UQCRC1

protein-coding

ubiquinol-cytochrome c reductase core protein 1, the group of Mitochondrial complex III: ubiquinol-cytochrome c reductase complex subunits|M16 metallopeptidases

Gene summary

Enables ubiquitin protein ligase binding activity. Predicted to be involved in obsolete protein processing involved in protein targeting to mitochondrion. Predicted to act upstream of or within mitochondrial electron transport, ubiquinol to cytochrome c. Located in mitochondrial inner membrane. Implicated in Alzheimer's disease and late onset Parkinson's disease. Biomarker of Alzheimer's disease. [provided by Alliance of Genome Resources, Jun 2026]

MANE transcript

NM_003365.3

Inheritance

ClinVar variants

P:4U:95B:3

Top phenotype

Parkinsonism with polyneuropathy

gnomAD constraint

pLI —, LoF o/e 0.3

Max pathogenic AF

—

Genomic locus

chr3:48,599,002-48,610,976

External References & Databases

Ensembl (ENSG00000010256)

Transcript & Mutation Effects

hg38 • Region Span ~12.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial diseaseNO_KNOWN

Inheritance Pattern: AD

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *UQCRC1* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of January 27, 2025. The *UQCRC1* gene encodes ubiquinol-cytochrome *c* reductase core protein 1, a subunit of mitochondrial respiratory chain complex III, and enables ubiquitin protein ligase binding activity. *UQCRC1* has been associated with one disease entity to date; autosomal dominant parkinsonism with polyneuropathy [OMIM# 619279]. This gene-disease association was described in 2020 (PMID: 33141179), in three individuals with parkinsonism with polyneuropathy who had single variants in *UQCRC1* suspected to be causing an autosomal dominant disorder. These cases were not included in this curation as the phenotype (parkinsonism with polyneuropathy) is not commonly associated with primary mitochondrial disorders when occurring in isolation. Furthermore, the mechanism by which these reported autosomal dominant variants could cause these medical concerns is unclear. Several additional single variants were found in a cohort of individuals with parkinsonism in subsequent publications (PMIDs: 337796942, 37984314), however no functional evidence supporting a deleterious effect of these variants is available. Experimental evidence supporting the gene-disease relationship includes biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416) and a knock-in *Drosophila melanogaster* model showing age-dependent locomotor deficits, loss of tyrosine hydroxylase-positive neurons, and presynaptic neuromuscular junction defects (PMID: 33141179). In summary, the evidence supporting the relationship between *UQCRC1* and autosomal dominant primary mitochondrial disease has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role this gene plays in this disease. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on January 27, 2025 (SOP Version 11).

parkinsonism with polyneuropathyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0036193

Submitter: Ambry Genetics

parkinsonism with polyneuropathyLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0036193

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Parkinsonism with polyneuropathyAD

Manifestation: Neurologic

Intervention: Neurologic

Rationale: Response to levodopa and anticholinergics has been described

Refs: 33141179

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UQCRC1 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 79

Parkinsonism with polyneuropathyTotal: 12

not providedTotal: 3

UQCRC1-related disorderTotal: 2

Hypertrophic cardiomyopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003365.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous						0
missense	2 clinvar	2 clinvar	88 clinvar	3 clinvar		95
nonsense			1 clinvar			1
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	2	2	95	3	0	102

Highest pathogenic variant AF is 0.000050658753

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 78 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003365.3	RefSeq	NP_003356.2	13	MANE Select
ENST00000203407.6	Ensembl	ENSP00000203407.5	13	MANE Select
ENST00000412343.6	Ensembl	ENSP00000388660.1	2	Standard
ENST00000415995.5	Ensembl	ENSP00000393696.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cardiac muscle contraction - Homo sapiens (human)
Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
Alzheimer,s disease - Homo sapiens (human)
Huntington,s disease - Homo sapiens (human)
Thermogenesis - Homo sapiens (human)

Biological Process

oxidative phosphorylation
mitochondrial electron transport, ubiquinol to cytochrome c
proteolysis
response to activity
response to alkaloid

Molecular Function

ubiquinol-cytochrome-c reductase activity
ubiquitin protein ligase binding
protein-containing complex binding
metal ion binding

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial respirasome
cytosol
myelin sheath

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000203407
Coding exons: 13
Length: 11975
Individuals with no LoFs: 125719
Homozygous LoFs: 0
Heterozygous LoFs: 28
Defined: 125747
p: 0.000111

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.555	275	302	0.910	0.0000178	3091
Missense (PolyPhen)		114	126.28	0.90278		1271
Synonymous	-1.07	131	116	1.13	0.00000629	980
Loss of Function	3.32	8	26.4	0.303	0.00000136	285

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: This is a component of the ubiquinol-cytochrome c reductase complex (complex III or cytochrome b-c1 complex), which is part of the mitochondrial respiratory chain. This protein may mediate formation of the complex between cytochromes c and c1.;

Recessive Scores

pRec: 0.241

Intolerance Scores

LoFtool: 0.364
RVIS EVS: -0.27
RVIS percentile EVS: 34.71

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.945

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium