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

The protein encoded by this gene is a serine/threonine protein kinase that is activated by autophosphorylation after binding to dsRNA. The activated form of the encoded protein can phosphorylate translation initiation factor EIF2S1, which in turn inhibits protein synthesis. This protein is also activated by manganese ions and heparin. The encoded protein plays an important role in the innate immune response against multiple DNA and RNA viruses. [provided by RefSeq, Jul 2021]

GeneReviews OMIM ResearchGenerating clinical summary…

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

5 unique Pathogenic / Likely Pathogenic· 151 VUS of 272 total submissions

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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GeneReview available — EIF2AK2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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 OE?0.30 (0.18–0.52)

0≤0.351.4

Missense OE?0.79 (0.70–0.88)

0≤0.61.4

Synonymous OE?1.05

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

This gene — mechanism propensity

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.1

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

References

1.PMID 32197074 ↗

ClinVar Variant Classifications

272 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic4

VUS151

Likely Benign74

Benign14

Conflicting9

Pathogenic

Likely Pathogenic

151

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	0	0	0	1
Likely Pathogenic	1	3	0	0	4
VUS	12	128	7	4	151
Likely Benign	1	18	25	30	74
Benign	0	2	6	6	14
Conflicting	—				9
Total	15	151	38	40	253

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

View in ClinVar →

17 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap EIF2AK2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →