LRRFIP1

Summary

LRRFIP1 (LRR binding FLII interacting protein 1, HGNC:6702) is a protein-coding gene on chromosome 2q37.3, encoding Leucine-rich repeat flightless-interacting protein 1 (Q32MZ4). Transcriptional repressor which preferentially binds to the GC-rich consensus sequence (5’-AGCCCCCGGCG-3’) and may regulate expression of TNF, EGFR and PDGFA.

Enables DNA-binding transcription repressor activity, RNA polymerase II-specific; RNA polymerase II cis-regulatory region sequence-specific DNA binding activity; and protein homodimerization activity. Involved in negative regulation of transcription by RNA polymerase II. Located in cytosol and plasma membrane.

Source: NCBI Gene 9208 — RefSeq curated summary.

At a glance

• Gene–disease (curated): schizophrenia (No Known Disease Relationship, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 172 total
• Druggable target: yes
• Transcription factor: yes — 17 downstream targets (CollecTRI)
• MANE Select transcript: NM_001137550

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6702
Approved symbol	LRRFIP1
Name	LRR binding FLII interacting protein 1
Location	2q37.3
Locus type	gene with protein product
Status	Approved
Aliases	FLAP-1, FLIIAP1, TRIP, GCF-2, HUFI-1, GCF2
Ensembl gene	ENSG00000124831
Ensembl biotype	protein_coding
OMIM	603256
Entrez	9208

Gene structure

Transcript identifiers

Ensembl transcripts: 145 — 134 protein_coding, 5 retained_intron, 5 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000244815, ENST00000289175, ENST00000308482, ENST00000392000, ENST00000420665, ENST00000464608, ENST00000465870, ENST00000468950, ENST00000473815, ENST00000474195, ENST00000478958, ENST00000483443, ENST00000489295, ENST00000489603, ENST00000498053, ENST00000698097, ENST00000698098, ENST00000863708, ENST00000863709, ENST00000863710, ENST00000863711, ENST00000863712, ENST00000863713, ENST00000863714, ENST00000863715, ENST00000863716, ENST00000863717, ENST00000863718, ENST00000863719, ENST00000863720, ENST00000863721, ENST00000863722, ENST00000863723, ENST00000863724, ENST00000863725, ENST00000863726, ENST00000863727, ENST00000863728, ENST00000863729, ENST00000863730, ENST00000863731, ENST00000863732, ENST00000863733, ENST00000863734, ENST00000863735, ENST00000863736, ENST00000863737, ENST00000863738, ENST00000933070, ENST00000933071, ENST00000933072, ENST00000933073, ENST00000933074, ENST00000933075, ENST00000970842, ENST00000970843, ENST00000970844, ENST00000970845, ENST00000970846, ENST00000970847, ENST00000970848, ENST00000970849, ENST00000970850, ENST00000970851, ENST00000970852, ENST00000970853, ENST00000970854, ENST00000970855, ENST00000970856, ENST00000970857, ENST00000970858, ENST00000970859, ENST00000970860, ENST00000970861, ENST00000970862, ENST00000970863, ENST00000970864, ENST00000970865, ENST00000970866, ENST00000970867, ENST00000970868, ENST00000970869, ENST00000970870, ENST00000970871, ENST00000970872, ENST00000970873, ENST00000970874, ENST00000970875, ENST00000970876, ENST00000970877, ENST00000970878, ENST00000970879, ENST00000970880, ENST00000970881, ENST00000970882, ENST00000970883, ENST00000970884, ENST00000970885, ENST00000970886, ENST00000970887, ENST00000970888, ENST00000970889, ENST00000970890, ENST00000970891, ENST00000970892, ENST00000970893, ENST00000970894, ENST00000970895, ENST00000970896, ENST00000970897, ENST00000970898, ENST00000970899, ENST00000970900, ENST00000970901, ENST00000970902, ENST00000970903, ENST00000970904, ENST00000970905, ENST00000970906, ENST00000970907, ENST00000970908, ENST00000970909, ENST00000970910, ENST00000970911, ENST00000970912, ENST00000970913, ENST00000970914, ENST00000970915, ENST00000970916, ENST00000970917, ENST00000970918, ENST00000970919, ENST00000970920, ENST00000970921, ENST00000970922, ENST00000970923, ENST00000970924, ENST00000970925, ENST00000970926, ENST00000970927, ENST00000970928, ENST00000970929, ENST00000970930, ENST00000970931, ENST00000970932

RefSeq mRNA: 5 — MANE Select: NM_001137550 NM_001137550, NM_001137551, NM_001137552, NM_001137553, NM_004735

CCDS: CCDS2521, CCDS46551, CCDS46552, CCDS46553

Canonical transcript exons

ENST00000308482 — 24 exons

Exon	Start	End
ENSE00000850747	237723548	237723586
ENSE00000850748	237727876	237727935
ENSE00000850751	237739232	237739309
ENSE00000850761	237757456	237757548
ENSE00000850762	237758729	237758821
ENSE00001510385	237627587	237627740
ENSE00001697805	237751200	237751271
ENSE00003464813	237708544	237708630
ENSE00003475410	237733774	237733818
ENSE00003484739	237735268	237735333
ENSE00003491175	237772866	237772945
ENSE00003535792	237769943	237769992
ENSE00003550812	237772081	237772198
ENSE00003571965	237753309	237753479
ENSE00003617596	237774358	237774462
ENSE00003623655	237756095	237756187
ENSE00003625487	237714259	237714276
ENSE00003628508	237749199	237749324
ENSE00003641532	237717762	237717809
ENSE00003652146	237719523	237719567
ENSE00003660091	237720772	237720822
ENSE00003669880	237760064	237760205
ENSE00003676482	237748364	237748399
ENSE00003677240	237779422	237781643

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 99.82.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 46.0741 / max 1770.1024, expressed in 1813 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
26278	23.4059	1791
26259	10.8327	1559
26279	10.2193	1535
26280	1.0584	420
26274	0.5412	166
26273	0.0166	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
renal medulla	UBERON:0000362	99.82	gold quality
endothelial cell	CL:0000115	99.75	gold quality
cervix squamous epithelium	UBERON:0006922	99.70	gold quality
cardia of stomach	UBERON:0001162	99.69	gold quality
nipple	UBERON:0002030	99.65	gold quality
pylorus	UBERON:0001166	99.60	gold quality
visceral pleura	UBERON:0002401	99.54	gold quality
superior surface of tongue	UBERON:0007371	99.51	gold quality
buccal mucosa cell	CL:0002336	99.50	gold quality
pharyngeal mucosa	UBERON:0000355	99.47	gold quality
pericardium	UBERON:0002407	99.46	gold quality
ventral tegmental area	UBERON:0002691	99.45	gold quality
blood vessel layer	UBERON:0004797	99.44	gold quality
trigeminal ganglion	UBERON:0001675	99.42	gold quality
saphenous vein	UBERON:0007318	99.34	gold quality
skin of hip	UBERON:0001554	99.32	gold quality
superficial temporal artery	UBERON:0001614	99.31	gold quality
cranial nerve II	UBERON:0000941	99.30	gold quality
urethra	UBERON:0000057	99.28	gold quality
medulla oblongata	UBERON:0001896	99.28	gold quality
mammalian vulva	UBERON:0000997	99.27	gold quality
subthalamic nucleus	UBERON:0001906	99.27	gold quality
pleura	UBERON:0000977	99.26	gold quality
penis	UBERON:0000989	99.25	gold quality
inferior vagus X ganglion	UBERON:0005363	99.23	gold quality
superior vestibular nucleus	UBERON:0007227	99.23	gold quality
tendon of biceps brachii	UBERON:0008188	99.22	gold quality
trabecular bone tissue	UBERON:0002483	99.20	gold quality
mucosa of paranasal sinus	UBERON:0005030	99.19	gold quality
parietal pleura	UBERON:0002400	99.17	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	25.19
E-MTAB-9221	yes	17.41
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

17 targets.

Target	Regulation
EGFR	Repression
ERVW-1
FLG
IFNB1	Activation
KIR3DL2
KRAS
MYD88
NGF
NTRK1
PDGFA	Repression
PTH
RHOA
SERPINE1	Unknown
SLC1A2
SLC1A3	Repression
TFAP2A
TNF	Repression

miRNA regulators (miRDB)

70 targeting LRRFIP1, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-4517	99.76	69.19	1867
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-132-3P	99.73	70.56	1424
HSA-MIR-212-3P	99.73	70.65	1424

Literature-anchored findings (GeneRIF, showing 14)

• GCF2/LRRFIP1 appears to act as a repressor and occupies the -308 site in cells that do not make TNF-alpha. (PMID:16199883)
• Immediately following lipopolysaccharide stimulation, both LRRFIP2 and Flap-1/LRRFIP1 compete with Fliih for interacting with MyD88 to activate the signaling. (PMID:19265123)
• An association study of 6 of the 63 genes in 4235 cases and 6379 controls showed a putative association with myocardial infarction for COMMD7 (COMM domain-containing protein 7) and a major deviation from the null hypo thesis for LRRFIP1. (PMID:20833976)
• LRRFIP1 is phosphorylated in response to immunologic stimuli and it is directed to lysosomal structures. (PMID:21102652)
• GCF2/LRRFIP1 plays an important role in colorectal cancer metastasis by regulating RhoA-induced cell adhesion. (PMID:22750095)
• The FLI-interacting domain of LRRFIP1 forms a classic parallel, homodimeric coiled coil with 10 heptad repeats and 22 helical turns. (PMID:23099021)
• Eight SNPs (rs7575941, rs3769053, rs11689421, rs3820808, rs11680012, rs3806505, rs6739130, and rs11686141) showed evidence of association with at least two adiposity phenotypes and plasma levels of one marker of inflammation. (PMID:23505185)
• Data indicate that LRRFIP1 knockdown increased resting TNF mRNA level altered the ncRNA abundance at the LRRFIP1 binding region. (PMID:24567534)
• Higher baseline LRRFIP1 expression in human glioblastoma multiforme tissue (n=60) is associated with better prognosis upon later treatment with teniposide. (PMID:24690174)
• High GCF2 expression is associated with hepatoma. (PMID:24761896)
• Silencing of LRRFIP1 reverses the epithelial-mesenchymal transition via inhibition of the Wnt/beta-catenin signaling pathway. (PMID:26047573)
• Results show that LRRFIP-1 is mainly produced by keratinocytes in the unwounded skin but is upregulated in both keratinocytes and fibroblasts in response to wounding, suggesting a role in the wound repair process. (PMID:29996558)
• LRRFIP1/GCF2 is a bioregulator in multidisciplinary systems of the human body and its dysregulation can cause diverse human diseases. (PMID:30709060)
• LRRFIP1, an epigenetically regulated gene, is a prognostic biomarker and predicts malignant phenotypes of glioma. (PMID:35338570)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	lrrfip1a	ENSDARG00000030012
mus_musculus	Lrrfip1	ENSMUSG00000026305
rattus_norvegicus	Lrrfip1	ENSRNOG00000019892
drosophila_melanogaster	CG8578	FBGN0030699
caenorhabditis_elegans		WBGENE00018998

Paralogs (1): LRRFIP2 (ENSG00000093167)

Protein

Protein identifiers

Leucine-rich repeat flightless-interacting protein 1 — Q32MZ4 (reviewed: Q32MZ4)

Alternative names: GC-binding factor 2, TAR RNA-interacting protein

All UniProt accessions (5): A0A0F7NGI8, A0A8V8TLX7, A0A8V8TMX2, C9JTC6, Q32MZ4

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional repressor which preferentially binds to the GC-rich consensus sequence (5’-AGCCCCCGGCG-3’) and may regulate expression of TNF, EGFR and PDGFA. May control smooth muscle cells proliferation following artery injury through PDGFA repression. May also bind double-stranded RNA. Positively regulates Toll-like receptor (TLR) signaling in response to agonist probably by competing with the negative FLII regulator for MYD88-binding.

Subunit / interactions. Homodimer. May also form higher oligomers. Interacts with FLII. Interacts with MYD88. Competes with FLII for MyD88-binding, even in the absence of LPS.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Ubiquitously expressed.

Domain organisation. The DNA-binding domain is intrinsically unstructured. The coiled coil mediates dimerization.

