ETF1

Summary

ETF1 (eukaryotic translation termination factor 1, HGNC:3477) is a protein-coding gene on chromosome 5q31.2, encoding Eukaryotic peptide chain release factor subunit 1 (P62495). Component of the eRF1-eRF3-GTP ternary complex, a ternary complex that mediates translation termination in response to the termination codons. It is a common-essential gene (DepMap: required in 99.9% of cancer cell lines) and haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a class-1 polypeptide chain release factor. The encoded protein plays an essential role in directing termination of mRNA translation from the termination codons UAA, UAG and UGA. This protein is a component of the SURF complex which promotes degradation of prematurely terminated mRNAs via the mechanism of nonsense-mediated mRNA decay (NMD). Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 6, 7, and X.

Source: NCBI Gene 2107 — RefSeq curated summary.

At a glance

• Gene–disease (curated): craniosynostosis 4 (Definitive, ClinGen) — +4 more curated relationships
• GWAS associations: 12
• Clinical variants (ClinVar): 332 total — 29 pathogenic, 21 likely-pathogenic
• Phenotypes (HPO): 86
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.9% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_004730

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3477
Approved symbol	ETF1
Name	eukaryotic translation termination factor 1
Location	5q31.2
Locus type	gene with protein product
Status	Approved
Aliases	eRF1, TB3-1, RF1
Ensembl gene	ENSG00000120705
Ensembl biotype	protein_coding
OMIM	600285
Entrez	2107

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 12 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000360541, ENST00000499810, ENST00000503014, ENST00000503183, ENST00000506345, ENST00000507939, ENST00000512198, ENST00000514005, ENST00000572514, ENST00000866192, ENST00000866193, ENST00000913607, ENST00000971807, ENST00000971808, ENST00000971809, ENST00000971810

RefSeq mRNA: 6 — MANE Select: NM_004730 NM_001256302, NM_001282185, NM_001291974, NM_001291975, NM_001364160, NM_004730

CCDS: CCDS4207, CCDS75313, CCDS75314

Canonical transcript exons

ENST00000360541 — 11 exons

Exon	Start	End
ENSE00001129265	138508669	138508816
ENSE00001129268	138510565	138510629
ENSE00001129273	138511045	138511200
ENSE00001129277	138511475	138511604
ENSE00001963786	138506095	138508387
ENSE00002085161	138543097	138543236
ENSE00003504891	138518692	138518867
ENSE00003548588	138512764	138512954
ENSE00003559355	138513568	138513706
ENSE00003570311	138517561	138517700
ENSE00003643344	138542833	138542936

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 96.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.1914 / max 272.2934, expressed in 1802 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63705	34.8333	1822
181164	31.1914	1802
63704	14.0693	1786
63702	2.5650	1307
63703	0.8950	655
63706	0.1244	57

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
islet of Langerhans	UBERON:0000006	96.76	gold quality
upper leg skin	UBERON:0004262	96.71	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.67	gold quality
adrenal tissue	UBERON:0018303	96.53	gold quality
skin of abdomen	UBERON:0001416	96.46	gold quality
cartilage tissue	UBERON:0002418	96.43	gold quality
lower lobe of lung	UBERON:0008949	96.30	gold quality
zone of skin	UBERON:0000014	96.20	gold quality
smooth muscle tissue	UBERON:0001135	96.16	gold quality
gastrocnemius	UBERON:0001388	96.08	gold quality
skin of leg	UBERON:0001511	96.07	gold quality
esophagus squamous epithelium	UBERON:0006920	96.01	gold quality
placenta	UBERON:0001987	95.98	gold quality
bone marrow	UBERON:0002371	95.97	gold quality
esophagus mucosa	UBERON:0002469	95.90	gold quality
upper arm skin	UBERON:0004263	95.85	gold quality
mucosa of stomach	UBERON:0001199	95.82	gold quality
muscle of leg	UBERON:0001383	95.75	gold quality
epithelium of esophagus	UBERON:0001976	95.72	gold quality
colonic mucosa	UBERON:0000317	95.71	gold quality
gall bladder	UBERON:0002110	95.69	gold quality
mucosa of urinary bladder	UBERON:0001259	95.68	gold quality
pericardium	UBERON:0002407	95.66	gold quality
rectum	UBERON:0001052	95.62	gold quality
left ventricle myocardium	UBERON:0006566	95.62	gold quality
esophagus	UBERON:0001043	95.61	gold quality
stromal cell of endometrium	CL:0002255	95.47	gold quality
heart right ventricle	UBERON:0002080	95.43	gold quality
upper lobe of lung	UBERON:0008948	95.32	gold quality
myocardium	UBERON:0002349	95.30	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-8884	no	207.29
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP3

miRNA regulators (miRDB)

143 targeting ETF1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 99.9% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 26)

• bacterial polypeptide release factor RF2 is structurally distinct from eukaryotic eRF1 (PMID:11779511)
• The invariant uridine of stop codons contacts the conserved NIKSR loop in the ribosome (PMID:12356746)
• codon dependence of human eRF1 binding to the mRNA-ribosome complex (PMID:12909007)
• the intracellular concentration of the eukaryotic release factor 1 (eRF1) is a critical parameter influencing the efficiency of amino acid incorporation by nonsense suppression (PMID:15716307)
• Glu55 and Tyr125 residues in the N domain of eRF1 are important for eRF1’s decoding function. (PMID:16282590)
• we describe a novel complex that contains the NMD factors SMG-1 and Upf1, and the translation termination release factors eRF1 and eRF3 (SURF). (PMID:16452507)
• Results shows eRF1 promotes GTP binding by eRF3. (PMID:16797113)
• Interface of the interaction of the middle domain of human translation termination factor eRF1 with eukaryotic ribosomes (PMID:19140327)
• Molecular dynamics simulations show that there is no structural effect on the free RF1 release factor caused by methylation of glutamine185, suggesting that its role is intimately associated with the ribosome environment. (PMID:19265422)
• Data show that depleting eRF1 increased the Gag-Pol to Gag ratio in cells infected with replication-competent virus. (PMID:20418372)
• By molecular modeling, the eRF1 molecule can be fitted to the A site proximal to the P-site-bound tRNA and to a stop codon in mRNA via a large conformational change to one of its three domains. (PMID:20688868)
• Molecular modeling of eRF1 in the 80S termination complex showed that eRF1 fragments neighboring guanines and adenines of stop signals are compatible with different N domain conformations of eRF1. (PMID:21602268)
• Authors propose that structural variability in the GTS loop may underline the switching between omnipotency and unipotency of eRF1, implying the direct access of the GTS loop to the stop codon. (PMID:22383581)
• The NMR data show that the N-domain of human eRF1 exists in two conformational states. (PMID:22517631)
• This work provides mechanistic insight into the coordination between GTP hydrolysis by eRF3 and subsequent peptide release by eRF1. (PMID:23091004)
• The role of the 41 invariant and conserved N-domain residues in stop codon decoding by human eRF1 was determined. (PMID:23435318)
• C4 lysyl hydroxylation of eRF1 is required for optimal translational termination (PMID:24486019)
• We characterized a region of the eRF1 N-terminal domain, the P1 pocket, that we had previously shown to be involved in termination efficiency. We identified two residues, arginine 65 and lysine 109, as critical for recognition of the three stop codons. (PMID:25735746)
• cryo-electron microscopy (cryo-EM) structures at 3.5-3.8 A resolution of ribosomal complexes containing eRF1 interacting with each of the three stop codons in the A-site (PMID:26245381)
• New information has been presented on architecture of the eRF1 binding site on mammalian ribosome at various translation termination steps and on conformational rearrangements induced by binding of the release factors. (PMID:26655225)
• The GTS loop forms a switch that is key for the multiple codon recognition capability of eRF1. (PMID:26725946)
• Report molecular dynamics free energy calculations on termination complexes, where relative eRF1 binding free energies to different cognate and near-cognate codons are evaluated. The simulations show a high and uniform discrimination against the near-cognate codons, that differ from the cognate ones by a single nucleotide, and reveal the structural mechanisms behind the precise decoding by eRF1. (PMID:29127299)
• We show that knockdown of human XRN1, CNOT6 and ETF1 genes in HepG2 cells led to significant alteration in stability of specific mRNAs, alterations in half-life were inversely associated with transcription rates, mostly not resulting in changes in abundance (PMID:31116665)
• eRF1 accumulates within elaborate nuclear envelope invaginations in patient induced pluripotent stem cell (iPSC) neurons and postmortem tissue and mediates a protective shift from protein translation to nonsense-mediated decay -dependent mRNA degradation. (PMID:32059759)
• A small molecule that induces translational readthrough of CFTR nonsense mutations by eRF1 depletion. (PMID:34272367)
• Functional Activity of Isoform 2 of Human eRF1. (PMID:39063238)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	etf1b	ENSDARG00000043976
danio_rerio	etf1a	ENSDARG00000105210
mus_musculus	Etf1	ENSMUSG00000024360
rattus_norvegicus	Etf1	ENSRNOG00000019450
drosophila_melanogaster	eRF1	FBGN0036974
caenorhabditis_elegans		WBGENE00020269

Protein

Protein identifiers

Eukaryotic peptide chain release factor subunit 1 — P62495 (reviewed: P62495)

Alternative names: Protein Cl1, TB3-1

All UniProt accessions (5): B7Z7P8, D6RCB3, D6RJE8, I3L492, P62495

UniProt curated annotations — full annotation on UniProt →

Function. Component of the eRF1-eRF3-GTP ternary complex, a ternary complex that mediates translation termination in response to the termination codons. The eRF1-eRF3-GTP complex binds to a stop codon in the ribosomal A-site. ETF1/ERF1 is responsible for stop codon recognition and inducing hydrolysis of peptidyl-tRNA. Following GTP hydrolysis, eRF3 (GSPT1/ERF3A or GSPT2/ERF3B) dissociates, permitting ETF1/eRF1 to accommodate fully in the A-site and mediate hydrolysis of peptidyl-tRNA. Component of the transient SURF complex which recruits UPF1 to stalled ribosomes in the context of nonsense-mediated decay (NMD) of mRNAs containing premature stop codons. Required for SHFL-mediated translation termination which inhibits programmed ribosomal frameshifting (-1PRF) of mRNA from viruses and cellular genes.

Subunit / interactions. Component of the eRF1-eRF3-GTP ternary complex, composed of ETF1/ERF1 and eRF3 (GSPT1/ERF3A or GSPT2/ERF3B) and GTP. Component of the transient SURF (SMG1-UPF1-eRF1-eRF3) complex. Interacts with JMJD4. The ETF1-GSPT1 complex interacts with JMJD4.

Subcellular location. Cytoplasm.

Post-translational modifications. Methylated at Gln-185 by N6AMT1. Hydroxylation at Lys-63 by JMJD4 promotes its translational termination efficiency. Ubiquitinated at Lys-279 via ‘Lys-6’-linked polyubiquitin chains by RNF14 and RNF25 in response to ribosome collisions (ribosome stalling), leading to its degradation by the proteasome and rescue of stalled ribosomes.

Similarity. Belongs to the eukaryotic release factor 1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P62495-1	1	yes
P62495-2	2

RefSeq proteins (6): NP_001243231, NP_001269114, NP_001278903, NP_001278904, NP_001351089, NP_004721* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004403	Peptide_chain-rel_eRF1/aRF1	Family
IPR005140	eRF1_Pelota-like_N	Domain
IPR005141	eRF1_2	Domain
IPR005142	eRF1_3	Domain
IPR024049	eRF1_1_sf	Homologous_superfamily
IPR029064	Ribosomal_eL30-like_sf	Homologous_superfamily
IPR042226	eFR1_2_sf	Homologous_superfamily

Pfam: PF03463, PF03464, PF03465

UniProt features (69 total): strand 29, helix 15, turn 11, modified residue 4, mutagenesis site 3, cross-link 3, initiator methionine 1, chain 1, splice variant 1, short sequence motif 1

Structure

Experimental structures (PDB)

33 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9I2D	ELECTRON MICROSCOPY	2.19
8ZHC	ELECTRON MICROSCOPY	2.3
9S3D	ELECTRON MICROSCOPY	2.32
9S3B	ELECTRON MICROSCOPY	2.38
9S3C	ELECTRON MICROSCOPY	2.42
9QLO	ELECTRON MICROSCOPY	2.47
8SCB	ELECTRON MICROSCOPY	2.5
9QLQ	ELECTRON MICROSCOPY	2.57
9RHU	ELECTRON MICROSCOPY	2.65
1DT9	X-RAY DIFFRACTION	2.7
9QLP	ELECTRON MICROSCOPY	2.75
6XA1	ELECTRON MICROSCOPY	2.8
6ZME	ELECTRON MICROSCOPY	3
6D90	ELECTRON MICROSCOPY	3.2
5LZV	ELECTRON MICROSCOPY	3.35
3JAH	ELECTRON MICROSCOPY	3.45
3JAG	ELECTRON MICROSCOPY	3.65
3JAI	ELECTRON MICROSCOPY	3.65
5LZT	ELECTRON MICROSCOPY	3.65
5LZU	ELECTRON MICROSCOPY	3.75
3E1Y	X-RAY DIFFRACTION	3.8
5A8L	ELECTRON MICROSCOPY	3.8
6IP8	ELECTRON MICROSCOPY	3.9
4D5N	ELECTRON MICROSCOPY	9
4D61	ELECTRON MICROSCOPY	9
3J5Y	ELECTRON MICROSCOPY	9.7
2HST	SOLUTION NMR
2KTU	SOLUTION NMR
2KTV	SOLUTION NMR
2LGT	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P62495-F1	85.16	0.45

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (7): 2, 63, 185, 347, 87, 279, 404

Mutagenesis-validated functional residues (3):

Position	Phenotype
63	loss of hydroxylation.
183–184	in aaq mutant; abolished ability to mediate translation termination. can recognize stop codons in ribosomal a-site, but
185	abolishes methylation by n6amt1.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-72764	Eukaryotic Translation Termination
R-HSA-9010553	Regulation of expression of SLITs and ROBOs
R-HSA-9629569	Protein hydroxylation
R-HSA-975956	Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)
R-HSA-975957	Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC)

MSigDB gene sets: 790 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GOBP_CYTOPLASMIC_TRANSLATION, RNGTGGGC_UNKNOWN, FXR_IR1_Q6, ELVIDGE_HYPOXIA_DN, E2F_Q4_01, YAATNRNNNYNATT_UNKNOWN, MYOGENIN_Q6, YAGI_AML_WITH_INV_16_TRANSLOCATION, GGGNRMNNYCAT_UNKNOWN, BROWNE_HCMV_INFECTION_8HR_UP, GCANCTGNY_MYOD_Q6, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN

GO Biological Process (7): nuclear-transcribed mRNA catabolic process, nonsense-mediated decay (GO:0000184), cytoplasmic translational termination (GO:0002184), translational termination (GO:0006415), regulation of translational termination (GO:0006449), protein methylation (GO:0006479), translation (GO:0006412), ribosome disassembly (GO:0032790)

GO Molecular Function (8): RNA binding (GO:0003723), translation release factor activity (GO:0003747), peptidyl-tRNA hydrolase activity (GO:0004045), translation termination factor activity (GO:0008079), translation release factor activity, codon specific (GO:0016149), ribosome binding (GO:0043022), sequence-specific mRNA binding (GO:1990825), protein binding (GO:0005515)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), translation release factor complex (GO:0018444), cytosolic ribosome (GO:0022626)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Nonsense-Mediated Decay (NMD)	2
Translation	1
Signaling by ROBO receptors	1
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
translational termination	4
cytosol	2
cellular anatomical structure	2
cytoplasm	2
nuclear-transcribed mRNA catabolic process	1
cytoplasmic translation	1
translation	1
protein-containing complex disassembly	1
regulation of translation	1
regulation of protein-containing complex disassembly	1
protein alkylation	1
macromolecule methylation	1
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
organelle disassembly	1
nucleic acid binding	1
translation termination factor activity	1
carboxylic ester hydrolase activity	1
catalytic activity, acting on a tRNA	1
translation factor activity	1
translation release factor activity	1
ribonucleoprotein complex binding	1
mRNA binding	1
binding	1
intracellular anatomical structure	1
protein-containing complex	1
ribosome	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

120 interactions, top by confidence:

A	B	Type	Score
KEAP1	ETF1	psi-mi:“MI:0915”(physical association)	0.830
ETF1	KEAP1	psi-mi:“MI:0915”(physical association)	0.830
ETF1	GSPT1	psi-mi:“MI:0407”(direct interaction)	0.790
ETF1	GSPT1	psi-mi:“MI:0914”(association)	0.790
GSPT1	ETF1	psi-mi:“MI:0915”(physical association)	0.790
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ETF1	GSPT2	psi-mi:“MI:0915”(physical association)	0.670
KPNB1	POM121C	psi-mi:“MI:0914”(association)	0.530
MAPT	KIF2A	psi-mi:“MI:0914”(association)	0.530
SNRNP27	UBA6	psi-mi:“MI:0914”(association)	0.530
GSPT2	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
USP47	DENR	psi-mi:“MI:0914”(association)	0.530
RNF26	NME2P1	psi-mi:“MI:0914”(association)	0.530
CYP1A1	SNX3	psi-mi:“MI:0914”(association)	0.530
ARID1A	ACTL6A	psi-mi:“MI:0914”(association)	0.530
RBM8A	RPS16	psi-mi:“MI:0914”(association)	0.530
SLC38A7	ETF1	psi-mi:“MI:0914”(association)	0.530
ETF1	RAB34	psi-mi:“MI:0915”(physical association)	0.400
ETF1	MLF1	psi-mi:“MI:0915”(physical association)	0.400
MLF2	ETF1	psi-mi:“MI:0915”(physical association)	0.400
ETF1	PSMD2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (193): KEAP1 (Two-hybrid), ETF1 (Affinity Capture-MS), ETF1 (Affinity Capture-MS), ETF1 (Affinity Capture-MS), ETF1 (Affinity Capture-MS), ETF1 (Affinity Capture-MS), ETF1 (Affinity Capture-MS), ETF1 (Affinity Capture-MS), KEAP1 (Two-hybrid), EIF2S1 (Co-fractionation), EIF2S2 (Co-fractionation), ETF1 (Co-fractionation), ETF1 (Co-fractionation), ETF1 (Co-fractionation), ETF1 (Co-fractionation)

ESM2 similar proteins: A0A1S4A695, A0A6P7EFR0, A4F267, A6QR22, O97556, P07144, P21796, P42055, P42056, P45879, P45880, P50395, P50397, P50399, P62495, P62496, P62497, P62498, P68002, P68003, P81004, P81155, P82013, P86223, Q0VCK5, Q0VCX5, Q1W374, Q1W375, Q1W376, Q1W377, Q29380, Q5R4C7, Q5R7V4, Q5RCE1, Q5U2Q7, Q60930, Q60931, Q60932, Q61598, Q6Q7J2

Diamond homologs: A4FX39, A5ULL8, A6UPD8, A6UUY1, A6VG76, A9AAH5, B0R748, B6YU52, B9LRF2, C5ZZZ5, D2K759, D2K760, D5LHJ0, O16520, O26964, O29048, O59264, O59948, P12385, P33309, P35614, P35615, P58227, P61731, P62495, P62496, P62497, P62498, Q0VCX5, Q12V98, Q18FC0, Q2NEL3, Q39097, Q58239, Q5CD84, Q5CD96, Q5CG95, Q5JGK6, Q5R4C7, Q5U2Q7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ETF1	“form complex”	“Translation release factor ERF1-ERF3”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 139 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Processing of Capped Intron-Containing Pre-mRNA	9	7.1×	2e-03
mRNA Splicing - Major Pathway	12	6.3×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of miRNA transcription	6	13.8×	2e-03
translation	10	8.2×	5e-04
mRNA splicing, via spliceosome	10	7.3×	8e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

332 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	29
Likely pathogenic	21
Uncertain significance	164
Likely benign	56
Benign	15

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1064659	NC_000019.10:g.42227530_42259211del	Pathogenic
1070490	NC_000019.9:g.(?_42759120)_42759196del	Pathogenic
1502851	NM_006494.4(ERF):c.911_913del (p.Ser304del)	Pathogenic
2122554	NM_006494.4(ERF):c.272dup (p.Arg92fs)	Pathogenic
2133130	NM_006494.4(ERF):c.1021del (p.Gln341fs)	Pathogenic
218956	NM_006494.4(ERF):c.23-2A>G	Pathogenic
218957	NM_006494.4(ERF):c.1A>G (p.Met1Val)	Pathogenic
267443	NM_006494.4(ERF):c.266A>G (p.Tyr89Cys)	Pathogenic
2683998	NM_006494.4(ERF):c.11del (p.Pro4fs)	Pathogenic
2683999	NM_006494.4(ERF):c.136dup (p.Ile46fs)	Pathogenic
2684000	NM_006494.4(ERF):c.1509del (p.Phe504fs)	Pathogenic
2810553	NM_006494.4(ERF):c.997_1034del (p.Leu332_His333insTer)	Pathogenic
3339269	NM_006494.4(ERF):c.506C>A (p.Ser169Ter)	Pathogenic
3654560	NM_006494.4(ERF):c.856dup (p.Met286fs)	Pathogenic
3686735	NM_006494.4(ERF):c.253del (p.Leu85fs)	Pathogenic
4082546	NM_006494.4(ERF):c.103G>T (p.Glu35Ter)	Pathogenic
4250662	NM_006494.4(ERF):c.65del (p.Pro22fs)	Pathogenic
4618797	NM_006494.4(ERF):c.679dup (p.His227fs)	Pathogenic
4715860	NM_006494.4(ERF):c.121G>T (p.Glu41Ter)	Pathogenic
476627	NM_006494.4(ERF):c.619C>T (p.Arg207Ter)	Pathogenic
476628	NM_006494.4(ERF):c.733del (p.Leu245fs)	Pathogenic
520696	NM_006494.4(ERF):c.785del (p.Pro262fs)	Pathogenic
543070	NM_006494.4(ERF):c.566_567del (p.Asp188_Cys189insTer)	Pathogenic
55923	NM_006494.4(ERF):c.547C>T (p.Arg183Ter)	Pathogenic
55927	NM_006494.4(ERF):c.1270C>T (p.Gln424Ter)	Pathogenic
582072	NM_006494.4(ERF):c.223C>T (p.Gln75Ter)	Pathogenic
583126	NM_006494.4(ERF):c.-44_22+11del	Pathogenic
936483	NM_006494.4(ERF):c.144G>A (p.Trp48Ter)	Pathogenic
985387	NM_006494.4(ERF):c.697C>T (p.Arg233Ter)	Pathogenic
1018043	NM_006494.4(ERF):c.110T>C (p.Leu37Pro)	Likely pathogenic

SpliceAI

1648 predictions. Top by Δscore:

Variant	Effect	Δscore
5:138508383:GATAC:G	acceptor_gain	1.0000
5:138508384:ATAC:A	acceptor_gain	1.0000
5:138508385:TAC:T	acceptor_gain	1.0000
5:138508386:AC:A	acceptor_gain	1.0000
5:138508387:CC:C	acceptor_gain	1.0000
5:138508388:C:CC	acceptor_gain	1.0000
5:138508664:CTCA:C	donor_loss	1.0000
5:138508665:TCAC:T	donor_loss	1.0000
5:138508666:CACC:C	donor_loss	1.0000
5:138508667:A:AG	donor_loss	1.0000
5:138508668:CCT:C	donor_gain	1.0000
5:138508813:CGGT:C	acceptor_gain	1.0000
5:138508817:C:CC	acceptor_gain	1.0000
5:138508829:CCA:C	acceptor_gain	1.0000
5:138508830:C:CT	acceptor_gain	1.0000
5:138508830:C:T	acceptor_gain	1.0000
5:138508831:A:C	acceptor_gain	1.0000
5:138508831:A:T	acceptor_gain	1.0000
5:138510630:C:CC	acceptor_gain	1.0000
5:138510638:T:TC	acceptor_gain	1.0000
5:138511207:T:TC	acceptor_gain	1.0000
5:138511472:TA:T	donor_loss	1.0000
5:138511477:A:AC	donor_gain	1.0000
5:138511478:T:C	donor_gain	1.0000
5:138511562:C:CT	acceptor_gain	1.0000
5:138511600:AACCT:A	acceptor_gain	1.0000
5:138511601:ACCT:A	acceptor_gain	1.0000
5:138511602:CCTC:C	acceptor_gain	1.0000
5:138511603:CT:C	acceptor_gain	1.0000
5:138511605:C:CC	acceptor_gain	1.0000

AlphaMissense

2870 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:138508378:C:G	R414P	1.000
5:138508381:A:C	L413W	1.000
5:138508387:C:T	G411D	1.000
5:138508669:C:G	G411R	1.000
5:138508671:C:A	G410V	1.000
5:138508671:C:T	G410E	1.000
5:138508672:C:G	G410R	1.000
5:138508672:C:T	G410R	1.000
5:138508677:C:A	G408V	1.000
5:138508677:C:T	G408E	1.000
5:138508678:C:G	G408R	1.000
5:138508678:C:T	G408R	1.000
5:138508682:A:C	F406L	1.000
5:138508682:A:T	F406L	1.000
5:138508683:A:G	F406S	1.000
5:138508684:A:C	F406V	1.000
5:138508684:A:G	F406L	1.000
5:138508684:A:T	F406I	1.000
5:138508686:C:T	G405E	1.000
5:138508687:C:G	G405R	1.000
5:138508687:C:T	G405R	1.000
5:138508695:A:G	F402S	1.000
5:138508697:C:A	Q401H	1.000
5:138508697:C:G	Q401H	1.000
5:138508704:C:A	G399V	1.000
5:138508704:C:T	G399E	1.000
5:138508705:C:A	G399W	1.000
5:138508705:C:G	G399R	1.000
5:138508705:C:T	G399R	1.000
5:138508722:G:A	T393I	1.000

dbSNP variants (sampled 300 via entrez): RS1000035316 (5:138523937 G>A), RS1000040215 (5:138522909 G>A), RS1000327808 (5:138540839 G>A), RS1000333879 (5:138533863 G>A), RS1000506638 (5:138544757 T>C), RS1000574205 (5:138519756 A>C,G), RS1000686320 (5:138514194 G>C), RS1000844238 (5:138541408 A>C,G), RS1000848009 (5:138517030 T>A,C), RS1000893736 (5:138530423 G>A), RS1000907185 (5:138509164 C>G,T), RS1000923063 (5:138517290 G>A), RS1001139760 (5:138530766 T>C), RS1001223756 (5:138532842 T>C), RS1001330934 (5:138540754 C>G)

Disease associations

OMIM: gene MIM:600285 | disease phenotypes: MIM:123100, MIM:617180, MIM:163950, MIM:600775, MIM:254500

GenCC curated gene-disease

Disease	Classification	Inheritance
craniosynostosis 4	Definitive	Autosomal dominant
Chitayat syndrome	Definitive	Autosomal dominant
Noonan syndrome	Strong	Autosomal dominant
Crouzon syndrome	Supportive	Autosomal dominant
isolated scaphocephaly	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
craniosynostosis 4	Definitive	AD

Mondo (10): TWIST1-related craniosynostosis (MONDO:0007399), Chitayat syndrome (MONDO:0014956), Noonan syndrome (MONDO:0018997), multiple congenital anomalies/dysmorphic syndrome (MONDO:0019042), craniosynostosis 4 (MONDO:0010929), neurodevelopmental disorder (MONDO:0700092), craniosynostosis (MONDO:0015469), plasma cell myeloma (MONDO:0009693), Crouzon syndrome (MONDO:0007405), (MONDO:0018112)

Orphanet (6): OBSOLETE: Isolated oxycephaly (Orphanet:63440), Noonan syndrome (Orphanet:648), Multiple congenital anomalies/dysmorphic syndrome (Orphanet:68341), Craniosynostosis (Orphanet:1531), Multiple myeloma (Orphanet:29073), AL amyloidosis (Orphanet:85443)

