EIF2AK1
Chr 7ADeukaryotic translation initiation factor 2 alpha kinase 1
Also known as: HCR, HRI, hHRI
EIF2AK1 encodes a metabolic stress-sensing kinase that phosphorylates eukaryotic translation initiation factor 2 alpha in response to heme deficiency, oxidative stress, and mitochondrial dysfunction, thereby regulating protein synthesis and cellular stress responses. Mutations cause leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (LOEUF 0.71), indicating that such variants are likely pathogenic.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Mild missense constraint
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.
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.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
413 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 2 | 0 | 40 | 0 | 42 |
Likely Pathogenic | 1 | 0 | 3 | 0 | 4 |
VUS | 11 | 176 | 29 | 3 | 219 |
Likely Benign | 1 | 5 | 28 | 51 | 85 |
Benign | 0 | 5 | 9 | 5 | 19 |
Conflicting | — | 3 | |||
| Total | 15 | 186 | 109 | 59 | 372 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
EIF2AK1 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools