COX6A2

Chr 16

cytochrome c oxidase subunit 6A2

Also known as: COX6AH, COXVIAH, COXVIa-M, MC4DN18

NCBI Gene: 1339 ENSG00000156885 UniProt: Q02221

The COX6A2 protein is a structural subunit of cytochrome c oxidase (complex IV) that is specifically expressed in heart and skeletal muscle, where it contributes to the assembly and stabilization of this terminal enzyme in the mitochondrial respiratory chain. Mutations cause autosomal recessive mitochondrial complex IV deficiency, presenting as a multisystem disorder affecting high-energy demanding tissues including muscle, heart, brain, and liver. Clinical manifestations typically include myopathy, cardiomyopathy, developmental delays, and metabolic acidosis with variable age of onset from infancy to childhood.

ResearchSummary from RefSeq, UniProt

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 polypeptide 2 (heart/muscle isoform) of subunit VIa, and polypeptide 2 is present only in striated muscles. Polypeptide 1 (liver isoform) of subunit VIa is encoded by a different gene, and is found in all non-muscle tissues. These two polypeptides share 66% amino acid sequence identity. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.58

Clinical Summary— COX6A2

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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 0.19) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 23 VUS of 29 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 →

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?

1.58LOEUF

pLI 0.189

Z-score 0.93

OE 0.38 (0.13–1.58)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.24Z-score

OE missense 0.90 (0.70–1.17)

41 obs / 45.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.38 (0.13–1.58)

0≤0.351.4

Missense OE?0.90 (0.70–1.17)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 1 / 2.6Missense obs/exp: 41 / 45.5Syn Z: 0.35

This gene — mechanism propensity

0.76top 25%

GOF

0.6442th %ile

LOF

0.3647th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction 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

29 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS23

Likely Benign1

Benign1

Conflicting2

Likely 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	0	0	0	0
Likely Pathogenic	0	1	0	0	1
VUS	0	23	0	0	23
Likely Benign	0	0	0	1	1
Benign	0	0	0	1	1
Conflicting	—				2
Total	0	24	0	2	28

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap COX6A2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →