COX16

Chr 14

cytochrome c oxidase assembly factor COX16

Also known as: C14orf112, HSPC203, MC4DN22, hCOX16

NCBI Gene: 51241 ENSG00000133983 UniProt: Q9P0S2

COX16 encodes a protein required for assembly of mitochondrial respiratory chain complex IV (cytochrome c oxidase), specifically promoting copper insertion into cytochrome c oxidase subunit II and facilitating merging of assembly intermediates. Mutations cause mitochondrial complex IV deficiency, nuclear type 22, which follows autosomal recessive inheritance. This gene appears relatively tolerant to loss-of-function variants based on constraint metrics.

ResearchSummary from RefSeq, OMIM, UniProt

Involved in mitochondrial cytochrome c oxidase assembly. Located in mitochondrial inner membrane. Implicated in mitochondrial complex IV deficiency nuclear type 22. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 1.78

Clinical Summary— COX16

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 14 VUS of 19 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.78LOEUF

pLI 0.000

Z-score -0.10

OE 1.04 (0.58–1.78)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.25Z-score

OE missense 0.90 (0.71–1.15)

48 obs / 53.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.04 (0.58–1.78)

0≤0.351.4

Missense OE?0.90 (0.71–1.15)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 7 / 6.7Missense obs/exp: 48 / 53.2Syn Z: -0.46

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCOX16-related developmental disorderLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.78top 25%

GOF

0.6832th %ile

LOF

0.3259th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

19 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic1

VUS14

Likely Benign3

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	1	0	0	0	1
VUS	0	13	1	0	14
Likely Benign	0	0	0	3	3
Benign	0	0	0	0	0
Total	2	13	1	3	19

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 10) ClinVar copy-number / structural variants overlap COX16 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →