EIF2AK1

Chr 7AD

eukaryotic translation initiation factor 2 alpha kinase 1

Also known as: HCR, HRI, hHRI

NCBI Gene: 27102 ENSG00000086232 UniProt: Q9BQI3 OMIM: 613635

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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.711 OMIM phenotype

Clinical Summary— EIF2AK1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 201 VUS of 356 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.71LOEUF

pLI 0.000

Z-score 2.89

OE 0.47 (0.32–0.71)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.43Z-score

OE missense 0.93 (0.85–1.02)

312 obs / 334.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.47 (0.32–0.71)

0≤0.351.4

Missense OE?0.93 (0.85–1.02)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 16 / 34.2Missense obs/exp: 312 / 334.4Syn Z: -0.69

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedEIF2AK1-related neurodevelopmental syndromeOTHERAD

This gene — mechanism propensity

0.75top 25%

GOF

0.6443th %ile

LOF

0.3357th %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

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.

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

ClinVar Variant Classifications

356 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic1

VUS201

Likely Benign85

Benign19

Conflicting4

Pathogenic

Likely Pathogenic

201

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	0	3	0	5
Likely Pathogenic	1	0	0	0	1
VUS	11	175	12	3	201
Likely Benign	1	5	28	51	85
Benign	0	5	9	5	19
Conflicting	—				4
Total	15	185	52	59	315

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

View in ClinVar →

41 pathogenic / likely-pathogenic (of 58) ClinVar copy-number / structural variants overlap EIF2AK1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →