EIF4A2

Chr 3ADAR

eukaryotic translation initiation factor 4A2

Also known as: BM-010, DDX2B, EIF4A, EIF4F, NEDHSS, eIF-4A-II, eIF4A-II

NCBI Gene: 1974 ENSG00000156976 UniProt: Q14240 OMIM: 601102

EIF4A2 encodes an ATP-dependent RNA helicase that unwinds secondary structures in the 5'-untranslated regions of mRNAs to facilitate ribosome binding and translation initiation. Mutations cause neurodevelopmental disorder with hypotonia and speech delay, with or without seizures, inherited in either autosomal dominant or autosomal recessive patterns. The gene is highly constrained against loss-of-function variation (pLI 0.998, LOEUF 0.205), indicating that complete loss of protein function is likely not tolerated.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

Enables ATP hydrolysis activity. Involved in negative regulation of RNA-dependent RNA polymerase activity. Located in perinuclear region of cytoplasm. Implicated in neurodevelopmental disorder with hypotonia and speech delay. [provided by Alliance of Genome Resources, Jul 2025]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/ARLOEUF 0.201 OMIM phenotype

Clinical Summary— EIF4A2

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

20 unique Pathogenic / Likely Pathogenic· 66 VUS of 120 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — EIF4A2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.20LOEUF

pLI 0.998

Z-score 4.26

OE 0.04 (0.01–0.20)

Highly constrained

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

Missense Constraint?

3.89Z-score

OE missense 0.27 (0.22–0.33)

60 obs / 224.1 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.20)

0≤0.351.4

Missense OE?0.27 (0.22–0.33)

0≤0.61.4

Synonymous OE?1.36

0≤1.21.6

LoF obs/exp: 1 / 23.1Missense obs/exp: 60 / 224.1Syn Z: -2.41

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedEIF4A2-related neurodevelopmental disorderOTHERAR

moderateEIF4A2-related neurodevelopmental disorder with hypotonia and epilepsyOTHERAD

This gene — mechanism propensity

0.4487th %ile

GOF

0.4085th %ile

LOF

0.67top 25%

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

LOFprediction above median · 30% of P/LP variants are LoF · LOEUF 0.20

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

ClinVar Variant Classifications

120 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic14

VUS66

Likely Benign9

Benign3

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	4	0	0	6
Likely Pathogenic	4	10	0	0	14
VUS	19	43	2	2	66
Likely Benign	0	0	3	6	9
Benign	0	0	2	1	3
Conflicting	—				1
Total	25	57	7	9	99

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

View in ClinVar →

43 pathogenic / likely-pathogenic (of 48) ClinVar copy-number / structural variants overlap EIF4A2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →