RNF220

Chr 1AR

ring finger protein 220

Also known as: C1orf164, HLD23

NCBI Gene: 55182 ENSG00000187147 UniProt: Q5VTB9 OMIM: 616136

This E3 ubiquitin ligase regulates Wnt signaling through beta-catenin stabilization and plays a critical role in nuclear lamina regulation. Biallelic mutations cause autosomal recessive hypomyelinating leukodystrophy 23, a multisystem disorder involving ataxia, deafness, liver dysfunction, and dilated cardiomyopathy. The gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.20), indicating intolerance to protein disruption.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Enables beta-catenin binding activity. Involved in positive regulation of canonical Wnt signaling pathway. Acts upstream of or within positive regulation of DNA-binding transcription factor activity and protein monoubiquitination. Located in nuclear lamina and nucleoplasm. Part of protein-containing complex. Implicated in hypomyelinating leukodystrophy 23. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.201 OMIM phenotype

Clinical Summary— RNF220

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.20LOEUF

pLI 1.000

Z-score 4.84

OE 0.06 (0.03–0.20)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.22Z-score

OE missense 0.67 (0.60–0.74)

234 obs / 351.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.06 (0.03–0.20)

0≤0.351.4

Missense OE?0.67 (0.60–0.74)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 2 / 31.1Missense obs/exp: 234 / 351.3Syn Z: 0.02

This gene — mechanism propensity

0.2897th %ile

GOF

0.1799th %ile

LOF

0.85top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.20

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.