LNX1

Summary

LNX1 (ligand of numb-protein X 1, HGNC:6657) is a protein-coding gene on chromosome 4q12, encoding E3 ubiquitin-protein ligase LNX (Q8TBB1). E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of NUMB.

This gene encodes a membrane-bound protein that is involved in signal transduction and protein interactions. The encoded product is an E3 ubiquitin-protein ligase, which mediates ubiquitination and subsequent proteasomal degradation of proteins containing phosphotyrosine binding (PTB) domains. This protein may play an important role in tumorogenesis. Alternatively spliced transcript variants encoding distinct isoforms have been described. A pseudogene, which is located on chromosome 17, has been identified for this gene.

Source: NCBI Gene 84708 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 123 total
• Phenotypes (HPO): 33
• MANE Select transcript: NM_001126328

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6657
Approved symbol	LNX1
Name	ligand of numb-protein X 1
Location	4q12
Locus type	gene with protein product
Status	Approved
Aliases	MPDZ, PDZRN2
Ensembl gene	ENSG00000072201
Ensembl biotype	protein_coding
OMIM	609732
Entrez	84708

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 10 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000263925, ENST00000306888, ENST00000504299, ENST00000504605, ENST00000507168, ENST00000510143, ENST00000511398, ENST00000512247, ENST00000513421, ENST00000871478, ENST00000941990, ENST00000941991

RefSeq mRNA: 2 — MANE Select: NM_001126328 NM_001126328, NM_032622

CCDS: CCDS3492, CCDS47057

Canonical transcript exons

ENST00000263925 — 11 exons

Exon	Start	End
ENSE00000341408	53507986	53508227
ENSE00000877896	53498641	53498843
ENSE00000969364	53496023	53496394
ENSE00000969365	53481720	53481854
ENSE00000969366	53478565	53478742
ENSE00000969367	53476753	53476981
ENSE00000969368	53461435	53461593
ENSE00001126725	53573623	53574088
ENSE00001356384	53459301	53461042
ENSE00002073967	53591388	53591486
ENSE00003547118	53507317	53507469

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 98.70.

FANTOM5 (CAGE): breadth broad, TPM avg 5.0339 / max 223.0532, expressed in 887 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
52126	2.3933	307
52128	1.1358	339
52127	0.5242	185
52129	0.3386	203
52125	0.2460	138
52133	0.2377	77
52130	0.0863	43
52131	0.0402	20
52132	0.0316	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
esophagus squamous epithelium	UBERON:0006920	98.70	gold quality
middle temporal gyrus	UBERON:0002771	96.56	gold quality
parotid gland	UBERON:0001831	96.08	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.71	gold quality
endothelial cell	CL:0000115	94.68	gold quality
Brodmann (1909) area 46	UBERON:0006483	94.23	gold quality
oral cavity	UBERON:0000167	93.92	gold quality
amniotic fluid	UBERON:0000173	93.85	gold quality
superior frontal gyrus	UBERON:0002661	93.24	gold quality
upper arm skin	UBERON:0004263	93.24	gold quality
jejunal mucosa	UBERON:0000399	93.15	gold quality
postcentral gyrus	UBERON:0002581	92.41	gold quality
epithelial cell of pancreas	CL:0000083	92.37	gold quality
parietal lobe	UBERON:0001872	92.07	gold quality
entorhinal cortex	UBERON:0002728	92.06	gold quality
buccal mucosa cell	CL:0002336	91.72	gold quality
upper leg skin	UBERON:0004262	90.87	gold quality
renal medulla	UBERON:0000362	90.86	gold quality
palpebral conjunctiva	UBERON:0001812	90.74	gold quality
primary visual cortex	UBERON:0002436	90.53	gold quality
nasal cavity epithelium	UBERON:0005384	90.48	gold quality
pharyngeal mucosa	UBERON:0000355	90.10	gold quality
occipital lobe	UBERON:0002021	90.10	gold quality
oviduct epithelium	UBERON:0004804	90.08	gold quality
sperm	CL:0000019	89.76	gold quality
placenta	UBERON:0001987	88.83	gold quality
pancreatic ductal cell	CL:0002079	88.82	gold quality
kidney epithelium	UBERON:0004819	88.63	gold quality
prefrontal cortex	UBERON:0000451	88.00	gold quality
tendon of biceps brachii	UBERON:0008188	87.86	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.89

