ATP5F1E

protein-coding

ATP synthase F1 subunit epsilon, the group of Mitochondrial complex V: ATP synthase subunits

Gene summary

This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. ATP synthase is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, comprising the proton channel. The catalytic portion of mitochondrial ATP synthase consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled with a stoichiometry of 3 alpha, 3 beta, and a single representative of the other 3. The proton channel consists of three main subunits (a, b, c). This gene encodes the epsilon subunit of the catalytic core. Two pseudogenes of this gene are located on chromosomes 4 and 13. Read-through transcripts that include exons from this gene are expressed from the upstream gene SLMO2.[provided by RefSeq, Mar 2011]

Previous symbols:

ATP5E

MANE transcript

NM_006886.4

Inheritance

ClinVar variants

P:1U:12B:8

Top phenotype

Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3

gnomAD constraint

pLI —, LoF o/e 0.85

Max pathogenic AF

—

Genomic locus

chr20:59,025,475-59,032,345

External References & Databases

Ensembl (ENSG00000124172)

Transcript & Mutation Effects

hg38 • Region Span ~6.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial diseaseLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *ATP5F1E* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of February 9, 2026. The *ATP5F1E* gene encodes the ATP synthase F(1) subunit epsilon, a subunit of oxidative phosphorylation complex V. The *ATP5F1E* gene was first reported in relation to autosomal recessive primary mitochondrial disease in 2010 (PMID: 20566710). *ATP5F1E* has been associated with a single disease entity to date; mitochondrial complex V (ATP synthase) deficiency, nuclear type 3 [OMIM# 614053]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and is considered a primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included one homozygous missense variant identified in three unrelated cases from two publications (PMIDs: 20566710, 34954817). Affected individuals had neonatal lactic acidosis, myopathy, neuropathy, developmental delay, seizures, left ventricular hypertrophy, hearing loss, and cataracts. Complex V activity was decreased in fibroblasts. The mechanism of disease is suspected to be 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). In summary, there is limited evidence to support this gene-disease relationship. 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 February 9, 2026 (SOP Version 11).

mitochondrial proton-transporting ATP synthase complex deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014471

Submitter: Orphanet

mitochondrial complex V (ATP synthase) deficiency, nuclear type 3LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013547

Submitter: Ambry Genetics

mitochondrial complex V (ATP synthase) deficiency, nuclear type 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013547

Submitter: PanelApp Australia

mitochondrial complex V (ATP synthase) deficiency, nuclear type 3LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0013547

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3AR

Manifestation: Audiologic/Otolaryngologic; Biochemical; Cardiovascular; Neurologic

Intervention: Audiologic/Otolaryngologic; Cardiovascular

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; Cardiomyopathy has been described, and awareness may enable early diagnosis and management

Refs: 18953340; 20566710; 34954817

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATP5F1E variants in ClinVar

4 Conditions Cataloged

not providedTotal: 25

ATP5F1E-related disorderTotal: 2

Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3Total: 2

not specifiedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006886.4. 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				7 clinvar		7
missense	1 clinvar		10 clinvar	1 clinvar		12
nonsense			2 clinvar			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	1	0	12	8	0	21

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006886.4	RefSeq	NP_008817.1	2	MANE Select
ENST00000243997.8	Ensembl	ENSP00000243997.3	2	MANE Select
ENST00000395659.1	Ensembl	ENSP00000379019.1	2	Standard
ENST00000395659.2	Ensembl	ENSP00000379019.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Alzheimer,s disease - Homo sapiens (human)
Huntington,s disease - Homo sapiens (human)
Thermogenesis - Homo sapiens (human)
Doxorubicin Pathway (Cardiomyocyte Cell), Pharmacodynamics
Oxidative phosphorylation - Homo sapiens (human)

Biological Process

ATP biosynthetic process
cristae formation
mitochondrial ATP synthesis coupled proton transport
ATP hydrolysis coupled cation transmembrane transport

Molecular Function

ATPase activity
transmembrane transporter activity
proton-transporting ATP synthase activity, rotational mechanism

Cellular Component

mitochondrial proton-transporting ATP synthase complex, catalytic core F(1)
mitochondrial inner membrane
mitochondrial proton-transporting ATP synthase complex
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000243997
Coding exons: 2
Length: 6916
Individuals with no LoFs: 125739
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125746
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.173	28	25.5	1.10	0.00000124	324
Missense (PolyPhen)		8	8.1902	0.97678		111
Synonymous	-0.424	11	9.35	1.18	4.98e-7	93
Loss of Function	0.262	3	3.53	0.850	2.34e-7	37

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	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)	0.000040	0.000035	rare
South Asian	0	0.0	absent
Other	0.00018	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Mitochondrial membrane ATP synthase (F(1)F(0) ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F(1) - containing the extramembraneous catalytic core, and F(0) - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F(1) is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Part of the complex F(1) domain and of the central stalk which is part of the complex rotary element. Rotation of the central stalk against the surrounding alpha(3)beta(3) subunits leads to hydrolysis of ATP in three separate catalytic sites on the beta subunits (By similarity). {ECO:0000250}.;

Intolerance Scores

RVIS EVS: 0.26
RVIS percentile EVS: 69.83

Essentials

Essential (gene trap): E