EIF2AK2

Chr 2ADAR

eukaryotic translation initiation factor 2 alpha kinase 2

Also known as: PKR, PPP1R83, PRKR

NCBI Gene: 5610 ENSG00000055332 UniProt: P19525 OMIM: 176871

This protein is an interferon-induced kinase that phosphorylates translation initiation factor EIF2S1 to inhibit protein synthesis and mediate antiviral innate immune responses. Mutations cause dystonia and leukoencephalopathy with developmental delay and episodic neurologic regression, following both autosomal dominant and autosomal recessive inheritance patterns. The gene is moderately constrained against loss-of-function variants (LOEUF 0.515), reflecting its essential role in cellular stress responses and immune function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAD/ARLOEUF 0.522 OMIM phenotypes

Clinical Summary— EIF2AK2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.

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ClinVar Variants

21 unique Pathogenic / Likely Pathogenic· 152 VUS of 290 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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GeneReview available — EIF2AK2

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint

0.52LOEUF

pLI 0.018

Z-score 3.61

OE 0.30 (0.18–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

1.28Z-score

OE missense 0.79 (0.70–0.88)

222 obs / 282.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.30 (0.18–0.52)

0≤0.351.4

Missense OE0.79 (0.70–0.88)

0≤0.61.4

Synonymous OE1.05

0≤1.21.6

LoF obs/exp: 9 / 30.5Missense obs/exp: 222 / 282.3Syn Z: -0.37

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongEIF2AK2-related developmental delay, leukoencephalopathy, and neurologic decompensationOTHERAD

0.86top 5%

GOF

0.83top 10%

LOF

0.1796th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNTherefore, given that EIF2AK1 and EIF2AK2 require dimerization to phosphorylate their downstream target, the most likely pathogenic mechanism of the de novo missense variants are dominant-negative mutations affecting the function of the wild-type protein.PMID:32197074

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.