RNF216

Chr 7AR

ring finger protein 216

ENSG00000011275UniProt: Q9NWF9

E3 ubiquitin ligase which accepts ubiquitin from specific E2 ubiquitin-conjugating enzymes, and then transfers it to substrates promoting their ubiquitination (PubMed:34998453). Plays a role in the regulation of antiviral responses by promoting the degradation of TRAF3, TLR4 and TLR9 (PubMed:15107846, PubMed:19893624). In turn, down-regulates NF-kappa-B and IRF3 activation as well as beta interferon production. Also participates in the regulation of autophagy by ubiquitinating BECN1 leading to its degradation and autophagy inhibition (PubMed:25484083). Plays a role in ARC-dependent synaptic plasticity by mediating ARC ubiquitination resulting in its rapid proteasomal degradation (PubMed:24945773). Plays aso an essential role in spermatogenesis and male fertility (By similarity). Mechanistically, regulates meiosis by promoting the degradation of PRKACB through the ubiquitin-mediated lysosome pathway (By similarity). Modulates the gonadotropin-releasing hormone signal pathway by affecting the stability of STAU2 that is required for the microtubule-dependent transport of neuronal RNA from the cell body to the dendrite (By similarity)

Primary Disease Associations & Inheritance

Cerebellar ataxia and hypogonadotropic hypogonadismMIM #212840
AR
UniProtGordon Holmes syndrome
200
ClinVar variants
16
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— RNF216
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
16 Pathogenic / Likely Pathogenic· 111 VUS of 200 total submissions
Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.55LOEUF
pLI 0.000
Z-score 4.11
OE 0.38 (0.26–0.55)
Moderately constrained

More LoF-intolerant than ~75% 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.
-1.23Z-score
OE missense 1.15 (1.08–1.23)
598 obs / 519.0 exp
Tolerant

Tolerant to missense variation

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.0.38 (0.26–0.55)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.15 (1.08–1.23)
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.1.30
0≤1.21.6
LoF obs/exp: 19 / 50.6Missense obs/exp: 598 / 519.0Syn Z: -3.25

ClinVar Variant Classifications

200 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11
Likely Pathogenic5
VUS111
Likely Benign67
Benign5
Conflicting1
11
Pathogenic
5
Likely Pathogenic
111
VUS
67
Likely Benign
5
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
10
0
11
Likely Pathogenic
2
1
2
0
5
VUS
1
104
6
0
111
Likely Benign
0
4
21
42
67
Benign
0
0
2
3
5
Conflicting
—1
Total41094145200

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

View in ClinVar →

Protein Context — Lollipop Plot

RNF216 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Cerebellar ataxia and hypogonadotropic hypogonadism

MIM #212840

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical and genetic spectrum of RNF216-related disorder: a new case and literature review.
Wu C et al.·J Med Genet
2024Review
Structural basis of K63-ubiquitin chain formation by the Gordon-Holmes syndrome RBR E3 ubiquitin ligase RNF216.
Cotton TR et al.·Mol Cell
2022
Ataxia and Hypogonadism: a Review of the Associated Genes and Syndromes.
De Michele G et al.·Cerebellum
2024Review
Whole-Exome Sequencing Identified a Novel Mutation in RNF216 in a Family with Gordon Holmes Syndrome.
Chen KL et al.·J Mol Neurosci
2022
Ring finger protein 216 loss-of-function induces white matter hyperintensities by inhibiting oligodendroglia proliferation.
Xu W et al.·Cell Biochem Funct
2024
GnRH Deficient Patients With Congenital Hypogonadotropic Hypogonadism: Novel Genetic Findings in ANOS1, RNF216, WDR11, FGFR1, CHD7, and POLR3A Genes in a Case Series and Review of the Literature.
Neocleous V et al.·Front Endocrinol (Lausanne)
2020Review
Copy number variations in RNF216 and postsynaptic membrane-associated genes are associated with bipolar disorder: a case-control study in the Japanese population.
Nakatochi M et al.·Psychiatry Clin Neurosci
2025
RNF216 mutations as a novel cause of autosomal recessive Huntington-like disorder.
Santens P et al.·Neurology
2015
A novel mutation in RNF216 gene in a Turkish case with Gordon Holmes syndrome.
Durmaz Çelik N et al.·BMC Med Genomics
2023Case report
[Screening of interacting proteins of idiopathic gonadotropin-releasing hormone deficiency pathogenic gene RNF216].
Dai W et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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