UFD1

Summary

UFD1 (ubiquitin recognition factor in ER associated degradation 1, HGNC:12520) is a protein-coding gene on chromosome 22q11.21, encoding Ubiquitin recognition factor in ER-associated degradation protein 1 (Q92890). Essential component of the ubiquitin-dependent proteolytic pathway which degrades ubiquitin fusion proteins. It is a common-essential gene (DepMap: required in 99.8% of cancer cell lines).

The protein encoded by this gene forms a complex with two other proteins, nuclear protein localization-4 and valosin-containing protein, and this complex is necessary for the degradation of ubiquitinated proteins. In addition, this complex controls the disassembly of the mitotic spindle and the formation of a closed nuclear envelope after mitosis. Mutations in this gene have been associated with Catch 22 syndrome as well as cardiac and craniofacial defects. Alternative splicing results in multiple transcript variants encoding different isoforms. A related pseudogene has been identified on chromosome 18.

Source: NCBI Gene 7353 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 55 total — 2 pathogenic
• Phenotypes (HPO): 131
• Cancer dependency (DepMap): dependent in 99.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_005659

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12520
Approved symbol	UFD1
Name	ubiquitin recognition factor in ER associated degradation 1
Location	22q11.21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000070010
Ensembl biotype	protein_coding
OMIM	601754
Entrez	7353

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 13 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000263202, ENST00000399523, ENST00000421968, ENST00000447868, ENST00000459854, ENST00000466373, ENST00000474226, ENST00000484101, ENST00000489406, ENST00000494054, ENST00000895843, ENST00000914081, ENST00000914082, ENST00000914083, ENST00000914084, ENST00000914085, ENST00000914086

RefSeq mRNA: 3 — MANE Select: NM_005659 NM_001035247, NM_001362910, NM_005659

CCDS: CCDS13761, CCDS33600

Canonical transcript exons

ENST00000263202 — 12 exons

Exon	Start	End
ENSE00000650767	19454749	19454830
ENSE00001935556	19479083	19479193
ENSE00003508606	19456587	19456634
ENSE00003552070	19475068	19475100
ENSE00003553313	19465202	19465274
ENSE00003593582	19456853	19456918
ENSE00003597851	19475470	19475602
ENSE00003631959	19471687	19471808
ENSE00003688668	19458071	19458139
ENSE00003705536	19449911	19450744
ENSE00003788165	19467873	19468003
ENSE00003791391	19455680	19455768

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 97.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 63.4012 / max 568.7488, expressed in 1823 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193155	53.8403	1822
193154	5.2606	1558
193156	1.8110	1154
209384	1.5433	970
193153	0.9460	494

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	97.50	gold quality
islet of Langerhans	UBERON:0000006	97.19	gold quality
corpus epididymis	UBERON:0004359	96.66	gold quality
adult organism	UBERON:0007023	96.60	gold quality
gastrocnemius	UBERON:0001388	96.23	gold quality
stromal cell of endometrium	CL:0002255	96.07	gold quality
muscle of leg	UBERON:0001383	95.83	gold quality
palpebral conjunctiva	UBERON:0001812	95.61	gold quality
upper leg skin	UBERON:0004262	95.58	gold quality
oral cavity	UBERON:0000167	95.57	gold quality
placenta	UBERON:0001987	95.57	gold quality
gluteal muscle	UBERON:0002000	95.53	gold quality
mammalian vulva	UBERON:0000997	95.42	gold quality
penis	UBERON:0000989	95.33	gold quality
left testis	UBERON:0004533	95.24	gold quality
cauda epididymis	UBERON:0004360	95.23	gold quality
right testis	UBERON:0004534	95.18	gold quality
eye	UBERON:0000970	95.00	gold quality
trabecular bone tissue	UBERON:0002483	94.99	gold quality
tibial artery	UBERON:0007610	94.97	gold quality
popliteal artery	UBERON:0002250	94.96	gold quality
type B pancreatic cell	CL:0000169	94.91	gold quality
skin of hip	UBERON:0001554	94.91	gold quality
triceps brachii	UBERON:0001509	94.84	gold quality
skeletal muscle organ	UBERON:0014892	94.81	gold quality
muscle organ	UBERON:0001630	94.80	gold quality
aorta	UBERON:0000947	94.75	gold quality
endometrium epithelium	UBERON:0004811	94.74	gold quality
smooth muscle tissue	UBERON:0001135	94.68	gold quality
nasal cavity mucosa	UBERON:0001826	94.63	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	7.29
E-MTAB-6379	no	817.32
E-GEOD-110499	no	551.44
E-MTAB-6524	no	143.17
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

40 targeting UFD1, 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-4795-3P	100.00	74.62	4024
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-6758-3P	99.57	67.55	1078
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-520F-5P	99.34	70.40	1632
HSA-MIR-8065	99.19	70.38	1289
HSA-MIR-5100	99.11	67.52	1098
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-3158-3P	98.45	64.25	560
HSA-MIR-7156-3P	98.25	67.66	859
HSA-MIR-4684-3P	98.24	69.91	1075
HSA-MIR-4691-3P	98.11	66.83	1204
HSA-MIR-6757-5P	98.08	65.50	724

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 26)

• a functional analysis of its 5’ regulatory region (PMID:11979512)
• Ufd1l is localized around the nucleus and it does not interfere with Fas-and ceramide-mediated apoptosis. (PMID:12910480)
• Ufd1-nuclear protein localization 4 is a negative regulator of retrotranslocation, delaying the retrotranslocation of endoplasmic reticulum-associated degradation substrates independently of its association with VCP (PMID:17331469)
• This study identifies Ufd1 as a cofactor of gp78, reveals an unappreciated function of Ufd1 in the ubiquitination reaction during endoplasmic reticulum -associated degradation, and illustrates that Ufd1 plays a critical role in cholesterol metabolism. (PMID:17681147)
• allelic associations of the UFD1L locus identified; 4-SNP haplotype analysis showed strong association with schizophrenia; possibility that a disease-resistant variant may be carried by two or more haplotypes due to frequent recombination during meiosis. (PMID:18270977)
• This favors the model where the Ufd1-Npl4 dimer forms a regulatory gate at the exit from the retrotranslocone, rather than actively promoting retrotranslocation like the p97VCP ATPase. (PMID:18586029)
• This study suggested that AA genotype of UFD1L gene, which is involved in neurodevelopmental processes, may contribute to early-onset schizophrenia. Therefore, rs5992403 polymorphism may not be a risk factor for schizophrenia. (PMID:20471029)
• Data suggest that the human cytomegalovirus dislocation reaction in US2 cells is independent of the p97 cofactor Ufd1-Npl4, and different retrotranslocation mechanisms can employ distinct p97 ATPase complexes to dislocate substrates. (PMID:20702414)
• Data establish Cdc48/p97-Ufd1-Npl4 as a crucial negative regulator of Aurora B early in mitosis of human somatic cells and suggest that the activity of Aurora B on chromosomes needs to be restrained to ensure faithful chromosome segregation. (PMID:21486945)
• Ubiquitin-recognition protein Ufd1 couples the endoplasmic reticulum (ER) stress response to cell cycle control (PMID:21571647)
• increased corpus callosum volume in children with 22q11DS is associated with UFD1L polymorphism. (PMID:22763378)
• Data indicate that Npl4-Ufd1 heterodimer is required for VCP-FAF1 interaction. (PMID:23293021)
• This study demonistrated that UFD1L may participate in the core cognitive deficits observed in schizophrenia. (PMID:23623450)
• In coordination with the P97-UFD1-NPL4 complex (P97(UFD1/NPL4)), NUB1L promotes transfer of NEDD8 to proteasome for degradation. (PMID:24019527)
• Data indicate that the p97-UFD1L-NPL4 protein complex specifically associates with ubiquitinated IkappaBalpha via the interactions between p97 and the SCF(beta-TRCP) ubiquitin ligase. (PMID:24248593)
• p97-Ufd1-Npl4 is an integral part of G2/M checkpoint signaling and thereby suppresses chromosome instability. (PMID:24429874)
• The study revealed a regulatory role of the p97-Npl4-Ufd1 complex in regulating a partial degradation of the NF-kappaB subunit p100. (PMID:26112410)
• We demonstrate that WT p97 can unfold proteins and that this activity is dependent on the p97 adaptor NPLOC4-UFD1L, ATP hydrolysis, and substrate ubiquitination, with branched chains providing maximal stimulation. (PMID:28512218)
• CHOP inactivation or BCL2 overexpression is sufficient to rescue tumor cell apoptosis induced by UFD1 knockdown. (PMID:29743725)
• results support that Ufd1 S229 phosphorylation status mediated by PKA serves as a key regulatory point for the VCP-Ufd1 interaction and functional ERAD. (PMID:31477623)
• Multisystem proteinopathy mutations in VCP/p97 increase NPLOC4-UFD1L binding and substrate processing. (PMID:31623962)
• Involvement of VCP/UFD1/Nucleolin in the viral entry of Enterovirus A species. (PMID:32289342)
• PCBP2 Posttranscriptional Modifications Induce Breast Cancer Progression via Upregulation of UFD1 and NT5E. (PMID:33037085)
• Seesaw conformations of Npl4 in the human p97 complex and the inhibitory mechanism of a disulfiram derivative. (PMID:33402676)
• Multiple UBX proteins reduce the ubiquitin threshold of the mammalian p97-UFD1-NPL4 unfoldase. (PMID:35920641)
• Structural basis for the interaction between human Npl4 and Npl4-binding motif of human Ufd1. (PMID:36087575)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ufd1l	ENSDARG00000010051
mus_musculus	Ufd1	ENSMUSG00000005262
rattus_norvegicus	Ufd1	ENSRNOG00000047394
drosophila_melanogaster	Ufd1	FBGN0036136
caenorhabditis_elegans		WBGENE00006733

Protein

Protein identifiers

Ubiquitin recognition factor in ER-associated degradation protein 1 — Q92890 (reviewed: Q92890)

Alternative names: Ubiquitin fusion degradation protein 1

All UniProt accessions (6): Q92890, C9IZG3, C9J6N9, C9J7C8, C9JNP9, Q541A5

UniProt curated annotations — full annotation on UniProt →

Function. Essential component of the ubiquitin-dependent proteolytic pathway which degrades ubiquitin fusion proteins. The ternary complex containing UFD1, VCP and NPLOC4 binds ubiquitinated proteins and is necessary for the export of misfolded proteins from the ER to the cytoplasm, where they are degraded by the proteasome. The NPLOC4-UFD1-VCP complex regulates spindle disassembly at the end of mitosis and is necessary for the formation of a closed nuclear envelope. It may be involved in the development of some ectoderm-derived structures. Acts as a negative regulator of type I interferon production via the complex formed with VCP and NPLOC4, which binds to RIGI and recruits RNF125 to promote ubiquitination and degradation of RIGI.

Subunit / interactions. Heterodimer with NPLOC4, this heterodimer binds VCP and inhibits Golgi membrane fusion. Interacts with USP13. Interacts with ZFAND2B; probably through VCP.

Subcellular location. Nucleus. Cytoplasm. Cytosol.

Tissue specificity. Found in adult heart, skeletal muscle and pancreas, and in fetal liver and kidney.

Pathway. Protein degradation; proteasomal ubiquitin-dependent pathway.

Miscellaneous. Major isoform.

Similarity. Belongs to the UFD1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q92890-2	Short	yes
Q92890-1	Long
Q92890-3	3

RefSeq proteins (3): NP_001030324, NP_001349839, NP_005650* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004854	UFD1-like	Family
IPR042299	UFD1-like_Nn	Homologous_superfamily
IPR055417	UFD1_N1	Domain
IPR055418	UFD1_N2	Domain

Pfam: PF03152, PF24842

UniProt features (34 total): strand 13, modified residue 6, helix 4, sequence conflict 3, region of interest 2, splice variant 2, turn 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
5B6C	X-RAY DIFFRACTION	1.55
7WWQ	X-RAY DIFFRACTION	2.72
9YRC	ELECTRON MICROSCOPY	2.97
5C1B	X-RAY DIFFRACTION	3.08
9YW2	ELECTRON MICROSCOPY	3.27
11TA	ELECTRON MICROSCOPY	3.58
11VE	ELECTRON MICROSCOPY	3.85
11SY	ELECTRON MICROSCOPY	4.28
2YUJ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92890-F1	74.64	0.38

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 (6): 1, 129, 231, 245, 247, 299

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-110320	Translesion Synthesis by POLH
R-HSA-5689880	Ub-specific processing proteases
R-HSA-8951664	Neddylation
R-HSA-9755511	KEAP1-NFE2L2 pathway
R-HSA-9918487	Dengue Virus Genome Translation and Replication
R-HSA-9954709	Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide

MSigDB gene sets: 0 (showing top):

GO Biological Process (9): skeletal system development (GO:0001501), ubiquitin-dependent protein catabolic process (GO:0006511), retrograde protein transport, ER to cytosol (GO:0030970), negative regulation of type I interferon production (GO:0032480), ERAD pathway (GO:0036503), negative regulation of RIG-I signaling pathway (GO:0039536), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), cellular response to misfolded protein (GO:0071218), proteasomal protein catabolic process (GO:0010498)

GO Molecular Function (4): cysteine-type deubiquitinase activity (GO:0004843), polyubiquitin modification-dependent protein binding (GO:0031593), K48-linked polyubiquitin modification-dependent protein binding (GO:0036435), protein binding (GO:0005515)

GO Cellular Component (6): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), VCP-NPL4-UFD1 AAA ATPase complex (GO:0034098), UFD1-NPL4 complex (GO:0036501), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	1
Deubiquitination	1
Post-translational protein modification	1
Cellular response to chemical stress	1
Dengue Virus Infection	1
Ribosome-associated quality control	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
proteasomal protein catabolic process	2
cytoplasm	2
system development	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
protein exit from endoplasmic reticulum	1
ERAD pathway	1
endoplasmic reticulum to cytosol transport	1
negative regulation of cytokine production	1
regulation of type I interferon production	1
type I interferon production	1
response to endoplasmic reticulum stress	1
response to chemical	1
RIG-I signaling pathway	1
negative regulation of cytoplasmic pattern recognition receptor signaling pathway	1
regulation of RIG-I signaling pathway	1
ubiquitin-dependent protein catabolic process	1
cellular response to topologically incorrect protein	1
response to misfolded protein	1
protein catabolic process	1
cysteine-type peptidase activity	1
deubiquitinase activity	1
modification-dependent protein binding	1
polyubiquitin modification-dependent protein binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
endoplasmic reticulum membrane	1
UFD1-NPL4 complex	1
membrane protein complex	1
endoplasmic reticulum protein-containing complex	1
protein-containing complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1896 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UFD1	VCP	P55072	999
UFD1	NPLOC4	Q8TAT6	999
UFD1	FAF1	Q9UNN5	935
UFD1	FAF2	Q96CS3	902
UFD1	DERL1	Q9BUN8	894
UFD1	AMFR	P26442	846
UFD1	SYVN1	Q86TM6	843
UFD1	OS9	Q13438	842
UFD1	UBXN7	O94888	827
UFD1	ANKZF1	Q9H8Y5	823
UFD1	PLAA	Q9Y263	823
UFD1	UBE4A	Q14139	820
UFD1	UBE4B	O95155	814
UFD1	SEL1L	Q9UBV2	797
UFD1	MARCHF6	O60337	793

IntAct

109 interactions, top by confidence:

A	B	Type	Score
NPLOC4	VCP	psi-mi:“MI:0915”(physical association)	0.950
VCP	UFD1	psi-mi:“MI:0407”(direct interaction)	0.880
UFD1	VCP	psi-mi:“MI:0914”(association)	0.880
FAF2	VCP	psi-mi:“MI:0914”(association)	0.870
NPLOC4	UFD1	psi-mi:“MI:0915”(physical association)	0.860
UBXN7	VCP	psi-mi:“MI:0914”(association)	0.820
VCP	UBXN7	psi-mi:“MI:0914”(association)	0.820
GET4	GET3	psi-mi:“MI:0914”(association)	0.800
UBXN1	VCP	psi-mi:“MI:0914”(association)	0.740
UBXN8	VCP	psi-mi:“MI:0914”(association)	0.690
VCP	UBXN8	psi-mi:“MI:0914”(association)	0.690
HTT	UFD1	psi-mi:“MI:0915”(physical association)	0.670
FAF1	VCP	psi-mi:“MI:0915”(physical association)	0.640
FAF1	VCP	psi-mi:“MI:0914”(association)	0.640
UBXN10	VCP	psi-mi:“MI:0914”(association)	0.600

BioGRID (289): UFD1L (Affinity Capture-MS), UFD1L (Affinity Capture-MS), UFD1L (Affinity Capture-RNA), NPLOC4 (Co-crystal Structure), UFD1L (Affinity Capture-MS), UFD1L (Affinity Capture-MS), UFD1L (Biochemical Activity), UFD1L (Affinity Capture-MS), UFD1L (Affinity Capture-MS), UFD1L (Affinity Capture-MS), CHMP2A (Two-hybrid), CHMP2A (Reconstituted Complex), UFD1L (Two-hybrid), ARMC1 (Co-fractionation), ARPC5L (Co-fractionation)

ESM2 similar proteins: A2VE39, A4IG62, D2HRF1, F1R777, F4KFV7, O00763, O13768, O42915, O60870, P19447, P42285, P49135, P53044, P70362, Q02870, Q04499, Q1MTD3, Q1RMT1, Q28E61, Q28FT4, Q295E6, Q38861, Q4G005, Q5R981, Q5RA62, Q5U2U7, Q5U2Z5, Q5ZJT0, Q60HG1, Q681Q7, Q6GN29, Q6GQ76, Q6PA06, Q6PCL9, Q7ZVV1, Q803R5, Q86U44, Q8C3P7, Q8IYB8, Q8K339

Diamond homologs: O42915, P53044, P70362, Q19584, Q55BK0, Q92890, Q9ES53, Q9VTF9

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
UFD1	“down-regulates quantity by destabilization”	CD4	binding
NPLOC4	“up-regulates activity”	UFD1	binding
VCP	“up-regulates activity”	UFD1	binding
UFD1	“up-regulates activity”	AMFR	binding
UFD1	“form complex”	“RQC complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 104 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
Defective CFTR causes cystic fibrosis	5	15.2×	4e-03
R-HSA-425366	5	12.6×	5e-03
KEAP1-NFE2L2 pathway	6	10.0×	4e-03
Transport of small molecules	12	4.2×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
neurotransmitter transport	5	22.9×	4e-04
ERAD pathway	11	21.7×	3e-09
ubiquitin-dependent protein catabolic process	11	8.9×	2e-05
proteasome-mediated ubiquitin-dependent protein catabolic process	11	6.2×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	24
Likely benign	4
Benign	15

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1456987	NC_000022.10:g.(?18900668)(19747220_?)del	Pathogenic
1879565	GRCh37/hg19 22q11.21(chr22:18834445-21414817)x1	Pathogenic

SpliceAI

1728 predictions. Top by Δscore:

Variant	Effect	Δscore
22:19454826:TTCCT:T	acceptor_gain	1.0000
22:19454827:TCCT:T	acceptor_gain	1.0000
22:19454828:CCTC:C	acceptor_gain	1.0000
22:19454829:CT:C	acceptor_gain	1.0000
22:19454829:CTCT:C	acceptor_loss	1.0000
22:19454830:TC:T	acceptor_loss	1.0000
22:19454831:C:CC	acceptor_gain	1.0000
22:19454831:CTGT:C	acceptor_loss	1.0000
22:19456585:A:AC	donor_gain	1.0000
22:19456586:C:CC	donor_gain	1.0000
22:19456586:CG:C	donor_gain	1.0000
22:19456631:CTTC:C	acceptor_gain	1.0000
22:19456633:TC:T	acceptor_gain	1.0000
22:19456633:TCCTG:T	acceptor_loss	1.0000
22:19456634:CC:C	acceptor_gain	1.0000
22:19456634:CCTGA:C	acceptor_loss	1.0000
22:19456636:T:G	acceptor_loss	1.0000
22:19456639:C:CT	acceptor_gain	1.0000
22:19456640:A:T	acceptor_gain	1.0000
22:19456928:C:CT	acceptor_gain	1.0000
22:19456928:C:T	acceptor_gain	1.0000
22:19456929:A:T	acceptor_gain	1.0000
22:19456933:T:TC	acceptor_gain	1.0000
22:19456934:T:C	acceptor_gain	1.0000
22:19456935:T:C	acceptor_gain	1.0000
22:19456935:T:TC	acceptor_gain	1.0000
22:19458069:A:AC	donor_gain	1.0000
22:19458070:C:CT	donor_gain	1.0000
22:19458070:CGTT:C	donor_gain	1.0000
22:19458099:G:GA	donor_gain	1.0000

AlphaMissense

2034 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:19450715:G:C	F293L	1.000
22:19450715:G:T	F293L	1.000
22:19450717:A:G	F293L	1.000
22:19454782:T:A	R272S	1.000
22:19454782:T:G	R272S	1.000
22:19454783:C:A	R272I	1.000
22:19454783:C:G	R272T	1.000
22:19454789:A:G	F270S	1.000
22:19455737:C:T	G237E	1.000
22:19455743:A:G	L235P	1.000
22:19455743:A:T	L235Q	1.000
22:19455745:T:A	R234S	1.000
22:19455745:T:G	R234S	1.000
22:19455752:C:T	G232D	1.000
22:19455758:C:T	G230E	1.000
22:19455763:G:C	F228L	1.000
22:19455763:G:T	F228L	1.000
22:19455765:A:G	F228L	1.000
22:19456902:G:T	P194H	1.000
22:19456910:A:C	F191L	1.000
22:19456910:A:T	F191L	1.000
22:19456911:A:C	F191C	1.000
22:19456911:A:G	F191S	1.000
22:19456912:A:C	F191V	1.000
22:19456912:A:G	F191L	1.000
22:19456917:A:G	V189A	1.000
22:19456917:A:T	V189E	1.000
22:19458075:A:C	M187R	1.000
22:19458075:A:T	M187K	1.000
22:19458077:G:C	D186E	1.000

dbSNP variants (sampled 300 via entrez): RS1000095856 (22:19469291 C>T), RS1000193431 (22:19462435 G>A), RS1000331124 (22:19457675 G>A), RS1000366213 (22:19476577 C>T), RS1000468056 (22:19469033 A>G), RS1000488468 (22:19451137 A>AT), RS1000524567 (22:19464271 A>T), RS1000555462 (22:19464573 C>T), RS1000608512 (22:19451368 A>G), RS1000687103 (22:19476781 T>C,G), RS1000696074 (22:19470557 T>C), RS1000747050 (22:19470773 T>C), RS1000775238 (22:19458010 G>A), RS1000808381 (22:19450309 A>C,G), RS1001021717 (22:19464481 T>C)

Disease associations

OMIM: gene MIM:601754 | disease phenotypes: MIM:188400

GenCC curated gene-disease

Mondo (1): DiGeorge syndrome (MONDO:0008564)

Orphanet (1): 22q11.2 deletion syndrome (Orphanet:567)

HPO phenotypes

131 total (30 of 131 shown, HPO-id order):

HPO	Term
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000076	Vesicoureteral reflux
HP:0000089	Renal hypoplasia
HP:0000113	Polycystic kidney dysplasia
HP:0000130	Abnormality of the uterus
HP:0000160	Narrow mouth
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000262	Turricephaly
HP:0000272	Malar flattening
HP:0000276	Long face
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000385	Small earlobe
HP:0000389	Chronic otitis media
HP:0000396	Overfolded helix
HP:0000405	Conductive hearing impairment
HP:0000414	Bulbous nose
HP:0000426	Prominent nasal bridge
HP:0000431	Wide nasal bridge
HP:0000453	Choanal atresia

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D004062	DiGeorge Syndrome	C05.660.207.103.500; C14.240.400.021.500; C14.280.400.044.500; C15.604.451.249.500; C16.131.077.019.500; C16.131.240.400.021.500; C16.131.260.019.500; C16.131.482.249.500; C16.131.621.207.103.500; C16.320.180.019.500; C19.642.482.500.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	5
sodium arsenite	decreases expression, increases expression	3
Valproic Acid	affects expression, increases expression	3
cobaltous chloride	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Quercetin	decreases phosphorylation, increases expression	2
Cyclosporine	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
NMS-873	affects binding, increases reaction	1
triphenyl phosphate	affects expression	1
kojic acid	increases expression	1
methylparaben	increases expression	1
cupric chloride	increases expression	1
microcystin RR	increases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
14-deoxy-11,12-didehydroandrographolide	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
bromovanin	decreases 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
1-(4-(6-bromobenzo(1,3)dioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta(c)quinolin-8-yl)ethanone	decreases phosphorylation	1
STA 9090	decreases expression	1
bisphenol S	increases expression	1
Bortezomib	increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00395538	PHASE3	TERMINATED	Effects of PTH Replacement on Bone in Hypoparathyroidism
NCT00576407	PHASE2	COMPLETED	Thymus Transplantation in DiGeorge Syndrome #668
NCT00576836	PHASE2	COMPLETED	Thymus Transplantation Dose in DiGeorge #932
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT05149898	PHASE2	COMPLETED	Open-Label Study of ZYN002 Administered as a Transdermal Gel to Children and Adolescents With 22q11.2 Deletion Syndrome (INSPIRE)
NCT07284641	PHASE2	RECRUITING	Hematopoietic Stem Cell Transplantation (HSCT) for Common Variable Immunodeficiency (CVID) and Other Autoimmune Manifestations of Primary Immune Regulatory Disorders (PIRD)
NCT00566488	PHASE1	COMPLETED	Parathyroid and Thymus Transplantation in DiGeorge #931
NCT00579709	PHASE1	COMPLETED	Thymus Transplantation With Immunosuppression
NCT00849888	PHASE1	TERMINATED	Serum-Free Thymus Transplantation in DiGeorge Anomaly
NCT02895906	PHASE1	COMPLETED	Safety and Efficacy Study of NFC-1 in Subjects Aged 12-17 Years With 22q11.2DS & Associated Neuropsychiatric Conditions
NCT00579527	PHASE1/PHASE2	COMPLETED	Phase I/II Thymus Transplantation With Immunosuppression #950
NCT00004351	Not specified	COMPLETED	Study of Phenotype and Genotype Correlations in Patients With Contiguous Gene Deletion Syndromes
NCT00005102	Not specified	UNKNOWN	Immunologic Evaluation in Patients With DiGeorge Syndrome or Velocardiofacial Syndrome
NCT00105274	Not specified	COMPLETED	Velocardiofacial (VCFS; 22q11.2; DiGeorge) Syndrome Study
NCT00278005	Not specified	TERMINATED	Infection in DiGeorge Following CHD Surgery
NCT00556530	Not specified	RECRUITING	Examining Genetic Factors That Affect the Severity of 22q11.2 Deletion Syndrome
NCT00916955	Not specified	COMPLETED	Genetic Modifiers for 22q11.2 Syndrome
NCT01220531	Not specified	COMPLETED	Thymus Transplantation Safety-Efficacy
NCT01781923	Not specified	COMPLETED	Cognitive Remediation in 22q11DS
NCT02381457	Not specified	COMPLETED	SNP-based Microdeletion and Aneuploidy RegisTry (SMART)
NCT02430584	Not specified	UNKNOWN	Whole Blood Specimen Collection From Pregnant Subjects
NCT02460328	Not specified	COMPLETED	Resolution of Primary Immune Defect in 22q11.2 Deletion Syndrome
NCT02787486	Not specified	COMPLETED	Expanded Noninvasive Genomic Medical Assessment: The Enigma Study
NCT03284060	Not specified	TERMINATED	Social Cognition Training and Cognitive Remediation
NCT04141540	Not specified	COMPLETED	Molecular Variants Associated With Schizophrenia: Differential Analysis of Monozygotic Twins With Variable Phenotypic 22q11
NCT04373226	Not specified	TERMINATED	Arithmetic Abilities in Children With 22q11.2DS
NCT04639388	Not specified	RECRUITING	Understanding of Psychotic Disorders in Children With 22q11.2DS
NCT04639960	Not specified	TERMINATED	Neuroprotective Effects of Risperdal on Brain and Cognition in 22q11 Deletion Syndrome
NCT04647500	Not specified	COMPLETED	Effects of Methylphenidate on Brain and Cognition in 22q11 Deletion Syndrome
NCT05924347	Not specified	RECRUITING	Early Scoliotic Changes in Children at Increased Risk for Scoliosis Development
NCT07493096	Not specified	RECRUITING	Intensive Multimodal Neurorehabilitation Targeting Neuroplasticity in Pediatric Neurodevelopmental and Chromosomal Disorders