Similarity. Belongs to the LRRFIP family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q32MZ4-1	1	yes
Q32MZ4-2	2
Q32MZ4-3	3
Q32MZ4-4	4

RefSeq proteins (5): NP_001131022, NP_001131023, NP_001131024, NP_001131025, NP_004726 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019139	LRRFIP1/2	Family

Pfam: PF09738

UniProt features (63 total): modified residue 16, compositionally biased region 13, splice variant 8, sequence variant 8, sequence conflict 7, region of interest 4, cross-link 2, initiator methionine 1, chain 1, coiled-coil region 1, helix 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4H22	X-RAY DIFFRACTION	2.89

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q32MZ4-F1	55.90	0.19

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 (18): 2, 16, 115, 116, 120, 124, 555, 564, 581, 618, 638, 676, 714, 733, 766, 768, 305, 606

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-1839117	Signaling by cytosolic FGFR1 fusion mutants
R-HSA-3134973	LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production
R-HSA-5655302	Signaling by FGFR1 in disease
R-HSA-1226099	Signaling by FGFR in disease
R-HSA-1643685	Disease
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-1834949	Cytosolic sensors of pathogen-associated DNA
R-HSA-1839124	FGFR1 mutant receptor activation
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers

MSigDB gene sets: 238 (showing top): RNGTGGGC_UNKNOWN, REACTOME_INNATE_IMMUNE_SYSTEM, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, SRF_Q5_01, BILD_HRAS_ONCOGENIC_SIGNATURE, ONKEN_UVEAL_MELANOMA_UP, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, FOSTER_TOLERANT_MACROPHAGE_UP, BLALOCK_ALZHEIMERS_DISEASE_UP, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, MODULE_123, PU1_Q6, HOEBEKE_LYMPHOID_STEM_CELL_UP, IK2_01

GO Biological Process (3): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), regulation of DNA-templated transcription (GO:0006355)

GO Molecular Function (8): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription repressor activity, RNA polymerase II-specific (GO:0001227), DNA binding (GO:0003677), double-stranded RNA binding (GO:0003725), protein homodimerization activity (GO:0042803), cadherin binding (GO:0045296), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
FGFR1 mutant receptor activation	1
Cytosolic sensors of pathogen-associated DNA	1
Signaling by FGFR in disease	1
Diseases of signal transduction by growth factor receptors and second messengers	1
Immune System	1
Innate Immune System	1
Signaling by FGFR1 in disease	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
cellular anatomical structure	2
negative regulation of DNA-templated transcription	1
regulation of DNA-templated transcription	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
nucleic acid binding	1
RNA binding	1
identical protein binding	1
protein dimerization activity	1
cell adhesion molecule binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cytoplasm	1
intracellular membraneless organelle	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

938 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LRRFIP1	FLII	Q13045	982
LRRFIP1	CTNNB1	P35222	908
LRRFIP1	GCFC2	P16383	845
LRRFIP1	IFI16	Q16666	744
LRRFIP1	DDX41	Q9UJV9	738
LRRFIP1	DHX36	Q9H2U1	700
LRRFIP1	RBM8A	Q9Y5S9	687
LRRFIP1	MYD88	P78397	668
LRRFIP1	IRF3	Q14653	660
LRRFIP1	SLC1A2	P43004	630
LRRFIP1	TFAP2A	P05549	619
LRRFIP1	DHX9	Q08211	594
LRRFIP1	AIM2	O14862	575
LRRFIP1	CGAS	Q8N884	535
LRRFIP1	DDX1	Q92499	533

IntAct

68 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
FLII	LRRFIP1	psi-mi:“MI:0915”(physical association)	0.690
LRRFIP1	FLII	psi-mi:“MI:0407”(direct interaction)	0.690
RUVBL2	POLR3A	psi-mi:“MI:0914”(association)	0.640
FLII	TMOD1	psi-mi:“MI:0914”(association)	0.640
HTT	LRRFIP1	psi-mi:“MI:0915”(physical association)	0.560
PFKL	PFKP	psi-mi:“MI:0914”(association)	0.530
IFT74	LRRFIP1	psi-mi:“MI:0914”(association)	0.530
TMOD1	GSN	psi-mi:“MI:0914”(association)	0.530
MTMR9	CENPF	psi-mi:“MI:0914”(association)	0.530
	AP3D1	psi-mi:“MI:0914”(association)	0.460
TSG101	LRRFIP1	psi-mi:“MI:0407”(direct interaction)	0.440
LRRFIP1	NUMA1	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
PA	LRRFIP1	psi-mi:“MI:0915”(physical association)	0.370
MAPT	MEX3A	psi-mi:“MI:0914”(association)	0.350
VMP1	TPM3	psi-mi:“MI:0914”(association)	0.350
	FLII	psi-mi:“MI:0914”(association)	0.350
TB8.4	NRAS	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
CTBP1	GSN	psi-mi:“MI:0914”(association)	0.350
N	MRPL45	psi-mi:“MI:0914”(association)	0.350
BMI1	HMGB1P1	psi-mi:“MI:0914”(association)	0.350
RYBP	PIPSL	psi-mi:“MI:0914”(association)	0.350

