GRPEL1
Chr 4GrpE like 1, mitochondrial
Also known as: GrpE, HMGE, mt-GrpE#1
The GRPEL1 protein is an essential component of the PAM complex that controls mitochondrial HSP70 binding to substrate proteins during ATP-dependent protein import into the mitochondrial matrix. Mutations cause autosomal recessive mitochondrial disease with early infantile onset, characterized by severe developmental delay, seizures, hypotonia, and progressive neurodegeneration. The gene shows moderate constraint against loss-of-function variants, consistent with recessive inheritance where heterozygous carriers are typically unaffected.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Tolerant to missense variation
The highest-scoring mechanism for this gene is dominant-negative.
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
123 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 | 0 | 0 | 80 | 0 | 80 |
Likely Pathogenic | 0 | 0 | 4 | 0 | 4 |
VUS | 0 | 28 | 3 | 0 | 31 |
Likely Benign | 0 | 1 | 0 | 0 | 1 |
Benign | 0 | 0 | 0 | 0 | 0 |
| Total | 0 | 29 | 87 | 0 | 116 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
GRPEL1 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
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