USP6NL

Chr 10

USP6 N-terminal like

Also known as: RNTRE, TRE2NL, USP6NL-IT1

NCBI Gene: 9712ENSG00000148429UniProt: Q92738

The protein acts as a GTPase-activating protein for several RAB proteins and is involved in receptor trafficking and retrograde transport from endosomes to the Golgi apparatus. Mutations cause autosomal recessive developmental and epileptic encephalopathy with microcephaly, typically presenting in early infancy. The gene is highly constrained against loss-of-function variants, suggesting intolerance to protein disruption.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
6
Pubs (1 yr)
21
P/LP submissions
0%
P/LP missense
0.42
LOEUF
Multiple*
Mechanism· predicted
Clinical Summary— USP6NL
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.
📋
ClinVar Variants
21 unique Pathogenic / Likely Pathogenic· 153 VUS of 203 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint
0.42LOEUF
pLI 0.121
Z-score 4.43
OE 0.25 (0.15–0.42)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
-0.15Z-score
OE missense 1.02 (0.94–1.10)
468 obs / 459.2 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.25 (0.15–0.42)
0≤0.351.4
Missense OE1.02 (0.94–1.10)
0≤0.61.4
Synonymous OE1.08
0≤1.21.6
LoF obs/exp: 10 / 40.3Missense obs/exp: 468 / 459.2Syn Z: -0.88
DN
0.74top 25%
GOF
0.7126th %ile
LOF
0.3357th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

203 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21
VUS153
Likely Benign6
Benign1
21
Pathogenic
153
VUS
6
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
21
0
21
Likely Pathogenic
0
0
0
0
0
VUS
0
140
13
0
153
Likely Benign
0
6
0
0
6
Benign
0
0
1
0
1
Total0146350181

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

View in ClinVar →

Protein Context — Lollipop Plot

USP6NL · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

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Clinical Literature
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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 3 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
USP6NL and MSX2 as the novel diagnostic markers in gastric cancer patients.
Basirat Z et al.·Cancer Treat Res Commun
2025Cohort
USP6NL knockdown suppresses colorectal cancer progression by inducing CASP9-Mediated apoptosis and disrupting FOXC2/SNAI1-Driven EMT and angiogenesis.
Mohammed MA et al.·Funct Integr Genomics
2025
Ubiquitin-Specific Protease 6 n-Terminal-like Protein (USP6NL) and the Epidermal Growth Factor Receptor (EGFR) Signaling Axis Regulates Ubiquitin-Mediated DNA Repair and Temozolomide-Resistance in Glioblastoma.
Su IC et al.·Biomedicines
2022Open Access
USP6NL mediated by LINC00689/miR-142-3p promotes the development of triple-negative breast cancer.
Ma T et al.·BMC Cancer
2020Open Access
Tre2 (USP6NL) promotes colorectal cancer cell proliferation via Wnt/β-catenin pathway.
Sun K et al.·Cancer Cell Int
2019Open Access
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