EIF2S3

Chr XXLR

eukaryotic translation initiation factor 2 subunit gamma

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

NCBI Gene: 1968 ENSG00000130741 UniProt: P41091 OMIM: 300161

The gamma subunit of eukaryotic initiation factor 2 (eIF2) forms a ternary complex with GTP and initiator tRNA that binds to the 40S ribosomal subunit during the early steps of protein synthesis. X-linked recessive mutations cause MEHMO syndrome, a severe neurodevelopmental disorder characterized by intellectual disability, epilepsy, hypogonadism, microcephaly, and obesity. This gene is highly constrained against loss-of-function variants (pLI 0.96), reflecting the critical nature of protein synthesis initiation in cellular function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismXLRLOEUF 0.321 OMIM phenotype

Clinical Summary— EIF2S3

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Gene-Disease Validity (ClinGen)

MEHMO syndrome · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.07 (0.02–0.32)

0≤0.351.4

Missense OE?0.24 (0.18–0.31)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 1 / 14.7Missense obs/exp: 42 / 177.1Syn Z: -0.13

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongEIF2S3-related syndromic intellectual disability with severe microcephalyLOFXLR

This gene — mechanism propensity

0.3793th %ile

GOF

0.4085th %ile

LOF

0.75top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.32

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.