UHRF2

Chr 9

ubiquitin like with PHD and ring finger domains 2

Also known as: NIRF, RNF107, TDRD23, URF2

NCBI Gene: 115426 ENSG00000147854 UniProt: Q96PU4 OMIM: 615211

This gene encodes an E3 ubiquitin ligase that regulates cell cycle progression, DNA methylation, histone modifications, and DNA repair through ubiquitination of various substrates including cyclins and DNA damage response proteins. The gene is highly constrained against loss-of-function variants (pLI=1.0, LOEUF=0.25), indicating that mutations are likely to cause severe developmental consequences. However, no specific human disease phenotype has been definitively associated with UHRF2 mutations in the current literature.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a nuclear protein which is involved in cell-cycle regulation. The encoded protein is a ubiquitin-ligase capable of ubiquinating PCNP (PEST-containing nuclear protein), and together they may play a role in tumorigenesis. The encoded protein contains an NIRF_N domain, a PHD finger, a set- and ring-associated (SRA) domain, and a RING finger domain and several of these domains have been shown to be essential for the regulation of cell proliferation. This protein may also have a role in intranuclear degradation of polyglutamine aggregates. Alternative splicing results in multiple transcript variants some of which are non-protein coding. [provided by RefSeq, Feb 2012]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.24

Clinical Summary— UHRF2

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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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ClinVar Variants

60 VUS of 85 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.24LOEUF

pLI 0.999

Z-score 5.37

OE 0.12 (0.06–0.24)

Highly constrained

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

Missense Constraint?

3.32Z-score

OE missense 0.55 (0.50–0.62)

244 obs / 440.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.12 (0.06–0.24)

0≤0.351.4

Missense OE?0.55 (0.50–0.62)

0≤0.61.4

Synonymous OE?1.25

0≤1.21.6

LoF obs/exp: 5 / 43.0Missense obs/exp: 244 / 440.0Syn Z: -2.44

This gene — mechanism propensity

0.2598th %ile

GOF

0.2895th %ile

LOF

0.73top 10%

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

LOFprediction above median · LOEUF 0.24

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

ClinVar Variant Classifications

85 submitted variants in ClinVar

ClinVar

Classification Summary

VUS60

Likely Benign4

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	60	0	60
Likely Benign	3	1	4
Benign	0	0	0
Total	63	1	64

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

View in ClinVar →

155 pathogenic / likely-pathogenic (of 161) ClinVar copy-number / structural variants overlap UHRF2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →