LRRFIP2

Summary

LRRFIP2 (LRR binding FLII interacting protein 2, HGNC:6703) is a protein-coding gene on chromosome 3p22.2, encoding Leucine-rich repeat flightless-interacting protein 2 (Q9Y608). May function as activator of the canonical Wnt signaling pathway, in association with DVL3, upstream of CTNNB1/beta-catenin.

The protein encoded by this gene, along with MYD88, binds to the cytosolic tail of toll-like receptor 4 (TLR4), which results in activation of nuclear factor kappa B signaling. The ubiquitin-like protein FAT10 prevents the interaction of the encoded protein and TLR4, thereby inactivating the nuclear factor kappa B signaling pathway. In addition, this protein can downregulate the NLRP3 inflammasome by recruiting the caspase-1 inhibitor Flightless-I to the inflammasome complex.

Source: NCBI Gene 9209 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 126 total — 3 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_006309

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6703
Approved symbol	LRRFIP2
Name	LRR binding FLII interacting protein 2
Location	3p22.2
Locus type	gene with protein product
Status	Approved
Aliases	HUFI-2
Ensembl gene	ENSG00000093167
Ensembl biotype	protein_coding
OMIM	614043
Entrez	9209

Gene structure

Transcript identifiers

Ensembl transcripts: 321 — 312 protein_coding, 5 protein_coding_CDS_not_defined, 4 retained_intron

ENST00000336686, ENST00000354379, ENST00000396428, ENST00000416425, ENST00000421276, ENST00000434749, ENST00000436858, ENST00000438374, ENST00000440230, ENST00000440742, ENST00000452742, ENST00000460646, ENST00000461672, ENST00000481682, ENST00000482466, ENST00000483306, ENST00000487246, ENST00000490597, ENST00000496479, ENST00000496825, ENST00000900385, ENST00000900386, ENST00000900387, ENST00000900388, ENST00000900389, ENST00000900390, ENST00000900391, ENST00000900392, ENST00000900393, ENST00000900394, ENST00000900395, ENST00000900396, ENST00000900397, ENST00000900398, ENST00000900399, ENST00000900400, ENST00000900401, ENST00000900402, ENST00000900403, ENST00000900404, ENST00000900405, ENST00000900406, ENST00000900407, ENST00000900408, ENST00000900409, ENST00000900410, ENST00000900411, ENST00000900412, ENST00000900413, ENST00000900414, ENST00000900415, ENST00000900416, ENST00000900417, ENST00000900418, ENST00000900419, ENST00000900420, ENST00000900421, ENST00000900422, ENST00000900423, ENST00000900424, ENST00000900425, ENST00000900426, ENST00000900427, ENST00000900428, ENST00000900429, ENST00000900430, ENST00000900431, ENST00000900432, ENST00000900433, ENST00000900434, ENST00000900435, ENST00000900436, ENST00000900437, ENST00000900438, ENST00000900439, ENST00000900440, ENST00000900441, ENST00000900442, ENST00000900443, ENST00000900444, ENST00000900445, ENST00000900446, ENST00000900447, ENST00000900448, ENST00000900449, ENST00000900450, ENST00000900451, ENST00000900452, ENST00000900453, ENST00000900454, ENST00000900455, ENST00000900456, ENST00000900457, ENST00000900458, ENST00000900459, ENST00000900460, ENST00000900461, ENST00000900462, ENST00000900463, ENST00000900464, ENST00000900465, ENST00000900466, ENST00000900467, ENST00000900468, ENST00000900469, ENST00000932428, ENST00000932429, ENST00000932430, ENST00000932431, ENST00000932432, ENST00000932433, ENST00000932434, ENST00000952768, ENST00000952769, ENST00000952770, ENST00000952771, ENST00000952772, ENST00000952773, ENST00000952774, ENST00000952775, ENST00000952776, ENST00000952777, ENST00000952778, ENST00000952779, ENST00000952780, ENST00000952781, ENST00000952782, ENST00000952783, ENST00000952784, ENST00000952785, ENST00000952786, ENST00000952787, ENST00000952788, ENST00000952789, ENST00000952790, ENST00000952791, ENST00000952792, ENST00000952793, ENST00000952794, ENST00000952795, ENST00000952796, ENST00000952797, ENST00000952798, ENST00000952799, ENST00000952800, ENST00000952801, ENST00000952802, ENST00000952803, ENST00000952804, ENST00000952805, ENST00000952806, ENST00000952807, ENST00000952808, ENST00000952809, ENST00000952810, ENST00000952811, ENST00000952812, ENST00000952813, ENST00000952814, ENST00000952815, ENST00000952816, ENST00000952817, ENST00000952818, ENST00000952819, ENST00000952820, ENST00000952821, ENST00000952822, ENST00000952823, ENST00000952824, ENST00000952825, ENST00000952826, ENST00000952827, ENST00000952828, ENST00000952829, ENST00000952830, ENST00000952831, ENST00000952832, ENST00000952833, ENST00000952834, ENST00000952835, ENST00000952836, ENST00000952837, ENST00000952838, ENST00000952839, ENST00000952840, ENST00000952841, ENST00000952842, ENST00000952843, ENST00000952844, ENST00000952845, ENST00000952846, ENST00000952847, ENST00000952848, ENST00000952849, ENST00000952850, ENST00000952851, ENST00000952852, ENST00000952853, ENST00000952854, ENST00000952855, ENST00000952856, ENST00000952857, ENST00000952858, ENST00000952859, ENST00000952860, ENST00000952861, ENST00000952862, ENST00000952863, ENST00000952864, ENST00000952865, ENST00000952866, ENST00000952867, ENST00000952868, ENST00000952869, ENST00000952870, ENST00000952871, ENST00000952872, ENST00000952873, ENST00000952874, ENST00000952875, ENST00000952876, ENST00000952877, ENST00000952878, ENST00000952879, ENST00000952880, ENST00000952881, ENST00000952882, ENST00000952883, ENST00000952884, ENST00000952885, ENST00000952886, ENST00000952887, ENST00000952888, ENST00000952889, ENST00000952890, ENST00000952891, ENST00000952892, ENST00000952893, ENST00000952894, ENST00000952895, ENST00000952896, ENST00000952897, ENST00000952898, ENST00000952899, ENST00000952900, ENST00000952901, ENST00000952902, ENST00000952903, ENST00000952904, ENST00000952905, ENST00000952906, ENST00000952907, ENST00000952908, ENST00000952909, ENST00000952910, ENST00000952911, ENST00000952912, ENST00000952913, ENST00000952914, ENST00000952915, ENST00000952916, ENST00000952917, ENST00000952918, ENST00000952919, ENST00000952920, ENST00000952921, ENST00000952922, ENST00000952923, ENST00000952924, ENST00000952925, ENST00000952926, ENST00000952927, ENST00000952928, ENST00000952929, ENST00000952930, ENST00000952931, ENST00000952932, ENST00000952933, ENST00000952934, ENST00000952935, ENST00000952936, ENST00000952937, ENST00000952938, ENST00000952939, ENST00000952940, ENST00000952941, ENST00000952942, ENST00000952943, ENST00000952944, ENST00000952945, ENST00000952946, ENST00000952947, ENST00000952948, ENST00000952949, ENST00000952950, ENST00000952951, ENST00000952952, ENST00000952953, ENST00000952954, ENST00000952955, ENST00000952956, ENST00000952957, ENST00000952958, ENST00000952959, ENST00000952960, ENST00000952961, ENST00000952962, ENST00000952963, ENST00000952964, ENST00000952965, ENST00000952966, ENST00000952967, ENST00000952968, ENST00000952969, ENST00000952970, ENST00000952971, ENST00000952972, ENST00000952973, ENST00000952974, ENST00000952975, ENST00000952976

RefSeq mRNA: 19 — MANE Select: NM_006309 NM_001134369, NM_001282691, NM_001348297, NM_001348298, NM_001348299, NM_001348300, NM_001348301, NM_001348302, NM_001348303, NM_001348304, NM_001348305, NM_001348306, NM_001348307, NM_001348308, NM_001348309, NM_001348310, NM_001348311, NM_006309, NM_017724

CCDS: CCDS2664, CCDS2665, CCDS46791, CCDS63592

Canonical transcript exons

ENST00000336686 — 28 exons

Exon	Start	End
ENSE00000492074	37108637	37108684
ENSE00000760286	37115054	37115095
ENSE00000760311	37112915	37112980
ENSE00000760403	37109653	37109703
ENSE00000760520	37109527	37109571
ENSE00000760563	37108073	37108129
ENSE00000760579	37105455	37105523
ENSE00000760580	37102924	37103013
ENSE00000760648	37083636	37083806
ENSE00000760675	37072790	37072882
ENSE00000825530	37127630	37127680
ENSE00000825531	37121635	37121691
ENSE00000825532	37121492	37121536
ENSE00000966409	37066224	37066325
ENSE00001408281	37052626	37053961
ENSE00001430531	37174539	37174582
ENSE00003482091	37063742	37063791
ENSE00003527824	37065810	37065942
ENSE00003569021	37054411	37054515
ENSE00003585587	37096616	37096660
ENSE00003608037	37055086	37055165
ENSE00003631998	37058790	37058910
ENSE00003633744	37110991	37111065
ENSE00003635395	37148894	37149038
ENSE00003675708	37094792	37094908
ENSE00003685433	37091467	37091538
ENSE00003784020	37129063	37129149
ENSE00003784377	37075024	37075116

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 98.30.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 63.5321 / max 908.5516, expressed in 1825 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
41688	56.6682	1825
41687	4.8808	1506
41689	0.7836	427
41684	0.4787	192
41685	0.4124	175
41686	0.3084	105

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	98.30	gold quality
calcaneal tendon	UBERON:0003701	98.12	gold quality
tendon	UBERON:0000043	97.47	gold quality
right atrium auricular region	UBERON:0006631	97.35	gold quality
apex of heart	UBERON:0002098	97.23	gold quality
sural nerve	UBERON:0015488	97.05	gold quality
tendon of biceps brachii	UBERON:0008188	96.77	gold quality
cardiac atrium	UBERON:0002081	96.61	gold quality
gastrocnemius	UBERON:0001388	96.49	gold quality
left testis	UBERON:0004533	96.46	gold quality
right testis	UBERON:0004534	96.42	gold quality
heart left ventricle	UBERON:0002084	96.41	gold quality
muscle of leg	UBERON:0001383	96.34	gold quality
cardiac ventricle	UBERON:0002082	96.30	gold quality
cerebellar hemisphere	UBERON:0002245	96.29	gold quality
colonic epithelium	UBERON:0000397	96.27	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.25	gold quality
cerebellar cortex	UBERON:0002129	96.11	gold quality
lower esophagus mucosa	UBERON:0035834	95.97	gold quality
mucosa of stomach	UBERON:0001199	95.92	gold quality
heart	UBERON:0000948	95.89	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.80	gold quality
descending thoracic aorta	UBERON:0002345	95.71	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.61	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.45	gold quality
stromal cell of endometrium	CL:0002255	95.27	gold quality
cerebellum	UBERON:0002037	95.20	gold quality
testis	UBERON:0000473	95.17	gold quality
muscle organ	UBERON:0001630	95.11	gold quality
esophagus mucosa	UBERON:0002469	95.11	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-99795	yes	200.32
E-CURD-112	yes	32.20
E-HCAD-6	yes	20.55
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

46 targeting LRRFIP2, 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-3692-3P	99.98	70.27	2139
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-544A	99.84	68.66	1965
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-577	99.78	69.13	2479
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-4687-3P	99.48	66.41	968
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-6839-3P	99.39	68.86	1301
HSA-MIR-6853-3P	99.36	70.79	1558
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-888-5P	99.30	70.15	1855
HSA-MIR-6770-5P	98.97	66.76	1853
HSA-MIR-455-5P	98.74	67.31	795
HSA-MIR-6837-3P	98.42	66.71	1149
HSA-MIR-6792-3P	98.41	66.86	1359
HSA-MIR-4691-5P	98.41	66.77	1343

Literature-anchored findings (GeneRIF, showing 6)

• These data suggest that LRRFIP2 plays an important role in transducing Wnt signals. (PMID:15677333)
• LRR-binding MyD88 interactor LRRFIP2 is a positive regulator of NF-kappa B activity and is also a positive regulator of cytokine production in lipopolysaccharide-stimulated macrophages, suggesting a functional role in TLR4-mediated inflammatory response. (PMID:19265123)
• Unambiguous characterization of site-specific phosphorylation of leucine-rich repeat Fli-I-interacting protein 2 (LRRFIP2) in Toll-like receptor 4 (TLR4)-mediated signaling. (PMID:21220426)
• A novel exonic rearrangement affecting MLH1 and the contiguous LRRFIP2 is a founder mutation in Portuguese Lynch syndrome families (PMID:21785361)
• FATylation of LRRFIP2 occurs on two distinct sites, each being modified by a single FAT10 moiety. (PMID:23036196)
• Data show that the ability of Ca(2+) to accentuate the activity of NLRP3 inflammasome is abrogated in Flightless-I (FliI) and leucine-rich repeat FliI-interaction protein 2 (LRRFIP2)-knockdown macrophages. (PMID:27431477)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	lrrfip2	ENSDARG00000010400
mus_musculus	Lrrfip2	ENSMUSG00000032497
rattus_norvegicus	Lrrfip2	ENSRNOG00000021047
drosophila_melanogaster	CG8578	FBGN0030699
caenorhabditis_elegans		WBGENE00018998

Paralogs (1): LRRFIP1 (ENSG00000124831)

Protein

Protein identifiers

Leucine-rich repeat flightless-interacting protein 2 — Q9Y608 (reviewed: Q9Y608)

All UniProt accessions (8): Q9Y608, A0A1S5UZ17, C9J0U5, C9J321, C9JC17, C9JJC9, C9JSU1, H7C3N9

UniProt curated annotations — full annotation on UniProt →

Function. May function as activator of the canonical Wnt signaling pathway, in association with DVL3, upstream of CTNNB1/beta-catenin. Positively regulates Toll-like receptor (TLR) signaling in response to agonist probably by competing with the negative FLII regulator for MYD88-binding.

Subunit / interactions. Interacts (via N-terminus) with DVL3. Interacts with FLII. Weakly interacts with MYD88 in resting cells. Following LPS-stimulation, the interaction with MYD88 is rapidly enhanced; the complex gradually dissociates to basal levels after 6 hours of stimulation. Interaction with MYD88 is regulated by LPS-induced phosphorylation at Ser-202. In the presence of LPS, competes with FLII for MYD88-binding.

Tissue specificity. Widely expressed, with highest levels in heart and skeletal muscle.

Post-translational modifications. Ser-190 and Ser-202 are phosphorylated in response to LPS stimulation. Ser-202 phosphorylation regulates the LPS-induced interaction with MYD88.

Similarity. Belongs to the LRRFIP family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9Y608-1	1	yes
Q9Y608-2	2
Q9Y608-3	3
Q9Y608-4	4
Q9Y608-5	5

RefSeq proteins (19): NP_001127841, NP_001269620, NP_001335226, NP_001335227, NP_001335228, NP_001335229, NP_001335230, NP_001335231, NP_001335232, NP_001335233, NP_001335234, NP_001335235, NP_001335236, NP_001335237, NP_001335238, NP_001335239, NP_001335240, NP_006300, NP_060194 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019139	LRRFIP1/2	Family

Pfam: PF09738

UniProt features (38 total): modified residue 15, splice variant 9, mutagenesis site 4, region of interest 3, coiled-coil region 3, compositionally biased region 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y608-F1	68.23	0.39

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 (15): 190, 202, 309, 312, 320, 324, 328, 331, 332, 333, 96, 101, 168, 173, 18

Mutagenesis-validated functional residues (4):