HPO phenotypes

86 total (30 of 86 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000189	Narrow palate
HP:0000238	Hydrocephalus
HP:0000248	Brachycephaly
HP:0000256	Macrocephaly
HP:0000262	Turricephaly
HP:0000272	Malar flattening
HP:0000278	Retrognathia
HP:0000316	Hypertelorism
HP:0000327	Hypoplasia of the maxilla
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000348	High forehead
HP:0000365	Hearing impairment
HP:0000396	Overfolded helix
HP:0000405	Conductive hearing impairment
HP:0000431	Wide nasal bridge
HP:0000444	Convex nasal ridge
HP:0000453	Choanal atresia
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000509	Conjunctivitis
HP:0000520	Proptosis
HP:0000609	Optic nerve hypoplasia
HP:0000612	Iris coloboma
HP:0000646	Amblyopia
HP:0000648	Optic atrophy
HP:0000750	Delayed speech and language development
HP:0000767	Pectus excavatum

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST002539_60	Schizophrenia	5.000000e-09
GCST004521_139	Autism spectrum disorder or schizophrenia	2.000000e-09
GCST004625_215	Monocyte count	5.000000e-10
GCST004946_112	Schizophrenia	1.000000e-09
GCST006803_68	Schizophrenia	7.000000e-10
GCST006990_3	Cerebrospinal AB1-42 levels in Alzheimer’s disease dementia	7.000000e-08
GCST007201_314	Schizophrenia	1.000000e-08
GCST007201_54	Schizophrenia	2.000000e-10
GCST007325_121	General risk tolerance (MTAG)	3.000000e-11
GCST008158_119	Body mass index	7.000000e-06
GCST009305_3	California verbal learning test score	4.000000e-06
GCST010143_27	Meat-related diet	3.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0005091	monocyte count
EFO:0004670	beta-amyloid 1-42 measurement
EFO:0008579	risk-taking behaviour
EFO:0004340	body mass index
EFO:0004874	memory performance
EFO:0008111	diet measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D003394	Craniofacial Dysostosis	C05.116.099.370.231; C05.660.207.231; C16.131.621.207.231
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364
D009101	Multiple Myeloma	C04.557.595.500; C14.907.454.460; C15.378.147.780.650; C15.378.463.515.460; C20.683.515.845; C20.683.780.650
D065886	Neurodevelopmental Disorders	F03.625
D009634	Noonan Syndrome	C05.660.207.690; C14.240.400.787; C14.280.400.787; C16.131.240.400.784; C16.131.621.207.690; C17.300.690

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066354 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

44 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
bisphenol A	affects expression, decreases expression	2
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Particulate Matter	decreases expression, increases abundance	2
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	increases expression, decreases expression, affects cotreatment, affects localization	1
tris(2-butoxyethyl) phosphate	affects expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
ochratoxin A	increases expression	1
di-n-butylphosphoric acid	affects expression	1
deguelin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
jinfukang	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
PCI 5002	increases expression, affects cotreatment	1
bisphenol AF	increases expression	1
Sunitinib	increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Benzene	increases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Estradiol	increases expression	1
Fluorouracil	affects reaction, decreases expression	1
Furaldehyde	increases expression, affects cotreatment, affects localization	1
Ivermectin	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651386	Binding	Binding affinity to human ETF1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

297 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05474924	PHASE4	UNKNOWN	The Role of Budesonide Intrapolyp Injection in CRSwNP
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT00722436	PHASE4	TERMINATED	Tranexamic Acid for Craniofacial Surgery
NCT02188576	PHASE4	COMPLETED	The Efficacy and Population Pharmacokinetics of Tranexamic Acid for Craniosynostosis Surgery
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00104104	PHASE4	COMPLETED	A Multiple Myeloma Trial in Patients With Bone Metastases
NCT00211211	PHASE4	COMPLETED	FREE Study - Fracture Reduction Evaluation
NCT00242528	PHASE4	WITHDRAWN	Open-label Study, to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Bone Lesions Secondary to Multiple Myeloma.
NCT00257114	PHASE4	COMPLETED	Evaluation of VELCADE Given as Retreatment to Multiple Myeloma Patients for Efficacy, Safety and Tolerability
NCT00352703	PHASE4	COMPLETED	PROMPT - Palifermin in Reduction of Oral Mucositis in PBSC Transplantation
NCT00361140	PHASE4	COMPLETED	Busulfan Safety/Efficacy as Conditioning Prior to Hematopoietic Cell Transplantation (HCT)
NCT00622505	PHASE4	COMPLETED	Zoledronic Acid Treatment (Every 4 or 12 Weeks) to Prevent Skeletal Complications in Advanced Multiple Myeloma Participants
NCT00652041	PHASE4	COMPLETED	Bortezomib/Adriamycine/Melfalan/Prednisone (VAMP)/Thalidomide/Cyclophosphamide/Dexamethasone (TaCyDex) or Bortezomib/Melfalan/Prednisone (V-MP)/TaCyDex) in Refractary or Relapsed Multiple Myeloma
NCT00733538	PHASE4	COMPLETED	Stage I Multiple Myeloma Treatment
NCT01087008	PHASE4	COMPLETED	Zoledronic Acid in Patients With Multiple Myeloma and Asymptomatic Biochemical Relapse
NCT01249690	PHASE4	UNKNOWN	Efficacy Study of PAD and TAD in Newly Diagnosed Multiple Myeloma
NCT01410929	PHASE4	WITHDRAWN	Evaluation of Vertebral Compression Fracture Fixation With RF Kyphoplasty in Patients With Multiple Myeloma
NCT01731886	PHASE4	COMPLETED	Lenalidomide and Dexamethasone With/Without Stem Cell Transplant in Patients With Multiple Myeloma
NCT01868828	PHASE4	UNKNOWN	A Study of PAD Versus Velcade, Cyclophosphamide and Dexamethasone (VCD) Treatment in Subjects With Multiple Myeloma
NCT02268890	PHASE4	COMPLETED	A Pharmacokinetic Study of Bortezomib in Taiwanese Participants With Multiple Myeloma
NCT02286830	PHASE4	COMPLETED	Prolonged Protection From Bone Disease in Multiple Myeloma
NCT02559154	PHASE4	UNKNOWN	Modified Bortezomib-based Combination Therapy for Multiple Myeloma
NCT02577783	PHASE4	UNKNOWN	PDD vs PAD to Treat Initially Diagnosed MM
NCT02773550	PHASE4	TERMINATED	Treatment With a Scheme With Low Doses of Bortezomib / Melphalan / Prednisone (MPV) in Patients With Multiple Myeloma
NCT02958969	PHASE4	COMPLETED	Apixaban for Primary Prevention of Venous Thromboembolism in Patients With Multiple Myeloma
NCT03173092	PHASE4	TERMINATED	A Study of Ixazomib (NINLARO®) in Combination With Lenalidomide and Dexamethasone (IRD) for the Treatment of Participants With Multiple Myeloma (MM)
NCT03619252	PHASE4	COMPLETED	Pneumococcal Vaccination of Multiple Myeloma Patients on Novel Agents
NCT03768960	PHASE4	COMPLETED	A Study of DARZALEX (Daratumumab) In Indian Participants With Relapsed and Refractory Multiple Myeloma, Whose Prior Therapy Included a Proteasome Inhibitor and an Immunomodulatory Agent
NCT03829371	PHASE4	ACTIVE_NOT_RECRUITING	STUDY COMPARING TWO STANDARD TREATMENTS IN AUTOLOGOUS STEM CELL TRANSPLANTATION INELIGIBLE POPULATION AFFECTED BY MULTIPLE MYELOMA
NCT03908138	PHASE4	UNKNOWN	RDD Versus VDD in Newly Diagnosed Patients With Multiple Myeloma
NCT04217967	PHASE4	COMPLETED	Ixazomib, Lenalidomide, and Combination for Maintenance in NDMM Patients
NCT04952766	PHASE4	COMPLETED	Study Evaluating SARS-CoV-2 (COVID-19) Humoral Response After BNT162b2 Vaccine in Immunocompromised Adults Compared to Healthy Adults
NCT04989140	PHASE4	UNKNOWN	Study of Pomalidomide, Oral Dexamethasone and Ixazomib in Patients With Relapsed MM Who Have Received Lenalidomide
NCT05183139	PHASE4	WITHDRAWN	A Multicenter In-class Transition Study of Ixazomib Combined With Pomalidomide and Dexamethasone or With Lenalidomide and Dexamethasone in Adults With Relapsed/Refractory Multiple Myeloma
NCT05201781	PHASE4	RECRUITING	A Long-term Study for Participants Previously Treated With Ciltacabtagene Autoleucel
NCT05429515	PHASE4	NOT_YET_RECRUITING	Effect of HFR-SUPRA in the Treatment of Multiple Myeloma-related Acute Kidney Injury
NCT05511428	PHASE4	COMPLETED	Home Based Daratumumab Administration for Patients With Multiple Myeloma
NCT05545202	PHASE4	UNKNOWN	A Randomized, Comparative, Double-blind Trial of Pentaisomaltose and Dimethyl Sulphoxide for Cryoprotection of Hematopoietic Stem Cells in Subjects With Multiple Myeloma or Malignant Lymphoma With a Need for Autologous Transplantation
NCT05555329	PHASE4	COMPLETED	Alternative Dosing Scheme of Pomalidomide 4 mg Every Other Day Versus Pomalidomide 2 mg and 4 mg Every Day; the POMAlternative Study