COA6

Chr 1

cytochrome c oxidase assembly factor 6

Also known as: C1orf31, CEMCOX4, MC4DN13

NCBI Gene: 388753 ENSG00000168275 UniProt: Q5JTJ3

The protein functions as a cytochrome c oxidase assembly factor in the mitochondrial intermembrane space, facilitating proper assembly of mitochondrial respiratory complex IV. Mutations cause mitochondrial complex IV deficiency, nuclear type 13, which presents as fatal infantile cardiomyopathy and follows an autosomal recessive inheritance pattern. The pathogenic mechanism involves gain-of-function effects.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the cytochrome c oxidase subunit 6B family. The encoded protein associates with cytochrome c oxidase may act has an cytochrome c oxidase mitochondrial respiratory complex VI assembly factor. Mutations in this gene may be associated with fatal infantile cardiomyopathy. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2014]

GeneReviews ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.45

Clinical Summary— COA6

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

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ClinVar Variants

5 unique Pathogenic / Likely Pathogenic· 24 VUS of 84 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — COA6

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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?

1.45LOEUF

pLI 0.006

Z-score 0.81

OE 0.65 (0.32–1.45)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.72Z-score

OE missense 0.75 (0.60–0.95)

50 obs / 66.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.65 (0.32–1.45)

0≤0.351.4

Missense OE?0.75 (0.60–0.95)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 4 / 6.2Missense obs/exp: 50 / 66.5Syn Z: -0.02

This gene — mechanism propensity

0.6744th %ile

GOF

0.6638th %ile

LOF

0.3065th %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

84 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic3

VUS24

Likely Benign27

Benign17

Conflicting1

Pathogenic

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	2	0	0	2
Likely Pathogenic	3	0	0	0	3
VUS	2	22	0	0	24
Likely Benign	0	1	11	15	27
Benign	0	3	14	0	17
Conflicting	—				1
Total	5	28	25	15	74

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

View in ClinVar →

44 pathogenic / likely-pathogenic (of 56) ClinVar copy-number / structural variants overlap COA6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →