COX6C

Chr 8

cytochrome c oxidase subunit 6C

NCBI Gene: 1345 ENSG00000164919 UniProt: P09669 OMIM: 124090

The COX6C protein is a structural subunit of cytochrome c oxidase (complex IV), the terminal enzyme in the mitochondrial respiratory chain that catalyzes the reduction of oxygen to water during oxidative phosphorylation. Mutations in COX6C cause autosomal recessive mitochondrial complex IV deficiency, typically presenting in infancy with hypotonia, developmental delay, and multi-organ dysfunction affecting the brain, heart, and skeletal muscle. The gene shows low constraint to loss-of-function variants, consistent with recessive inheritance patterns.

OMIM ResearchSummary from RefSeq, UniProt

Cytochrome c oxidase, 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 VIc, which has 77% amino acid sequence identity with mouse subunit VIc. This gene is up-regulated in prostate cancer cells. A pseudogene has been found on chromosomes 16p12. [provided by RefSeq, Jul 2010]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.68

Clinical Summary— COX6C

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.05) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

13 VUS of 23 total submissions

💊

Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.68LOEUF

pLI 0.049

Z-score 0.64

OE 0.62 (0.25–1.68)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.08Z-score

OE missense 0.97 (0.76–1.24)

45 obs / 46.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.62 (0.25–1.68)

0≤0.351.4

Missense OE?0.97 (0.76–1.24)

0≤0.61.4

Synonymous OE?0.48

0≤1.21.6

LoF obs/exp: 2 / 3.2Missense obs/exp: 45 / 46.6Syn Z: 1.57

This gene — mechanism propensity

0.85top 5%

GOF

0.5857th %ile

LOF

0.1994th %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

23 submitted variants in ClinVar

ClinVar

Classification Summary

VUS13

Likely Benign1

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	13	13
Likely Benign	1	1
Benign	0	0
Total	14	14

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

View in ClinVar →

35 pathogenic / likely-pathogenic (of 44) ClinVar copy-number / structural variants overlap COX6C — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →