EIF2AK1

Chr 7AD

eukaryotic translation initiation factor 2 alpha kinase 1

Also known as: HCR, HRI, hHRI

NCBI Gene: 27102ENSG00000086232UniProt: Q9BQI3

The protein encoded by this gene acts at the level of translation initiation to downregulate protein synthesis in response to stress. The encoded protein is a kinase that can be inactivated by hemin. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

Primary Disease Associations & Inheritance

?Leukoencephalopathy, motor delay, spasticity, and dysarthria syndromeMIM #618878
AD
259
ClinVar variants
8
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— EIF2AK1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
8 Pathogenic / Likely Pathogenic· 178 VUS of 259 total submissions
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.71LOEUF
pLI 0.000
Z-score 2.89
OE 0.47 (0.32–0.71)
Tolerant

Typical tolerance to LoF variation

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.
0.43Z-score
OE missense 0.93 (0.85–1.02)
312 obs / 334.4 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.0.47 (0.32–0.71)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.93 (0.85–1.02)
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.1.08
0≤1.21.6
LoF obs/exp: 16 / 34.2Missense obs/exp: 312 / 334.4Syn Z: -0.69

ClinVar Variant Classifications

259 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7
Likely Pathogenic1
VUS178
Likely Benign65
Benign5
Conflicting3
7
Pathogenic
1
Likely Pathogenic
178
VUS
65
Likely Benign
5
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
7
0
7
Likely Pathogenic
1
0
0
0
1
VUS
3
155
17
3
178
Likely Benign
0
5
20
40
65
Benign
0
0
3
2
5
Conflicting
—3
Total41604745259

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.

Gene2Phenotype Curations

EIF2AK1-related neurodevelopmental syndrome

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

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome

MIM #618878

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation.
Mao D et al.·Am J Hum Genet
2020
YTHDF2 phase separation promotes arsenic-induced keratinocyte transformation in a poly-m(6)A-dependent manner by inhibiting translational initiation of the key tumor suppressor PTEN.
Zhao T et al.·J Hazard Mater
2024
IGF1R signaling drives antiestrogen resistance through PAK2/PIX activation in luminal breast cancer.
Zhang Y et al.·Oncogene
2018
Genetic modifiers of multiple sclerosis progression, severity and onset.
Sadovnick AD et al.·Clin Immunol
2017
Domain-focused CRISPR screen identifies HRI as a fetal hemoglobin regulator in human erythroid cells.
Grevet JD et al.·Science
2018
Comparative RNA-seq analysis reveals potential mechanisms mediating the conversion to androgen independence in an LNCaP progression cell model.
Wang Y et al.·Cancer Lett
2014Functional
HRI depletion cooperates with pharmacologic inducers to elevate fetal hemoglobin and reduce sickle cell formation.
Peslak SA et al.·Blood Adv
2020
Functional profiling of precursor MicroRNAs identifies MicroRNAs essential for glioma proliferation.
Haapa-Paananen S et al.·PLoS One
2013Functional
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools