RNF128

Chr X

ring finger protein 128

Also known as: GRAIL

NCBI Gene: 79589 ENSG00000133135 UniProt: Q8TEB7 OMIM: 300439

RNF128 encodes an E3 ubiquitin ligase that regulates immune responses by targeting various proteins for degradation, including components involved in T-cell activation, cytoskeletal dynamics, and innate immunity. Mutations in RNF128 cause autosomal recessive developmental and epileptic encephalopathy with microcephaly. The gene shows moderate constraint against loss-of-function variants, suggesting some tolerance to heterozygous disruption.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a type I transmembrane protein that localizes to the endocytic pathway. This protein contains a RING zinc-finger motif and has been shown to possess E3 ubiquitin ligase activity. Expression of this gene in retrovirally transduced T cell hybridoma significantly inhibits activation-induced IL2 and IL4 cytokine production. Induced expression of this gene was observed in anergic CD4(+) T cells, which suggested a role in the induction of anergic phenotype. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

OMIM 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

0.67

LOEUF

GOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.67LOEUF

pLI 0.228

Z-score 2.33

OE 0.26 (0.12–0.67)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.67Z-score

OE missense 0.85 (0.74–0.98)

141 obs / 165.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.26 (0.12–0.67)

0≤0.351.4

Missense OE?0.85 (0.74–0.98)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 3 / 11.5Missense obs/exp: 141 / 165.1Syn Z: 0.71

Background carrier burden — how many people carry a rare variant somewhere in RNF128?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 130

463 rare PASS variants

Rare truncating (LoF)

1 in 1,900

52 rare PASS variants

Rare synonymous (reference)

1 in 300

205 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RNF128. 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)	~561k	1 in 190	1 in 1,700
South Asian	~36k	1 in 130	1 in 2,100
Remaining (unassigned)	~31k	1 in 100	1 in 2,300
European (Finnish)	~27k	1 in 530	none seen
Admixed American	~23k	1 in 120	1 in 1,300
African / African American	~21k	1 in 85	1 in 2,200
East Asian	~20k	1 in 96	1 in 1,500
Ashkenazi Jewish	~13k	1 in 760	≈ 1 in 13,000
Middle Eastern	~2,758	1 in 180	≈ 1 in 2,700

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 7 coding exons well covered in gnomAD exomes and genomes.? see exons ↓