EEF2

protein-coding

eukaryotic translation elongation factor 2, the group of Small nucleolar RNA protein coding host genes

Gene summary

This gene encodes a member of the GTP-binding translation elongation factor family. This protein is an essential factor for protein synthesis. It promotes the GTP-dependent translocation of the nascent protein chain from the A-site to the P-site of the ribosome. This protein is completely inactivated by EF-2 kinase phosporylation. [provided by RefSeq, Jul 2008]

Previous symbols:

MANE transcript

NM_001961.4

Inheritance

ClinVar variants

P:6U:257B:176

Top phenotype

Spinocerebellar ataxia 26

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr19:3,976,056-3,985,463

External References & Databases

Ensembl (ENSG00000167658)

Transcript & Mutation Effects

hg38 • Region Span ~9.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spinocerebellar ataxia type 26STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012246

Submitter: Labcorp Genetics (formerly Invitae)

spinocerebellar ataxia type 26SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012246

Submitter: Orphanet

neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

spinocerebellar ataxia type 26STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012246

Submitter: PanelApp Australia

spinocerebellar ataxia type 26MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012246

Submitter: ClinGen

Eukaryotic translation elongation factor 2 (*EEF2*) was first reported in relation to autosomal dominant spinocerebellar ataxia 26 (SCA26) in 2012 (Hekman et al., PMID 23001565). The first report of a de novo neurodevelopmental disease was from Nabais Sá in 2021 (PMID: 33355653). Disease related to variation in *EEF2* can include but is not limited to: progressive ataxia, nystagmus, dysarthria, cerebellar atrophy, developmental delay, abnormal cerebral morphology, and dysmorphic features. Age of onset for *EEF2* related disease has been reported in adults for the SCA26 entity with an earlier onset in childhood for the de novo neurodevelopmental disease. Per criteria outlined by the ClinGen Lumping and Splitting Working Group there were no differences in the allelic requirement or genetic mechanism between spinocerebellar ataxia 26 (OMIM:609306) and a disease entity characterized by de novo variants and referred to as *EEF2*-Related Neurodevelopmental Disorder in at least one 2024 report (PMID 39359947). No cases have been described with both early onset neurodevelopmental disorder features and late onset progressive ataxia at the time of this curation. It is possible however that the cases with de novo *EEF2* variants were too young for late onset ataxia features to develop. 9 variants (8 missense, and 1 nonsense) that have been reported in 9 probands/families in 6 publications and 1 ClinVar submission (PMIDs 23001565, 39812846; SCV002549140.2) are included in this curation. The initial family in PMID 23001565 included segregation data with haplotype data for three generations and a total of 24 affected with the p.Pro596His variant and 28 unaffected without the variant. The mechanism of pathogenicity appears to be loss of function that involves altering protein translation at the ribosome by affecting -1 programmed ribosomal frameshifting and termination codon recognition. This gene-disease relationship is also supported by a mouse model, yeast model, and in vitro functional data of a reduction in GTP hydrolysis (PMIDs 35993189, 23001565, 36470424). The heterozygous, homologous *EEF2* knockout mouse model did not show any features of ataxia but did show an impact to social behavior and similar dysfunctional protein synthesis found in a yeast model expressing the same variant. In summary, there is moderate evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship.This classification was approved by the ClinGen Cerebellar Ataxia GCEP on the meeting date September 9, 2026 (SOP Version 12).

neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Spinocerebellar ataxia 26AD

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 15732118; 23001565

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EEF2 variants in ClinVar

9 Conditions Cataloged

not providedTotal: 446

not specifiedTotal: 191

EEF2-related disorderTotal: 22

Spinocerebellar ataxia type 26Total: 12

Neurodevelopmental disorderTotal: 1

Motor delayTotal: 1

Spinocerebellar ataxia type 19/22Total: 1

EEF2-related neurodevelopmental disorder with multiple anomaliesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001961.4. 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			15 clinvar	150 clinvar	23 clinvar	188
missense	2 clinvar	2 clinvar	222 clinvar	3 clinvar		229
nonsense		1 clinvar	2 clinvar			3
start loss			1 clinvar			1
frameshift		1 clinvar	9 clinvar			10
splice donor/acceptor (+/-2bp)			8 clinvar			8
Total	2	4	257	153	23	439

Highest pathogenic variant AF is 0.0000013715389

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 61 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001961.4	RefSeq	NP_001952.1	15	MANE Select
ENST00000309311.7	Ensembl	ENSP00000307940.5	15	MANE Select
ENST00000600794.1	Ensembl	ENSP00000471265.1	2	Standard
ENST00000858184.1	Ensembl	ENSP00000528243.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Oxytocin signaling pathway - Homo sapiens (human)
AMPK signaling pathway - Homo sapiens (human)
Translation Factors
AMP-activated Protein Kinase (AMPK) Signaling
Brain-Derived Neurotrophic Factor (BDNF) signaling pathway

Biological Process

hematopoietic progenitor cell differentiation
response to ischemia
skeletal muscle contraction
translational elongation
aging

Molecular Function

p53 binding
RNA binding
translation elongation factor activity
GTPase activity
protein binding

Cellular Component

extracellular region
nucleus
cytoplasm
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000309311
Coding exons: 15
Length: 9414
Individuals with no LoFs: 125639
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125641
p: 0.00000796

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.88	235	560	0.420	0.0000368	5597
Missense (PolyPhen)		61	255.81	0.23845		2502
Synonymous	-6.67	387	252	1.53	0.0000198	1664
Loss of Function	5.31	2	36.7	0.0545	0.00000182	417

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the GTP-dependent ribosomal translocation step during translation elongation. During this step, the ribosome changes from the pre-translocational (PRE) to the post- translocational (POST) state as the newly formed A-site-bound peptidyl-tRNA and P-site-bound deacylated tRNA move to the P and E sites, respectively. Catalyzes the coordinated movement of the two tRNA molecules, the mRNA and conformational changes in the ribosome.;
Disease: DISEASE: Spinocerebellar ataxia 26 (SCA26) [MIM:609306]: A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. {ECO:0000269|PubMed:23001565}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.506

Intolerance Scores

LoFtool: 0.101
RVIS EVS: -2.28
RVIS percentile EVS: 1.24

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.963

Gene Damage Prediction

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