HERC2
Chr 15ARHECT and RLD domain containing E3 ubiquitin protein ligase 2
Also known as: D15F37S1, MRT38, SHEP1, jdf2, p528
This gene encodes an E3 ubiquitin-protein ligase that regulates DNA damage repair by controlling ubiquitin-dependent retention of repair proteins on damaged chromosomes and modulates iron metabolism and insulin-like growth factor receptor signaling. Biallelic mutations cause autosomal recessive intellectual developmental disorder with onset typically in early childhood. The gene is highly constrained against loss-of-function variants in the general population, indicating that such variants are likely to be pathogenic when present in the homozygous or compound heterozygous state.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Highly missense-constrained (top ~0.1%)
Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.
The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
500 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 | 1 | 0 | 6 | 0 | 7 |
Likely Pathogenic | 3 | 1 | 1 | 0 | 5 |
VUS | 0 | 314 | 11 | 2 | 327 |
Likely Benign | 0 | 7 | 3 | 42 | 52 |
Benign | 0 | 0 | 0 | 0 | 0 |
Conflicting | — | 1 | |||
| Total | 4 | 322 | 21 | 44 | 392 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
HERC2 · 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