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

65 targeting LNX1, 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-3163	100.00	77.23	8605
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-374C-5P	99.80	72.06	2910

Literature-anchored findings (GeneRIF, showing 16)

• identifed ligand of Numb protein X as an Np9-interacting partner; findings point to the possibility that Np9 affects tumorigenesis through the LNX/Numb/Notch pathway (PMID:15367597)
• The presence of multiple protein binding domains involved in signal transduction and interaction with Numb and SKIP suggested an important role for LNX in tumorogenesis. (PMID:16002321)
• A direct interaction between ErbB2 and mouse LNX1 was identified, suggesting that LNX1 may be involved in neuregulin-1/ErbB signaling in perisynaptic Schwann cells. (PMID:16122940)
• LNX was closely related to human gliomas and suggested it plays an important role in gliomas by notch signaling. (PMID:16324299)
• Describes various glioblastoma multiforms containing the amplicon on chromosomal segment 4q12, including the LNX1 gene. (PMID:17504929)
• The interaction of c-Src with LNX1 depends on the C-terminal PDZ ligand of c-Src. (PMID:17936276)
• Both gene sequence alterations and amplifications of LNX1 and Numbl are present in a subset of human gliomas. (PMID:18940473)
• LNX and RhoC might be part of a larger protein complex that would have important functions in signaling transduction about regulating the transcriptional activities of AP-1. (PMID:19701800)
• Down-regulation of LNX could result in cell cycle arrest in G0/G1 phase through inhibition of beta-catenin, MAPK, NFkappaB, c-Myc-dependent pathway and activation of p53, TGF-beta-dependent pathway. (PMID:21104141)
• LNX1 and LNX2 interact with CD8alpha and promote its ubiquitylation and endocytosis (PMID:22045731)
• The authors found a high level of LNX1 and LNX2 mRNAs in endocarditis, the principal manifestation of chronic Q fever, but not in acute Q fever. (PMID:22066909)
• identify and confirm six novel LNX1 binding partners: KCNA4, PAK6, PLEKHG5, PKC-alpha1, TYK2 and PBK, and suggest that LNX1 functions as a signalling scaffold. (PMID:22087225)
• LNX1-mediated ubiquitination and degradation of PBK inhibited cell proliferation and enhanced sensitivity to doxorubicin-induced apoptosis. (PMID:22889411)
• study provided the evidences that LNX1 signaling plays important roles in regulating the stemness of colon cancer cells (PMID:29190716)
• Study reveals how the LNX1 RING domain is structurally and mechanistically dependent on other motifs for its E3 ligase activity, and describes how dimeric LNX1 recruits ubiquitin (Ub)-loaded Ubc13 for Ub transfer via E3 ligase-mediated catalysis. (PMID:29496391)
• The tyrosine phosphorylation of the LDNPAY sequence motif in mouse LNX could generate a binding site for the phosphorylation-dependent binding of other PTB domain-containing proteins. (PMID:9535908)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	lnx1	ENSDARG00000043323
mus_musculus	Lnx1	ENSMUSG00000029228
rattus_norvegicus	Lnx1	ENSRNOG00000002272
caenorhabditis_elegans		WBGENE00001492
caenorhabditis_elegans		WBGENE00021406

Paralogs (5): MPDZ (ENSG00000107186), PATJ (ENSG00000132849), LNX2 (ENSG00000139517), STXBP4 (ENSG00000166263), FRMPD2 (ENSG00000170324)

Protein

Protein identifiers

E3 ubiquitin-protein ligase LNX — Q8TBB1 (reviewed: Q8TBB1)

Alternative names: Ligand of Numb-protein X 1, Numb-binding protein 1, PDZ domain-containing RING finger protein 2, RING-type E3 ubiquitin transferase LNX

All UniProt accessions (5): Q8TBB1, A0A0B4J209, D6RAH9, D6RB76, D6RE08

UniProt curated annotations — full annotation on UniProt →

Function. E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of NUMB. E3 ubiquitin ligases accept ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Mediates ubiquitination of isoform p66 and isoform p72 of NUMB, but not that of isoform p71 or isoform p65. Isoform 2 provides an endocytic scaffold for IGSF5/JAM4.

Subunit / interactions. Interacts with the phosphotyrosine interaction domain of all isoforms of NUMB. Interacts with MAGEB18 and MAGEF1. Interacts with the Coxsackievirus and adenovirus receptor CXADR. Interacts with endogenous retrovirus K protein Np9. IGSF5/JAM4 interacts with isoform 2 through the second PDZ domain, other isoforms may also interact with IGSF5/JAM4.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in heart, placenta, kidney, pancreas and brain.

Domain organisation. The NPXY motif is required for the interaction with the PID domain of NUMB. It is however not sufficient. The PDZ 1 domain participates in the interaction with the PID domain of NUMB, and participates in the isoform-specific ubiquitination of NUMB. The PDZ 2 domain of isoform 2 participates in the interaction with IGSF5/JAM4, other isoforms containing this domain may also interact with IGSF5/JAM4.

Pathway. Protein modification; protein ubiquitination.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8TBB1-1	1	yes
Q8TBB1-2	2

RefSeq proteins (2): NP_001119800, NP_116011 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001478	PDZ	Domain
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR018957	Znf_C3HC4_RING-type	Domain
IPR036034	PDZ_sf	Homologous_superfamily
IPR051342	PDZ_scaffold	Family

Pfam: PF00097, PF00595

UniProt features (40 total): helix 10, strand 10, domain 4, sequence conflict 4, turn 4, region of interest 3, chain 1, modified residue 1, splice variant 1, zinc finger region 1, short sequence motif 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
5H7R	X-RAY DIFFRACTION	1.7
3B76	X-RAY DIFFRACTION	1.75
5H7S	X-RAY DIFFRACTION	3.49

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TBB1-F1	72.11	0.32

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 (1): 441

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-983169	Class I MHC mediated antigen processing & presentation

MSigDB gene sets: 298 (showing top): AP1_01, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GCANCTGNY_MYOD_Q6, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, KEGG_TIGHT_JUNCTION, CAGCTG_AP4_Q5, HUMMERICH_SKIN_CANCER_PROGRESSION_UP, BEIER_GLIOMA_STEM_CELL_DN, GOBP_CELL_JUNCTION_ORGANIZATION, AP1_Q4_01, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4

GO Biological Process (4): ubiquitin-dependent protein catabolic process (GO:0006511), protein ubiquitination (GO:0016567), synapse maturation (GO:0060074), nervous system development (GO:0007399)

GO Molecular Function (8): ubiquitin-protein transferase activity (GO:0004842), zinc ion binding (GO:0008270), PDZ domain binding (GO:0030165), identical protein binding (GO:0042802), ubiquitin protein ligase activity (GO:0061630), protein binding (GO:0005515), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (3): cytoplasm (GO:0005737), hippocampal mossy fiber to CA3 synapse (GO:0098686), postsynapse (GO:0098794)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
protein ubiquitination	1
modification-dependent protein catabolic process	1
protein modification by small protein conjugation	1
nervous system development	1
developmental maturation	1
synapse organization	1
system development	1
ubiquitin-like protein transferase activity	1
transition metal ion binding	1
protein domain specific binding	1
protein binding	1
ubiquitin-protein transferase activity	1
ubiquitin-like protein ligase activity	1
binding	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
thorny excrescence	1
neuron to neuron synapse	1
hippocampal mossy fiber expansion	1
synapse	1

Protein interactions and networks

STRING

1908 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LNX1	NUMBL	Q9Y6R0	989
LNX1	NUMB	P49757	980
LNX1	MAGEB18	Q96M61	969
LNX1	CXADR	P78310	881
LNX1	KCNV2	Q8TDN2	777
LNX1	NFIB	O00712	664
LNX1	IGSF5	Q9NSI5	646
LNX1	PALS1	Q8N3R9	636
LNX1	TJP2	Q9UDY2	608
LNX1	SLC1A1	P43005	591
LNX1	PICK1	Q9NRD5	589
LNX1	ZNF469	Q96JG9	575
LNX1	SCFD2	Q8WU76	566
LNX1	NAALADL2	Q58DX5	558
LNX1	ZDHHC21	Q8IVQ6	548

IntAct

2677 interactions, top by confidence:

A	B	Type	Score
MAGEB18	LNX1	psi-mi:“MI:0915”(physical association)	0.890
LNX1	MAGEB18	psi-mi:“MI:0915”(physical association)	0.890
CLK2	LNX1	psi-mi:“MI:0915”(physical association)	0.830
LNX1	SAT1	psi-mi:“MI:0915”(physical association)	0.830
LNX1	AIMP2	psi-mi:“MI:0915”(physical association)	0.830
TRIP13	LNX1	psi-mi:“MI:0915”(physical association)	0.830
LNX1	APIP	psi-mi:“MI:0915”(physical association)	0.830
LNX1	CLK2	psi-mi:“MI:0915”(physical association)	0.830
AIMP2	LNX1	psi-mi:“MI:0915”(physical association)	0.830
LNX1	TRIP13	psi-mi:“MI:0915”(physical association)	0.830
APIP	LNX1	psi-mi:“MI:0915”(physical association)	0.830
LNX1	CDA	psi-mi:“MI:0915”(physical association)	0.810
ATPAF2	LNX1	psi-mi:“MI:0915”(physical association)	0.810
CDA	LNX1	psi-mi:“MI:0915”(physical association)	0.810
HSBP1	LNX1	psi-mi:“MI:0915”(physical association)	0.780
LNX1	MAPK9	psi-mi:“MI:0915”(physical association)	0.780
LNX1	SSNA1	psi-mi:“MI:0915”(physical association)	0.780
PCBD1	LNX1	psi-mi:“MI:0915”(physical association)	0.780
KCTD1	LNX1	psi-mi:“MI:0915”(physical association)	0.780
LNX1	KRTAP4-2	psi-mi:“MI:0915”(physical association)	0.780
LNX1	TRIM54	psi-mi:“MI:0915”(physical association)	0.780
DNPEP	LNX1	psi-mi:“MI:0915”(physical association)	0.780
VCP	LNX1	psi-mi:“MI:0915”(physical association)	0.780
LNX1	MRFAP1L1	psi-mi:“MI:0915”(physical association)	0.780
TSSK3	LNX1	psi-mi:“MI:0915”(physical association)	0.780
LNX1	NME7	psi-mi:“MI:0915”(physical association)	0.780
MAPK9	LNX1	psi-mi:“MI:0915”(physical association)	0.780

BioGRID (710): LNX1 (Two-hybrid), LNX1 (Two-hybrid), LNX1 (Two-hybrid), LNX1 (Two-hybrid), LNX1 (Two-hybrid), LNX1 (Two-hybrid), LNX1 (Two-hybrid), LNX1 (Two-hybrid), LNX1 (Two-hybrid), LNX1 (Two-hybrid), LNX1 (Two-hybrid), LNX1 (Two-hybrid), LNX1 (Two-hybrid), LNX1 (Two-hybrid), LNX1 (Two-hybrid)

ESM2 similar proteins: A0A0G2K2P5, A1A5G4, A8E0R9, G9CGD6, O08874, O54785, O70263, O88382, O97758, P15056, P28028, P34908, P39447, P53666, P53667, P53668, P53669, P53670, P53671, P97879, Q04982, Q07157, Q16513, Q32L23, Q5F488, Q5TCQ9, Q6ZWJ1, Q80T23, Q812E4, Q86UL8, Q8N448, Q8QFP8, Q8TBB1, Q8TDW5, Q8TEW8, Q91XL2, Q925T6, Q95168, Q96NE9, Q9C0E4

Diamond homologs: A7XUJ6, B5DF45, B6CJY4, B6CJY5, D3YY23, O13033, O70263, P15919, P39428, P43254, P68907, P70196, P93471, Q02084, Q13077, Q17RB8, Q1L5Z9, Q28DL4, Q3MV19, Q3UWA4, Q3ZCC3, Q6CTZ8, Q6DJN2, Q6IWL4, Q6J2U6, Q6MFY8, Q6Q0C0, Q6ZMN7, Q865W2, Q8TBB1, Q91187, Q922B6, Q9D4H7, Q9D9R0, Q9ET26, Q9FNI6, Q9Y4K3, P15918, P39429, Q1XHT8

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
LNX1	down-regulates	NUMB	ubiquitination
Ub:E2	“up-regulates activity”	LNX1	ubiquitination
LNX1	“down-regulates quantity by destabilization”	ZBTB8A	polyubiquitination
LNX1	“down-regulates quantity by destabilization”	PBK	ubiquitination
LNX1	“down-regulates quantity by destabilization”	BCR	ubiquitination
LNX1	“down-regulates quantity”	SUFU	ubiquitination
LNX1	“down-regulates quantity by destabilization”	KCNA4	ubiquitination
LNX1	“down-regulates quantity by destabilization”	CLDN17	ubiquitination
LNX1	“down-regulates quantity by destabilization”	GRIN1	ubiquitination
LNX1	“down-regulates quantity by destabilization”	ABCA1	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	107
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

14367 predictions. Top by Δscore:

Variant	Effect	Δscore
4:53459301:G:GG	acceptor_gain	1.0000
4:53459301:GT:G	acceptor_gain	1.0000
4:53459301:GTA:G	acceptor_gain	1.0000
4:53459301:GTAAT:G	acceptor_gain	1.0000
4:53459421:A:T	donor_gain	1.0000
4:53459472:ATATT:A	donor_gain	1.0000
4:53461038:CACAT:C	acceptor_gain	1.0000
4:53461039:ACAT:A	acceptor_gain	1.0000
4:53461040:CAT:C	acceptor_gain	1.0000
4:53461040:CATC:C	acceptor_gain	1.0000
4:53461041:AT:A	acceptor_gain	1.0000
4:53461043:C:CC	acceptor_gain	1.0000
4:53461044:T:A	acceptor_loss	1.0000
4:53461429:TATTA:T	donor_loss	1.0000
4:53461431:TTACC:T	donor_loss	1.0000
4:53461432:TA:T	donor_loss	1.0000
4:53461433:A:C	donor_loss	1.0000
4:53461434:C:CA	donor_loss	1.0000
4:53461437:AATT:A	donor_gain	1.0000
4:53461438:A:C	donor_gain	1.0000
4:53461443:T:TA	donor_gain	1.0000
4:53461591:CAC:C	acceptor_gain	1.0000
4:53481714:CCTCA:C	donor_loss	1.0000
4:53481715:CTCA:C	donor_loss	1.0000
4:53481716:TCA:T	donor_loss	1.0000
4:53481717:CA:C	donor_loss	1.0000
4:53481718:A:T	donor_loss	1.0000
4:53481784:T:TA	donor_gain	1.0000
4:53498844:C:CC	acceptor_gain	1.0000
4:53507981:CTCA:C	donor_loss	1.0000

AlphaMissense

4784 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:53461534:A:G	F651S	0.999
4:53573690:A:G	C105R	0.999
4:53573780:A:G	C75R	0.999
4:53573820:G:C	C61W	0.999
4:53573880:G:C	C41W	0.999
4:53573882:A:G	C41R	0.999
4:53460941:A:G	L718P	0.998
4:53573688:G:C	C105W	0.998
4:53573778:A:C	C75W	0.998
4:53573811:G:C	C64W	0.998
4:53573813:A:G	C64R	0.998
4:53573822:A:G	C61R	0.998
4:53573871:G:C	C44W	0.998
4:53573873:A:G	C44R	0.998
4:53573881:C:T	C41Y	0.998
4:53461034:T:A	D687V	0.997
4:53461564:A:G	L641S	0.997
4:53476972:A:G	L558S	0.997
4:53508224:A:C	C128W	0.997
4:53508225:C:T	C128Y	0.997
4:53508226:A:G	C128R	0.997
4:53573689:C:T	C105Y	0.997
4:53573821:C:T	C61Y	0.997
4:53573954:A:G	C17R	0.997
4:53461019:A:T	V692D	0.996
4:53461023:C:G	A691P	0.996
4:53461034:T:G	D687A	0.996
4:53478663:A:T	V522D	0.996
4:53508225:C:G	C128S	0.996
4:53508226:A:T	C128S	0.996

dbSNP variants (sampled 300 via entrez): RS1000010609 (4:53584896 A>G), RS1000023650 (4:53626087 G>A), RS10000315 (4:53570427 T>A,C), RS10000457 (4:53555372 C>G,T), RS1000047807 (4:53507148 CT>C), RS1000063703 (4:53526388 A>G), RS10001337 (4:53485362 C>T), RS1000137437 (4:53620462 A>G), RS1000154165 (4:53530810 T>C), RS1000174199 (4:53487427 A>G), RS1000180356 (4:53531809 G>C), RS1000184765 (4:53475796 G>A,T), RS1000187153 (4:53620103 C>G), RS10002285 (4:53576165 T>C), RS1000249368 (4:53578063 A>G)

Disease associations

OMIM: gene MIM:609732 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): lip and oral cavity carcinoma (MONDO:0023644)

Orphanet (0):

HPO phenotypes

33 total (30 of 33 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000358	Posteriorly rotated ears
HP:0000407	Sensorineural hearing impairment
HP:0000414	Bulbous nose
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000505	Visual impairment
HP:0000567	Chorioretinal coloboma
HP:0000612	Iris coloboma
HP:0000648	Optic atrophy
HP:0001104	Macular hypoplasia
HP:0001137	Alternating esotropia
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001270	Motor delay
HP:0001274	Agenesis of corpus callosum
HP:0001334	Communicating hydrocephalus
HP:0001339	Lissencephaly
HP:0001583	Rotary nystagmus
HP:0001631	Atrial septal defect
HP:0001999	Abnormal facial shape
HP:0002007	Frontal bossing
HP:0002119	Ventriculomegaly
HP:0002282	Gray matter heterotopia
HP:0003577	Congenital onset
HP:0009879	Simplified gyral pattern

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002058_19	DNA methylation (variation)	9.000000e-07
GCST002700_5	Cervical artery dissection	2.000000e-08
GCST003475_5	Beard thickness	1.000000e-08
GCST006462_22	Uterine fibroids	8.000000e-10
GCST006979_431	Heel bone mineral density	1.000000e-18
GCST008163_125	Height	7.000000e-06
GCST008514_7	Peginterferon alfa-2a treatment response in chronic hepatitis B infection	4.000000e-06
GCST009158_34	Uterine fibroids	5.000000e-18

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0022599	DNA methylation
EFO:0009270	heel bone mineral density
EFO:0010103	response to peginterferon alfa-2a

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	5
trichostatin A	affects cotreatment, increases expression	3
Estradiol	affects cotreatment, decreases expression	3
arsenite	affects binding, decreases reaction, increases methylation	2
mercuric bromide	affects cotreatment, increases expression	2
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, increases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
lead acetate	affects cotreatment, decreases expression	1
terbufos	increases methylation	1
afimoxifene	decreases expression, decreases reaction	1
zinc protoporphyrin	affects cotreatment, decreases expression	1
sodium arsenite	decreases expression	1
avobenzone	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases expression, increases response to substance	1
licochalcone B	decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation	1
Doxorubicin	decreases expression	1
Fonofos	increases methylation	1
Estrogens	decreases expression, decreases reaction	1
Lead	affects expression	1
Parathion	increases methylation	1
Phthalic Acids	decreases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01418118	PHASE4	COMPLETED	Assessment of the Effects of Pressors on Graft Blood Flow After Free Tissue Transfer Surgery
NCT03017053	PHASE4	UNKNOWN	The Optimal Neck Treatments Strategy of Early Oral Cancer Based on Adverse Pathological Factor
NCT03684707	PHASE4	UNKNOWN	Cancer Chemoprevention by Metformin Hydrochloride Compared to Placebo in Oral Potentially Malignant Lesions
NCT00158652	PHASE3	COMPLETED	Accelerated Radiotherapy and Concomitant Chemo-radiotherapy in HNSCC
NCT00158678	PHASE3	COMPLETED	IMRT Plus Cisplatin Versus Conventional Radiotherapy Plus Cisplatin in Stage III-IV HNSCC
NCT00402779	PHASE3	COMPLETED	Erlotinib Prevention of Oral Cancer (EPOC)
NCT00655421	PHASE3	UNKNOWN	Oral Cancer Screening in Mumbai, India by Primary Health Care Workers
NCT00750503	PHASE3	COMPLETED	Workplace Tobacco Cessation And Oral Cancer Screening Study
NCT00964977	PHASE3	COMPLETED	Effectiveness of Adjuvant Radiotherapy in Small Oropharyngeal Squamous Cell Cancer and Single Lymph Node Metastasis.
NCT01039298	PHASE3	UNKNOWN	Efficacy of Optically-guided Surgery in the Management of Early-staged Oral Cancer - COOLS TRIAL
NCT03685409	PHASE3	UNKNOWN	Cancer Chemoprevention by Metformin Hydrochloride in Oral Potentially Malignant Lesions
NCT05721755	PHASE3	ACTIVE_NOT_RECRUITING	Combining Radiation Therapy With Immunotherapy for the Treatment of Metastatic Squamous Cell Carcinoma of the Head and Neck
NCT06589804	PHASE3	RECRUITING	Testing the Addition of Anti-Cancer Drug, Cetuximab, to Standard of Care Treatment (Pembrolizumab) for Returning or Spreading Head and Neck Cancer After Previous Treatment
NCT06737822	PHASE3	RECRUITING	Upfront Surgery Vs Induction Chemotherapy Followed By Surgery In Oral Cancers:
NCT07402538	PHASE3	NOT_YET_RECRUITING	Surgery With or Without Neoadjuvant Treatment of SBRT Plus Chemoimmunotherapy in Resectable Locally Advanced Oral and HPV-unrelated Oropharyngeal Squamous Cell Carcinoma
NCT07441681	PHASE3	NOT_YET_RECRUITING	Comparing Radiation Plus Cetuximab to Radiation Plus Chemotherapy in People With Head and Neck Cancer Who Cannot Receive Cisplatin
NCT00330382	PHASE2	COMPLETED	Bowman-Birk Inhibitor Concentrate in Preventing Cancer in Patients With Oral Leukoplakia
