HECTD4

Chr 12AR

HECT domain E3 ubiquitin protein ligase 4

Also known as: C12ord51, C12orf51, HEEL, NEDSSCC, POTAGE

NCBI Gene: 283450ENSG00000173064UniProt: Q9Y4D8OMIM: 620209

The protein functions as an E3 ubiquitin-protein ligase that transfers ubiquitin to targeted substrates and is involved in glucose homeostasis. Biallelic mutations cause autosomal recessive neurodevelopmental disorder with seizures, spasticity, and complete or partial agenesis of the corpus callosum. The gene is highly constrained against loss-of-function variants, indicating it is essential for normal cellular function.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismARLOEUF 0.131 OMIM phenotype
Clinical Summary— HECTD4
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
14 unique Pathogenic / Likely Pathogenic· 71 VUS of 91 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint
0.13LOEUF
pLI 1.000
Z-score 12.02
OE 0.08 (0.06–0.13)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint
6.94Z-score
OE missense 0.60 (0.57–0.63)
1429 obs / 2382.6 exp
Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios
LoF OE0.08 (0.06–0.13)
0≤0.351.4
Missense OE0.60 (0.57–0.63)
0≤0.61.4
Synonymous OE0.94
0≤1.21.6
LoF obs/exp: 17 / 200.7Missense obs/exp: 1429 / 2382.6Syn Z: 1.43
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
moderateHECTD4-related neurodevelopmental disorder with seizures, hypotonia, spasticity, and agenesis of the corpus callosumOTHERAR

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

DN
0.3196th %ile
GOF
0.3094th %ile
LOF
0.74top 10%

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

91 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12
Likely Pathogenic2
VUS71
Likely Benign1
Benign5
12
Pathogenic
2
Likely Pathogenic
71
VUS
1
Likely Benign
5
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
2
7
0
12
Likely Pathogenic
2
0
0
0
2
VUS
0
70
1
0
71
Likely Benign
0
0
0
1
1
Benign
0
0
0
5
5
Total5728691

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

View in ClinVar →

Protein Context — Lollipop Plot

HECTD4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 4 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients