HACE1

Chr 6AR

HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1

Also known as: SPPRS

NCBI Gene: 57531ENSG00000085382UniProt: Q8IYU2

This gene encodes a HECT domain and ankyrin repeat-containing ubiquitin ligase. The encoded protein is involved in specific tagging of target proteins, leading to their subcellular localization or proteasomal degradation. The protein is a potential tumor suppressor and is involved in the pathophysiology of several tumors, including Wilm's tumor. [provided by RefSeq, Mar 2016]

Primary Disease Associations & Inheritance

Spastic paraplegia and psychomotor retardation with or without seizuresMIM #616756
AR
371
ClinVar variants
53
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— HACE1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
53 Pathogenic / Likely Pathogenic· 125 VUS of 371 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.36 (0.25–0.52)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.54 (0.49–0.60)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.05
0≤1.21.6
LoF obs/exp: 19 / 53.2Missense obs/exp: 259 / 480.7Syn Z: -0.47

ClinVar Variant Classifications

371 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic37
Likely Pathogenic16
VUS125
Likely Benign146
Benign20
Conflicting4
37
Pathogenic
16
Likely Pathogenic
125
VUS
146
Likely Benign
20
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
1
33
1
37
Likely Pathogenic
12
2
2
0
16
VUS
1
101
20
3
125
Likely Benign
0
5
63
78
146
Benign
0
1
13
6
20
Conflicting
—4
Total1511013188348

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.

Gene2Phenotype Curations

HACE1-related disorder

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Spastic paraplegia and psychomotor retardation with or without seizures

MIM #616756

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
HMBOX1 reverses autophagy mediated 5-fluorouracil resistance through promoting HACE1-induced ubiquitination and degradation of ATG5 in colorectal cancer.
Gao Y et al.·Autophagy
2025
HACE1, GLRX5, and ELP2 gene variant cause spastic paraplegies.
Sager G et al.·Acta Neurol Belg
2022
Tumor-suppressive role of HACE1 in hepatocellular carcinoma and its clinical significance.
Gao ZF et al.·Oncol Rep
2016
Ubiquitylation of active Rac1 by the E3 ubiquitin-ligase HACE1.
Mettouchi A et al.·Small GTPases
2012Review
A Retrospective Review of 18 Patients With Childhood-Onset Hereditary Spastic Paraplegia, Nine With Novel Variants.
Kilic MA et al.·Pediatr Neurol
2024Review
A Missense Variant in HACE1 Is Associated with Intellectual Disability, Epilepsy, Spasticity, and Psychomotor Impairment in a Pakistani Kindred.
Usmani MA et al.·Genes (Basel)
2024Case report
Loss of HACE1 promotes colorectal cancer cell migration via upregulation of YAP1.
Zhou Z et al.·J Cell Physiol
2019
HACE1 expression in heart failure patients might promote mitochondrial oxidative stress and ferroptosis by targeting NRF2.
Yin P et al.·Aging (Albany NY)
2023Cohort
Comprehensive Genomic Analysis of Cemento-Ossifying Fibroma.
Gomez RS et al.·Mod Pathol
2024
Oxygen sensor FIH inhibits HACE1-dependent ubiquitination of Rac1 to enhance metastatic potential in breast cancer cells.
Kim I et al.·Oncogene
2019
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools