EIF2S3

Chr XXLR

eukaryotic translation initiation factor 2 subunit gamma

Also known as: EIF2, EIF2G, EIF2gamma, MEHMO, MRXSBRK, eIF-2gA, eIF2gX

NCBI Gene: 1968ENSG00000130741UniProt: P41091

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. [provided by RefSeq, Jan 2010]

Primary Disease Associations & Inheritance

MEHMO syndromeMIM #300148
XLR
140
ClinVar variants
69
Pathogenic / LP
0.96
pLI score· haploinsufficient
0
Active trials
Clinical Summary— EIF2S3
🧬
Gene-Disease Validity (ClinGen)
MEHMO syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
69 Pathogenic / Likely Pathogenic· 49 VUS of 140 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.32LOEUF
pLI 0.964
Z-score 3.32
OE 0.07 (0.02–0.32)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.61Z-score
OE missense 0.24 (0.18–0.31)
42 obs / 177.1 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.07 (0.02–0.32)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.24 (0.18–0.31)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.02
0≤1.21.6
LoF obs/exp: 1 / 14.7Missense obs/exp: 42 / 177.1Syn Z: -0.13

ClinVar Variant Classifications

140 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic66
Likely Pathogenic3
VUS49
Likely Benign15
Benign4
Conflicting3
66
Pathogenic
3
Likely Pathogenic
49
VUS
15
Likely Benign
4
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
65
0
66
Likely Pathogenic
0
3
0
0
3
VUS
0
37
10
2
49
Likely Benign
0
1
2
12
15
Benign
0
1
0
3
4
Conflicting
—3
Total0437717140

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

EIF2S3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

EIF2S3-related syndromic intellectual disability with severe microcephaly

strong
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

MEHMO syndrome

MIM #300148

Molecular basis of disorder known

X-linked recessive
📖
GeneReview available — EIF2S3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Congenital hyperinsulinism: recent updates on molecular mechanisms, diagnosis and management.
Giri D et al.·J Pediatr Endocrinol Metab
2021Review
mRNA analysis revealed a novel pathogenic EIF2S3 variant causing MEHMO syndrome.
Ivanova N et al.·Eur J Med Genet
2022Case report
Novel pathogenic EIF2S3 missense variants causing clinically variable MEHMO syndrome with impaired eIF2γ translational function, and literature review.
Kotzaeridou U et al.·Clin Genet
2020Review
piRNA PROPER Suppresses DUSP1 Translation by Targeting N(6)-Methyladenosine-Mediated RNA Circularization to Promote Oncogenesis of Prostate Cancer.
Ben S et al.·Adv Sci (Weinh)
2024
EIF2S3 Mutations Associated with Severe X-Linked Intellectual Disability Syndrome MEHMO.
Skopkova M et al.·Hum Mutat
2017
Impaired EIF2S3 function associated with a novel phenotype of X-linked hypopituitarism with glucose dysregulation.
Gregory LC et al.·EBioMedicine
2019
Broadening the phenotypic spectrum and physiological insights related to EIF2S3 variants.
Moortgat S et al.·Hum Mutat
2021
Neonatal hypoglycemia, early-onset diabetes and hypopituitarism due to the mutation in EIF2S3 gene causing MEHMO syndrome.
Stanik J et al.·Physiol Res
2018
X chromosome dosage and the genetic impact across human tissues.
Viuff M et al.·Genome Med
2023
Two novel EIF2S3 mutations associated with syndromic intellectual disability with severe microcephaly, growth retardation, and epilepsy.
Moortgat S et al.·Am J Med Genet A
2016
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools