RNF220

Chr 1AR

ring finger protein 220

Also known as: C1orf164, HLD23

NCBI Gene: 55182ENSG00000187147UniProt: Q5VTB9

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]

Primary Disease Associations & Inheritance

Leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathyMIM #619688
AR
88
ClinVar variants
10
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— RNF220
⚡
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.
📋
ClinVar Variants
10 Pathogenic / Likely Pathogenic· 72 VUS of 88 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.20LOEUF
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?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.
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?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.0.06 (0.03–0.20)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.67 (0.60–0.74)
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.1.00
0≤1.21.6
LoF obs/exp: 2 / 31.1Missense obs/exp: 234 / 351.3Syn Z: 0.02

ClinVar Variant Classifications

88 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9
Likely Pathogenic1
VUS72
Likely Benign5
Benign1
9
Pathogenic
1
Likely Pathogenic
72
VUS
5
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
7
0
9
Likely Pathogenic
0
0
1
0
1
VUS
1
63
8
0
72
Likely Benign
0
0
0
5
5
Benign
0
0
1
0
1
Total16517588

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

View in ClinVar →

Protein Context — Lollipop Plot

RNF220 · 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

Leukodystrophy, hypomyelinating, 23, with ataxia, deafness, liver dysfunction, and dilated cardiomyopathy

MIM #619688

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — RNF220
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Smurf1 and Smurf2 mediated polyubiquitination and degradation of RNF220 suppresses Shh-group medulloblastoma.
Li Y et al.·Cell Death Dis
2023
Sequential stabilization of RNF220 by RLIM and ZC4H2 during cerebellum development and Shh-group medulloblastoma progression.
Li Y et al.·J Mol Cell Biol
2022
RNF220 mediates K63-linked polyubiquitination of STAT1 and promotes host defense.
Guo X et al.·Cell Death Differ
2021
Biallelic mutations in RNF220 cause laminopathies featuring leukodystrophy, ataxia and deafness.
Sferra A et al.·Brain
2021
ZC4H2 stabilizes RNF220 to pattern ventral spinal cord through modulating Shh/Gli signaling.
Ma P et al.·J Mol Cell Biol
2020
N-Terminal deleted isoforms of E3 ligase RNF220 are ubiquitously expressed and required for mouse muscle differentiation.
Choi S et al.·Mol Cells
2025Functional
RNF220 is required for cerebellum development and regulates medulloblastoma progression through epigenetic modulation of Shh signaling.
Ma P et al.·Development
2020
Overview of genetic variants in a cohort of Iranian patients with leukodystrophy.
Fathi M et al.·Sci Rep
2025Review
Haploinsufficiency of the TDP43 ubiquitin E3 ligase RNF220 leads to ALS-like motor neuron defects in the mouse.
Ma P et al.·J Mol Cell Biol
2021Functional
Rapid and accurate multi-phenotype imputation for millions of individuals.
Gu LL et al.·Nat Commun
2025
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