EIF2AK2

Chr 2

eukaryotic translation initiation factor 2 alpha kinase 2

Also known as: PKR, PPP1R83, PRKR

NCBI Gene: 5610ENSG00000055332UniProt: P19525

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]

Primary Disease Associations & Inheritance

UniProtLeukoencephalopathy, developmental delay, and episodic neurologic regression syndrome
UniProtDystonia 33
269
ClinVar variants
20
Pathogenic / LP
0.02
pLI score
1
Active trials
Clinical Summary— EIF2AK2
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.
📋
ClinVar Variants
20 Pathogenic / Likely Pathogenic· 152 VUS of 269 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.52LOEUF
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?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.
1.28Z-score
OE missense 0.79 (0.70–0.88)
222 obs / 282.3 exp
Tolerant

Mild missense constraint

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.0.30 (0.18–0.52)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.79 (0.70–0.88)
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.1.05
0≤1.21.6
LoF obs/exp: 9 / 30.5Missense obs/exp: 222 / 282.3Syn Z: -0.37

ClinVar Variant Classifications

269 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic15
Likely Pathogenic5
VUS152
Likely Benign73
Benign15
Conflicting9
15
Pathogenic
5
Likely Pathogenic
152
VUS
73
Likely Benign
15
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
15
0
15
Likely Pathogenic
0
3
2
0
5
VUS
8
125
15
4
152
Likely Benign
1
17
25
30
73
Benign
0
2
7
6
15
Conflicting
—9
Total91476440269

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

View in ClinVar →

Protein Context — Lollipop Plot

EIF2AK2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

EIF2AK2-related developmental delay, leukoencephalopathy, and neurologic decompensation

strong
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — EIF2AK2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Genetics and Pathogenesis of Dystonia.
Thomsen M et al.·Annu Rev Pathol
2024Review
Dysregulated RNA editing of EIF2AK2 in polycystic ovary syndrome: clinical relevance and functional implications.
Kong FS et al.·BMC Med
2024Functional
De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation.
Mao D et al.·Am J Hum Genet
2020
Calreticulin regulates the expression of MMP14 and ADAR1 through EIF2AK2 signaling to promote the proliferation and progression of malignant melanoma cells.
Liang L et al.·Neoplasma
2024
Identifying and validating immunological biomarkers in obstructive sleep apnea through bioinformatics analysis.
Zhou EH et al.·Sci Rep
2025
EIF2AK2 Missense Variants Associated with Early Onset Generalized Dystonia.
Kuipers DJS et al.·Ann Neurol
2021
Genetic Diversity and Expanded Phenotypes in Dystonia: Insights From Large-Scale Exome Sequencing.
Thomsen M et al.·Ann Clin Transl Neurol
2025
Clinical and therapeutic potential of protein kinase PKR in cancer and metabolism.
Garcia-Ortega MB et al.·Expert Rev Mol Med
2017Review
Genome sequencing reanalysis increases the diagnostic yield in dystonia.
Fellner A et al.·Parkinsonism Relat Disord
2024
Identification and verification of inflammatory biomarkers for primary Sjögren's syndrome.
Liu X et al.·Clin Rheumatol
2024
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
TOR1APANK2HPRT1

Deep Brain Stimulation (DBS) MatchMaker

ENROLLING BY INVITATION
NCT06912841Boston Children's HospitalStarted 2024-12-01

External Resources

Links to major genomics databases and tools