COX20

Chr 1

cytochrome c oxidase assembly factor COX20

Also known as: FAM36A, MC4DN11

NCBI Gene: 116228 ENSG00000203667 UniProt: Q5RI15

This gene encodes a protein that assembles cytochrome C oxidase (complex IV) in the mitochondrial respiratory chain. Autosomal recessive mutations cause mitochondrial complex IV deficiency, presenting with ataxia and muscle hypotonia. The pathogenic mechanism involves loss of function mutations that disrupt complex IV assembly.

ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a protein that plays a role in the assembly of cytochrome C oxidase, an important component of the respiratory pathway. It contains two transmembrane helices and localizes to the mitochondrial membrane. Mutations in this gene can cause mitochondrial complex IV deficiency, which results in ataxia and muscle hypotonia. There are multiple pseudogenes for this gene. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2015]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.48

Clinical Summary— COX20

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

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ClinVar Variants

16 unique Pathogenic / Likely Pathogenic· 67 VUS of 171 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?

1.48LOEUF

pLI 0.020

Z-score 0.85

OE 0.59 (0.27–1.48)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.29Z-score

OE missense 0.89 (0.71–1.13)

51 obs / 57.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.59 (0.27–1.48)

0≤0.351.4

Missense OE?0.89 (0.71–1.13)

0≤0.61.4

Synonymous OE?1.29

0≤1.21.6

LoF obs/exp: 3 / 5.1Missense obs/exp: 51 / 57.2Syn Z: -1.01

This gene — mechanism propensity

0.93top 5%

GOF

0.7028th %ile

LOF

0.1498th %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

171 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic9

VUS67

Likely Benign59

Benign17

Conflicting5

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	1	4	2	0	7
Likely Pathogenic	7	1	1	0	9
VUS	7	56	4	0	67
Likely Benign	2	4	32	21	59
Benign	0	1	14	2	17
Conflicting	—				5
Total	17	66	53	23	164

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

View in ClinVar →

97 pathogenic / likely-pathogenic (of 109) ClinVar copy-number / structural variants overlap COX20 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →