HUWE1

Chr XX-linked

HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1

Also known as: ARF-BP1, HECTH9, HSPC272, Ib772, LASU1, MRXST, MULE, URE-B1

NCBI Gene: 10075ENSG00000086758UniProt: Q7Z6Z7

This gene encodes a protein containing a C-terminal HECT (E6AP type E3 ubiquitin protein ligase) domain that functions as an E3 ubiquitin ligase. The encoded protein is required for the ubiquitination and subsequent degradation of the anti-apoptotic protein Mcl1 (myeloid cell leukemia sequence 1 (BCL2-related)). This protein also ubiquitinates the p53 tumor suppressor, core histones, and DNA polymerase beta. Mutations in this gene are associated with Turner type X-linked syndromic cognitive disability. [provided by RefSeq, Aug 2013]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, X-linked syndromic, Turner typeMIM #309590
X-linked
290
ClinVar variants
5
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— HUWE1
🧬
Gene-Disease Validity (ClinGen)
non-syndromic X-linked intellectual disability · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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
5 Pathogenic / Likely Pathogenic· 142 VUS of 290 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.06LOEUF
pLI 1.000
Z-score 11.18
OE 0.03 (0.01–0.06)
Highly constrained

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

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.
8.87Z-score
OE missense 0.40 (0.38–0.43)
697 obs / 1738.0 exp
Constrained

Extremely missense-constrained (top ~0.01%)

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.0.03 (0.01–0.06)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.40 (0.38–0.43)
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.0.97
0≤1.21.6
LoF obs/exp: 4 / 153.3Missense obs/exp: 697 / 1738.0Syn Z: 0.68

ClinVar Variant Classifications

290 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic5
VUS142
Likely Benign124
Benign18
Conflicting1
5
Likely Pathogenic
142
VUS
124
Likely Benign
18
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
0
0
0
Likely Pathogenic
0
4
1
0
5
VUS
1
127
10
4
142
Likely Benign
0
11
54
59
124
Benign
0
1
7
10
18
Conflicting
—1
Total11437273290

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

View in ClinVar →

Protein Context — Lollipop Plot

HUWE1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

HUWE1-related syndromic intellectual developmental disorder, Turner type

definitive
Monoallelic X HeterozygousUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder, X-linked syndromic, Turner type

MIM #309590

Molecular basis of disorder known

X-linked
📖
GeneReview available — HUWE1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Promoting anti-tumor immunity by targeting TMUB1 to modulate PD-L1 polyubiquitination and glycosylation.
Shi C et al.·Nat Commun
2022
HUWE1 variants cause dominant X-linked intellectual disability: a clinical study of 21 patients.
Moortgat S et al.·Eur J Hum Genet
2018Cohort
The structure and regulation of the E3 ubiquitin ligase HUWE1 and its biological functions in cancer.
Gong X et al.·Invest New Drugs
2020Review
Exploring the Clinical Spectrum of HUWE1 -Related Neurodevelopmental Disorder: Five New Patients and Literature Review.
De Falco A et al.·Am J Med Genet A
2025Review
A Potential Role for HUWE1 in Modulating Cisplatin Sensitivity.
Wenmaekers S et al.·Cells
2021Review
Xp11.22 Microduplications Including HUWE1: Case Report and Literature Review.
Orivoli S et al.·Neuropediatrics
2016Review
DEPTOR suppresses lymphomagenesis by promoting EGFR degradation via HUWE1 E3 ligase.
Xiong X et al.·Cell Death Differ
2025
HUWE1-mediated ubiquitination and degradation of oxidative damage repair gene ATM maintains mitochondrial quality control system in lens epithelial cells.
Wang C et al.·Biochim Biophys Acta Mol Basis Dis
2025
Genetic Variants and Clinical Phenotyping in 39 Pediatric Patients with Neuropathic Pain.
Quade A et al.·Neuropediatrics
2025Cohort
[Clinical features and genetic analysis of 17 Chinese pedigrees affected with X-linked intellectual disability].
Li Y et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2024
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