UQCC2

Chr 6AR

ubiquinol-cytochrome c reductase complex assembly factor 2

Also known as: C6orf125, C6orf126, Cbp6, M19, MC3DN7, MNF1, bA6B20.2

NCBI Gene: 84300 ENSG00000137288 UniProt: Q9BRT2 OMIM: 614461

The protein is required for assembly of mitochondrial respiratory chain complex III (ubiquinol-cytochrome c reductase) and regulates oxygen consumption, ATP production, skeletal muscle differentiation, and insulin secretion by pancreatic beta-cells. Mutations cause mitochondrial complex III deficiency with autosomal recessive inheritance. The condition affects multiple organ systems including skeletal muscle and pancreatic function due to impaired mitochondrial energy production.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a nucleoid protein localized to the mitochondria inner membrane. The encoded protein affects regulation of insulin secretion, mitochondrial ATP production, and myogenesis through modulation of mitochondrial respiratory chain activity. [provided by RefSeq, Oct 2012]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.041 OMIM phenotype

Clinical Summary— UQCC2

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ARModerate

Moderate evidence — consider for supplementary testing

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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

3 unique Pathogenic / Likely Pathogenic· 39 VUS of 85 total submissions

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?

1.04LOEUF

pLI 0.019

Z-score 1.50

OE 0.45 (0.22–1.04)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.50Z-score

OE missense 0.83 (0.68–1.03)

59 obs / 70.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.45 (0.22–1.04)

0≤0.351.4

Missense OE?0.83 (0.68–1.03)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

LoF obs/exp: 4 / 8.8Missense obs/exp: 59 / 70.8Syn Z: 0.26

This gene — mechanism propensity

0.87top 5%

GOF

0.75top 25%

LOF

0.1399th %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

85 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

VUS39

Likely Benign28

Benign12

Conflicting3

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	1	0	3
Likely Pathogenic	0	0	0	0	0
VUS	1	31	5	2	39
Likely Benign	0	2	20	6	28
Benign	0	1	10	1	12
Conflicting	—				3
Total	1	36	36	9	85

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 9) ClinVar copy-number / structural variants overlap UQCC2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →