LRIG1

Summary

LRIG1 (leucine rich repeats and immunoglobulin like domains 1, HGNC:17360) is a protein-coding gene on chromosome 3p14.1, encoding Leucine-rich repeats and immunoglobulin-like domains protein 1 (Q96JA1). Acts as a feedback negative regulator of signaling by receptor tyrosine kinases, through a mechanism that involves enhancement of receptor ubiquitination and accelerated intracellular degradation.

Predicted to act upstream of or within several processes, including innervation; otolith morphogenesis; and sensory perception of sound. Predicted to be located in plasma membrane. Predicted to be active in extracellular matrix and extracellular space.

Source: NCBI Gene 26018 — RefSeq curated summary.

At a glance

• GWAS associations: 40
• Clinical variants (ClinVar): 307 total
• MANE Select transcript: NM_015541

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17360
Approved symbol	LRIG1
Name	leucine rich repeats and immunoglobulin like domains 1
Location	3p14.1
Locus type	gene with protein product
Status	Approved
Aliases	LIG-1, DKFZP586O1624, LIG1
Ensembl gene	ENSG00000144749
Ensembl biotype	protein_coding
OMIM	608868
Entrez	26018

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 33 protein_coding, 6 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000273261, ENST00000383703, ENST00000475366, ENST00000491821, ENST00000495037, ENST00000495671, ENST00000496559, ENST00000497721, ENST00000498287, ENST00000895933, ENST00000895934, ENST00000895935, ENST00000895936, ENST00000895937, ENST00000895938, ENST00000895939, ENST00000895940, ENST00000895941, ENST00000895942, ENST00000895943, ENST00000895944, ENST00000895945, ENST00000895946, ENST00000930928, ENST00000930929, ENST00000930930, ENST00000930931, ENST00000930932, ENST00000930933, ENST00000930934, ENST00000930935, ENST00000930936, ENST00000930937, ENST00000930938, ENST00000930939, ENST00000930940, ENST00000966529, ENST00000966530, ENST00000966531, ENST00000966532

RefSeq mRNA: 7 — MANE Select: NM_015541 NM_001377344, NM_001377345, NM_001377346, NM_001377347, NM_001377348, NM_001377349, NM_015541

CCDS: CCDS33783

Canonical transcript exons

ENST00000273261 — 19 exons

Exon	Start	End
ENSE00000966919	66407348	66407491
ENSE00001076925	66410129	66410272
ENSE00001822299	66378797	66380489
ENSE00001888452	66500190	66501022
ENSE00003466778	66417129	66417266
ENSE00003476446	66398112	66398183
ENSE00003498573	66412871	66413014
ENSE00003510570	66414920	66415063
ENSE00003532425	66380577	66380861
ENSE00003545211	66381479	66381631
ENSE00003548146	66398970	66399041
ENSE00003573716	66405198	66405278
ENSE00003583845	66382982	66383401
ENSE00003592215	66451559	66451633
ENSE00003619609	66462438	66462509
ENSE00003627932	66382273	66382398
ENSE00003635458	66385981	66386301
ENSE00003649159	66383991	66384272
ENSE00003663376	66394040	66394203

Expression profiles

Bgee: expression breadth ubiquitous, 290 present calls, max score 99.01.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.0602 / max 184.7542, expressed in 1449 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42928	13.7092	1441
42929	0.2344	140
42927	0.0790	12
42924	0.0377	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.01	gold quality
bronchial epithelial cell	CL:0002328	98.02	gold quality
ventricular zone	UBERON:0003053	97.66	gold quality
body of pancreas	UBERON:0001150	97.61	gold quality
cardia of stomach	UBERON:0001162	97.54	gold quality
epithelium of bronchus	UBERON:0002031	97.54	gold quality
bronchus	UBERON:0002185	97.49	gold quality
mucosa of stomach	UBERON:0001199	97.19	gold quality
muscle layer of sigmoid colon	UBERON:0035805	96.95	gold quality
pylorus	UBERON:0001166	96.89	gold quality
medial globus pallidus	UBERON:0002477	96.58	gold quality
globus pallidus	UBERON:0001875	96.55	gold quality
mammary duct	UBERON:0001765	96.52	gold quality
lateral globus pallidus	UBERON:0002476	96.51	gold quality
epithelium of mammary gland	UBERON:0003244	96.43	gold quality
body of stomach	UBERON:0001161	95.97	gold quality
oocyte	CL:0000023	95.89	gold quality
stomach	UBERON:0000945	95.77	gold quality
epithelium of nasopharynx	UBERON:0001951	95.58	gold quality
nasopharynx	UBERON:0001728	95.56	gold quality
trachea	UBERON:0003126	95.56	gold quality
fundus of stomach	UBERON:0001160	95.48	gold quality
endocervix	UBERON:0000458	95.44	gold quality
smooth muscle tissue	UBERON:0001135	95.27	gold quality
sigmoid colon	UBERON:0001159	95.25	gold quality
subthalamic nucleus	UBERON:0001906	95.25	gold quality
urethra	UBERON:0000057	95.23	gold quality
CA1 field of hippocampus	UBERON:0003881	95.15	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.09	gold quality
descending thoracic aorta	UBERON:0002345	95.03	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-93593	yes	12.77
E-ANND-3	yes	6.23

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

139 targeting LRIG1, 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-5692A	100.00	74.40	6850
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-570-3P	99.96	72.41	4910
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-96-5P	99.95	72.80	2140
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-545-3P	99.95	70.74	2783
HSA-MIR-3910	99.95	71.13	2227

Literature-anchored findings (GeneRIF, showing 40)

• Down-regulation of LIG-1 is associated with cancer (PMID:12234026)
• Results demonstrate that LRIG1 is an integral cell-surface membrane protein that is expressed by specific cells in various human tissues and that its 143-kDa form might be cleaved into 111-kDa and 32-kDa fragments. (PMID:12684867)
• downregulation of LRIG1 is associated with renal cell carcinoma (PMID:14520461)
• LRIG1 evolved in mammals as a feedback negative attenuator of signaling by receptor tyrosine kinases (PMID:15282549)
• LRIG1-mediated receptor ubiquitination and degradation may contribute to the suppression of ErbB receptor function (PMID:15345710)
• A breast cancer linked gene is located within an amplicon containing the LRIG1 locus at 3p14.3. (PMID:16168117)
• Lrig1 maintains epidermal stem cells in a quiescent nondividing state, and Lrig1 down-regulation triggers proliferation (PMID:16877544)
• LRIG1 is a novel negative regulator of the Met receptor and opposes Met and Her2 synergy. (PMID:17178829)
• a role of LRIG1 in tumor suppression in the uterine cervix (PMID:17624990)
• Great heterogeneity in the expression of the LRIG1 protein in colorectal cancer, which was not related to gene dosage of the LRIG1 gene. (PMID:17851870)
• LRIG proteins may have a role in epidermal homeostasis and psoriasis (PMID:18037903)
• loss of LRIG1 in tumors may contribute to a permissive environment for EGFRvIII overexpression, contributing to EGFRvIII oncogenesis. (PMID:18542056)
• Suppression of the negative regulator LRIG1 contributes to ErbB2 overexpression in breast cancer. (PMID:18922900)
• Down-regulation of LRIG1 is associated with malignant glioma. (PMID:19300910)
• ERBB2 and LRIG1 copy number is increased in breast cancer (PMID:19490591)
• the LRIG1 ectodomain can be proteolytically shed and can function as a non-cell-autonomous regulator of growth factor signaling (PMID:21087604)
• LRIG1 was a marker for good prognosis after prostatectomy, which might be due to its growth inhibiting properties (PMID:21128282)
• LRIG1-transduced cells treated with cisplatin had more severe DNA damage, cellular apoptosis, growth inhibition and reversal of invasion (PMID:21431282)
• LRIG1 and LRIG2 expressions were seen in precancerous cervical epithelium and found to increase with increasing grade. (PMID:21632100)
• ErbB2 activation antagonizes ERalpha-driven Lrig1 expression, providing a mechanistic explanation for Lrig1 loss in ErbB2-positive breast cancer. This work provides strong evidence for a growth-inhibitory role for Lrig1 in breast cancer. (PMID:21821674)
• our findings show that both upregulation of RTK signaling and attenuated TNFalpha expression caused by LRIG1 downregulation confers resistance to Smac mimetics (PMID:22241084)
• Observations suggest the tumor suppressor function of LRIG1 is lost in a subset of colorectal cancers. (PMID:22464327)
• Cytoplasmic expression of LRIG1 is associated with meningiomas. (PMID:22484910)
• These findings suggested that LRIG1-targeting siRNA can exert a dramatically inhibitory effect on RNA transcription and protein expression of LRIG1. (PMID:22528225)
• This study revealed that the previously described up-regulation of EGFR and down-regulation of ERBB4 occurred in all analyzed renal cell carcinoma types, whereas down-regulation of ERBB2 and LRIG1 was only present in clear cell renal cell carcinoma. (PMID:22554477)
• Downregulation of LRIG1 expression promotes the aggressive properties of glioma cells via EGFR/Akt/c-Myc activation. (PMID:23124613)
• High LRIG1 expression is associated with cervical adenocarcinoma progression. (PMID:23165628)
• LRIG1 mediates degradation of Met by SAIT301 and this degradation does not require Met activation. (PMID:23208509)
• LRIG1 Loss of heterozygosity (LOH) is frequent across cancers and its loss is an early event in the development of human squamous carcinomas. (PMID:23208928)
• These findings suggest that upregulation of LRIG1 expression enhances the CDDP sensitivity in the glioma cell line U251. (PMID:23581227)
• LRIG1 downregulation in cancer cells enhances EGFR-MAPK-SPHK1 signaling and ECM remodeling activity, leading to malignant phenotypes of head and neck cancers (PMID:23624915)
• Data indicate that Lrig3 opposes Lrig1 negative regulatory action and enhances ErbB receptors ERBB2, ERBB3 and ERBB4 stability. (PMID:23723069)
• LRIG1 inhibits EGFR expression and the downstream signaling activation, interferes with Bcl-2/Topo-2 expressions and eventually sensitizes glioma cells to TMZ (PMID:23850692)
• LRIG1 evolved in bladder cancer as a rare feedback negative attenuator of EGFR. (PMID:24314030)
• LRIG1 immunoreactivity could be a clinically important prognostic marker in HPV-associated oropharyngeal cancer. (PMID:24548859)
• findings indicate that downregulation of LRIG1 is possibly a novel potential marker of transformation and tumorigenesis in OSSN cases. (PMID:24709893)
• USP8 is involved in deubiquitination of LRIG1, influencing the efficiency of Met degradation. (PMID:24828152)
• Loss of LRIG1 was independently associated with risk of any relapse. (PMID:24879564)
• LRIG1 can enhance chemosensitivity in glioblastoma by inhibition of BCL-2 and MnSOD (PMID:25449296)
• Based on these results, we concluded that the upregulation of LRIG1 expression inhibited the EGFR signaling pathway, activated the mitochondrial pathway of apoptosis and eventually increased the sensitivity of bladder cancer cells to CDDP. (PMID:25695283)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	lrig1	ENSDARG00000075625
mus_musculus	Lrig1	ENSMUSG00000030029
rattus_norvegicus	Lrig1	ENSRNOG00000012952
drosophila_melanogaster	lbk	FBGN0034083

Paralogs (22): CHADL (ENSG00000100399), LGI1 (ENSG00000108231), LGR6 (ENSG00000133067), CHAD (ENSG00000136457), LRIG3 (ENSG00000139263), LGR5 (ENSG00000139292), LRRTM2 (ENSG00000146006), LRIT1 (ENSG00000148602), LGI2 (ENSG00000153012), LGI4 (ENSG00000153902), LRRC52 (ENSG00000162763), ELFN2 (ENSG00000166897), LGI3 (ENSG00000168481), LRG1 (ENSG00000171236), CPN2 (ENSG00000178772), LRIT3 (ENSG00000183423), LRRC26 (ENSG00000184709), LRIG2 (ENSG00000198799), LGR4 (ENSG00000205213), ELFN1 (ENSG00000225968), LRRC24 (ENSG00000254402), TRIL (ENSG00000255690)

Protein

Protein identifiers

Leucine-rich repeats and immunoglobulin-like domains protein 1 — Q96JA1 (reviewed: Q96JA1)

All UniProt accessions (1): Q96JA1

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a feedback negative regulator of signaling by receptor tyrosine kinases, through a mechanism that involves enhancement of receptor ubiquitination and accelerated intracellular degradation.

Subunit / interactions. Interacts (via extracellular LRR and Ig-like domains) with EGFR/ERBB1, ERBB2, ERBB3 and ERBB4 (via extracellular domain). The physiological relevance of the interaction is controversial; LRIG1 may have low affinity for EGFR, and interaction may occur only when high levels of both proteins are present.

Subcellular location. Cell membrane.

Tissue specificity. Widely expressed.

Domain organisation. Contains LRR and Ig-domains that can mediate low-affinity interaction with EGFR. The LRRs and the Ig-domains are each sufficient for EGFR/ERBB1 binding. This interaction is abolished only when both the LRRs and the Ig-domains are deleted.

Induction. By EGF.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96JA1-1	1	yes
Q96JA1-2	2

RefSeq proteins (7): NP_001364273, NP_001364274, NP_001364275, NP_001364276, NP_001364277, NP_001364278, NP_056356* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000372	LRRNT	Domain
IPR000483	Cys-rich_flank_reg_C	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013098	Ig_I-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR025875	Leu-rich_rpt_4	Repeat
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050467	LRFN	Family

Pfam: PF01463, PF07679, PF12799, PF13855, PF13927

UniProt features (124 total): strand 45, repeat 15, helix 15, turn 11, sequence variant 7, glycosylation site 6, disulfide bond 6, domain 5, sequence conflict 5, topological domain 2, region of interest 2, splice variant 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4U7L	X-RAY DIFFRACTION	2.3
4U7M	X-RAY DIFFRACTION	2.76

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96JA1-F1	75.13	0.53

Functional residue map

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

Disulfide bonds (6): 45–54, 444–468, 446–489, 516–577, 620–672, 714–763

Glycosylation sites (6): 74, 150, 246, 292, 318, 684

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-177929	Signaling by EGFR
R-HSA-6807004	Negative regulation of MET activity
R-HSA-9725554	Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-6806834	Signaling by MET
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases
R-HSA-9734767	Developmental Cell Lineages

MSigDB gene sets: 713 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GOBP_CHROMOSOME_ORGANIZATION, REACTOME_DNA_REPLICATION, GNF2_MSH2, E2F4DP1_01, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_CELL_CYCLE_DNA_REPLICATION, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, TGCACTT_MIR519C_MIR519B_MIR519A, ENK_UV_RESPONSE_KERATINOCYTE_UP, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_DNA_STRAND_ELONGATION_INVOLVED_IN_DNA_REPLICATION, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, GOBP_TELOMERE_ORGANIZATION, KAUFFMANN_DNA_REPAIR_GENES

GO Biological Process (4): sensory perception of sound (GO:0007605), hair cycle process (GO:0022405), otolith morphogenesis (GO:0032474), innervation (GO:0060384)

GO Molecular Function (2): signaling receptor activity (GO:0038023), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Signaling by Receptor Tyrosine Kinases	2
Signaling by MET	1
Developmental Cell Lineages of the Integumentary System	1
Signal Transduction	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sensory perception of mechanical stimulus	1
molting cycle process	1
hair cycle	1
inner ear morphogenesis	1
embryonic morphogenesis	1
otolith development	1
nerve development	1
multicellular organismal process	1
molecular transducer activity	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1647 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LRIG1	EGFR	P00533	817
LRIG1	HOPX	Q9BPY8	743
LRIG1	BMI1	P35226	682
LRIG1	OLFM4	Q6UX06	676
LRIG1	R4GMX3	R4GMX3	676
LRIG1	DIRC1	Q969H9	649
LRIG1	EGF	P01133	642
LRIG1	ASCL2	Q99929	629
LRIG1	KRT15	P19012	627
LRIG1	BMPR1A	P36894	607
LRIG1	RET	P07949	601
LRIG1	CBL	P22681	597
LRIG1	MSI1	O43347	591
LRIG1	CDH1	P12830	590
LRIG1	HSPBAP1	Q96EW2	588

IntAct

91 interactions, top by confidence:

A	B	Type	Score
HLA-DRA	HLA-DRB1	psi-mi:“MI:0914”(association)	0.880
LRIG1	ERBB2	psi-mi:“MI:0915”(physical association)	0.750
LRIG1	ERBB2	psi-mi:“MI:0403”(colocalization)	0.750
LRIG1	EGFR	psi-mi:“MI:0915”(physical association)	0.740
LRIG1	LRIG3	psi-mi:“MI:0915”(physical association)	0.640
FGL1	LCMT2	psi-mi:“MI:0914”(association)	0.640
LRIG1	ERBB4	psi-mi:“MI:0915”(physical association)	0.590
LRIG1	LRIG2	psi-mi:“MI:0914”(association)	0.530
GAL3ST1	NDUFA3	psi-mi:“MI:0914”(association)	0.530
CNPY3	SELENOT	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
DEFA1	MANBA	psi-mi:“MI:0914”(association)	0.530
CLGN	NPC1	psi-mi:“MI:0914”(association)	0.530

BioGRID (105): LRIG1 (Affinity Capture-MS), LRIG1 (Affinity Capture-MS), LRIG1 (Affinity Capture-MS), LRIG1 (Affinity Capture-MS), LRIG1 (Affinity Capture-MS), LRIG1 (Affinity Capture-MS), LRIG3 (Affinity Capture-MS), LRRC40 (Affinity Capture-MS), RAB4A (Affinity Capture-MS), CNPY4 (Affinity Capture-MS), LRIG1 (Affinity Capture-MS), LRIG1 (Affinity Capture-MS), SCRIB (Affinity Capture-MS), MTFR1L (Affinity Capture-MS), LRIG2 (Affinity Capture-MS)

ESM2 similar proteins: A1A4H9, A2ARI4, A2VDH3, A6H793, D4A6D8, E9Q7T7, F1MLX5, F1MT22, O75325, P59034, P59035, Q13641, Q149C3, Q3URE9, Q3UVD5, Q3UY51, Q4KLL3, Q4R8Y9, Q50LG9, Q5M8M9, Q5PQV5, Q5R6B1, Q5RDJ4, Q5VT99, Q6GQU6, Q6UY18, Q6ZSA7, Q7M6Z0, Q7TQ62, Q80WD1, Q86UE6, Q86UN2, Q86UN3, Q86WK6, Q8BHA1, Q8K0S5, Q8K377, Q8N7C0, Q91ZV8, Q96FE5

Diamond homologs: A0A1Y9G8H0, A0A452E9Y6, A1KZ92, A2A8L5, A2AJ76, A4IFW2, A4IGL7, A4IIW9, A5JUY8, A7MBJ4, A8WGA3, A8WQH2, B0BNK7, B3A0P3, D2HFT7, D3YXG0, D4A1J9, D4ABX8, G5EBF1, G5EG78, H2A0M7, O15146, O35158, O55005, O89026, P05164, P07202, P09933, P0C6S8, P0C7J6, P11247, P11678, P14650, P16621, P22079, P23468, P35419, P49290, P70193, P80025

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
CBL	down-regulates	LRIG1	ubiquitination
CBLC	down-regulates	LRIG1	ubiquitination
LRIG1	up-regulates	CBL	binding
LRIG1	up-regulates	CBLC	binding
LRIG1	down-regulates	EGFR	binding
LRIG1	down-regulates	ERBB2	ubiquitination
LRIG1	down-regulates	ERBB3	ubiquitination
LRIG1	down-regulates	ERBB4	ubiquitination
LRIG1	down-regulates	ERBB2
LRIG1	down-regulates	ERBB4
LRIG1	down-regulates	LRIG3
LRIG1	down-regulates	“ErbB receptor family”	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 79 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
SHC1 events in ERBB2 signaling	5	47.6×	1e-05
Signaling by ERBB2 TMD/JMD mutants	5	47.6×	1e-05
Signaling by ERBB2 KD Mutants	5	42.3×	1e-05
Constitutive Signaling by Aberrant PI3K in Cancer	6	15.2×	1e-04
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	6	11.6×	4e-04
RAF/MAP kinase cascade	8	9.8×	6e-05
PIP3 activates AKT signaling	6	8.0×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
cell surface receptor protein tyrosine kinase signaling pathway	6	14.9×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	213
Likely benign	40
Benign	27

Top pathogenic / likely-pathogenic (0)

SpliceAI

9641 predictions. Top by Δscore:

Variant	Effect	Δscore
19:48115731:ACCTG:A	acceptor_loss	1.0000
19:48115867:CCTCA:C	donor_loss	1.0000
19:48115868:CTCA:C	donor_loss	1.0000
19:48115871:A:AC	donor_gain	1.0000
19:48115871:A:AG	donor_loss	1.0000
19:48115872:C:CC	donor_gain	1.0000
19:48115928:C:CT	acceptor_gain	1.0000
19:48115929:G:T	acceptor_gain	1.0000
19:48117792:C:CT	acceptor_gain	1.0000
19:48119132:CTCA:C	donor_loss	1.0000
19:48119133:TCAC:T	donor_loss	1.0000
19:48119134:CACCT:C	donor_loss	1.0000
19:48119135:A:AC	donor_gain	1.0000
19:48119135:ACCTT:A	donor_loss	1.0000
19:48119136:C:CC	donor_gain	1.0000
19:48119136:C:CG	donor_loss	1.0000
19:48119186:CCAAG:C	acceptor_gain	1.0000
19:48119187:CAAG:C	acceptor_gain	1.0000
19:48119187:CAAGC:C	acceptor_gain	1.0000
19:48119188:AAG:A	acceptor_gain	1.0000
19:48119189:AG:A	acceptor_gain	1.0000
19:48119190:GC:G	acceptor_loss	1.0000
19:48119191:C:CC	acceptor_gain	1.0000
19:48119191:CTG:C	acceptor_loss	1.0000
19:48121132:C:A	donor_gain	1.0000
19:48121189:T:TA	donor_gain	1.0000
19:48121194:A:AC	donor_gain	1.0000
19:48121194:ACTGT:A	donor_gain	1.0000
19:48121195:C:CC	donor_gain	1.0000
19:48121195:CTGTC:C	donor_gain	1.0000

AlphaMissense

7146 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:66384002:A:G	L687P	1.000
3:66384166:C:A	W632C	1.000
3:66384166:C:G	W632C	1.000
3:66386180:C:A	W530C	1.000
3:66386180:C:G	W530C	1.000
3:66386182:A:G	W530R	1.000
3:66386182:A:T	W530R	1.000
3:66383172:G:C	N767K	0.999
3:66383172:G:T	N767K	0.999
3:66383295:C:A	W726C	0.999
3:66383295:C:G	W726C	0.999
3:66383297:A:G	W726R	0.999
3:66383297:A:T	W726R	0.999
3:66384009:C:G	A685P	0.999
3:66384034:G:C	N676K	0.999
3:66384034:G:T	N676K	0.999
3:66384041:G:T	A674D	0.999
3:66384046:A:C	C672W	0.999
3:66384047:C:G	C672S	0.999
3:66384048:A:G	C672R	0.999
3:66384048:A:T	C672S	0.999
3:66384054:A:C	Y670D	0.999
3:66384060:C:A	G668W	0.999
3:66384065:T:C	D666G	0.999
3:66384143:A:C	F640C	0.999
3:66384167:C:G	W632S	0.999
3:66384168:A:G	W632R	0.999
3:66384168:A:T	W632R	0.999
3:66384204:A:G	C620R	0.999
3:66384209:A:G	L618P	0.999

dbSNP variants (sampled 300 via entrez): RS1000019978 (3:66378571 A>G), RS1000053341 (3:66436151 C>A), RS1000068972 (3:66444641 C>G), RS1000071140 (3:66481123 G>A,C,T), RS1000083929 (3:66435893 G>A), RS1000100149 (3:66476374 T>C), RS1000123702 (3:66408469 C>A,T), RS1000150052 (3:66463578 T>A,C), RS1000160903 (3:66502594 T>C), RS1000177401 (3:66466695 C>A,T), RS1000210363 (3:66431265 A>C), RS1000212726 (3:66502212 C>G), RS1000217457 (3:66387996 A>C,T), RS1000231128 (3:66395171 G>C), RS1000248958 (3:66461498 T>C)

Disease associations

OMIM: gene MIM:608868 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

40 associations (top):

Study	Trait	p-value
GCST000872_5	QRS duration	1.000000e-08
GCST001231_2	Carotid intima media thickness	4.000000e-07
GCST001610_10	Renal function-related traits (BUN)	1.000000e-19
GCST001998_1	Adverse response to chemotherapy (neutropenia/leucopenia) (all platinum-based drugs)	4.000000e-06
GCST002004_6	Adverse response to chemotherapy (neutropenia/leucopenia) (carboplatin)	6.000000e-06
GCST002280_6	Antibody status in Tripanosoma cruzi seropositivity	4.000000e-07
GCST002363_5	Response to anti-retroviral therapy (ddI/d4T) in HIV-1 infection (Grade 3 peripheral neuropathy)	6.000000e-08
GCST002806_3	Type 2 diabetes	4.000000e-06
GCST003017_2	Colorectal cancer	3.000000e-08
GCST003017_8	Colorectal cancer	2.000000e-08
GCST003598_12	QRS duration	1.000000e-07
GCST003598_39	QRS duration	5.000000e-08
GCST003844_25	QRS duration	6.000000e-09
GCST004348_16	Non-glioblastoma glioma	8.000000e-09
GCST004602_129	Mean corpuscular volume	1.000000e-09
GCST004630_117	Mean corpuscular hemoglobin	7.000000e-14
GCST005986_33	Blood urea nitrogen levels	1.000000e-29
GCST006061_160	Atrial fibrillation	5.000000e-11
GCST006394_35	Intraocular pressure	4.000000e-14
GCST006414_77	Atrial fibrillation	1.000000e-10
GCST007096_80	Pulse pressure	5.000000e-11
GCST007099_228	Systolic blood pressure	4.000000e-07
GCST007856_86	Colorectal cancer or advanced adenoma	7.000000e-08
GCST007916_15	Hyperuricemia	3.000000e-16
GCST007917_19	Estimated glomerular filtration rate	2.000000e-16
GCST007918_2	Serum uric acid levels	2.000000e-16
GCST007919_8	Creatinine levels	2.000000e-16
GCST007920_3	Chronic kidney disease	2.000000e-16
GCST008362_102	Birth weight	1.000000e-08
GCST009724_31	Vertical cup-disc ratio (multi-trait analysis)	2.000000e-08

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0000180	HIV-1 infection
EFO:0005054	QRS complex
EFO:0004527	mean corpuscular hemoglobin
EFO:0004695	intraocular pressure measurement
EFO:0005763	pulse pressure measurement
EFO:0006335	systolic blood pressure
EFO:0009104	hyperuricemia
EFO:0004761	uric acid measurement
EFO:0004344	birth weight
EFO:0006939	cup-to-disc ratio measurement
EFO:0010698	retinal break
EFO:0004327	electrocardiography
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, increases expression	7
trichostatin A	affects cotreatment, decreases expression	3
Benzo(a)pyrene	affects methylation, decreases expression	3
Tetrachlorodibenzodioxin	decreases expression	3
Tobacco Smoke Pollution	decreases expression	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
sodium arsenite	increases abundance, increases expression, decreases expression, affects cotreatment	2
Vorinostat	affects cotreatment, decreases expression	2
Panobinostat	decreases expression, affects cotreatment	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Arsenic	affects expression, affects cotreatment, increases abundance, increases expression	2
Cisplatin	affects localization, decreases reaction, increases phosphorylation, increases response to substance, affects cotreatment (+1 more)	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tamoxifen	affects expression, affects cotreatment, decreases expression	2
Aflatoxin B1	decreases methylation, decreases expression	2
Raloxifene Hydrochloride	affects expression, affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
bisphenol A	affects cotreatment, increases methylation, decreases methylation	1
sulforaphane	increases expression	1
9,10-dihydro-9,10-dihydroxybenzo(a)pyrene	decreases expression	1
manganese chloride	increases expression, affects cotreatment, increases abundance	1
benzo(e)pyrene	increases methylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
di-n-butylphosphoric acid	affects 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, decreases expression	1

Clinical trials (associated diseases)

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