UFM1

Summary

UFM1 (ubiquitin fold modifier 1, HGNC:20597) is a protein-coding gene on chromosome 13q13.3, encoding Ubiquitin-fold modifier 1 (P61960). Ubiquitin-like modifier which can be covalently attached via an isopeptide bond to lysine residues of substrate proteins as a monomer or a lysine-linked polymer. It is a selective cancer dependency (DepMap: 58.1% of cell lines).

UFM1 is a ubiquitin-like protein that is conjugated to target proteins by E1-like activating enzyme UBA5 (UBE1DC1; MIM 610552) and E2-like conjugating enzyme UFC1 (MIM 610554) in a manner analogous to ubiquitylation (see UBE2M; MIM 603173) (Komatsu et al., 2004 [PubMed 15071506]).

Source: NCBI Gene 51569 — RefSeq curated summary.

At a glance

• Gene–disease (curated): leukodystrophy, hypomyelinating, 14 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 60 total — 3 likely-pathogenic
• Phenotypes (HPO): 15
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 58.1% of screened cell lines
• MANE Select transcript: NM_016617

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20597
Approved symbol	UFM1
Name	ubiquitin fold modifier 1
Location	13q13.3
Locus type	gene with protein product
Status	Approved
Aliases	bA131P10.1
Ensembl gene	ENSG00000120686
Ensembl biotype	protein_coding
OMIM	610553
Entrez	51569

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 2 retained_intron

ENST00000239878, ENST00000379649, ENST00000437952, ENST00000464423, ENST00000494372, ENST00000891122, ENST00000891123, ENST00000891124, ENST00000933493

RefSeq mRNA: 5 — MANE Select: NM_016617 NM_001286703, NM_001286704, NM_001286705, NM_001286706, NM_016617

CCDS: CCDS66533, CCDS9366

Canonical transcript exons

ENST00000239878 — 6 exons

Exon	Start	End
ENSE00000817162	38354239	38354296
ENSE00000817163	38358093	38358132
ENSE00000817164	38359301	38359333
ENSE00001801205	38360711	38363619
ENSE00001823289	38349851	38349921
ENSE00003601097	38349999	38350055

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 98.19.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 82.6038 / max 2282.4590, expressed in 1821 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
134800	79.5682	1820
134799	1.5078	1002
207008	0.7504	357
134801	0.6519	343
134798	0.1255	46

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus epididymis	UBERON:0004359	98.19	gold quality
choroid plexus epithelium	UBERON:0003911	98.11	gold quality
caput epididymis	UBERON:0004358	98.09	gold quality
seminal vesicle	UBERON:0000998	97.93	gold quality
medial globus pallidus	UBERON:0002477	97.64	gold quality
cauda epididymis	UBERON:0004360	97.49	gold quality
body of pancreas	UBERON:0001150	97.47	gold quality
calcaneal tendon	UBERON:0003701	97.39	gold quality
endometrium	UBERON:0001295	97.32	gold quality
globus pallidus	UBERON:0001875	97.29	gold quality
sperm	CL:0000019	97.22	gold quality
synovial joint	UBERON:0002217	97.22	gold quality
tendon	UBERON:0000043	97.08	gold quality
subthalamic nucleus	UBERON:0001906	97.07	gold quality
mammary duct	UBERON:0001765	97.06	gold quality
decidua	UBERON:0002450	97.00	gold quality
tendon of biceps brachii	UBERON:0008188	96.98	gold quality
amniotic fluid	UBERON:0000173	96.97	gold quality
epithelium of mammary gland	UBERON:0003244	96.96	gold quality
CA1 field of hippocampus	UBERON:0003881	96.93	gold quality
parotid gland	UBERON:0001831	96.82	gold quality
penis	UBERON:0000989	96.80	gold quality
cardia of stomach	UBERON:0001162	96.79	gold quality
urethra	UBERON:0000057	96.77	gold quality
male germ cell	CL:0000015	96.64	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.64	gold quality
pericardium	UBERON:0002407	96.60	gold quality
medulla oblongata	UBERON:0001896	96.56	gold quality
pylorus	UBERON:0001166	96.53	gold quality
superficial temporal artery	UBERON:0001614	96.44	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-46	yes	34.72
E-HCAD-9	yes	15.43
E-MTAB-10553	yes	9.33
E-MTAB-6524	no	113.88
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): XBP1

miRNA regulators (miRDB)

144 targeting UFM1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 58.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 35)

• The solution structure and dynamics of human Ufm1 (hsUfm1) by nuclear magnetic resonance spectroscopy was analysed. (PMID:16527251)
• A novel type of E3 ligase for the Ufm1 conjugation system. (PMID:20018847)
• the Ufm1 system plays a critical role in vesicle trafficking, and its inhibition may lead to protein overload in the ER and UPR activation. (PMID:23152784)
• Thus, UfSP2 proteins have protease- and Ufm1-independent functions in GPCR biogenesis. (PMID:24603482)
• NCAM140 interacts with ufc1 and its trafficking and endocytosis is upregulated in the presense of Ufm1. (PMID:24726913)
• transcription downregulation of the Ufm1 and FAT10 conjugation system in liver Mallory-Denk bodies formation (PMID:24893112)
• results of an in vitro truncation assay suggest that Uba5 residues 57-363 comprise the minimal fragment required for the high-efficiency activation of Ufm1 (PMID:24915089)
• binding of ATP to Uba5 approximately Ufm1 thioester was required for efficient transfer of Ufm1 from Uba5 to Ufc1 via transthiolation. (PMID:24966333)
• ASC1 is a target for ufmylation and that UFBP1 is an essential component for ASC1 ufmylation. (PMID:25219498)
• Meta analysis identified a new gene, UFM1, that is associated with low von Willebrand factor levels. (PMID:26486471)
• data imply that the combination of a hypomorphic p.Ala371Thr variant in trans with a loss-of-function allele in UBA5 underlies a severe infantile-onset encephalopathy (PMID:27545674)
• Biallelic Variants in UBA5 Reveal that Disruption of the UFM1 Cascade Can Result in Early-Onset Encephalopathy (PMID:27545681)
• These findings explicitly elucidate the role of UBA5 dimerization in UFM1 activation. (PMID:27653677)
• in the absence of UFSP2, a deconjugating enzyme for UFM1, ectopic expression of both UFL1 and UFBP1, which serve as the E3-ligase complex for the UFM1-system, dramatically increases UFM1-conjugate formation at the endoplasmic reticulum. (PMID:27926783)
• UFM1 His 70 resembles UBA5 His336 and enters a negatively charged pocked on the other UFM1 molecule. (PMID:28360427)
• This study, focused on identifying the mutated gene in patients with hypomyelination with atrophy of the basal ganglia and cerebellum without TUBB4A mutations, revealed a homozygous 3-bp deletion in the UFM1 promoter area, which perfectly segregates with the disease. (PMID:28931644)
• results make a connection between the binding of UFM1 to UBA5 and the latter’s affinity to ATP, so we propose a novel mechanism for the regulation of ATP’s binding to E1. (PMID:29295865)
• Ufmylation may participate in regulation of the vascular smooth muscle cells phenotypic switch and endothelial cell injury, which may help in the understanding of vascular remodeling. (PMID:29461087)
• that the Ufm1 system is essential for cardiac homeostasis through regulation of endoplasmic reticulum function and that upregulation of myocardial Ufl1 could be protective against heart failure (PMID:30354401)
• Stimulates transfer of UFM1 from UBA5 to the E2, UFC1. (PMID:30412706)
• MRE11-mediated UFMylation promotes ATM activation. (PMID:30783677)
• UFM1 conjugation plays an essential role in DNA damage response. (Review) (PMID:31368785)
• Low UFM1 expression is associated with gastric cancer invasiveness. (PMID:31533855)
• A homozygous UBA5 pathogenic variant causes a fatal congenital neuropathy. (PMID:32179706)
• Decrypting UFMylation: How Proteins Are Modified with UFM1. (PMID:33066455)
• The UFM1 Pathway Impacts HCMV US2-Mediated Degradation of HLA Class I. (PMID:33430125)
• A Concerted Action of UBA5 C-Terminal Unstructured Regions Is Important for Transfer of Activated UFM1 to UFC1. (PMID:34299007)
• Structure and dynamics of UBA5-UFM1 complex formation showing new insights in the UBA5 activation mechanism. (PMID:34508858)
• Structural basis for UFM1 transfer from UBA5 to UFC1. (PMID:34588452)
• Modification of ERalpha by UFM1 Increases Its Stability and Transactivity for Breast Cancer Development. (PMID:35680375)
• Human UFSP1 is an active protease that regulates UFM1 maturation and UFMylation. (PMID:35926457)
• Emerging role of protein modification by UFM1 in cancer. (PMID:36344165)
• Modification of PLAC8 by UFM1 affects tumorous proliferation and immune response by impacting PD-L1 levels in triple-negative breast cancer. (PMID:36543379)
• Mechanistic insights into the roles of the UFM1 E3 ligase complex in ufmylation and ribosome-associated protein quality control. (PMID:37595036)
• Inhibition of UFM1 expression suppresses cancer progression and is linked to the dismal prognosis and immune infiltration in oral squamous cell carcinoma. (PMID:37980168)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ufm1	ENSDARG00000043857
mus_musculus	Ufm1	ENSMUSG00000027746
rattus_norvegicus	Ufm1	ENSRNOG00000038176
drosophila_melanogaster	Ufm1	FBGN0085220
caenorhabditis_elegans		WBGENE00044324

Protein

Protein identifiers

Ubiquitin-fold modifier 1 — P61960 (reviewed: P61960)

All UniProt accessions (2): P61960, H0Y614

UniProt curated annotations — full annotation on UniProt →

Function. Ubiquitin-like modifier which can be covalently attached via an isopeptide bond to lysine residues of substrate proteins as a monomer or a lysine-linked polymer. The so-called ufmylation, requires the UFM1-activating E1 enzyme UBA5, the UFM1-conjugating E2 enzyme UFC1, and the UFM1-ligase E3 enzyme UFL1. Ufmylation is involved in various processes, such as ribosome recycling, response to DNA damage, transcription or reticulophagy (also called ER-phagy) induced in response to endoplasmic reticulum stress.

Subunit / interactions. Interacts with UBA5. Interacts with UFC1.

Subcellular location. Nucleus. Cytoplasm.

Post-translational modifications. UFM1 precursor is cleaved by UFSP1, promoting its maturation: processing of the C-terminal Ser-Cys dipeptide is required to expose its C-terminal conserved Gly residue.

Disease relevance. Leukodystrophy, hypomyelinating, 14 (HLD14) [MIM:617899] An autosomal recessive, severe disorder characterized by atrophy of the basal ganglia and cerebellum, hypomyelination, severe developmental delay, typically without intentional movements and language development, and microcephaly. Almost all patients exhibit spasticity, extrapyramidal movement abnormalities, and severe drug-resistant epilepsy. Disease onset is early in infancy, and most patients die in the first years of life. The disease is caused by variants affecting the gene represented in this entry. The disease-causing variant may be a homozygous 3-bp deletion in the promoter region of the UFM1 gene, which segregates with the disorder in affected families. In vitro expression studies in different cell lines showed that the mutation significantly reduces transcriptional activity in certain neuronal cell lines (SY5Y and U373), but not in other cell lines, including HeLa and HOF-F2.

Induction. Up-regulated by thapsigargin.

Similarity. Belongs to the UFM1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P61960-1	1	yes
P61960-2	2

RefSeq proteins (5): NP_001273632, NP_001273633, NP_001273634, NP_001273635, NP_057701* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005375	UFM1	Family
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily

Pfam: PF03671

UniProt features (24 total): strand 7, mutagenesis site 6, helix 3, sequence conflict 2, cross-link 2, chain 1, propeptide 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
7W3N	X-RAY DIFFRACTION	1.6
8BZR	X-RAY DIFFRACTION	1.78
5IAA	X-RAY DIFFRACTION	1.85
5IA7	X-RAY DIFFRACTION	2
5IA8	X-RAY DIFFRACTION	2
5L95	X-RAY DIFFRACTION	2.1
6H77	X-RAY DIFFRACTION	2.1
5HKH	X-RAY DIFFRACTION	2.55
8OJ5	ELECTRON MICROSCOPY	2.9
9GY4	ELECTRON MICROSCOPY	3
8OHD	ELECTRON MICROSCOPY	3.1
8QFC	ELECTRON MICROSCOPY	3.2
8OJ0	ELECTRON MICROSCOPY	3.3
1WXS	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P61960-F1	91.84	0.88

Functional residue map

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

Post-translational modifications (2): 69, 83

Mutagenesis-validated functional residues (6):

Position	Phenotype
83–85	abolished activity.
83	confers resistance to cleavage.
21	abolished ability to be activated by uba5.
38	abolished ability to be activated by uba5.
48	abolished ability to be activated by uba5.
79	slightly reduced interaction with uba5.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 213 (showing top): HONMA_DOCETAXEL_RESISTANCE, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_10, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_REGULATION_OF_INTRACELLULAR_STEROID_HORMONE_RECEPTOR_SIGNALING_PATHWAY, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, CAGCTG_AP4_Q5, chr13q13, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_MACROAUTOPHAGY, GOBP_NUCLEAR_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT

GO Biological Process (8): brain development (GO:0007420), regulation of intracellular estrogen receptor signaling pathway (GO:0033146), response to endoplasmic reticulum stress (GO:0034976), negative regulation of protein import into nucleus (GO:0042308), negative regulation of apoptotic process (GO:0043066), reticulophagy (GO:0061709), protein ufmylation (GO:0071569), protein K69-linked ufmylation (GO:1990592)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	2
central nervous system development	1
animal organ development	1
head development	1
estrogen receptor signaling pathway	1
regulation of intracellular steroid hormone receptor signaling pathway	1
cellular response to stress	1
protein import into nucleus	1
regulation of protein import into nucleus	1
negative regulation of nucleocytoplasmic transport	1
negative regulation of intracellular protein transport	1
negative regulation of protein localization to nucleus	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
macroautophagy	1
protein modification by small protein conjugation	1
protein polyufmylation	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1
endomembrane system	1

Protein interactions and networks

STRING

1546 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UFM1	UBA5	Q9GZZ9	995
UFM1	UFC1	Q9Y3C8	991
UFM1	UFSP2	Q9NUQ7	987
UFM1	UFSP1	Q6NVU6	985
UFM1	DDRGK1	Q96HY6	961
UFM1	UFL1	O94874	943
UFM1	URM1	Q9BTM9	802
UFM1	UBE2M	P61081	797
UFM1	NEDD8	Q15843	776
UFM1	GABARAPL2	P60520	761
UFM1	CDK5RAP3	Q96JB5	711
UFM1	MOCS3	O95396	710
UFM1	UBD	O15205	694
UFM1	UBA3	Q8TBC4	678
UFM1	FAU	P35544	674

IntAct

53 interactions, top by confidence:

A	B	Type	Score
UBA5	GABARAPL2	psi-mi:“MI:0914”(association)	0.950
UBA5	UFM1	psi-mi:“MI:0915”(physical association)	0.890
UBA5	UFM1	psi-mi:“MI:0914”(association)	0.890
CDK5RAP3	UFL1	psi-mi:“MI:0914”(association)	0.870
DDRGK1	UFL1	psi-mi:“MI:0914”(association)	0.710
CDK5RAP3	UFM1	psi-mi:“MI:0914”(association)	0.670
UFM1	S100A6	psi-mi:“MI:0915”(physical association)	0.590
UFM1	KCTD21	psi-mi:“MI:0915”(physical association)	0.560
UFM1	INCA1	psi-mi:“MI:0915”(physical association)	0.560
UBA5	GAPDHS	psi-mi:“MI:0914”(association)	0.530
CDK5RAP3	PLD2	psi-mi:“MI:0914”(association)	0.530
PCARE	ARPC3	psi-mi:“MI:0914”(association)	0.510
UFM1		psi-mi:“MI:0915”(physical association)	0.370
UFM1	relA	psi-mi:“MI:0915”(physical association)	0.370
UFM1	iglC2	psi-mi:“MI:0915”(physical association)	0.370
DIABLO	UFM1	psi-mi:“MI:0915”(physical association)	0.370
GSK3B	UFM1	psi-mi:“MI:0915”(physical association)	0.370
RPS6KA6	UFM1	psi-mi:“MI:0915”(physical association)	0.370
ARHGDIA	UFM1	psi-mi:“MI:0915”(physical association)	0.370
UFM1	ARHGDIB	psi-mi:“MI:0915”(physical association)	0.370
Ufl1	PRSS1	psi-mi:“MI:0914”(association)	0.350
UBA5	P4HA1	psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
DLD	NFKBIE	psi-mi:“MI:0914”(association)	0.350
UBA5	PGK1	psi-mi:“MI:0914”(association)	0.350
PSPC1	MCRIP1	psi-mi:“MI:0914”(association)	0.350
RPL11	RPS3A	psi-mi:“MI:0914”(association)	0.350

BioGRID (130): CRIP1 (Co-fractionation), CSRP1 (Co-fractionation), MSI2 (Co-fractionation), PAICS (Co-fractionation), PPA2 (Co-fractionation), PSAT1 (Co-fractionation), RFK (Co-fractionation), TRAP1 (Co-fractionation), UFM1 (Co-fractionation), UFM1 (Co-fractionation), UFM1 (Co-fractionation), UFM1 (Co-fractionation), UFM1 (Co-fractionation), UFM1 (Co-fractionation), UFM1 (Co-fractionation)

ESM2 similar proteins: A0A1I1P2K9, A8D888, A8DYH2, A8Q8M5, A8XEZ1, B0WK43, B3DL37, B4GBR1, B4JVK9, B4KSR4, B4LP65, B5E0K3, B5LVL2, C1BJ98, P34661, P61960, P61961, P84193, Q00457, Q05921, Q09219, Q09JK2, Q176V0, Q2KJG2, Q2M3Z7, Q2M3Z8, Q38SD2, Q4N927, Q4PMC9, Q4R4I2, Q580P9, Q5BJP3, Q5PU89, Q5R4N5, Q5RJW4, Q5ZMK7, Q61E22, Q6DDB9, Q6VBQ6, Q6VEU3

Diamond homologs: A8D888, A8DYH2, A8Q8M5, B0G186, B0WK43, B3DL37, B4GBR1, B4JVK9, B4KSR4, B4LP65, B5E0K3, B5LVL2, B9ENM6, C1BJ98, P34661, P61960, P61961, Q09JK2, Q176V0, Q2KJG2, Q4N927, Q4R4I2, Q5BJP3, Q5PU89, Q5R4N5, Q5RJW4, Q5ZMK7, Q61E22, Q7PXE2, Q803Y4, Q94DM8, Q94EY2, Q9CA23

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 46 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC)	7	23.6×	4e-06
Peptide chain elongation	6	21.8×	1e-05
Viral mRNA Translation	6	21.8×	1e-05
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	6	21.5×	1e-05
Selenocysteine synthesis	6	20.6×	1e-05
Eukaryotic Translation Termination	6	20.6×	1e-05
ZNF598 and the Ribosome-associated Quality Trigger (RQT) complex dissociate a ribosome stalled on a no-go mRNA	6	20.2×	1e-05
SRP-dependent cotranslational protein targeting to membrane	7	20.0×	4e-06

GO biological processes:

GO term	Partners	Fold	FDR
response to endoplasmic reticulum stress	7	27.8×	6e-07
cytoplasmic translation	6	26.5×	6e-06
translation	7	17.1×	8e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	3
Uncertain significance	20
Likely benign	18
Benign	4

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
2428600	NM_016617.4(UFM1):c.1A>G (p.Met1Val)	Likely pathogenic
3358901	NM_016617.4(UFM1):c.2+1G>A	Likely pathogenic
559446	NM_016617.4(UFM1):c.241C>T (p.Arg81Cys)	Likely pathogenic

SpliceAI

687 predictions. Top by Δscore:

Variant	Effect	Δscore
13:38350054:GT:G	donor_gain	1.0000
13:38350056:G:GG	donor_gain	1.0000
13:38358091:A:AG	acceptor_gain	1.0000
13:38358092:G:GG	acceptor_gain	1.0000
13:38349922:G:GG	donor_gain	0.9900
13:38350052:AAGT:A	donor_gain	0.9900
13:38350053:AGTGT:A	donor_loss	0.9900
13:38350054:GTGT:G	donor_loss	0.9900
13:38350055:TG:T	donor_loss	0.9900
13:38350057:T:TC	donor_loss	0.9900
13:38350058:GAG:G	donor_loss	0.9900
13:38350059:AGT:A	donor_loss	0.9900
13:38354297:G:GG	donor_gain	0.9900
13:38359334:G:GG	donor_gain	0.9900
13:38359337:A:AC	donor_loss	0.9900
13:38360110:T:TA	donor_gain	0.9900
13:38360111:A:AA	donor_gain	0.9900
13:38354237:A:AG	acceptor_gain	0.9800
13:38354238:G:GG	acceptor_gain	0.9800
13:38354294:GAA:G	donor_gain	0.9800
13:38354969:A:AG	acceptor_gain	0.9800
13:38354969:AAAAT:A	acceptor_gain	0.9800
13:38358092:GTTT:G	acceptor_gain	0.9800
13:38358092:GTTTA:G	acceptor_gain	0.9800
13:38359330:GCTG:G	donor_gain	0.9800
13:38360705:GTATA:G	acceptor_loss	0.9800
13:38360707:ATAGG:A	acceptor_loss	0.9800
13:38358092:GT:G	acceptor_gain	0.9700
13:38359295:TTCTA:T	acceptor_loss	0.9700
13:38359296:TCTAG:T	acceptor_loss	0.9700

AlphaMissense

540 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:38354274:T:A	V32D	1.000
13:38354288:G:C	A37P	1.000
13:38359331:C:A	A63D	1.000
13:38360717:T:A	V66D	1.000
13:38360756:G:T	R79I	1.000
13:38350013:T:C	F6S	0.999
13:38354247:T:A	V23D	0.999
13:38354265:T:C	F29S	0.999
13:38354282:T:C	F35L	0.999
13:38354283:T:C	F35S	0.999
13:38354284:T:A	F35L	0.999
13:38354284:T:G	F35L	0.999
13:38354286:C:A	A36E	0.999
13:38358094:T:C	F40S	0.999
13:38358114:A:C	S47R	0.999
13:38358116:T:A	S47R	0.999
13:38358116:T:G	S47R	0.999
13:38358117:G:C	A48P	0.999
13:38358118:C:A	A48E	0.999
13:38358121:T:A	I49N	0.999
13:38358124:T:A	I50N	0.999
13:38358124:T:G	I50S	0.999
13:38358127:C:T	T51I	0.999
13:38359303:G:A	G54R	0.999
13:38359303:G:C	G54R	0.999
13:38359304:G:A	G54E	0.999
13:38359304:G:T	G54V	0.999
13:38359309:G:A	G56R	0.999
13:38359309:G:C	G56R	0.999
13:38359310:G:A	G56E	0.999

dbSNP variants (sampled 300 via entrez): RS1000002318 (13:38352965 A>C,G), RS1000276384 (13:38360456 T>C), RS1000427756 (13:38360068 G>T), RS1000894375 (13:38354365 G>A), RS1001009757 (13:38354736 G>A,C), RS1001014396 (13:38359768 A>G), RS1001123248 (13:38348198 G>A), RS1001484241 (13:38352919 TA>T), RS1002195787 (13:38351929 C>T), RS1002511803 (13:38349632 G>A), RS1002759567 (13:38357197 G>A), RS1002840988 (13:38359002 CATT>C), RS1002936412 (13:38363952 G>A), RS1002937001 (13:38357280 T>C), RS1003110881 (13:38350586 C>T)

Disease associations

OMIM: gene MIM:610553 | disease phenotypes: MIM:617899, MIM:192500

GenCC curated gene-disease

Disease	Classification	Inheritance
leukodystrophy, hypomyelinating, 14	Definitive	Autosomal recessive
hypomyelinating leukodystrophy 6	Supportive	Autosomal dominant

Mondo (3): leukodystrophy, hypomyelinating, 14 (MONDO:0033486), familial long QT syndrome (MONDO:0019171), hypomyelinating leukodystrophy 6 (MONDO:0012905)

Orphanet (2): Romano-Ward syndrome (Orphanet:101016), Congenital long QT syndrome (Orphanet:768)

HPO phenotypes

15 total (15 of 15 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000618	Blindness
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001272	Cerebellar atrophy
HP:0001290	Generalized hypotonia
HP:0001332	Dystonia
HP:0001344	Absent speech
HP:0001510	Growth delay
HP:0002059	Cerebral atrophy
HP:0002093	Respiratory insufficiency
HP:0011968	Feeding difficulties

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST003210_5	Low vWF levels	3.000000e-08
GCST003473_25	Aggressiveness in attention deficit hyperactivity disorder	9.000000e-06
GCST007201_181	Schizophrenia	8.000000e-07
GCST011768_18	Schizophrenia	3.000000e-08
GCST012190_8	Body mass index and diastolic blood pressure (bivariate analysis)	2.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0006336	diastolic blood pressure

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567314	Leukodystrophy, Hypomyelinating, 6 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066523 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.42	Kd	38.2	nM	CHEMBL5653589
7.42	ED50	38.2	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149724: Binding affinity to human UFM1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0382	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	4
Cyclosporine	increases expression	4
Tobacco Smoke Pollution	affects expression, increases expression	3
Valproic Acid	decreases expression, increases expression	3
bisphenol A	affects expression, increases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
aristolochic acid I	decreases expression, increases expression	1
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
trichostatin A	increases expression	1
methylparaben	increases expression	1
cobaltous chloride	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
pentabromodiphenyl ether	increases expression	1
K 7174	increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
elesclomol	decreases reaction, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
jinfukang	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Acetylcysteine	decreases reaction, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652766	Binding	Binding affinity to human UFM1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

3 cell lines: 2 transformed cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3KU	Abcam HEK293T UFM1 KO	Transformed cell line	Female
CVCL_D9VE	Ubigene HEK293 UFM1 KO	Transformed cell line	Female
CVCL_TW22	HAP1 UFM1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02425189	Not specified	COMPLETED	The Canadian National Long QT Syndrome Registry
NCT02439645	Not specified	TERMINATED	A Registry to Determine the Clinical and Genetic Risk Factors for Torsade De Pointes
NCT02439658	Not specified	UNKNOWN	Genetics of QT Prolongation With Antiarrhythmics
NCT02549664	Not specified	COMPLETED	Exercise in Genetic Cardiovascular Conditions
NCT02581241	Not specified	COMPLETED	Abnormal QT-Response to the Sudden Tachycardia Provoked by Standing in Individuals With Drug-induced Long QT Syndrome
NCT02680080	Not specified	COMPLETED	Effect of Grapefruit on QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome
NCT02775513	Not specified	UNKNOWN	Metabolism of Patients With Genetically Caused Cardiac Arrhythmia
NCT02814981	Not specified	UNKNOWN	Hydroxyzine and Risk of Prolongation of QT Interval
NCT02876380	Not specified	COMPLETED	Prospective Identification of Long QT Syndrome in Fetal Life
NCT03182777	Not specified	COMPLETED	Safety of Local Dental Anesthesia in Patients With Cardiac Channelopathies
NCT03544918	Not specified	COMPLETED	Prevalence of Congenital Long QT Syndrome and Acquired QT Prolongation in a Hospital Cohort
NCT03642405	Not specified	UNKNOWN	Drug-induced Repolarization ECG Changes
NCT03678311	Not specified	COMPLETED	Long QT Syndrome and Sleep Apnea