UBR1

Chr 15

ubiquitin protein ligase E3 component n-recognin 1

Also known as: JBS

NCBI Gene: 197131 ENSG00000159459 UniProt: Q8IWV7

The protein functions as an E3 ubiquitin-protein ligase that recognizes proteins with destabilizing N-terminal residues and targets them for ubiquitination and degradation through the N-end rule pathway, and also negatively regulates the leucine-mTOR signaling pathway that controls cell growth. Mutations cause Johanson-Blizzard syndrome, which follows an autosomal recessive inheritance pattern. Loss of this protein's function disrupts normal protein degradation and cellular growth regulation mechanisms.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

The N-end rule pathway is one proteolytic pathway of the ubiquitin system. The recognition component of this pathway, encoded by this gene, binds to a destabilizing N-terminal residue of a substrate protein and participates in the formation of a substrate-linked multiubiquitin chain. This leads to the eventual degradation of the substrate protein. The protein described in this record has a RING-type zinc finger and a UBR-type zinc finger. Mutations in this gene have been associated with Johanson-Blizzard syndrome. [provided by RefSeq, Jul 2008]

GeneReviews ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtJohanson-Blizzard syndrome

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Johanson-Blizzard syndrome · AR · ClinGen 2025

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.35

LOEUF· LoF intol.

LOF

Mechanism· G2P

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GeneReview available — UBR1

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.35LOEUF

pLI 0.005

Z-score 7.15

OE 0.25 (0.19–0.35)

Highly constrained

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

Missense Constraint?

2.40Z-score

OE missense 0.78 (0.73–0.83)

714 obs / 918.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.25 (0.19–0.35)

0≤0.351.4

Missense OE?0.78 (0.73–0.83)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 27 / 106.7Missense obs/exp: 714 / 918.4Syn Z: -0.55

Background carrier burden — how many people carry a rare variant somewhere in UBR1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 40

1,936 rare PASS variants

Rare truncating (LoF)

1 in 1,400

200 rare PASS variants

Rare synonymous (reference)

1 in 50

757 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for UBR1. 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 50	1 in 400
South Asian	~43k	1 in 36	1 in 900
Remaining (unassigned)	~30k	1 in 35	1 in 690
European (Finnish)	~27k	1 in 110	1 in 2,400
Admixed American	~22k	1 in 38	1 in 1,300
African / African American	~21k	1 in 31	1 in 960
East Asian	~20k	1 in 32	≈ 1 in 6,600
Ashkenazi Jewish	~13k	1 in 110	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 39	≈ 1 in 2,800

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): 43 of 47 coding exons well covered in gnomAD exomes; exons 18, 20, 34, 36 marginal. Genomes: all 47.? see exons ↓