COX6B1

Chr 19

cytochrome c oxidase subunit 6B1

Also known as: COX6B, COXG, COXVIb1, MC4DN7

NCBI Gene: 1340 ENSG00000126267 UniProt: P14854

The COX6B1 protein is a nuclear-encoded structural subunit of cytochrome c oxidase (complex IV) that regulates assembly of this terminal mitochondrial respiratory chain enzyme responsible for electron transfer from cytochrome c to oxygen. Mutations cause mitochondrial complex IV deficiency nuclear type 7, presenting as severe infantile encephalomyopathy with autosomal recessive inheritance. The pathogenic mechanism involves impaired complex IV assembly leading to defective mitochondrial respiration.

ResearchSummary from RefSeq, OMIM, 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 subunit VIb. Mutations in this gene are associated with severe infantile encephalomyopathy. Three pseudogenes COX6BP-1, COX6BP-2 and COX6BP-3 have been found on chromosomes 7, 17 and 22q13.1-13.2, respectively. [provided by RefSeq, Jan 2010]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 1.17

Clinical Summary— COX6B1

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.12) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 24 VUS of 71 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?

1.17LOEUF

pLI 0.121

Z-score 1.34

OE 0.37 (0.15–1.17)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.75Z-score

OE missense 0.72 (0.56–0.94)

40 obs / 55.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.37 (0.15–1.17)

0≤0.351.4

Missense OE?0.72 (0.56–0.94)

0≤0.61.4

Synonymous OE?0.79

0≤1.21.6

LoF obs/exp: 2 / 5.4Missense obs/exp: 40 / 55.7Syn Z: 0.76

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCOX6B1-related mitochondrial complex IV deficiencyLOFAR

This gene — mechanism propensity

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

0.6453th %ile

GOF

0.6249th %ile

LOF

0.2483th %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

71 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic2

VUS24

Likely Benign27

Benign6

Conflicting5

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	2	0	0	2
VUS	0	20	4	0	24
Likely Benign	0	0	18	9	27
Benign	0	0	5	1	6
Conflicting	—				5
Total	0	22	27	10	64

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap COX6B1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →