COX20

Chr 1AR

cytochrome c oxidase assembly factor COX20

Also known as: FAM36A, MC4DN11

NCBI Gene: 116228ENSG00000203667UniProt: Q5RI15

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]

Primary Disease Associations & Inheritance

Mitochondrial complex IV deficiency, nuclear type 11MIM #619054
AR
273
ClinVar variants
113
Pathogenic / LP
0.02
pLI score
0
Active trials
Clinical Summary— COX20
🧬
Gene-Disease Validity (ClinGen)
mitochondrial disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
113 Pathogenic / Likely Pathogenic· 79 VUS of 273 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.29Z-score
OE missense 0.89 (0.71–1.13)
51 obs / 57.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.59 (0.27–1.48)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.89 (0.71–1.13)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.29
0≤1.21.6
LoF obs/exp: 3 / 5.1Missense obs/exp: 51 / 57.2Syn Z: -1.01

ClinVar Variant Classifications

273 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic97
Likely Pathogenic16
VUS79
Likely Benign59
Benign17
Conflicting5
97
Pathogenic
16
Likely Pathogenic
79
VUS
59
Likely Benign
17
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
4
92
0
97
Likely Pathogenic
5
0
11
0
16
VUS
6
55
18
0
79
Likely Benign
1
4
32
22
59
Benign
0
1
14
2
17
Conflicting
—5
Total136416724273

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

View in ClinVar →

Protein Context — Lollipop Plot

COX20 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Mitochondrial complex IV deficiency, nuclear type 11

MIM #619054

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical and genetic characteristics of children with COX20-associated mitochondrial disorder: case report and literature review.
Chen L et al.·BMC Med Genomics
2023Review
Novel pathogenic COX20 variants causing dysarthria, ataxia, and sensory neuropathy.
Otero MG et al.·Ann Clin Transl Neurol
2018
Genetic and Clinical Features of 10 Families With Hereditary Sensory Neuropathies.
Xu K et al.·J Peripher Nerv Syst
2025
Bi-allelic loss of function variants in COX20 gene cause autosomal recessive sensory neuronopathy.
Dong HL et al.·Brain
2021
Observation of novel COX20 mutations related to autosomal recessive axonal neuropathy and static encephalopathy.
Xu H et al.·Hum Genet
2019Case report
ZHX2 promotes HIF1α oncogenic signaling in triple-negative breast cancer.
Fang W et al.·Elife
2021
Recessive dystonia-ataxia syndrome in a Turkish family caused by a COX20 (FAM36A) mutation.
Doss S et al.·J Neurol
2014
Mitochondrial Complex IV Deficiency Nuclear Type 11 Caused by a Novel Start-Lost Variant in the COX20 Gene.
Kuchina A et al.·Genes (Basel)
2025Case report
ITPR1 Deletion in a Patient With Sensory Ataxic Neuropathy and Sjögren Syndrome.
Haddad S et al.·J Peripher Nerv Syst
2025Case report
Expanding the genotype-phenotype correlation of childhood sensory polyneuropathy of genetic origin.
Chakravorty S et al.·Sci Rep
2020
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools