RNF216

Chr 7AR

ring finger protein 216

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

NCBI Gene: 54476 ENSG00000011275 UniProt: Q9NWF9 OMIM: 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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a cytoplasmic protein which specifically colocalizes and interacts with the serine/threonine protein kinase, receptor-interacting protein (RIP). Zinc finger domains of the encoded protein are required for its interaction with RIP and for inhibition of TNF- and IL1-induced NF-kappa B activation pathways. The encoded protein may also function as an E3 ubiquitin-protein ligase which accepts ubiquitin from E2 ubiquitin-conjugating enzymes and transfers it to substrates. Several alternatively spliced transcript variants have been described for this locus but the full-length natures of only some are known. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.551 OMIM phenotype

Clinical Summary— RNF216

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

18 unique Pathogenic / Likely Pathogenic· 170 VUS of 313 total submissions

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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 OE?0.38 (0.26–0.55)

0≤0.351.4

Missense OE?1.15 (1.08–1.23)

0≤0.61.4

Synonymous OE?1.30

0≤1.21.6

LoF obs/exp: 19 / 50.6Missense obs/exp: 598 / 519.0Syn Z: -3.25

This gene — mechanism propensity

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

313 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13

Likely Pathogenic5

VUS170

Likely Benign103

Benign6

Conflicting1

Pathogenic

Likely Pathogenic

170

VUS

103

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	11	2	0	0	13
Likely Pathogenic	2	1	1	1	5
VUS	1	166	2	1	170
Likely Benign	0	9	24	70	103
Benign	0	0	2	4	6
Conflicting	—				1
Total	14	178	29	76	298

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

View in ClinVar →

50 pathogenic / likely-pathogenic (of 68) ClinVar copy-number / structural variants overlap RNF216 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →