RNF169

Chr 11

ring finger protein 169

NCBI Gene: 254225 ENSG00000166439 UniProt: Q8NCN4 OMIM: 618650

The protein functions as an E3 ubiquitin ligase that regulates DNA double-strand break repair by competing with other repair factors to favor homologous recombination over other repair pathways. Mutations cause an autosomal recessive neurodevelopmental disorder with intellectual disability, seizures, and brain malformations. The gene shows moderate constraint against loss-of-function variants, with neurological symptoms typically manifesting in early childhood.

OMIM ResearchSummary from RefSeq, UniProt

Enables K63-linked polyubiquitin modification-dependent protein binding activity; nucleosome binding activity; and ubiquitin-modified histone reader activity. Involved in double-strand break repair via homologous recombination and negative regulation of double-strand break repair. Located in cytosol; nuclear lumen; and site of double-strand break. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.55

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.55LOEUF

pLI 0.040

Z-score 3.20

OE 0.29 (0.17–0.55)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.36Z-score

OE missense 0.94 (0.86–1.04)

303 obs / 321.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.29 (0.17–0.55)

0≤0.351.4

Missense OE?0.94 (0.86–1.04)

0≤0.61.4

Synonymous OE?1.22

0≤1.21.6

LoF obs/exp: 7 / 23.9Missense obs/exp: 303 / 321.1Syn Z: -1.89

Background carrier burden — how many people carry a rare variant somewhere in RNF169?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 63

951 rare PASS variants

Rare truncating (LoF)

1 in 2,600

82 rare PASS variants

Rare synonymous (reference)

1 in 120

427 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RNF169. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 79	1 in 2,400
South Asian	~43k	1 in 61	1 in 3,100
Remaining (unassigned)	~30k	1 in 62	1 in 4,100
European (Finnish)	~27k	1 in 190	≈ 1 in 27,000
Admixed American	~22k	1 in 58	1 in 1,300
African / African American	~21k	1 in 61	1 in 2,300
East Asian	~20k	1 in 64	≈ 1 in 4,700
Ashkenazi Jewish	~13k	1 in 400	≈ 1 in 4,400
Middle Eastern	~2,884	1 in 56	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 4 of 6 coding exons well covered in gnomAD exomes; exons 1, 2 marginal. Genomes: all 6.? see exons ↓