NCT00400205	PHASE2	TERMINATED	Study of Induction Docetaxel, Cisplatin and 5-Fluorouracil
NCT00933387	PHASE2	COMPLETED	A Study of Neoadjuvant Bio-C/T Followed by Concurrent Bio-R/T in High-risk Locally Advanced Oral Squamous Cell Carcinoma
NCT01440270	PHASE2	COMPLETED	Neo-adjuvant Erbitux-based Chemotherapy for Locally Advanced Oral/Oropharyngeal Cancer
NCT01733797	PHASE2	COMPLETED	Trismus Trial of Therabite vs Wooden Spatula in Head and Neck Cancer Patients
NCT02734537	PHASE2	RECRUITING	Radiation Therapy With or Without Cisplatin in Treating Patients With Stage III-IVA Squamous Cell Carcinoma of the Head and Neck Who Have Undergone Surgery
NCT02960724	PHASE2	UNKNOWN	uPAR PET/CT for Staging Advanced and Localised Oral and Oropharyngeal Cancer
NCT03008694	PHASE2	UNKNOWN	Effect of FDG-PET/CT for Simulation and Radiation Treatment Planning in Oral Cancer Patients
NCT03174275	PHASE2	ACTIVE_NOT_RECRUITING	Carboplatin, Nab-Paclitaxel, Durvalumab Before Surgery and Adjuvant Therapy in Head and Neck Squamous Cell Carcinoma
NCT03383094	PHASE2	ACTIVE_NOT_RECRUITING	Chemoradiation vs Immunotherapy and Radiation for Head and Neck Cancer
NCT03529422	PHASE2	ACTIVE_NOT_RECRUITING	Durvalumab With Radiotherapy for Adjuvant Treatment of Intermediate Risk SCCHN
NCT04191460	PHASE2	RECRUITING	Fluorescence-guided Surgery Using cRGD-ZW800-1 in Oral Cancer
NCT04251949	PHASE2	COMPLETED	Evaluation of the Photobiomodulation Using LED Lamp for Curative Treatment of Radio-induced Mucositis.
NCT04541355	PHASE2	COMPLETED	Sodium Thiosulfate in Preventing Ototoxicity for Squamous Cell Cancer Patients Undergoing Chemoradiation With Cisplatin
NCT04862650	PHASE2	ACTIVE_NOT_RECRUITING	Cemiplimab, Low-Dose Paclitaxel and Carboplatin for the Treatment of Recurrent/Metastatic Squamous Cell Carcinoma of the Head and Neck
NCT05136196	PHASE2	RECRUITING	BiCaZO: A Study Combining Two Immunotherapies (Cabozantinib and Nivolumab) to Treat Patients With Advanced Melanoma or Squamous Cell Head and Neck Cancer, an immunoMATCH Pilot Study
NCT05172258	PHASE2	ACTIVE_NOT_RECRUITING	Testing the Addition of an Anti-cancer Drug, Ipatasertib, to the Usual Immunotherapy Treatment (Pembrolizumab) in Patients With Recurrent or Metastatic Squamous Cell Cancer of the Head and Neck
NCT05456022	PHASE2	UNKNOWN	Therapeutic Efficacy of Quercetin Versus Its Encapsulated Nanoparticle on Tongue Squamous Cell Carcinoma Cell Line
NCT05941338	PHASE2	RECRUITING	Tirelizumab in Combination With Carboplatin and Albumin-binding Paclitaxel for Neoadjuvant Therapy in HNSCC
NCT05980702	PHASE2	RECRUITING	4 Courses vs 2 Courses of Pembrolizumab Combined With Carboplatin and Albumin-binding Paclitaxel of Neoadjuvant Therapy in HNSCC
NCT06084845	PHASE2	WITHDRAWN	Testing the Addition of an Investigational Drug, Xevinapant, to Usual Radiation Therapy Plus Cisplatin/Carboplatin for Patients With Head and Neck Cancer
NCT06130332	PHASE2	RECRUITING	Neoadjuvant Tirellizumab Combined With Chemotherapy for Early Oral Squamous Cell Carcinoma(HNC-SYSU-004)
NCT06532279	PHASE2	RECRUITING	Testing the Addition of the Drug BMX-001, a Radioprotector, or a Placebo to the Usual Chemoradiation Therapy for Patients With Head and Neck Cancer
NCT06627270	PHASE2	RECRUITING	Antibiotic Treatment Effects on Intratumoral Bacteria Modulation in Surgical Patients With Oral Cancer