NEDD4L

Chr 18AD

NEDD4 like E3 ubiquitin protein ligase

Also known as: NEDD4-2, NEDD4.2, PVNH7, RSP5, hNEDD4-2

NCBI Gene: 23327ENSG00000049759UniProt: Q96PU5

This gene encodes a member of the Nedd4 family of HECT domain E3 ubiquitin ligases. HECT domain E3 ubiquitin ligases transfer ubiquitin from E2 ubiquitin-conjugating enzymes to protein substrates, thus targeting specific proteins for lysosomal degradation. The encoded protein mediates the ubiquitination of multiple target substrates and plays a critical role in epithelial sodium transport by regulating the cell surface expression of the epithelial sodium channel, ENaC. Single nucleotide polymorphisms in this gene may be associated with essential hypertension. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

Primary Disease Associations & Inheritance

Periventricular nodular heterotopia 7MIM #617201
AD
1262
ClinVar variants
11
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— NEDD4L
⚡
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
11 Pathogenic / Likely Pathogenic· 218 VUS of 1262 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.
0.20LOEUF
pLI 1.000
Z-score 6.75
OE 0.11 (0.06–0.20)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
3.73Z-score
OE missense 0.55 (0.51–0.61)
308 obs / 555.0 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.0.11 (0.06–0.20)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.55 (0.51–0.61)
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.0.94
0≤1.21.6
LoF obs/exp: 7 / 66.3Missense obs/exp: 308 / 555.0Syn Z: 0.69

ClinVar Variant Classifications

1262 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8
Likely Pathogenic3
VUS218
Likely Benign211
Benign24
Conflicting8
8
Pathogenic
3
Likely Pathogenic
218
VUS
211
Likely Benign
24
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
8
0
8
Likely Pathogenic
1
1
1
0
3
VUS
11
172
31
4
218
Likely Benign
1
10
127
73
211
Benign
0
14
10
0
24
Conflicting
—8
Total1319717777472

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

View in ClinVar →

Protein Context — Lollipop Plot

NEDD4L · protein map & ClinVar variants

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

Gene2Phenotype Curations

NEDD4L-related periventricular nodular heterotopia with intellectual disability, cleft palate, and 2-3 toe syndactyly

strong
ADUndeterminedAltered 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

Periventricular nodular heterotopia 7

MIM #617201

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
NEDD4L mediates intestinal epithelial cell ferroptosis to restrict inflammatory bowel diseases and colorectal tumorigenesis.
Liang J et al.·J Clin Invest
2024
Extracellular vesicle-packaged PIAT from cancer-associated fibroblasts drives neural remodeling by mediating m5C modification in pancreatic cancer mouse models.
Zheng S et al.·Sci Transl Med
2024Functional
PRDM16 deficiency promotes podocyte injury by impairing insulin receptor signaling.
Yuan Q et al.·Cell Death Differ
2025
LAPTM4B counteracts ferroptosis via suppressing the ubiquitin-proteasome degradation of SLC7A11 in non-small cell lung cancer.
Yan R et al.·Cell Death Dis
2024
Genome-wide association analysis provides insights into the molecular etiology of dilated cardiomyopathy.
Zheng SL et al.·Nat Genet
2024
Intratumoral Brevibacillus parabrevis enhances antitumor immunity by inhibiting NK cell ferroptosis in hepatocellular carcinoma.
Pan B et al.·Cell Death Dis
2025
Ubiquitin-specific protease 1 facilitates hepatocellular carcinoma progression by modulating mitochondrial fission and metabolic reprogramming via cyclin-dependent kinase 5 stabilization.
Bian S et al.·Cell Death Differ
2024
SLC7A11 upregulation via AR and NEDD4L ubiquitination contributes to ferroptosis inhibition and enzalutamide resistance in castration-resistant prostate cancer.
Tang M et al.·Cell Death Dis
2025
NEDD4L mediates ITGB4 ubiquitination and degradation to suppress esophageal carcinoma progression.
Shi Y et al.·Cell Commun Signal
2024
Genetic analysis of periventricular nodular heterotopia 7 caused by a novel NEDD4L missense mutation: Case and literature summary.
Liu J et al.·Mol Genet Genomic Med
2023Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Artesunate Ameliorates APAP-induced Liver Injury by Promoting NEDD4L-Mediated Ubiquitination and Degradation of TXNIP.
Zhang Z et al.·Adv Sci (Weinh)
2026
NEDD4L knockdown enhances synovial fibroblast migration, invasion, and inflammatory factor secretion via Wnt/β-Catenin signaling activation.
Zhang Y et al.·Clin Rheumatol
2026
Palmitic acid aggravates atopic dermatitis by regulating SGK1/NEDD4L-involved cutaneous neuroimmune inflammation through driving TRPV1 and MRGPRB2 S-palmitoylation.
Chen B et al.·Inflamm Res
2026🔓 Open Access
Activation of TGR5 Alleviates Renal Fibrosis by Promoting NEDD4L-Mediated p-Smad2/3 Ubiquitination.
Li M et al.·Acta Physiol (Oxf)
2026
YiQi GuBen formula targets EHMT2 and enhances NEDD4L transcription to combat epithelial-mesenchymal transition and airway remodeling in asthma.
Kong Y et al.·J Ethnopharmacol
2026Functional
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