EIF2S3

Summary

EIF2S3 (eukaryotic translation initiation factor 2 subunit gamma, HGNC:3267) is a protein-coding gene on chromosome Xp22.11, encoding Eukaryotic translation initiation factor 2 subunit 3 (P41091). Member of the eIF2 complex that functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

The protein encoded by this gene is the largest subunit of a heterotrimeric GTP-binding protein involved in the recruitment of methionyl-tRNA(i) to the 40 S ribosomal subunit.

Source: NCBI Gene 1968 — RefSeq curated summary.

At a glance

• Gene–disease (curated): MEHMO syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 169 total — 3 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 61
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_001415

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3267
Approved symbol	EIF2S3
Name	eukaryotic translation initiation factor 2 subunit gamma
Location	Xp22.11
Locus type	gene with protein product
Status	Approved
Aliases	EIF2gamma, EIF2
Ensembl gene	ENSG00000130741
Ensembl biotype	protein_coding
OMIM	300161
Entrez	1968

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 9 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000253039, ENST00000423068, ENST00000457332, ENST00000460032, ENST00000487075, ENST00000864815, ENST00000928831, ENST00000928832, ENST00000928833, ENST00000971837, ENST00000971838, ENST00000971839

RefSeq mRNA: 1 — MANE Select: NM_001415 NM_001415

CCDS: CCDS14210

Canonical transcript exons

ENST00000253039 — 12 exons

Exon	Start	End
ENSE00000666924	24057633	24057754
ENSE00000666989	24060088	24060182
ENSE00000863184	24057421	24057548
ENSE00000863191	24065998	24066092
ENSE00000863195	24067964	24068108
ENSE00000863200	24071558	24071727
ENSE00000896246	24062416	24062574
ENSE00000896249	24064201	24064335
ENSE00000978389	24073091	24073263
ENSE00001167220	24076722	24078810
ENSE00001895363	24054956	24055037
ENSE00003694649	24055615	24055678

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 99.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 44.2208 / max 331.5858, expressed in 1808 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195783	41.5060	1803
195781	1.7953	929
195782	0.9195	324

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
germinal epithelium of ovary	UBERON:0001304	99.28	gold quality
oviduct epithelium	UBERON:0004804	99.21	gold quality
parietal pleura	UBERON:0002400	99.03	gold quality
upper arm skin	UBERON:0004263	98.92	gold quality
visceral pleura	UBERON:0002401	98.70	gold quality
tibia	UBERON:0000979	98.68	gold quality
ileal mucosa	UBERON:0000331	98.56	gold quality
monocyte	CL:0000576	98.52	gold quality
leukocyte	CL:0000738	98.43	gold quality
epithelium of nasopharynx	UBERON:0001951	98.38	gold quality
nasopharynx	UBERON:0001728	98.36	gold quality
palpebral conjunctiva	UBERON:0001812	98.30	gold quality
ovary	UBERON:0000992	98.29	gold quality
colonic epithelium	UBERON:0000397	98.10	gold quality
left ovary	UBERON:0002119	98.09	gold quality
cardiac muscle of right atrium	UBERON:0003379	98.03	gold quality
tendon of biceps brachii	UBERON:0008188	98.02	gold quality
endometrium	UBERON:0001295	98.00	gold quality
eye	UBERON:0000970	97.99	gold quality
lymph node	UBERON:0000029	97.96	gold quality
body of pancreas	UBERON:0001150	97.94	gold quality
kidney epithelium	UBERON:0004819	97.89	gold quality
fallopian tube	UBERON:0003889	97.86	gold quality
tibialis anterior	UBERON:0001385	97.85	gold quality
right ovary	UBERON:0002118	97.82	gold quality
bone marrow cell	CL:0002092	97.78	gold quality
tonsil	UBERON:0002372	97.76	gold quality
smooth muscle tissue	UBERON:0001135	97.74	gold quality
epithelium of mammary gland	UBERON:0003244	97.72	gold quality
mammary duct	UBERON:0001765	97.71	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	4.45
E-GEOD-76312	no	3994.69
E-MTAB-7008	no	3120.10
E-CURD-97	no	1202.77
E-MTAB-10137	no	1118.61
E-MTAB-6108	no	556.95
E-GEOD-81608	no	18.06
E-MTAB-9801	no	4.40
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HAND2

miRNA regulators (miRDB)

85 targeting EIF2S3, 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-3613-3P	100.00	76.36	7965
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-548AG	99.77	69.25	1492
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-7154-5P	99.69	70.52	1900

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 10)

• The human X-chromosomal neurological disorder characterized by intellectual disability and microcephaly is caused by a missense mutation in eIF2gamma (encoded by EIF2S3), the core subunit of the heterotrimeric eIF2 complex. (PMID:23063529)
• Our data confirm that EIF2S3 mutation is implicated in a rare, but recognizable, form of syndromic intellectual disability. (PMID:27333055)
• Data suggest that more severe EIF2S3 mutations cause the full MEHMO phenotype, while less deleterious mutations cause a milder form of the syndrome with only a subset of the symptoms. (PMID:28055140)
• We aimed to provide more details on the endocrine phenotype in two previously reported male probands with MEHMO carrying a frame-shift mutation (I465fs) in the EIF2S3 gene (PMID:29303605)
• Results suggest that the I259M mutation impairs Met-tRNAiMet binding, causing altered control of protein synthesis that underlies MEHMO syndrome. (PMID:30517694)
• Our data suggest that the p.Pro432Ser mutation impairs eIF2gamma function leading to a relatively mild novel phenotype compared with previous EIF2S3 mutations. Our studies support a critical role for EIF2S3 in human hypothalamo-pituitary development and function, and glucose regulation, expanding the range of phenotypes associated with EIF2S3 mutations beyond classical MEHMO syndrome. (PMID:30878599)
• Novel pathogenic EIF2S3 missense variants causing clinically variable MEHMO syndrome with impaired eIF2gamma translational function, and literature review. (PMID:32799315)
• Eukaryotic initiation factor-2, gamma subunit, suppresses proliferation and regulates the cell cycle via the MAPK/ERK signaling pathway in acute myeloid leukemia. (PMID:34232382)
• mRNA analysis revealed a novel pathogenic EIF2S3 variant causing MEHMO syndrome. (PMID:34999262)
• Binding of human Cdc123 to eIF2gamma. (PMID:37507029)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	eif2s3	ENSDARG00000008292
drosophila_melanogaster	mEFTu2	FBGN0033184
drosophila_melanogaster	eIF2gamma	FBGN0263740
caenorhabditis_elegans	tufm-2	WBGENE00007001
caenorhabditis_elegans	eif-2gamma	WBGENE00021466

Paralogs (18): MTIF2 (ENSG00000085760), GTPBP1 (ENSG00000100226), EEF1A2 (ENSG00000101210), GSPT1 (ENSG00000103342), EFTUD2 (ENSG00000108883), HBS1L (ENSG00000112339), EEFSEC (ENSG00000132394), EFL1 (ENSG00000140598), GUF1 (ENSG00000151806), EEF1A1 (ENSG00000156508), EIF5B (ENSG00000158417), GFM2 (ENSG00000164347), EEF2 (ENSG00000167658), GFM1 (ENSG00000168827), GTPBP2 (ENSG00000172432), TUFM (ENSG00000178952), EIF2S3B (ENSG00000180574), GSPT2 (ENSG00000189369)

Protein

Protein identifiers

Eukaryotic translation initiation factor 2 subunit 3 — P41091 (reviewed: P41091)

Alternative names: Eukaryotic translation initiation factor 2 subunit gamma X

All UniProt accessions (2): P41091, H7BZU1

UniProt curated annotations — full annotation on UniProt →

Function. Member of the eIF2 complex that functions in the early steps of protein synthesis by forming a ternary complex with GTP and initiator tRNA. This complex binds to a 40S ribosomal subunit, followed by mRNA binding to form the 43S pre-initiation complex (43S PIC). Junction of the 60S ribosomal subunit to form the 80S initiation complex is preceded by hydrolysis of the GTP bound to eIF2 and release of an eIF2-GDP binary complex. In order for eIF2 to recycle and catalyze another round of initiation, the GDP bound to eIF2 must exchange with GTP by way of a reaction catalyzed by eIF-2B.

Subunit / interactions. Eukaryotic translation initiation factor 2 eIF2 is a heterotrimeric complex composed of an alpha (EIF2S1), a beta (EIF2S2) and a gamma (EIF2S3) chain. eIF2 is member of the 43S pre-initiation complex (43S PIC). Interacts (via C-terminus) with CDC123; the interaction is direct.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Expressed in testis, brain, liver and muscle.

Disease relevance. MEHMO syndrome (MEHMO) [MIM:300148] An X-linked recessive syndrome characterized by intellectual disability, epileptic seizures, hypogonadism and hypogenitalism, microcephaly, and obesity. The disease is caused by variants affecting the gene represented in this entry. Defects in EIF2S3 are the cause of hypopituitarism with glucose dysregulation.

Miscellaneous. Encoded by an chromosome X-linked gene which escapes inactivation. Does not have any homolog on chromosome Y.

Similarity. Belongs to the TRAFAC class translation factor GTPase superfamily. Classic translation factor GTPase family. EIF2G subfamily.

RefSeq proteins (1): NP_001406* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000795	T_Tr_GTP-bd_dom	Domain
IPR004161	EFTu-like_2	Domain
IPR009000	Transl_B-barrel_sf	Homologous_superfamily
IPR009001	Transl_elong_EF1A/Init_IF2_C	Homologous_superfamily
IPR015256	eIF2g_C	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR044127	eIF2g_dom_2	Domain
IPR044128	eIF2g_GTP-bd	Domain
IPR050543	eIF2G	Family

Pfam: PF00009, PF03144, PF09173

Enzyme classification (BRENDA):

• EC 3.6.5.3 — protein-synthesizing GTPase (BRENDA: 45 organisms, 101 substrates, 61 inhibitors, 66 Km, 48 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GTP	0.0003–0.27	53
ATP	0.12–0.2	2

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (66 total): strand 28, sequence variant 7, turn 7, helix 7, region of interest 6, binding site 3, sequence conflict 3, modified residue 2, initiator methionine 1, chain 1, domain 1

Structure

Experimental structures (PDB)

25 structures.

PDB	Method	Resolution (Å)
8PHV	X-RAY DIFFRACTION	1.97
8PHD	X-RAY DIFFRACTION	2.08
8PPL	ELECTRON MICROSCOPY	2.65
9HVE	ELECTRON MICROSCOPY	2.7
7F66	ELECTRON MICROSCOPY	2.76
6ZP4	ELECTRON MICROSCOPY	2.9
6O85	ELECTRON MICROSCOPY	3.03
8PJ4	ELECTRON MICROSCOPY	3.2
6O81	ELECTRON MICROSCOPY	3.21
8QZZ	X-RAY DIFFRACTION	3.35
8PJ1	ELECTRON MICROSCOPY	3.4
8PJ2	ELECTRON MICROSCOPY	3.4
7A09	ELECTRON MICROSCOPY	3.5
8OZ0	ELECTRON MICROSCOPY	3.5
7F67	ELECTRON MICROSCOPY	3.59
6ZMW	ELECTRON MICROSCOPY	3.7
7QP7	ELECTRON MICROSCOPY	3.7
8PJ3	ELECTRON MICROSCOPY	3.7
6YBV	ELECTRON MICROSCOPY	3.8
9HVF	ELECTRON MICROSCOPY	3.8
6K71	ELECTRON MICROSCOPY	4.3
7D43	ELECTRON MICROSCOPY	4.3
6K72	ELECTRON MICROSCOPY	4.6
7QP6	ELECTRON MICROSCOPY	4.7
6FEC	ELECTRON MICROSCOPY	6.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P41091-F1	85.34	0.37

Functional residue map

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

Ligand- & substrate-binding residues (3): 190–193; 225–227; 51–56

Post-translational modifications (2): 2, 16

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-156827	L13a-mediated translational silencing of Ceruloplasmin expression
R-HSA-381042	PERK regulates gene expression
R-HSA-382556	ABC-family protein mediated transport
R-HSA-72649	Translation initiation complex formation
R-HSA-72695	Formation of the ternary complex, and subsequently, the 43S complex
R-HSA-72702	Ribosomal scanning and start codon recognition
R-HSA-72706	GTP hydrolysis and joining of the 60S ribosomal subunit
R-HSA-72731	Recycling of eIF2:GDP
R-HSA-9633012	Response of EIF2AK4 (GCN2) to amino acid deficiency
R-HSA-9648895	Response of EIF2AK1 (HRI) to heme deficiency
R-HSA-9833482	PKR-mediated signaling
R-HSA-9840373	Cellular response to mitochondrial stress

MSigDB gene sets: 333 (showing top): GOBP_CYTOPLASMIC_TRANSLATION, AAGCAAT_MIR137, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, BHATI_G2M_ARREST_BY_2METHOXYESTRADIOL_DN, MODULE_150, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_TRANSLATIONAL_INITIATION, MODULE_16, GOMF_TRANSLATION_INITIATION_FACTOR_ACTIVITY, BOYLAN_MULTIPLE_MYELOMA_D_DN, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_FORMATION_OF_TRANSLATION_PREINITIATION_COMPLEX

GO Biological Process (4): formation of translation preinitiation complex (GO:0001731), cytoplasmic translational initiation (GO:0002183), translational initiation (GO:0006413), translation (GO:0006412)

GO Molecular Function (10): translation initiation factor activity (GO:0003743), GTPase activity (GO:0003924), GTP binding (GO:0005525), translation factor activity, RNA binding (GO:0008135), cadherin binding (GO:0045296), methionyl-initiator methionine tRNA binding (GO:1990856), tRNA binding (GO:0000049), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), eukaryotic translation initiation factor 2 complex (GO:0005850), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Cap-dependent Translation Initiation	4
Cellular responses to stress	2
Eukaryotic Translation Initiation	1
Unfolded Protein Response (UPR)	1
Transport of small molecules	1
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	1
Cellular response to starvation	1
Antimicrobial mechanism of IFN-stimulated genes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
translational initiation	3
translation	2
translation factor activity	2
RNA binding	2
cellular anatomical structure	2
cytoplasm	2
cytoplasmic translational initiation	1
protein-RNA complex assembly	1
cytoplasmic translation	1
formation of translation initiation ternary complex	1
metabolic process	1
peptidyltransferase activity	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
ribonucleoside triphosphate phosphatase activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cell adhesion molecule binding	1
tRNA binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
protein-containing complex	1
extracellular vesicle	1

Protein interactions and networks

STRING

3003 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EIF2S3	EIF2S2	P20042	999
EIF2S3	EIF2S1	P05198	998
EIF2S3	EIF2B5	Q13144	961
EIF2S3	EIF5	P55010	914
EIF2S3	EIF1	P41567	895
EIF2S3	EIF2B3	Q9NR50	847
EIF2S3	EIF3B	P55884	796
EIF2S3	EIF2AK2	P19525	735
EIF2S3	EIF2B1	Q14232	717
EIF2S3	EIF2B2	P49770	710
EIF2S3	EIF2B4	Q9UI10	708
EIF2S3	CDC123	O75794	705
EIF2S3	ABCE1	P61221	687
EIF2S3	EIF5B	O60841	667
EIF2S3	EIF3G	O75821	665

IntAct

249 interactions, top by confidence:

A	B	Type	Score
EIF2S3	EIF2S1	psi-mi:“MI:0407”(direct interaction)	0.820
EIF2S1	EIF2S3	psi-mi:“MI:0914”(association)	0.820
EIF2S2	EIF2S1	psi-mi:“MI:0407”(direct interaction)	0.810
EIF2S1	EIF2S2	psi-mi:“MI:0407”(direct interaction)	0.810
EIF2S2	EIF2S1	psi-mi:“MI:0914”(association)	0.810
EIF2S2	EIF2S3	psi-mi:“MI:0407”(direct interaction)	0.760
EIF2S2	CDC123	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CDC123	EIF2S2	psi-mi:“MI:0914”(association)	0.710
DCC	NTN1	psi-mi:“MI:0914”(association)	0.700
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
CDKN1A	EIF2S3	psi-mi:“MI:0915”(physical association)	0.560
DXO	EIF2S3	psi-mi:“MI:0915”(physical association)	0.560
GABPB1	EIF2S3	psi-mi:“MI:0915”(physical association)	0.560
EIF2S3	MAP3K5	psi-mi:“MI:0915”(physical association)	0.560
PER1	EIF2S3	psi-mi:“MI:0915”(physical association)	0.560
UBE2A	EIF2S3	psi-mi:“MI:0915”(physical association)	0.560
DPF1	EIF2S3	psi-mi:“MI:0915”(physical association)	0.560
SYNCRIP	EIF2S3	psi-mi:“MI:0915”(physical association)	0.560
POLR3F	EIF2S3	psi-mi:“MI:0915”(physical association)	0.560
EIF2S3	RASSF1	psi-mi:“MI:0915”(physical association)	0.560
BAHD1	EIF2S3	psi-mi:“MI:0915”(physical association)	0.560
LARP4B	EIF2S3	psi-mi:“MI:0915”(physical association)	0.560
RANGRF	EIF2S3	psi-mi:“MI:0915”(physical association)	0.560
WBP1L	EIF2S3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (457): EIF2S3 (Affinity Capture-MS), EIF2S3 (Affinity Capture-MS), EIF2S3 (Affinity Capture-RNA), EIF2S3 (Co-fractionation), EIF2S3 (Co-fractionation), EIF2S3 (Co-fractionation), EIF2S3 (Co-fractionation), EIF2S3 (Co-fractionation), EIF2S3 (Co-fractionation), EIF2S3 (Co-fractionation), RPS4X (Co-fractionation), WIBG (Co-fractionation), EIF2S3 (Affinity Capture-MS), EIF2S3 (Affinity Capture-MS), EIF2S3 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8EV45, C9WPN6, F1QGW6, F6RQL9, O73723, O77676, P00516, P0C605, P20461, P23258, P23330, P31321, P32392, P35250, P41091, P53033, P61157, P61158, P62482, P62483, P81795, P83887, P83888, Q05B83, Q0VCD2, Q13126, Q13303, Q13976, Q27955, Q2KHU8, Q2KJ81, Q2VIR3, Q32KM1, Q4V7C7, Q5R797, Q5R8R1, Q5ZHS1, Q5ZMS3, Q641P0, Q641W4

Diamond homologs: A1AVJ8, A1AX82, A1UBL1, A2BT83, A3CP09, A3PV96, A4FPM7, A4FWW9, A4VTQ7, A4VZZ3, A5CW32, A5GIP0, A5GW14, A6UPK8, A6UTL4, A6VGE8, A7HWP7, A8AWA0, A9AAA4, A9BCK0, B0R6Y7, B1ICR4, B1MGH7, B1VET1, B5E653, B6YW69, B8ZL95, B9DRL9, B9LSM6, C1C881, C1CF71, C1CLI6, C1CSB0, C9WPN6, F1QGW6, J9VR81, O26361, O29663, O36041, O59410

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
EIF2S3	“form complex”	Ternary_GTP_eIF2_tRNA_complex	binding
EIF2B5	“up-regulates activity”	EIF2S3	“guanine nucleotide exchange factor”
EIF2B1	“up-regulates activity”	EIF2S3	“guanine nucleotide exchange factor”
EIF2B2	“up-regulates activity”	EIF2S3	“guanine nucleotide exchange factor”
EIF2B3	“up-regulates activity”	EIF2S3	“guanine nucleotide exchange factor”
EIF2B4	“up-regulates activity”	EIF2S3	“guanine nucleotide exchange factor”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 145 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
Formation of the ternary complex, and subsequently, the 43S complex	8	17.4×	5e-06
Ribosomal scanning and start codon recognition	9	17.3×	1e-06
RAF activation	5	17.0×	5e-04
Signaling by high-kinase activity BRAF mutants	5	16.0×	7e-04
Translation initiation complex formation	8	15.4×	7e-06
MAP2K and MAPK activation	5	14.4×	9e-04
Signaling by RAF1 mutants	5	14.1×	9e-04
Negative regulation of MAPK pathway	5	13.4×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
formation of cytoplasmic translation initiation complex	5	45.3×	3e-05
translational initiation	8	23.1×	2e-06
regulation of translational initiation	6	22.6×	7e-05
fibroblast proliferation	5	15.8×	2e-03
positive regulation of fibroblast proliferation	5	11.9×	6e-03
Ras protein signal transduction	7	11.6×	6e-04
cytoplasmic translation	7	10.4×	9e-04
MAPK cascade	7	8.7×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	4
Uncertain significance	48
Likely benign	13
Benign	4

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1686856	NM_001415.4(EIF2S3):c.1294C>T (p.Pro432Ser)	Pathogenic
267205	NM_001415.4(EIF2S3):c.665T>C (p.Ile222Thr)	Pathogenic
267206	NM_001415.4(EIF2S3):c.777T>G (p.Ile259Met)	Pathogenic
1077096	NM_001415.4(EIF2S3):c.820C>G (p.Leu274Val)	Likely pathogenic
3024228	NM_001415.4(EIF2S3):c.620T>C (p.Ile207Thr)	Likely pathogenic
488501	NM_001415.4(EIF2S3):c.431C>T (p.Thr144Ile)	Likely pathogenic
804299	NM_001415.4(EIF2S3):c.433A>G (p.Met145Val)	Likely pathogenic

SpliceAI

1750 predictions. Top by Δscore:

Variant	Effect	Δscore
X:24055677:AGG:A	donor_loss	1.0000
X:24055679:GT:G	donor_loss	1.0000
X:24055680:T:G	donor_loss	1.0000
X:24057416:CATA:C	acceptor_loss	1.0000
X:24057418:TAG:T	acceptor_loss	1.0000
X:24057419:A:AG	acceptor_gain	1.0000
X:24057419:AGGT:A	acceptor_loss	1.0000
X:24057420:G:GG	acceptor_gain	1.0000
X:24057547:AGGT:A	donor_loss	1.0000
X:24057548:GGT:G	donor_loss	1.0000
X:24057549:GT:G	donor_loss	1.0000
X:24057550:T:G	donor_loss	1.0000
X:24057630:TAGAT:T	acceptor_loss	1.0000
X:24057631:A:AG	acceptor_gain	1.0000
X:24057631:AGATT:A	acceptor_loss	1.0000
X:24057632:G:GA	acceptor_gain	1.0000
X:24057632:GATTT:G	acceptor_gain	1.0000
X:24057737:G:T	donor_gain	1.0000
X:24057751:TCAG:T	donor_loss	1.0000
X:24057752:CAG:C	donor_loss	1.0000
X:24057755:G:A	donor_loss	1.0000
X:24057756:T:A	donor_loss	1.0000
X:24060086:A:AG	acceptor_gain	1.0000
X:24060087:G:GG	acceptor_gain	1.0000
X:24060087:GAC:G	acceptor_gain	1.0000
X:24060087:GACAT:G	acceptor_gain	1.0000
X:24060103:T:A	acceptor_gain	1.0000
X:24062414:AGCT:A	acceptor_gain	1.0000
X:24062415:GCTG:G	acceptor_gain	1.0000
X:24062570:CCAAG:C	donor_loss	1.0000

AlphaMissense

3065 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:24055674:C:A	N43K	1.000
X:24055674:C:G	N43K	1.000
X:24055678:G:C	G45R	1.000
X:24057421:G:A	G45D	1.000
X:24057427:T:A	I47N	1.000
X:24057429:G:C	G48R	1.000
X:24057429:G:T	G48C	1.000
X:24057430:G:A	G48D	1.000
X:24057430:G:T	G48V	1.000
X:24057433:A:G	H49R	1.000
X:24057434:T:A	H49Q	1.000
X:24057434:T:G	H49Q	1.000
X:24057435:G:C	V50L	1.000
X:24057435:G:T	V50L	1.000
X:24057436:T:A	V50E	1.000
X:24057436:T:C	V50A	1.000
X:24057442:A:G	H52R	1.000
X:24057444:G:A	G53R	1.000
X:24057444:G:C	G53R	1.000
X:24057444:G:T	G53W	1.000
X:24057445:G:A	G53E	1.000
X:24057445:G:C	G53A	1.000
X:24057445:G:T	G53V	1.000
X:24057447:A:C	K54Q	1.000
X:24057447:A:G	K54E	1.000
X:24057448:A:T	K54I	1.000
X:24057449:A:C	K54N	1.000
X:24057449:A:T	K54N	1.000
X:24057450:T:C	S55P	1.000
X:24057451:C:A	S55Y	1.000

dbSNP variants (sampled 300 via entrez): RS1000221815 (X:24069981 A>G), RS1000487662 (X:24070436 G>A), RS1000545267 (X:24067901 T>C,G), RS1000777537 (X:24072892 T>A,C), RS1001174119 (X:24058757 G>A), RS1001175079 (X:24058048 G>A), RS1001198243 (X:24069910 C>T), RS1001331145 (X:24060778 A>G), RS1002221472 (X:24055684 A>C,T), RS1002280944 (X:24075396 A>C,G), RS1002382992 (X:24066991 C>T), RS1002574161 (X:24056083 T>C), RS1002861699 (X:24059278 A>T), RS1002873529 (X:24067808 G>A,T), RS1002930205 (X:24077718 G>A)

Disease associations

OMIM: gene MIM:300161 | disease phenotypes: MIM:300148, MIM:300987

GenCC curated gene-disease

Disease	Classification	Inheritance
MEHMO syndrome	Definitive	X-linked
diabetes mellitus	Strong	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
MEHMO syndrome	Definitive	XL

Mondo (3): MEHMO syndrome (MONDO:0010258), intellectual disability (MONDO:0001071), diabetes mellitus (MONDO:0005015)

Orphanet (2): MEHMO syndrome (Orphanet:85282), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

61 total (30 of 61 shown, HPO-id order):

HPO	Term
HP:0000026	Male hypogonadism
HP:0000028	Cryptorchidism
HP:0000054	Micropenis
HP:0000175	Cleft palate
HP:0000194	Open mouth
HP:0000252	Microcephaly
HP:0000276	Long face
HP:0000293	Full cheeks
HP:0000311	Round face
HP:0000340	Sloping forehead
HP:0000343	Long philtrum
HP:0000400	Macrotia
HP:0000437	Depressed nasal tip
HP:0000455	Broad nasal tip
HP:0000486	Strabismus
HP:0000545	Myopia
HP:0000639	Nystagmus
HP:0000687	Widely spaced teeth
HP:0000713	Agitation
HP:0000718	Aggressive behavior
HP:0000750	Delayed speech and language development
HP:0000819	Diabetes mellitus
HP:0000823	Delayed puberty
HP:0000824	Decreased response to growth hormone stimulation test
HP:0001182	Tapered finger
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST004093_12	Prostate-specific antigen levels	1.000000e-13

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D003920	Diabetes Mellitus	C18.452.394.750; C19.246
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C537451	MEHMO syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tretinoin	decreases expression, increases expression	3
Aflatoxin B1	decreases methylation, increases methylation	2
Cadmium Chloride	decreases expression, increases expression	2
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
tamibarotene	affects expression	1
K 7174	increases expression	1
ICG 001	decreases expression	1
bisphenol B	increases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	decreases expression	1
bisphenol AF	increases expression	1
Bortezomib	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Benztropine	increases expression	1
Calcitriol	decreases expression	1
Clozapine	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	affects cotreatment, increases expression	1
Formaldehyde	decreases expression	1
Furaldehyde	affects cotreatment, affects localization, increases expression	1
Ivermectin	decreases expression	1
Lead	increases expression	1
Methyl Methanesulfonate	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Progesterone	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00044746	PHASE4	COMPLETED	Study Evaluating the Safety and Efficacy of Piperacillin/Tazobactam and Ampicillin/Sulbactam in Patients With Diabetic Foot Infections
NCT00069602	PHASE4	COMPLETED	Assessing Continuous Glucose Monitors in Healthy Children
NCT00079638	PHASE4	COMPLETED	Comparative Efficacy Evaluation of Lipids When Treated With Niaspan & Statin or Other Lipid-Modifying Therapies-COMPELL
NCT00095446	PHASE4	COMPLETED	NovoLog Observation Trial in Subjects With Type 1 and Type 2 Diabetes
NCT00101751	PHASE4	COMPLETED	INITIATE Plus (INITiation of Insulin to Reach A1c TargEt) Study
NCT00108615	PHASE4	COMPLETED	Effects of Insulin Sensitizers in Subjects With Impaired Glucose Tolerance
NCT00117780	PHASE4	COMPLETED	Comparison of Insulin Detemir Given Once or Twice Daily in Type 1 Diabetes
NCT00120341	PHASE4	COMPLETED	Anodyne Therapy in Diabetic Sensory Neuropathy
NCT00121355	PHASE4	COMPLETED	Novofine Autocover Safety Needle Versus BD Safety Glide
NCT00135226	PHASE4	ACTIVE_NOT_RECRUITING	ASCEND: A Study of Cardiovascular Events iN Diabetes
NCT00144937	PHASE4	UNKNOWN	Multifactorial Intervention on Cardiovascular Risk Factors in Subjects With Peripheral Arterial Disease
NCT00147251	PHASE4	COMPLETED	Stop Atherosclerosis in Native Diabetics Study
NCT00157638	PHASE4	COMPLETED	Integrating Family Medicine and Pharmacy to Advance Primary Care Therapeutics
NCT00162344	PHASE4	COMPLETED	A Study of Stress Heart Imaging in Patients With Diabetes at Risk for Coronary Disease.
NCT00177138	PHASE4	TERMINATED	Use of Campath for Induction and Maintenance Therapy in Pancreas After Kidney Transplantation
NCT00182494	PHASE4	UNKNOWN	Diabetes Prevention Program in Schizophrenia [DPPS]
NCT00184561	PHASE4	COMPLETED	Effectiveness and Safety of Biphasic Insulin Aspart 70/30 in Subjects With Type 2 Diabetes
NCT00184626	PHASE4	COMPLETED	Comparison of Insulin Glargine Versus Biphasic Insulin Aspart 30/70 or Biphasic Insulin Aspart 30/70 in Combination With Metformin in Subjects With Type 2 Diabetes.
NCT00202618	PHASE4	UNKNOWN	Rationale and Design for Shiga Microalbuminuria Reduction Trial
NCT00209170	PHASE4	COMPLETED	Depression-Diabetes Mechanisms: Urban African Americans
NCT00209417	PHASE4	TERMINATED	Renal Effects of Two Iodinated Contrast Media in Patients at Risk Undergoing Computed Tomography
NCT00212004	PHASE4	TERMINATED	Pioglitazone Protects Diabetes Mellitus (DM) Patients Against Re-Infarction (PPAR Study)
NCT00219440	PHASE4	COMPLETED	A Portion-controlled Diet Will Prevent Weight Gain in Diabetics Treated With ACTOS
NCT00225849	PHASE4	UNKNOWN	Japanese Primary Prevention Project With Aspirin
NCT00231894	PHASE4	COMPLETED	Pioglitazone as a Treatment for Lipid and Glucose Abnormalities In Patients With Schizophrenia
NCT00234871	PHASE4	COMPLETED	Tarka® vs. Lotrel® in Hypertensive, Diabetic Subjects With Renal Disease (TANDEM)
NCT00235014	PHASE4	COMPLETED	A Study for Prevention of Kidney Disease in Diabetic Patients (BENEDICT)
NCT00236379	PHASE4	COMPLETED	A Study of the Effects of Risperidone and Olanzapine on Blood Glucose (Sugar) in Patients With Schizophrenia or Schizoaffective Disorder
NCT00241904	PHASE4	COMPLETED	Reducing Total Cardiovascular Risk in an Urban Community
NCT00263393	PHASE4	COMPLETED	Rural Andhra Pradesh Cardiovascular Prevention Study (RAPCAPS)
NCT00264901	PHASE4	COMPLETED	Comparison of Self Adjustment Versus Standard of Care Treatment in Subjects With Type 2 Diabetes
NCT00274274	PHASE4	COMPLETED	Efficacy and Safety of a Fixed or a Flexible Supplementary Insulin Therapy in Type 2 Diabetes
NCT00282451	PHASE4	COMPLETED	Effect of Biphasic Insulin Compared to Biphasic Insulin Combined With Insulin Aspart, With or Without Metformin in Type 2 Diabetes
NCT00282659	PHASE4	COMPLETED	The Use of Magnesium to Improve Blood Pressure, Cholesterol, and Glucose Control
NCT00287820	PHASE4	COMPLETED	Comparative Effects of Chronic Treatment With Olanzapine and Risperidone on Glucose and Lipid Metabolism
NCT00295555	PHASE4	COMPLETED	Doxazosin Effects on ABPM in Hypertensive Patients With Diabetic Nephropathy
NCT00299169	PHASE4	TERMINATED	Randomized Trial Comparing N of 1 Trials to Standard Practice to Improve Adherence to Statins in Patients With Diabetes
NCT00301392	PHASE4	COMPLETED	Japan Prevention Trial of Diabetes by Pitavastatin in Patients With Impaired Glucose Tolerance (J-PREDICT)
NCT00306696	PHASE4	COMPLETED	Examining the Effect of Different Diuretics on Fluid Retention in Diabetics Treated With Rosiglitazone.
NCT00309465	PHASE4	COMPLETED	Perioperative Insulin Glargine Dosing Study