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: 10075 ENSG00000086758 UniProt: Q7Z6Z7 OMIM: 300697

The protein functions as an E3 ubiquitin ligase that targets multiple proteins for degradation, including MCL1, p53, core histones, and MYCN, playing critical roles in apoptosis regulation, DNA repair, and neural development. Mutations cause X-linked syndromic intellectual developmental disorder, Turner type, with X-linked inheritance affecting primarily males. The gene is highly constrained against loss-of-function variants (pLI=1, LOEUF=0.06), indicating that functional copies are essential for normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismX-linkedLOEUF 0.061 OMIM phenotype

Clinical Summary— HUWE1

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Gene-Disease Validity (ClinGen)

non-syndromic X-linked intellectual disability · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.03 (0.01–0.06)

0≤0.351.4

Missense OE?0.40 (0.38–0.43)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 4 / 153.3Missense obs/exp: 697 / 1738.0Syn Z: 0.68

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveHUWE1-related syndromic intellectual developmental disorder, Turner typeOTHERmonoallelic_X_heterozygous

This gene — mechanism propensity

0.16100th %ile

GOF

0.12100th %ile

LOF

0.85top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.06

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.