BioGRID (208): MED4 (Two-hybrid), CEP44 (Two-hybrid), LRRFIP1 (Affinity Capture-MS), LRRFIP1 (Affinity Capture-MS), LRRFIP1 (Affinity Capture-MS), LRRFIP1 (Affinity Capture-MS), LRRFIP1 (Two-hybrid), LRRFIP1 (Affinity Capture-MS), LRRFIP1 (Affinity Capture-MS), LRRFIP1 (Affinity Capture-MS), LRRFIP1 (Affinity Capture-MS), LRRFIP1 (Affinity Capture-MS), LRRFIP1 (Affinity Capture-MS), LRRFIP1 (Affinity Capture-MS), LRRFIP1 (Affinity Capture-MS)

ESM2 similar proteins: A0JM80, A6H8Y1, A7MBJ2, D3ZF42, E9Q6J5, F4I700, F4J3S1, F4KCE9, F6QRE9, O04251, O82345, P23497, P46100, P48785, P48786, Q04996, Q05B65, Q0WTB8, Q13342, Q15361, Q32MZ4, Q3UZ39, Q3ZBR9, Q4QSC8, Q571C7, Q5H9K5, Q5RHP9, Q61687, Q66HF9, Q7YQM3, Q7YQM4, Q7Z5L2, Q8BJM3, Q8C4A5, Q8C9B9, Q8GZ87, Q8H991, Q8IW19, Q92576, Q940Y3

Diamond homologs: B2GUE2, Q2T9W6, Q32MZ4, Q3UZ39, Q4V7E8, Q66HF9, Q6GNW0, Q91WK0, Q9Y608

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SYK	“up-regulates activity”	LRRFIP1	phosphorylation
LRRFIP1	“down-regulates quantity by repression”	EGFR	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 73 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
Striated Muscle Contraction	5	32.1×	2e-04
RHO GTPase Effectors	6	8.5×	4e-03
Signaling by Rho GTPases	9	6.4×	1e-03
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	9	6.3×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
muscle contraction	5	16.8×	2e-03
actin filament organization	6	11.5×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	126
Likely benign	8
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

4512 predictions. Top by Δscore:

Variant	Effect	Δscore
2:237692518:GCTG:G	donor_gain	1.0000
2:237692519:CTGG:C	donor_loss	1.0000
2:237692520:TGGT:T	donor_loss	1.0000
2:237692521:GGTA:G	donor_loss	1.0000
2:237692522:G:GA	donor_loss	1.0000
2:237692522:G:GG	donor_gain	1.0000
2:237692523:T:G	donor_loss	1.0000
2:237692530:A:T	donor_gain	1.0000
2:237708539:TTCA:T	acceptor_loss	1.0000
2:237708542:A:AG	acceptor_gain	1.0000
2:237708542:AGGC:A	acceptor_gain	1.0000
2:237708542:AGGCG:A	acceptor_gain	1.0000
2:237708543:G:GA	acceptor_gain	1.0000
2:237708543:GGCG:G	acceptor_gain	1.0000
2:237708543:GGCGG:G	acceptor_gain	1.0000
2:237708627:GGAG:G	donor_gain	1.0000
2:237708628:GAGG:G	donor_gain	1.0000
2:237708628:GAGGT:G	donor_loss	1.0000
2:237708629:AGGT:A	donor_loss	1.0000
2:237708630:GGTAA:G	donor_loss	1.0000
2:237708631:G:GA	donor_loss	1.0000
2:237708632:T:G	donor_loss	1.0000
2:237748258:G:GT	donor_gain	1.0000
2:237753279:A:AG	acceptor_gain	1.0000
2:237753304:CACA:C	acceptor_loss	1.0000
2:237753307:A:G	acceptor_loss	1.0000
2:237753308:G:A	acceptor_loss	1.0000
2:237753475:ACAAA:A	donor_gain	1.0000
2:237753476:CAAA:C	donor_gain	1.0000
2:237753477:AAA:A	donor_gain	1.0000

AlphaMissense

4209 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:237708580:G:C	A35P	0.999
2:237708586:G:C	A37P	0.999
2:237708611:T:C	L45P	0.999
2:237753345:G:C	A174P	0.999
2:237753360:G:C	A179P	0.999
2:237753367:T:C	L181P	0.999
2:237753409:T:C	L195P	0.999
2:237708574:G:C	A33P	0.998
2:237708589:C:A	R38S	0.998
2:237708590:G:C	R38P	0.998
2:237708598:C:A	R41S	0.998
2:237708599:G:C	R41P	0.998
2:237708617:G:C	R47P	0.998
2:237753354:T:C	S177P	0.998
2:237753430:T:C	L202P	0.998
2:237708557:T:C	L27P	0.997
2:237708562:G:C	A29P	0.997
2:237708567:A:C	K30N	0.997
2:237708567:A:T	K30N	0.997
2:237708569:G:C	R31P	0.997
2:237708571:G:C	A32P	0.997
2:237708577:C:A	R34S	0.997
2:237753364:A:C	Q180P	0.997
2:237753397:A:C	Q191P	0.997
2:237753442:T:C	L206P	0.997
2:237708550:G:C	A25P	0.996
2:237708578:G:C	R34P	0.996
2:237708596:T:C	I40T	0.996
2:237753316:T:C	L164P	0.996
2:237753336:T:G	Y171D	0.996

dbSNP variants (sampled 300 via entrez): RS1000030698 (2:237749804 A>G), RS1000056249 (2:237752387 C>G), RS1000061402 (2:237703292 C>T), RS1000063739 (2:237642383 G>A,T), RS1000072382 (2:237752570 C>G,T), RS1000084978 (2:237671342 C>T), RS1000094628 (2:237678743 A>C), RS1000114877 (2:237702782 CA>C), RS1000117347 (2:237750584 ACTCGGCCT>A), RS1000119060 (2:237715324 G>A), RS1000139106 (2:237753651 G>A), RS1000144892 (2:237664320 G>A,C), RS1000157681 (2:237681880 C>T), RS1000180070 (2:237637279 C>T), RS1000191140 (2:237639200 A>G)

Disease associations

OMIM: gene MIM:603256 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
schizophrenia	No Known Disease Relationship	Unknown

Mondo (2): myoepithelial tumor (MONDO:0002380), schizophrenia (MONDO:0005090)

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001583_1	Adiposity	4.000000e-06
GCST006658_5	Longevity	2.000000e-07
GCST010241_301	Apolipoprotein A1 levels	1.000000e-08
GCST010396_35	Gut microbiota (bacterial taxa, hurdle binary method)	7.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004614	apolipoprotein A 1 measurement
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D009208	Myoepithelioma	C04.557.435.585

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295838 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.64	Kd	227.8	nM	CHEMBL5653589
6.64	ED50	227.8	nM	CHEMBL5653589
5.46	Kd	3505	nM	CHEMBL3752910
5.46	ED50	3505	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 5 total; 2 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	2148668: Binding affinity to human LRRFIP1 incubated for 45 mins by Kinobead based pull down assay	kd	0.2278	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148668: Binding affinity to human LRRFIP1 incubated for 45 mins by Kinobead based pull down assay	kd	3.5054	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
sodium arsenite	decreases expression, increases expression, increases stability	3
Air Pollutants	increases expression, affects cotreatment, decreases expression, increases abundance, affects expression	3
bisphenol F	affects cotreatment, decreases methylation, increases expression	2
bisphenol A	affects expression, affects cotreatment, decreases methylation	2
entinostat	increases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment, decreases expression	2
Resveratrol	affects cotreatment, increases expression	2
Acetaminophen	affects expression, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Formaldehyde	decreases expression, increases expression	2
Ozone	affects cotreatment, decreases expression, increases abundance, affects expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Aflatoxin B1	increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	affects sumoylation	1
urushiol	increases expression	1
methylmercuric chloride	increases expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
sodium arsenate	decreases expression	1
trichostatin A	increases expression	1
beta-lapachone	increases expression	1
arsenite	decreases methylation	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	affects cotreatment, increases expression	1
coumarin	increases phosphorylation	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4119033	Binding	Binding affinity to LRRFIP1 in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety