MIEF2

protein-coding

mitochondrial elongation factor 2

Gene summary

This gene encodes an outer mitochondrial membrane protein that functions in the regulation of mitochondrial morphology. It can directly recruit the fission mediator dynamin-related protein 1 (Drp1) to the mitochondrial surface. The gene is located within the Smith-Magenis syndrome region on chromosome 17. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jun 2011]

Previous symbols:

SMCR7

MANE transcript

NM_139162.4

Inheritance

ClinVar variants

P:1U:101B:22

Top phenotype

Combined oxidative phosphorylation deficiency 49

gnomAD constraint

pLI —, LoF o/e 0.4

Max pathogenic AF

—

Genomic locus

chr17:18,260,597-18,266,552

External References & Databases

Ensembl (ENSG00000177427)

Transcript & Mutation Effects

hg38 • Region Span ~6.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

combined oxidative phosphorylation deficiency 49LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0033569

Submitter: PanelApp Australia

mitochondrial diseaseLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *MIEF2* and primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 11, 2025. The *MIEF2* gene encodes mitochondrial elongation factor 2, an outer mitochondrial membrane protein that regulates membrane dynamics and mitochondrial organization. The first and only report of *MIEF2* in relation to autosomal recessive primary mitochondrial disease was in 2018 (PMID: 29361167). *MIEF2* has been associated with a single disease entity to date; combined oxidative phosphorylation deficiency 49 [OMIM# 619024]. 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 nonsense variant identified in one case from one publication (PMID: 29361167). This proband had progressive muscle weakness, exercise intolerance, and intermittent muscle pain. Creatine kinase was elevated. Skeletal muscle showed ragged red fibers, COX-negative fibers, and deficiency of complexes I, II+III, and IV. 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) and functional alteration studies and rescue in patient cells (PMID: 29361167). In summary, there is limited evidence to support this gene-disease relationship. Although the gene curation point total is in the Moderate range, only one case has been reported. Therefore, the classification comes to Limited. 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 August 11, 2025 (SOP Version 11).

combined oxidative phosphorylation deficiency 49LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0033569

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Combined oxidative phosphorylation deficiency 49AR

Manifestation: Biochemical; Musculoskeletal

Intervention: Biochemical

Rationale: The condition has been described as involving muscle weakness and pain, and medical management (eg, with riboflavin and coenzyme Q10) has been described as beneficial

Refs: 29361167

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MIEF2 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 121

not providedTotal: 8

Combined oxidative phosphorylation deficiency 49Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_139162.4. 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				18 clinvar		18
missense			101 clinvar	4 clinvar		105
nonsense	1 clinvar					1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	1	0	101	22	0	124

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 31 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_139162.4	RefSeq	NP_631901.2	3	MANE Select
ENST00000323019.9	Ensembl	ENSP00000323591.4	3	MANE Select
NM_001144900.3	RefSeq	NP_001138372.1	3	Standard
NM_148886.2	RefSeq	NP_683684.2	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

mitochondrion organization
mitochondrial fusion
positive regulation of protein homooligomerization
positive regulation of mitochondrial fission
positive regulation of protein targeting to membrane

Molecular Function

protein binding
identical protein binding

Cellular Component

mitochondrion
mitochondrial outer membrane
peroxisome
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000395706
Coding exons: 4
Length: 6019
Individuals with no LoFs: 124881
Homozygous LoFs: 0
Heterozygous LoFs: 9
Defined: 124890
p: 0.0000360

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.513	269	294	0.916	0.0000201	2909
Missense (PolyPhen)		75	93.85	0.79915		1068
Synonymous	0.574	130	139	0.938	0.00000963	1070
Loss of Function	1.99	5	12.7	0.395	6.29e-7	128

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0.000068	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Mitochondrial outer membrane protein which regulates mitochondrial fission. Promotes the recruitment and association of the fission mediator dynamin-related protein 1 (DNM1L) to the mitochondrial surface independently of the mitochondrial fission FIS1 and MFF proteins. Regulates DNM1L GTPase activity. {ECO:0000269|PubMed:21508961, ECO:0000269|PubMed:23283981, ECO:0000269|PubMed:23530241, ECO:0000269|PubMed:23921378}.;

Recessive Scores

pRec: 0.107

Intolerance Scores

RVIS EVS: -0.53
RVIS percentile EVS: 20.78

Essentials

Essential (CRISPR): N
Essential (gene trap): N

Gene Damage Prediction

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