GUF1

protein-coding

GTP binding elongation factor GUF1

Gene summary

This gene encodes a GTPase that triggers back-translocation of the elongating ribosome during mitochondrial protein synthesis. The protein contains a highly conserved C-terminal domain not found in other GTPases that facilitates tRNA binding. The encoded protein is thought to prevent misincorporation of amino acids in stressful, suboptimal conditions. An allelic variant in this gene has been associated with early infantile epileptic encephalopathy-40. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

MANE transcript

NM_021927.3

Inheritance

ClinVar variants

P:3U:304B:98

Top phenotype

Developmental and epileptic encephalopathy 40

gnomAD constraint

pLI —, LoF o/e 0.84

Max pathogenic AF

—

Genomic locus

chr4:44,678,420-44,700,928

External References & Databases

Ensembl (ENSG00000151806)

Transcript & Mutation Effects

hg38 • Region Span ~22.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental and epileptic encephalopathyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0100620

Submitter: ClinGen

*GUF1* was first reported in relation to autosomal recessive developmental and epileptic encephalopathy (DEE) in 2016 (Alfaiz et al., PMID: 26486472). The study reported a homozygous missense variant (c.1825G>T, p.Ala609Ser) in three siblings with infantile spasms, refractory seizures, hypsarrhythmia, hypotonia, and global developmental delays. This variant is supported by a functional study in a yeast model described by Alfaiz et al. (PMID: 26486472). To date, the p.Ala609Ser variant is the only pathogenic variant in *GUF1* reported in ClinVar, with additional benign and/or unknown significance (VUS) missense, nonsense, and frameshift variants reported. A termination and splice site variant have also been reported (PMIDs: 37820178 & 32487729), however these individuals were scored at zero due to high allele frequency and high homozygote counts in gnomAD v4.1. In summary, there is limited 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 Epilepsy GCEP on the meeting date April 7, 2026 (SOP Version 12).

developmental and epileptic encephalopathy, 40LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014895

Submitter: PanelApp Australia

developmental and epileptic encephalopathy, 40LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014895

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Developmental and epileptic encephalopathy 40AR

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: 26486472

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GUF1 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 427

not specifiedTotal: 127

GUF1-related disorderTotal: 21

Developmental and epileptic encephalopathy, 40Total: 10

Long QT syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021927.3. 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			4 clinvar	73 clinvar	1 clinvar	78
missense	1 clinvar		242 clinvar	18 clinvar	4 clinvar	265
nonsense			15 clinvar	1 clinvar		16
start loss			1 clinvar			1
frameshift		2 clinvar	21 clinvar			23
splice donor/acceptor (+/-2bp)			21 clinvar		1 clinvar	22
Total	1	2	304	92	6	405

Highest pathogenic variant AF is 0.0009189143

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_021927.3	RefSeq	NP_068746.2	17	MANE Select
ENST00000281543.6	Ensembl	ENSP00000281543.5	17	MANE Select
NM_001345867.2	RefSeq	NP_001332796.1	9	Standard
NM_001345868.2	RefSeq	NP_001332797.1	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

translation
positive regulation of translation

Molecular Function

GTPase activity
GTP binding
ribosome binding

Cellular Component

mitochondrion
mitochondrial inner membrane
mitochondrial matrix

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000281543
Coding exons: 17
Length: 22500
Individuals with no LoFs: 121777
Homozygous LoFs: 231
Heterozygous LoFs: 3736
Defined: 125744
p: 0.0159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.152	325	333	0.977	0.0000161	4330
Missense (PolyPhen)		146	157.7	0.92582		2043
Synonymous	0.217	118	121	0.975	0.00000627	1300
Loss of Function	0.897	30	35.8	0.838	0.00000194	445

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0021	0.0021	notable
Latino/Admixed American	0.11	0.10	notable
Ashkenazi Jewish	0.0028	0.0026	notable
East Asian	0.0048	0.0047	notable
Finnish	0.00070	0.00069	rare
European (Non-Finnish)	0.0025	0.0024	notable
South Asian	0.0022	0.0020	notable
Other	0.013	0.013	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Promotes mitochondrial protein synthesis. May act as a fidelity factor of the translation reaction, by catalyzing a one- codon backward translocation of tRNAs on improperly translocated ribosomes. Binds to mitochondrial ribosomes in a GTP-dependent manner. {ECO:0000255|HAMAP-Rule:MF_03137}.;
Disease: DISEASE: Epileptic encephalopathy, early infantile, 40 (EIEE40) [MIM:617065]: A form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE40 inheritance is autosomal recessive. {ECO:0000269|PubMed:26486472}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.249

Intolerance Scores

LoFtool: 0.934
RVIS EVS: 0.24
RVIS percentile EVS: 69.51

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.226

Gene Damage Prediction

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