RNF168

Chr 3AR

ring finger protein 168

Also known as: RIDL, hRNF168

NCBI Gene: 165918 ENSG00000163961 UniProt: Q8IYW5 OMIM: 612688

RNF168 encodes an E3 ubiquitin ligase that is required for accumulating DNA repair proteins at sites of double-strand breaks and interstrand cross-links, promoting histone ubiquitination to recruit key repair factors like TP53BP1 and BRCA1. Biallelic mutations cause RIDDLE syndrome, an autosomal recessive disorder characterized by radiosensitivity, immunodeficiency, dysmorphic features, and learning difficulties. The gene is not highly constrained against loss-of-function variants (pLI near zero), consistent with the recessive inheritance pattern where heterozygous carriers are typically unaffected.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an E3 ubiquitin ligase protein that contains a RING finger, a motif present in a variety of functionally distinct proteins and known to be involved in protein-DNA and protein-protein interactions. The protein is involved in DNA double-strand break (DSB) repair. Mutations in this gene result in Riddle syndrome. [provided by RefSeq, Sep 2011]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 1.201 OMIM phenotype

Clinical Summary— RNF168

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Gene-Disease Validity (ClinGen)

RIDDLE syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

39 unique Pathogenic / Likely Pathogenic· 184 VUS of 405 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.20LOEUF

pLI 0.000

Z-score 0.76

OE 0.84 (0.60–1.20)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.39Z-score

OE missense 1.06 (0.97–1.17)

319 obs / 299.9 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.84 (0.60–1.20)

0≤0.351.4

Missense OE?1.06 (0.97–1.17)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 22 / 26.2Missense obs/exp: 319 / 299.9Syn Z: -0.51

ClinVar Variant Classifications

405 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27

Likely Pathogenic12

VUS184

Likely Benign148

Benign13

Conflicting11

Pathogenic

Likely Pathogenic

184

VUS

148

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	23	0	4	0	27
Likely Pathogenic	12	0	0	0	12
VUS	7	171	5	1	184
Likely Benign	0	8	41	99	148
Benign	0	7	3	3	13
Conflicting	—				11
Total	42	186	53	103	395

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

View in ClinVar →

89 pathogenic / likely-pathogenic (of 107) ClinVar copy-number / structural variants overlap RNF168 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →