RNF208

Chr 9

ring finger protein 208

NCBI Gene: 727800 ENSG00000212864 UniProt: Q9H0X6 OMIM: 618993

RNF208 encodes a ubiquitin-protein transferase that catalyzes protein autoubiquitination and localizes to the cytosol and nucleoplasm. The gene is highly constrained against loss-of-function variants (pLI 0.83, LOEUF 0.51), suggesting that mutations would likely cause severe developmental disorders. However, no specific disease associations or inheritance patterns have been established for RNF208 mutations in humans.

OMIM ResearchSummary from RefSeq

Enables ubiquitin-protein transferase activity. Involved in protein autoubiquitination. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.51

Clinical Summary— RNF208

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.83) — some intolerance to loss-of-function variants.

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ClinVar Variants

49 VUS of 49 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.51LOEUF

pLI 0.830

Z-score 2.24

OE 0.00 (0.00–0.51)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.24Z-score

OE missense 0.73 (0.63–0.85)

120 obs / 164.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.51)

0≤0.351.4

Missense OE?0.73 (0.63–0.85)

0≤0.61.4

Synonymous OE?1.27

0≤1.21.6

LoF obs/exp: 0 / 5.8Missense obs/exp: 120 / 164.8Syn Z: -1.88

This gene — mechanism propensity

0.3892th %ile

GOF

0.6540th %ile

LOF

0.62top 25%

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction 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

49 submitted variants in ClinVar

ClinVar

Classification Summary

VUS49

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	49	49
Likely Benign	0	0
Benign	0	0
Total	49	49

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

View in ClinVar →

95 pathogenic / likely-pathogenic (of 108) ClinVar copy-number / structural variants overlap RNF208 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →