 53.2 | 0.902 | 0.00000265 | 689 |
| Missense (PolyPhen) | 12 | 19.161 | 0.62627 | 263 | ||
| Synonymous | -0.455 | 20 | 17.6 | 1.14 | 8.45e-7 | 193 |
| Loss of Function | -0.0959 | 7 | 6.73 | 1.04 | 4.25e-7 | 77 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000065 | 0.000062 | rare |
| Latino/Admixed American | 0.00018 | 0.00017 | rare |
| Ashkenazi Jewish | 0.00011 | 0.000099 | rare |
| East Asian | 0.00017 | 0.00016 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00025 | 0.00025 | rare |
| South Asian | 0.00010 | 0.000098 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Required for the assembly of the mitochondrial respiratory chain complex IV (CIV), also known as cytochrome c oxidase (PubMed:29355485, PubMed:29381136). Promotes the insertion of copper into the active site of cytochrome c oxidase subunit II (MT-CO2/COX2) (PubMed:29355485, PubMed:29381136). Interacts specifically with newly synthesized MT-CO2/COX and its copper center-forming metallochaperones SCO1, SCO2 and COA6 (PubMed:29381136). Probably facilitates MT-CO2/COX2 association with the MITRAC assembly intermediate containing MT-CO1/COX1, thereby participating in merging the MT-CO1/COX1 and MT-CO2/COX2 assembly lines (PubMed:29381136). {ECO:0000269|PubMed:29355485, ECO:0000269|PubMed:29381136}.;
Intolerance Scores
- LoFtool
- 0.489
- RVIS EVS
- -0.1
- RVIS percentile EVS
- 46.2
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- K
- Indispensability pred.
- E
- Indispensability score
- 0.603
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |