UBR1

Summary

UBR1 (ubiquitin protein ligase E3 component n-recognin 1, HGNC:16808) is a protein-coding gene on chromosome 15q15.2, encoding E3 ubiquitin-protein ligase UBR1 (Q8IWV7). E3 ubiquitin-protein ligase which is a component of the N-end rule pathway.

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.

Source: NCBI Gene 197131 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Johanson-Blizzard syndrome (Definitive, ClinGen)
• GWAS associations: 4
• Clinical variants (ClinVar): 1,194 total — 45 pathogenic, 35 likely-pathogenic
• Phenotypes (HPO): 92
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_174916

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16808
Approved symbol	UBR1
Name	ubiquitin protein ligase E3 component n-recognin 1
Location	15q15.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000159459
Ensembl biotype	protein_coding
OMIM	605981
Entrez	197131

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 8 protein_coding, 5 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000290650, ENST00000546274, ENST00000562173, ENST00000563239, ENST00000564540, ENST00000566493, ENST00000568782, ENST00000569066, ENST00000569243, ENST00000569337, ENST00000569971, ENST00000627960, ENST00000914215, ENST00000914216, ENST00000914217, ENST00000914218

RefSeq mRNA: 1 — MANE Select: NM_174916 NM_174916

CCDS: CCDS10091

Canonical transcript exons

ENST00000290650 — 47 exons

Exon	Start	End
ENSE00001755560	42942897	42945470
ENSE00001918677	43105942	43106038
ENSE00003458414	43047161	43047289
ENSE00003469571	42952278	42952448
ENSE00003472051	43022702	43022801
ENSE00003486409	43002555	43002704
ENSE00003512892	43024829	43024983
ENSE00003515414	42963935	42964043
ENSE00003523849	43048392	43048491
ENSE00003530232	43003837	43003930
ENSE00003532387	42983897	42983993
ENSE00003536020	42960645	42960701
ENSE00003543936	42984887	42984942
ENSE00003562977	42950262	42950363
ENSE00003596159	42958013	42958090
ENSE00003598337	43085984	43086240
ENSE00003606842	43015688	43015869
ENSE00003629194	42977880	42977947
ENSE00003631587	42976717	42976867
ENSE00003632949	42988819	42988967
ENSE00003633134	42966153	42966286
ENSE00003638929	42970520	42970607
ENSE00003642721	43007079	43007284
ENSE00003648538	42990030	42990120
ENSE00003671520	43074979	43075089
ENSE00003692813	42998168	42998265
ENSE00003716063	43029944	43030068
ENSE00003716740	43017095	43017181
ENSE00003716847	43067898	43068036
ENSE00003717305	43058341	43058429
ENSE00003717540	43027776	43027828
ENSE00003718937	43059702	43059825
ENSE00003723089	43036528	43036593
ENSE00003723414	43082638	43082716
ENSE00003727964	43070795	43070925
ENSE00003732504	43056344	43056442
ENSE00003733430	43021275	43021375
ENSE00003736575	43025381	43025429
ENSE00003738928	43026561	43026663
ENSE00003739344	43059085	43059192
ENSE00003745531	43060052	43060114
ENSE00003746806	43037773	43037883
ENSE00003749668	43036178	43036279
ENSE00003751047	43032568	43032631
ENSE00003751696	43054742	43054899
ENSE00003752096	43043215	43043395
ENSE00003752218	43038171	43038232

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 99.27.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.7672 / max 274.5642, expressed in 1798 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
149582	11.2903	1738
149583	8.0137	1672
149584	0.4632	226

