USP6NL

Chr 10

USP6 N-terminal like

Also known as: RNTRE, TRE2NL, USP6NL-IT1

NCBI Gene: 9712 ENSG00000148429 UniProt: 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.

ResearchSummary from RefSeq, UniProt

Enables GTPase activator activity and small GTPase binding activity. Involved in several processes, including plasma membrane to endosome transport; positive regulation of GTPase activity; and retrograde transport, plasma membrane to Golgi. Located in cytoplasmic vesicle and plasma membrane. Is active in cytosol. [provided by Alliance of Genome Resources, Jun 2026]

ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.42

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.25 (0.15–0.42)

0≤0.351.4

Missense OE?1.02 (0.94–1.10)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 10 / 40.3Missense obs/exp: 468 / 459.2Syn Z: -0.88

Background carrier burden — how many people carry a rare variant somewhere in USP6NL?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 55

1,212 rare PASS variants

Rare truncating (LoF)

1 in 1,300

139 rare PASS variants

Rare synonymous (reference)

1 in 96

482 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for USP6NL. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 74	1 in 1,900
South Asian	~43k	1 in 58	1 in 730
Remaining (unassigned)	~30k	1 in 50	1 in 2,000
European (Finnish)	~27k	1 in 230	1 in 2,200
Admixed American	~22k	1 in 56	1 in 510
African / African American	~21k	1 in 55	1 in 1,200
East Asian	~20k	1 in 59	1 in 600
Ashkenazi Jewish	~13k	1 in 220	1 in 770
Middle Eastern	~2,884	1 in 41	≈ 1 in 580

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 14 coding exons well covered in gnomAD exomes and genomes.? see exons ↓