UQCRFS1

protein-coding

ubiquinol-cytochrome c reductase, Rieske iron-sulfur polypeptide 1, the group of Mitochondrial complex III: ubiquinol-cytochrome c reductase complex subunits

Gene summary

Predicted to enable oxidoreductase activity. Involved in mitochondrial respiratory chain complex III assembly and respiratory electron transport chain. Located in mitochondrial inner membrane. Part of respiratory chain complex III. Implicated in mitochondrial complex III deficiency. [provided by Alliance of Genome Resources, Jun 2026]

MANE transcript

NM_006003.3

Inheritance

ClinVar variants

P:3U:26B:8

Top phenotype

Mitochondrial complex III deficiency, nuclear type 10

gnomAD constraint

pLI —, LoF o/e 0.3

Max pathogenic AF

—

Genomic locus

chr19:29,205,320-29,213,151

External References & Databases

Ensembl (ENSG00000169021)

Transcript & Mutation Effects

hg38 • Region Span ~7.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial complex III deficiency, nuclear type 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032909

Submitter: G2P

mitochondrial diseaseMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *UQCRFS1* and *UQCRFS1*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of November 4, 2024. The *UQCRFS1* gene encodes the ubiquinol-cytochrome *c* reductase (mitochondrial respiratory chain complex III) subunit 5, which is also known as the Rieske iron-sulfur protein. The *UQCRFS1* gene was first reported in relation to autosomal recessive *UQCRFS1*-related primary mitochondrial disease in 2020 (PMID: 31883641). *UQCRFS1* has been associated with a single disease entity to date; mitochondrial complex III deficiency, nuclear type 10 [OMIM# 618775]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *UQCRFS1*-related primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included three variants (one splice variant resulting in an in-frame deletion, one missense variant, and one nonsense variant) identified in three unrelated cases from two publications (PMIDs: 31883641, 39421685). Disease onset in all three cases was very early life. Clinical features in affected individuals include fetal bradycardia, intrauterine growth restriction, low birth weight, feeding difficulties, hypertrophic cardiomyopathy, pericardial effusion, hypotonia, muscle weakness, developmental delay, thrombocytopenia, blood coagulation abnormalities, alopecia, sparse body hair, cholelithiasis, cataracts, hearing impairment, lactic acidosis, and elevated creatine kinase. Complex III activity and assembly were reduced. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416), mouse (PMID: 22028811) and yeast (PMID: 2538628) model systems, and rescue in patient cells (PMID: 31883641). In summary, there is moderate evidence to support the relationship between *UQCRFS1* and autosomal recessive *UQCRFS1*-related primary mitochondrial disease. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on November 4, 2024 (SOP Version 11).

mitochondrial complex III deficiency, nuclear type 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032909

Submitter: PanelApp Australia

mitochondrial complex III deficiency, nuclear type 10LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032909

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial complex III deficiency, nuclear type 10LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032909

Submitter: Ambry Genetics

mitochondrial complex III deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015448

Submitter: Orphanet

Clinical Genomic Database (CGD)

Mitochondrial complex III deficiency, nuclear type 10AR

Manifestation: Audiologic/Otolaryngologic; Biochemical; Cardiovascular; Neurologic

Intervention: Biochemical; Cardiovascular

Rationale: Individuals have been described as benefitting from medical management (with coenzyme Q10 supplementation); Individuals have been described with cardiomyopathy, and awareness may allow early detection and management

Refs: 31883641

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UQCRFS1 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 31

not providedTotal: 3

Mitochondrial complex III deficiency, nuclear type 10Total: 3

CardiomyopathyTotal: 2

Lactic acidosisTotal: 2

Propionic acidemiaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006003.3. 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				2 clinvar	1 clinvar	3
missense	1 clinvar		26 clinvar	5 clinvar		32
nonsense	1 clinvar					1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)	1 clinvar					1
Total	3	0	26	7	1	37

Highest pathogenic variant AF is 0.0000041048993

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006003.3	RefSeq	NP_005994.2	2	MANE Select
ENST00000304863.6	Ensembl	ENSP00000306397.3	2	MANE Select
ENST00000933914.1	Ensembl	ENSP00000603973.1	2	Standard
ENST00001123169.1	Ensembl	ENSP00000792974.1	1	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

mitochondrial electron transport, ubiquinol to cytochrome c
response to hormone
response to drug
response to antibiotic

Molecular Function

protein binding
ubiquinol-cytochrome-c reductase activity
protein-containing complex binding
metal ion binding
2 iron, 2 sulfur cluster binding

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial respiratory chain complex III
mitochondrial respiratory chain complex IV
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000304863
Coding exons: 2
Length: 6276
Individuals with no LoFs: 125357
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125359
p: 0.00000798

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.83	75	135	0.556	0.00000721	1718
Missense (PolyPhen)		27	66.207	0.40781		779
Synonymous	0.0250	55	55.2	0.996	0.00000315	590
Loss of Function	1.67	2	6.63	0.302	3.44e-7	99

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000062	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cytochrome b-c1 complex subunit Rieske, mitochondrial: Component of the mitochondrial ubiquinol-cytochrome c reductase complex dimer (complex III dimer), which is a respiratory chain that generates an electrochemical potential coupled to ATP synthesis (PubMed:28673544). Incorporation of UQCRFS1 is the penultimate step in complex III assembly (PubMed:28673544). {ECO:0000269|PubMed:28673544}.;

Recessive Scores

pRec: 0.220

Intolerance Scores

LoFtool: 0.249
RVIS EVS: -0.21
RVIS percentile EVS: 38.28

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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