Top tissues by expression

261 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
epithelial cell of pancreas	CL:0000083	99.27	gold quality
germinal epithelium of ovary	UBERON:0001304	97.82	gold quality
visceral pleura	UBERON:0002401	97.62	gold quality
endothelial cell	CL:0000115	97.38	gold quality
parietal pleura	UBERON:0002400	97.33	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.24	gold quality
oviduct epithelium	UBERON:0004804	96.62	gold quality
thymus	UBERON:0002370	96.07	gold quality
pancreatic ductal cell	CL:0002079	96.04	gold quality
epithelium of nasopharynx	UBERON:0001951	95.64	gold quality
tibia	UBERON:0000979	95.55	gold quality
deltoid	UBERON:0001476	95.35	gold quality
tibialis anterior	UBERON:0001385	95.19	gold quality
palpebral conjunctiva	UBERON:0001812	94.73	gold quality
left ventricle myocardium	UBERON:0006566	94.52	gold quality
oocyte	CL:0000023	94.47	gold quality
secondary oocyte	CL:0000655	94.46	gold quality
quadriceps femoris	UBERON:0001377	94.25	gold quality
vastus lateralis	UBERON:0001379	94.06	gold quality
substantia nigra pars compacta	UBERON:0001965	94.05	gold quality
urethra	UBERON:0000057	94.02	gold quality
cerebellar vermis	UBERON:0004720	93.77	gold quality
eye	UBERON:0000970	93.73	gold quality
ileal mucosa	UBERON:0000331	93.44	gold quality
amniotic fluid	UBERON:0000173	93.39	gold quality
superficial temporal artery	UBERON:0001614	93.38	gold quality
pericardium	UBERON:0002407	93.36	gold quality
gingival epithelium	UBERON:0001949	93.34	gold quality
saphenous vein	UBERON:0007318	93.11	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.10	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.74

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): STAT1

miRNA regulators (miRDB)

129 targeting UBR1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-432-3P	100.00	67.86	705
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-128-3P	99.95	71.17	2484

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 19)

• Deficiency of UBR1 perturbs the pancreas’ acinar cells and other organs, presumably owing to metabolic stabilization of specific substrates of the N-end rule pathway. (PMID:16311597)
• Sustained ERK5 activity and the E3 ligase UBR1 regulate the stability and subcellular localization of c-Fos. (PMID:17018293)
• Thus we propose that autoISGylation of EFP negatively regulates its ISG15 E3 ligase activity for 14-3-3sigma. (PMID:17222803)
• These results suggest that Rabring7 is involved in the endocytic trafficking of EGFR through its E3 ligase activity. (PMID:17462600)
• Thiazolidinediones modulate the expression of beta catenin and other cell cycle proteins by targeting UBR1 independently of PPARG. (PMID:17569795)
• E3 ubiquitin ligase is an essential downstream component of the RAS signal transduction pathway. (PMID:18089810)
• study reports on two apparently unrelated girls with Johanson-Blizzard syndrome, in both children caused by a homozygous IVS26+5G>A mutation in the UBR1 gene (PMID:19006206)
• Case Report: Johanson-Blizzard syndrome with mild phenotypic features confirmed by UBR1 gene testing. (PMID:19058315)
• Molecular studies revealed a novel homozygous nonsense mutation in exon 38 of the UBR1 gene, which confirmed the diagnosis of Johanson-Blizzard syndrome. (PMID:20556423)
• Ubc2/Rad6 ser(120) regulates ubiquitin-dependent N-end rule targeting by E3{alpha}/Ubr1 (PMID:21041297)
• Testing the fetus and the affected sibling with recurrent Johanson-Blizzard syndrome revealed a homozygous truncating mutation in UBR1. (PMID:21711208)
• Results confirmed the relevance of specific missense UBR1 alleles to JBS, and suggested that a residual activity of a missense allele is causally associated with milder variants of JBS. (PMID:21931868)
• For all previously reported and novel UBR1 mutations together with their clinical data, a mutation database has been established at LOVD. (PMID:24599544)
• Reduced UBR1 expression affects MGMT turnover and DNA repair in the smokers lungs. (PMID:26183928)
• The frequency of any non-synonymous or synonymous variants was not different between the patients with chronic pancreatitis and controls (PMID:27397733)
• UBR1 mutations of single or multi-exon deletions or duplications account for a substantial proportion of Johanson-Blizzard syndrome. (PMID:29178640)
• Ubr1-induced selective endophagy/autophagy protects against the endosomal and Ca(2+)-induced proteostasis disease stress. (PMID:35233680)
• Identification of Ubr1 as an amino acid sensor of steatosis in liver and muscle. (PMID:37057345)
• UBR1 is a prognostic biomarker and therapeutic target associated with immune cell infiltration in gastric cancer. (PMID:39181686)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	ubr1	ENSDARG00000060480
danio_rerio	UBR1	ENSDARG00000104306
mus_musculus	Ubr1	ENSMUSG00000027272
rattus_norvegicus	Ubr1	ENSRNOG00000037207
drosophila_melanogaster	Ubr1	FBGN0030809
caenorhabditis_elegans	ubr-1	WBGENE00016326

Paralogs (2): UBR2 (ENSG00000024048), UBR3 (ENSG00000144357)

Protein

Protein identifiers

E3 ubiquitin-protein ligase UBR1 — Q8IWV7 (reviewed: Q8IWV7)

Alternative names: N-recognin-1, Ubiquitin-protein ligase E3-alpha-1, Ubiquitin-protein ligase E3-alpha-I

All UniProt accessions (8): Q8IWV7, A0A087WTJ9, A0A0C4DGM0, H3BNQ6, H3BQF8, H3BS20, H3BUC4, H3BUZ4

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase which is a component of the N-end rule pathway. Recognizes and binds proteins bearing specific N-terminal residues that are destabilizing according to the N-end rule, leading to their ubiquitination and subsequent degradation. Recognizes both type-1 and type-2 N-degrons, containing positively charged amino acids (Arg, Lys and His) and bulky and hydrophobic amino acids, respectively. Does not ubiquitinate proteins that are acetylated at the N-terminus. In contrast, it strongly binds methylated N-degrons. Binds leucine and is a negative regulator of the leucine-mTOR signaling pathway, thereby controlling cell growth.

Subunit / interactions. Interacts with RECQL4.

Subcellular location. Cytoplasm. Cytosol.

Tissue specificity. Broadly expressed, with highest levels in skeletal muscle, kidney and pancreas. Present in acinar cells of the pancreas (at protein level).

Disease relevance. Johanson-Blizzard syndrome (JBS) [MIM:243800] This disorder includes congenital exocrine pancreatic insufficiency, multiple malformations such as nasal wing aplasia, and intellectual disability. Pancreas of individuals with JBS do not express UBR1 and show intrauterine-onset destructive pancreatitis. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by the small-molecule compound RF-C11, which bears two heterovalent ligands: RF-C11 inhibits activity toward both type-1 and type-2 N-degrons.

Domain organisation. The RING-H2 zinc finger is an atypical RING finger with a His ligand in place of the fourth Cys of the classical motif. The UBR-type zinc finger forms a pocket that mediates recognition of type 1 N-degrons. It exhibits preference for arginine in the first position. It binds N-degrons with a methylated arginine in the first position.

Pathway. Protein modification; protein ubiquitination.

Similarity. Belongs to the E3 ubiquitin-protein ligase UBR1-like family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IWV7-1	1	yes
Q8IWV7-2	2

RefSeq proteins (1): NP_777576* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003126	Znf_UBR	Domain
IPR003769	ClpS_core	Domain
IPR014719	Ribosomal_bL12_C/ClpS-like	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR039164	UBR1-like	Family
IPR042065	E3_ELL-like	Homologous_superfamily
IPR044046	E3_ligase_UBR-like_C	Domain
IPR047507	UBR-box_UBR1	Domain
IPR055194	UBR1-like_WH	Domain

Pfam: PF02207, PF02617, PF18995, PF22960

Enzyme classification (BRENDA):

• EC 3.4.17.20 — carboxypeptidase U (BRENDA: 12 organisms, 74 substrates, 104 inhibitors, 40 Km, 38 kcat entries)

Substrate kinetics (BRENDA)

17 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
HIPPURYL-ARGININE	—	7
P-ANISYLAZOFORMYL-L-ARGININE	0.0002	5
ANISYLAZOFORMYL-LYS	0.979–1.26	4
HIPPURYL-L-ARG	1.12–817	4
HIPPURYL-L-LYS	1.45–933	4
N-[3-(2-FURYLACRYLOYL)]-L-ALA-L-LYS	3.41–280	3
HIPPURYL-ARG	2.38–3.44	2
ARG6-LEU5-ENKEPHALIN	63	1
ARG6-MET5-ENKEPHALIN	140	1
BIOTINYL-(EPSILON-AMINOCAPROIC ACID)-(EPSILON-AM	0.012	1
BRADYKININ	10	1
HIPPURYL-L-ARGININIC ACID	240	1
LYS6-LEU5-ENKEPHALIN	110	1
LYS6-MET5-ENKEPHALIN	220	1
N-BENZOYL-2’-CYANO-L-PHE-L-ARG	0.02	1

UniProt features (85 total): binding site 36, sequence variant 24, sequence conflict 5, strand 4, modified residue 3, turn 3, zinc finger region 2, region of interest 2, splice variant 2, helix 2, initiator methionine 1, chain 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9MUX	X-RAY DIFFRACTION	1.29
9DNO	X-RAY DIFFRACTION	1.33
9V0K	X-RAY DIFFRACTION	1.54
5TDC	X-RAY DIFFRACTION	1.61
3NY1	X-RAY DIFFRACTION	2.08

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IWV7-F1	85.09	0.52

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (36): 115; 115; 124; 124; 127; 127; 127; 133; 133; 136; 136; 148 …

Post-translational modifications (3): 2, 21, 1179

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 388 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_ACID_CHEMICAL, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_ACID_CHEMICAL, CTATGCA_MIR153, STAT3_01, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, CATTTCA_MIR203, GOBP_NEGATIVE_REGULATION_OF_TOR_SIGNALING, TCF11_01

GO Biological Process (7): protein ubiquitination (GO:0016567), negative regulation of TOR signaling (GO:0032007), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), cellular response to L-leucine (GO:0071233), ubiquitin-dependent protein catabolic process via the N-end rule pathway (GO:0071596), ubiquitin-dependent protein catabolic process (GO:0006511), protein catabolic process (GO:0030163)

GO Molecular Function (7): zinc ion binding (GO:0008270), ubiquitin protein ligase activity (GO:0061630), L-leucine binding (GO:0070728), ubiquitin-protein transferase activity (GO:0004842), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (4): ubiquitin ligase complex (GO:0000151), proteasome complex (GO:0000502), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cation binding	2
intracellular protein-containing complex	2
cellular anatomical structure	2
protein modification by small protein conjugation	1
TOR signaling	1
regulation of TOR signaling	1
negative regulation of intracellular signal transduction	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
response to L-leucine	1
cellular response to amino acid stimulus	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
macromolecule catabolic process	1
protein metabolic process	1
transition metal ion binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
amino acid binding	1
carboxylic acid binding	1
ubiquitin-like protein transferase activity	1
binding	1
catalytic activity	1
transferase complex	1
endopeptidase complex	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

2392 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UBR1	UBR5	O95071	913
UBR1	UBE2B	P23567	903
UBR1	UBE2A	P49459	890
UBR1	UBR4	Q5T4S7	871
UBR1	RECQL4	O94761	865
UBR1	MARCHF6	O60337	805
UBR1	UBR2	Q8IWV8	793
UBR1	ATE1	O95260	729
UBR1	FAM120B	Q96EK7	720
UBR1	VCP	P55072	704
UBR1	NTAQ1	Q96HA8	697
UBR1	LTN1	O94822	687
UBR1	UBA1	P22314	679
UBR1	SYVN1	Q86TM6	677
UBR1	UBR7	Q8N806	661

IntAct

221 interactions, top by confidence:

A	B	Type	Score
CBX7	BMI1	psi-mi:“MI:0914”(association)	0.940
GFAP	NEFL	psi-mi:“MI:0914”(association)	0.850
VIM	NEFL	psi-mi:“MI:0914”(association)	0.840
TIRAP	TLR4	psi-mi:“MI:0914”(association)	0.810
NRP1	CSNK2A2	psi-mi:“MI:0914”(association)	0.790
SIL1	HSPA5	psi-mi:“MI:0914”(association)	0.740
DMTN	YWHAG	psi-mi:“MI:0914”(association)	0.670
FAF2	UBB	psi-mi:“MI:0914”(association)	0.640
CRHBP	CCNB2	psi-mi:“MI:0914”(association)	0.640
CRIPTO	AIP	psi-mi:“MI:0914”(association)	0.640
FGL1	LCMT2	psi-mi:“MI:0914”(association)	0.640
MRM2	HSPD1	psi-mi:“MI:0914”(association)	0.640
UBE2B	UBR1	psi-mi:“MI:0407”(direct interaction)	0.590
APBA1	LIN7A	psi-mi:“MI:0914”(association)	0.590
	UBR1	psi-mi:“MI:0407”(direct interaction)	0.560
UBR1	HEXB	psi-mi:“MI:0915”(physical association)	0.560
UBR1	TTR	psi-mi:“MI:0915”(physical association)	0.560
UBR1	SPRED1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (331): CDC6 (Reconstituted Complex), UBR1 (Affinity Capture-RNA), UBR1 (Affinity Capture-MS), UBR1 (Affinity Capture-MS), UBR1 (Affinity Capture-MS), UBR1 (Affinity Capture-MS), UBR1 (Affinity Capture-MS), UBR1 (Affinity Capture-MS), UBR1 (Affinity Capture-MS), UBR1 (Affinity Capture-MS), UBR1 (Affinity Capture-MS), UBR1 (Affinity Capture-MS), UBR1 (Affinity Capture-MS), UBR1 (Affinity Capture-MS), UBR1 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2K344, D3ZGS3, F1M386, F1MSG6, F1PBJ0, G5EF51, O00329, O02697, O35242, O35904, O70481, O88763, O94830, P32871, P42336, P42337, P42338, P42339, P42347, P42348, P48736, P50520, P54676, P70600, Q01968, Q14289, Q14BI7, Q16JS8, Q3MHU3, Q3UYK3, Q4KWH5, Q4KWH8, Q5D891, Q5ZI89, Q6AZN6, Q6GQ76, Q6NVF0, Q6PF93, Q7Z392, Q80Y98

Diamond homologs: O70481, Q6WKZ8, Q8IWV7, Q8IWV8, Q9VX91

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
UBR1	up-regulates	RECQL4	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

1194 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	45
Likely pathogenic	35
Uncertain significance	231
Likely benign	727
Benign	81

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1251994	NM_174916.3(UBR1):c.4054-2A>G	Pathogenic
1323737	NM_174916.3(UBR1):c.4524T>A (p.Tyr1508Ter)	Pathogenic
1409633	NM_174916.3(UBR1):c.5007dup (p.Ile1670fs)	Pathogenic
1457170	NC_000015.9:g.(?43262698)(43262825_?)del	Pathogenic
1709455	NM_174916.3(UBR1):c.2379+1G>C	Pathogenic
2060079	NM_174916.3(UBR1):c.4309dup (p.Tyr1437fs)	Pathogenic
208624	NM_174916.3(UBR1):c.4107T>A (p.Cys1369Ter)	Pathogenic
2696878	NM_174916.3(UBR1):c.336C>A (p.Cys112Ter)	Pathogenic
2701050	NM_174916.3(UBR1):c.1188T>A (p.Tyr396Ter)	Pathogenic
2736185	NM_174916.3(UBR1):c.4093C>T (p.Gln1365Ter)	Pathogenic
2736186	NM_174916.3(UBR1):c.1507C>T (p.Arg503Ter)	Pathogenic
2751937	NM_174916.3(UBR1):c.2626_2644dup (p.Leu882delinsGlnGlnSerAspTer)	Pathogenic
2752248	NM_174916.3(UBR1):c.4704del (p.Trp1568fs)	Pathogenic
2759332	NM_174916.3(UBR1):c.1333del (p.Leu445fs)	Pathogenic
2760612	NM_174916.3(UBR1):c.3526C>T (p.Gln1176Ter)	Pathogenic
2760818	NM_174916.3(UBR1):c.4372del (p.Leu1458fs)	Pathogenic
2762769	NC_000015.10:g.42970608del	Pathogenic
2805002	NM_174916.3(UBR1):c.1192C>T (p.Gln398Ter)	Pathogenic
2832497	NM_174916.3(UBR1):c.1417dup (p.Tyr473fs)	Pathogenic
2845105	NM_174916.3(UBR1):c.321_324dup (p.Thr109fs)	Pathogenic
2846901	NM_174916.3(UBR1):c.1615C>T (p.Gln539Ter)	Pathogenic
2869664	NM_174916.3(UBR1):c.453_454del (p.Cys151fs)	Pathogenic
2875291	NM_174916.3(UBR1):c.86G>A (p.Trp29Ter)	Pathogenic
2876365	NM_174916.3(UBR1):c.1384C>T (p.Gln462Ter)	Pathogenic
2876798	NM_174916.3(UBR1):c.4745dup (p.Asn1582fs)	Pathogenic
2900448	NM_174916.3(UBR1):c.2899C>T (p.Gln967Ter)	Pathogenic
2983873	NM_174916.3(UBR1):c.5020C>T (p.Arg1674Ter)	Pathogenic
2989151	NM_174916.3(UBR1):c.1228A>T (p.Arg410Ter)	Pathogenic
31918	NM_174916.3(UBR1):c.1440-1G>A	Pathogenic
3243919	NC_000015.9:g.(?43299257)(43299502_?)del	Pathogenic

SpliceAI

6529 predictions. Top by Δscore:

Variant	Effect	Δscore
15:42950260:A:AC	donor_gain	1.0000
15:42950261:C:CC	donor_gain	1.0000
15:42950261:CTT:C	donor_gain	1.0000
15:42950263:T:TA	donor_gain	1.0000
15:42950359:TGATT:T	acceptor_gain	1.0000
15:42950360:GATT:G	acceptor_gain	1.0000
15:42950361:ATT:A	acceptor_gain	1.0000
15:42950362:TT:T	acceptor_gain	1.0000
15:42950363:TCT:T	acceptor_loss	1.0000
15:42950364:C:CC	acceptor_gain	1.0000
15:42952270:CTA:C	donor_gain	1.0000
15:42952270:CTACT:C	donor_gain	1.0000
15:42952274:TCA:T	donor_loss	1.0000
15:42952275:CA:C	donor_loss	1.0000
15:42952276:A:AC	donor_gain	1.0000
15:42952276:ACTT:A	donor_loss	1.0000
15:42952277:C:CG	donor_gain	1.0000
15:42952277:CT:C	donor_gain	1.0000
15:42952277:CTTT:C	donor_gain	1.0000
15:42952451:C:CT	acceptor_gain	1.0000
15:42958007:CCTTA:C	donor_loss	1.0000
15:42958008:CTTA:C	donor_loss	1.0000
15:42958009:TTAC:T	donor_loss	1.0000
15:42958010:TA:T	donor_loss	1.0000
15:42958012:C:A	donor_loss	1.0000
15:42960715:C:CT	acceptor_gain	1.0000
15:42966304:C:CT	acceptor_gain	1.0000
15:42966304:C:T	acceptor_gain	1.0000
15:42970519:CCCA:C	donor_gain	1.0000
15:42976863:CCCAC:C	acceptor_gain	1.0000

AlphaMissense

11629 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:42950299:A:C	Y1691D	1.000
15:42952405:A:G	C1627R	1.000
15:43002625:A:G	C1197R	1.000
15:43007193:A:G	C1101R	1.000
15:43007200:G:C	C1098W	1.000
15:43007202:A:G	C1098R	1.000
15:43015765:G:C	F1044L	1.000
15:43015765:G:T	F1044L	1.000
15:43015766:A:G	F1044S	1.000
15:43015767:A:G	F1044L	1.000
15:43015787:A:G	M1037T	1.000
15:43015794:C:G	A1035P	1.000
15:43015808:C:G	R1030P	1.000
15:43015809:G:T	R1030S	1.000
15:43027786:C:G	A808P	1.000
15:43036545:C:G	D691H	1.000
15:43037792:C:T	G668E	1.000
15:43037794:A:C	N667K	1.000
15:43037794:A:T	N667K	1.000
15:43037797:T:A	R666S	1.000
15:43037797:T:G	R666S	1.000
15:43037798:C:A	R666I	1.000
15:43037798:C:G	R666T	1.000
15:43037803:C:A	W664C	1.000
15:43037803:C:G	W664C	1.000
15:43037805:A:G	W664R	1.000
15:43037805:A:T	W664R	1.000
15:43043246:G:C	S606R	1.000
15:43043246:G:T	S606R	1.000
15:43043248:T:G	S606R	1.000

dbSNP variants (sampled 300 via entrez): RS1000032021 (15:43049272 A>G), RS1000036640 (15:43087223 G>A), RS1000060575 (15:43093617 C>T), RS1000086111 (15:42970025 C>T), RS1000110311 (15:43001594 A>T), RS1000111585 (15:43065134 C>A,T), RS1000128592 (15:43058190 G>A), RS1000135319 (15:42980536 A>C), RS1000144629 (15:43102886 G>A), RS1000186921 (15:43064816 C>T), RS1000196263 (15:43023769 T>C), RS1000205788 (15:43033354 T>C), RS1000216682 (15:43064432 A>C), RS1000235718 (15:42976433 C>A), RS1000256767 (15:43079801 A>C)

Disease associations

OMIM: gene MIM:605981 | disease phenotypes: MIM:243800, MIM:260450

GenCC curated gene-disease

Disease	Classification	Inheritance
Johanson-Blizzard syndrome	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Johanson-Blizzard syndrome	Definitive	AR

Mondo (3): Johanson-Blizzard syndrome (MONDO:0009479), intellectual disability (MONDO:0001071), microcephaly (MONDO:0001149)

Orphanet (2): Johanson-Blizzard syndrome (Orphanet:2315), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

92 total (30 of 92 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000054	Micropenis
HP:0000126	Hydronephrosis
HP:0000142	Abnormal vagina morphology
HP:0000143	Rectovaginal fistula
HP:0000164	Abnormality of the dentition
HP:0000252	Microcephaly
HP:0000343	Long philtrum
HP:0000407	Sensorineural hearing impairment
HP:0000430	Underdeveloped nasal alae
HP:0000444	Convex nasal ridge
HP:0000486	Strabismus
HP:0000582	Upslanted palpebral fissure
HP:0000632	Lacrimation abnormality
HP:0000677	Oligodontia
HP:0000684	Delayed eruption of teeth
HP:0000691	Microdontia
HP:0000819	Diabetes mellitus
HP:0000821	Hypothyroidism
HP:0000832	Primary hypothyroidism
HP:0000954	Single transverse palmar crease
HP:0000957	Cafe-au-lait spot
HP:0000969	Edema
HP:0001092	Absent lacrimal punctum
HP:0001153	Septate vagina
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001290	Generalized hypotonia

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002897_4	Triglycerides	4.000000e-10
GCST003031_1	MGMT methylation in smokers	3.000000e-07
GCST90000025_210	Appendicular lean mass	9.000000e-14
GCST90013407_154	Liver enzyme levels (gamma-glutamyl transferase)	2.000000e-15

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0006959	gene methylation measurement
EFO:0004980	appendicular lean mass
EFO:0004532	serum gamma-glutamyl transferase measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C535880	Johanson Blizzard syndrome (supp.)
C564907	Pancreatic Insufficiency, Combined Exocrine (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL6066245 (SINGLE PROTEIN), CHEMBL6193816 (PROTEIN-PROTEIN INTERACTION), CHEMBL6193829 (PROTEIN-PROTEIN INTERACTION), CHEMBL6193830 (PROTEIN-PROTEIN INTERACTION)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

36 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, increases methylation	4
sodium arsenite	increases expression	2
potassium chromate(VI)	decreases expression, affects cotreatment	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases expression	1
trichostatin A	decreases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
chromium hexavalent ion	decreases expression	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Vehicle Emissions	increases expression	1
Caffeine	affects phosphorylation	1
Dexamethasone	affects cotreatment, increases expression	1
Dimethyl Sulfoxide	decreases expression	1
Doxorubicin	decreases expression	1
Hydrogen Peroxide	affects expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Methapyrilene	decreases methylation	1
Methyl Methanesulfonate	increases expression	1
Nickel	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Ribonucleotides	affects binding	1

ChEMBL screening assays

32 unique, capped per target: 32 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5518724	Binding	Binding affinity to UBR1 (unknown origin) expressed in HEK293T cells incubated for 3 hrs by pull-down assay	Degradation of Polo-like Kinase 1 by the Novel Poly-Arginine N-Degron Pathway PROTAC Regulates Tumor Growth in Nonsmall Cell Lung Cancer. — J Med Chem

Cellosaurus cell lines

5 cell lines: 3 cancer cell line, 1 induced pluripotent stem cell, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D1R8	Abcam K-562 UBR1 KO	Cancer cell line	Female
CVCL_D2MV	Abcam Raji UBR1 KO	Cancer cell line	Male
CVCL_D6R0	SDQLCHi079-A	Induced pluripotent stem cell	Male
CVCL_D7HQ	Ubigene HEK293T UBR1 KO	Transformed cell line	Female
CVCL_WQ77	Abcam Jurkat UBR1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

197 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders