RNF216

Chr 7AR

ring finger protein 216

Also known as: CAHH, TRIAD3, U7I1, UBCE7IP1, ZIN

NCBI Gene: 54476ENSG00000011275UniProt: Q9NWF9OMIM: 609948

RNF216 encodes an E3 ubiquitin ligase that transfers ubiquitin to substrates promoting their degradation, regulating processes including antiviral responses, autophagy, synaptic plasticity, and gonadotropin-releasing hormone signaling. Autosomal recessive mutations cause cerebellar ataxia and hypogonadotropic hypogonadism, affecting both the nervous system and reproductive endocrine function. The gene is highly constrained against loss-of-function variants in the population.

OMIMResearchSummary from RefSeq, OMIM, UniProt
DNmechanismARLOEUF 0.551 OMIM phenotype
Clinical Summary— RNF216
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
67 unique Pathogenic / Likely Pathogenic· 174 VUS of 378 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
0.55LOEUF
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
-1.23Z-score
OE missense 1.15 (1.08–1.23)
598 obs / 519.0 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.38 (0.26–0.55)
0≤0.351.4
Missense OE1.15 (1.08–1.23)
0≤0.61.4
Synonymous OE1.30
0≤1.21.6
LoF obs/exp: 19 / 50.6Missense obs/exp: 598 / 519.0Syn Z: -3.25
DN
0.6260th %ile
GOF
0.5464th %ile
LOF
0.2776th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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

378 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic49
Likely Pathogenic18
VUS174
Likely Benign109
Benign12
Conflicting1
49
Pathogenic
18
Likely Pathogenic
174
VUS
109
Likely Benign
12
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
10
3
36
0
49
Likely Pathogenic
3
2
12
1
18
VUS
0
158
15
1
174
Likely Benign
0
13
25
71
109
Benign
0
1
3
8
12
Conflicting
—1
Total131779181363

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.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
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
Structural basis of K63-ubiquitin chain formation by the Gordon-Holmes syndrome RBR E3 ubiquitin ligase RNF216.
Cotton TR et al.·Mol Cell
2022
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
Whole-Exome Sequencing Identified a Novel Mutation in RNF216 in a Family with Gordon Holmes Syndrome.
Chen KL et al.·J Mol Neurosci
2022
Ataxia and Hypogonadism: a Review of the Associated Genes and Syndromes.
De Michele G et al.·Cerebellum
2024Review
[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 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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