HACE1

Chr 6AR

HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1

Also known as: SPPRS

NCBI Gene: 57531ENSG00000085382UniProt: Q8IYU2OMIM: 610876

The protein is an E3 ubiquitin ligase that regulates Golgi membrane dynamics during cell division and mediates degradation of active RAC1, playing roles in cellular trafficking and host defense. Mutations cause autosomal recessive spastic paraplegia and psychomotor retardation with or without seizures. The gene is highly constrained against loss-of-function variants (LOEUF 0.524), suggesting complete loss of function is not well tolerated.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismARLOEUF 0.521 OMIM phenotype
Clinical Summary— HACE1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
56 unique Pathogenic / Likely Pathogenic· 127 VUS of 376 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
LoF Constraint
0.52LOEUF
pLI 0.000
Z-score 4.35
OE 0.36 (0.25–0.52)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
3.59Z-score
OE missense 0.54 (0.49–0.60)
259 obs / 480.7 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios
LoF OE0.36 (0.25–0.52)
0≤0.351.4
Missense OE0.54 (0.49–0.60)
0≤0.61.4
Synonymous OE1.05
0≤1.21.6
LoF obs/exp: 19 / 53.2Missense obs/exp: 259 / 480.7Syn Z: -0.47
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveHACE1-related disorderLOFAR

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

DN
0.6745th %ile
GOF
0.7029th %ile
LOF
0.2971th %ile

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.

ClinVar Variant Classifications

376 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic39
Likely Pathogenic17
VUS127
Likely Benign146
Benign20
Conflicting4
39
Pathogenic
17
Likely Pathogenic
127
VUS
146
Likely Benign
20
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
16
1
22
0
39
Likely Pathogenic
14
3
0
0
17
VUS
1
106
17
3
127
Likely Benign
0
5
63
78
146
Benign
0
1
13
6
20
Conflicting
—4
Total3111611587353

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

View in ClinVar →

Protein Context — Lollipop Plot

HACE1 · 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 5 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