Position	Phenotype
190	no change in lps-induced nfkb activity.
200	no change in lps-induced nfkb activity.
202	reduction in lps-induced nfkb activity.
202	no change in lps-induced nfkb activity. interacts with myd88 in an lps-inducible manner.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 144 (showing top): AP1_01, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, AAGTCCA_MIR422B_MIR422A, AREB6_01, HNF1_Q6, PAX2_01, GTGCCTT_MIR506, NFKB_C, RYTAAWNNNTGAY_UNKNOWN, chr3p22, TGANTCA_AP1_C, NRF2_Q4, AACTTT_UNKNOWN, HNF1_C, DBP_Q6

GO Biological Process (2): regulation of DNA-templated transcription (GO:0006355), Wnt signaling pathway (GO:0016055)

GO Molecular Function (2): LRR domain binding (GO:0030275), protein binding (GO:0005515)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cell surface receptor signaling pathway	1
protein domain specific binding	1
binding	1

Protein interactions and networks

STRING

684 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LRRFIP2	FLII	Q13045	939
LRRFIP2	MYD88	P78397	792
LRRFIP2	DVL1	O14640	708
LRRFIP2	DVL3	Q92997	520
LRRFIP2	LUZP4	Q9P127	479
LRRFIP2	EPM2AIP1	Q7L775	473
LRRFIP2	UACA	Q9BZF9	421
LRRFIP2	RBM47	A0AV96	419
LRRFIP2	CELF4	Q9BZC1	402
LRRFIP2	PNLDC1	Q8NA58	400
LRRFIP2	TTLL12	Q14166	371
LRRFIP2	TDRD7	Q8NHU6	369
LRRFIP2	A0A0A6YYG9	A0A0A6YYG9	348
LRRFIP2	SCIN	Q9Y6U3	329
LRRFIP2	BNIPL	Q7Z465	329

IntAct

94 interactions, top by confidence:

A	B	Type	Score
STAT3	STAT3	psi-mi:“MI:0914”(association)	0.840
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
LRRFIP2	ATPAF2	psi-mi:“MI:0915”(physical association)	0.670
ATPAF2	LRRFIP2	psi-mi:“MI:0915”(physical association)	0.670
FLII	TMOD1	psi-mi:“MI:0914”(association)	0.640
Haus4	HAUS5	psi-mi:“MI:0915”(physical association)	0.560
LRRFIP2	FLII	psi-mi:“MI:0915”(physical association)	0.550
TMOD1	GSN	psi-mi:“MI:0914”(association)	0.530
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
LRRFIP2	DVL3	psi-mi:“MI:0915”(physical association)	0.400
LRRFIP2	MYH14	psi-mi:“MI:0915”(physical association)	0.400
PYGL	LRRFIP2	psi-mi:“MI:0915”(physical association)	0.400
Gorasp1	CLIP-170	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
Lima1	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Tmod3	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
DBN1	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Samm50	ZC3H18	psi-mi:“MI:0914”(association)	0.350
Ufl1	PRSS1	psi-mi:“MI:0914”(association)	0.350
CAPZA2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
CFTR		psi-mi:“MI:0914”(association)	0.350

BioGRID (163): ATPAF2 (Two-hybrid), LRRFIP2 (Affinity Capture-MS), CAPZA1 (Co-fractionation), FLII (Co-fractionation), LRRFIP2 (Affinity Capture-MS), LRRFIP2 (Affinity Capture-MS), LRRFIP2 (Affinity Capture-MS), LRRFIP2 (Affinity Capture-MS), LRRFIP2 (Affinity Capture-MS), LRRFIP2 (Affinity Capture-MS), LRRFIP2 (Affinity Capture-MS), LRRFIP2 (Affinity Capture-MS), LRRFIP2 (Affinity Capture-MS), LRRFIP2 (Affinity Capture-MS), LRRFIP2 (Affinity Capture-MS)

ESM2 similar proteins: A0MZ67, A1L260, A2AMM0, A2VDA9, A4IGC3, A5PJI6, A9C3W3, B1PRL5, B9EKI3, O35711, O35867, O54724, O76878, O94876, O95810, P34609, P55326, P70302, P83093, P84903, P85125, Q0IIE0, Q13586, Q29EP6, Q32PN7, Q58CP9, Q5BKX8, Q5FWS6, Q63918, Q66H98, Q674X7, Q69ZS8, Q69ZZ6, Q6NZI2, Q6P0R8, Q6P402, Q7T019, Q8CJ96, Q8K2Q9, Q8MJK1

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

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
LRRFIP2	up-regulates	DVL3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 100 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	23.4×	1e-03
FCGR3A-mediated phagocytosis	5	14.2×	5e-03
Regulation of actin dynamics for phagocytic cup formation	5	13.9×	5e-03
Activation of STAT3 by cadherin engagement	5	12.4×	6e-03

GO biological processes:

GO term	Partners	Fold	FDR
actin polymerization or depolymerization	5	46.1×	2e-05
actin filament organization	10	14.3×	1e-06
muscle contraction	5	12.5×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	86
Likely benign	3
Benign	4

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1457251	NC_000003.11:g.(?37092052)(37100470_?)del	Pathogenic
29655	NC_000003.11:g.37089454_37101079del	Pathogenic
625694	GRCh37/hg19 3p22.2(chr3:37089011-37116538)	Pathogenic
3362906	NC_000003.12:g.(?37040183)(37063791_?)del	Likely pathogenic

SpliceAI

4303 predictions. Top by Δscore:

Variant	Effect	Δscore
3:37053825:A:AC	donor_gain	1.0000
3:37053853:A:AC	donor_gain	1.0000
3:37053854:C:CC	donor_gain	1.0000
3:37053854:CTG:C	donor_gain	1.0000
3:37053957:CGTAA:C	acceptor_gain	1.0000
3:37053958:GTAA:G	acceptor_gain	1.0000
3:37053959:TAA:T	acceptor_gain	1.0000
3:37053960:AA:A	acceptor_gain	1.0000
3:37053962:C:CC	acceptor_gain	1.0000
3:37054406:AGTAC:A	donor_loss	1.0000
3:37054407:GTAC:G	donor_loss	1.0000
3:37054408:TA:T	donor_loss	1.0000
3:37054409:A:AT	donor_loss	1.0000
3:37055077:AGTAC:A	donor_loss	1.0000
3:37055078:GTAC:G	donor_loss	1.0000
3:37055079:TAC:T	donor_loss	1.0000
3:37055080:AC:A	donor_loss	1.0000
3:37055081:CT:C	donor_loss	1.0000
3:37055084:A:AC	donor_gain	1.0000
3:37055084:AC:A	donor_loss	1.0000
3:37055085:C:CA	donor_gain	1.0000
3:37055085:CA:C	donor_gain	1.0000
3:37055085:CACT:C	donor_gain	1.0000
3:37055085:CACTT:C	donor_gain	1.0000
3:37055163:CTC:C	acceptor_gain	1.0000
3:37055165:CCTAG:C	acceptor_loss	1.0000
3:37058785:CCTA:C	donor_gain	1.0000
3:37058786:CTACT:C	donor_loss	1.0000
3:37058788:A:AC	donor_gain	1.0000
3:37058789:C:CA	donor_gain	1.0000

AlphaMissense

4716 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:37083770:C:G	A382P	1.000
3:37053909:A:G	L703P	0.999
3:37054427:C:G	R680P	0.999
3:37083706:A:G	L403P	0.999
3:37083755:C:G	A387P	0.999
3:37091525:A:G	L350P	0.999
3:37129094:C:G	R49P	0.999
3:37129107:C:G	A45P	0.999
3:37129113:C:G	A43P	0.999
3:37129115:C:G	R42P	0.999
3:37129119:C:G	A41P	0.999
3:37129122:C:G	A40P	0.999
3:37129124:C:G	R39P	0.999
3:37129126:T:A	K38N	0.999
3:37129126:T:G	K38N	0.999
3:37129136:A:G	L35P	0.999
3:37129143:C:G	A33P	0.999
3:37129149:C:G	A31P	0.999
3:37053897:A:G	L707P	0.998
3:37053900:C:G	R706P	0.998
3:37053952:C:G	A689P	0.998
3:37054415:C:G	R684P	0.998
3:37054421:A:G	L682P	0.998
3:37055118:C:G	A640P	0.998
3:37083761:A:G	S385P	0.998
3:37083779:A:C	Y379D	0.998
3:37129082:A:G	L53P	0.998
3:37129127:T:A	K38I	0.998
3:37129131:C:G	A37P	0.998
3:37129134:C:G	A36P	0.998

dbSNP variants (sampled 300 via entrez): RS1000030720 (3:37160509 G>A), RS1000037309 (3:37154461 A>T), RS1000043291 (3:37136016 C>A,T), RS1000109260 (3:37167699 C>A,T), RS1000120211 (3:37091715 G>C), RS1000137483 (3:37157094 A>T), RS1000142854 (3:37083153 T>A,C), RS1000149723 (3:37129330 C>G), RS1000172860 (3:37110790 G>A,C), RS1000192145 (3:37156791 G>A), RS1000226023 (3:37063244 G>A,C,T), RS1000226530 (3:37142973 C>A,T), RS1000242159 (3:37135613 A>G), RS1000262667 (3:37089914 G>A), RS1000289341 (3:37129641 C>T)

Disease associations

OMIM: gene MIM:614043 | disease phenotypes: MIM:609310, MIM:158320

GenCC curated gene-disease

Mondo (4): Lynch syndrome 2 (MONDO:0012249), hereditary neoplastic syndrome (MONDO:0015356), Muir-Torre syndrome (MONDO:0008018), Lynch syndrome (MONDO:0005835)

Orphanet (3): Lynch syndrome (Orphanet:144), Inherited cancer-predisposing syndrome (Orphanet:140162), Muir-Torre syndrome (Orphanet:587)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003158_2	Subjective response to lithium treatment	8.000000e-07
GCST004521_90	Autism spectrum disorder or schizophrenia	1.000000e-11
GCST012490_472	Femur bone mineral density x serum urate levels interaction	8.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D055847	Lynch Syndrome II	C04.700.250.500; C16.320.700.250.500
D055653	Muir-Torre Syndrome	C04.588.805.578.500; C04.700.250.500.500; C16.320.700.250.500.500; C17.800.794.712.500; C17.800.827.610; C17.800.882.712.500
D009386	Neoplastic Syndromes, Hereditary	C04.700; C16.320.700

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
sodium arsenite	affects cotreatment, increases abundance, increases expression	3
bisphenol A	affects cotreatment, increases methylation, decreases expression, decreases reaction, increases abundance	2
Estradiol	affects expression, increases expression	2
Tobacco Smoke Pollution	increases expression	2
Cyclosporine	increases expression	2
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases methylation	1
ginger extract	decreases expression, decreases reaction, increases abundance	1
triphenyl phosphate	affects expression	1
afimoxifene	decreases reaction, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
cobaltous chloride	increases expression	1
manganese chloride	increases expression, affects cotreatment, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
K 7174	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, increases methylation, decreases methylation	1
Acetaminophen	increases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Vehicle Emissions	decreases methylation	1
Caffeine	affects phosphorylation	1
Endosulfan	increases expression	1
Estrogens	decreases reaction, increases expression	1
Ivermectin	decreases expression	1
Ketoconazole	decreases expression	1
Lead	affects splicing	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Oils, Volatile	decreases expression, decreases reaction, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00566644	PHASE3	TERMINATED	Intrauterine Levonorgestrel and Observation or Observation Alone in Preventing Atypical Endometrial Hyperplasia and Endometrial Cancer in Women With Hereditary Non-Polyposis Colorectal Cancer or Lynch Syndrome
NCT02000089	PHASE3	RECRUITING	The Cancer of the Pancreas Screening-5 CAPS5)Study
NCT02813824	PHASE3	ACTIVE_NOT_RECRUITING	Effect of Chemoprevention by Low-dose Aspirin of New or Recurrent Colorectal Adenomas in Patients With Lynch Syndrome
NCT02912559	PHASE3	ACTIVE_NOT_RECRUITING	Combination Chemotherapy With or Without Atezolizumab in Treating Patients With Stage III Colon Cancer and Deficient DNA Mismatch Repair
NCT04711434	PHASE3	UNKNOWN	PD-1 Antibody for The Prevention of Adenomatous Polyps and Second Primary Tumors in Lynch Syndrome Patients
NCT07609901	PHASE3	NOT_YET_RECRUITING	Preventive Dendritic Cell Vaccination for Lynch Syndrome Carriers
NCT03631641	PHASE2	TERMINATED	Nivolumab in Preventing Colon Adenomas in Participants With Lynch Syndrome and a History of Partial Colectomy
NCT03831698	PHASE2	UNKNOWN	Omega 3 Fatty Acids in Colorectal Cancer (CRC) Prevention in Patients With Lynch Syndrome (COLYNE)
NCT04920149	PHASE2	RECRUITING	Mesalamine for Colorectal Cancer Prevention Program in Lynch Syndrome
NCT05411718	PHASE2	RECRUITING	A Phase IIa Randomized, Double-Blinded Clinical Trial of Naproxen or Aspirin for Cancer Immune Interception in Lynch Syndrome
NCT05419011	PHASE2	ACTIVE_NOT_RECRUITING	Testing a Combination of Vaccines for Cancer Prevention in Lynch Syndrome
NCT02052908	PHASE1	COMPLETED	Naproxen in Preventing DNA Mismatch Repair Deficient Colorectal Cancer in Patients With Lynch Syndrome
NCT02359565	PHASE1	ACTIVE_NOT_RECRUITING	Pembrolizumab in Treating Younger Patients With Recurrent, Progressive, or Refractory High-Grade Gliomas, Diffuse Intrinsic Pontine Gliomas, Hypermutated Brain Tumors, Ependymoma or Medulloblastoma
NCT04500548	PHASE1	WITHDRAWN	Testing the Combination of Two Immunotherapy Drugs (Nivolumab and Ipilimumab) in Children, Adolescent, and Young Adult Patients With Relapsed/Refractory Cancers That Have an Increased Number of Genetic Changes, The 3CI Study
NCT07163403	PHASE1	RECRUITING	First in Human Pilot Study to Assess the Safety and Efficacy of Dendritic Cells Loaded With Frameshift Derived Neopeptides for the Prevention of Cancer in of Lynch Syndrome Carriers
NCT00001496	Not specified	COMPLETED	Establishment of Normal Breast Epithelial Cell Lines From Patients at High Risk for Breast Cancer
NCT00001898	Not specified	COMPLETED	Microarray Analysis for Human Genetic Disease
NCT00026884	Not specified	RECRUITING	Collection of Serum and Tissue Samples From Patients With Biopsy-Proved or Suspected Malignant Disease
NCT02289326	Not specified	COMPLETED	Biomarker Monitoring in TP53 Mutation Carriers
NCT02958462	Not specified	RECRUITING	Pre-myeloid Cancer and Bone Marrow Failure Clinic Study
NCT03160274	Not specified	RECRUITING	Genetic Analysis of Pheochromocytomas, Paragangliomas and Associated Conditions
NCT03426878	Not specified	COMPLETED	Cancer Health Assessments Reaching Many
NCT03857594	Not specified	ACTIVE_NOT_RECRUITING	Integrative Sequencing In Germline and Hereditary Tumours
NCT03973450	Not specified	UNKNOWN	Epidemiology of Pituitary Tumours: Prevalence of Associated Neoplasia
NCT03979612	Not specified	UNKNOWN	Evaluation of the Adhesion to the GENEPY Network
NCT04261972	Not specified	ACTIVE_NOT_RECRUITING	Cell-free DNA in Hereditary And High-Risk Malignancies 1
NCT04494945	Not specified	RECRUITING	Identifying and Caring for Individuals With Inherited Cancer Syndrome
NCT04541654	Not specified	RECRUITING	Li-Fraumeni & TP53 (LiFT UP): Understanding and Progress
NCT04763915	Not specified	ACTIVE_NOT_RECRUITING	Improving Care After Inherited Cancer Testing
NCT05562778	Not specified	RECRUITING	Chatbot to Maximize Hereditary Cancer Genetic Risk Assessment
NCT05664867	Not specified	RECRUITING	Implementation of Population Cancer Genetic Services in Federally Qualified Health Centers (FQHC)
NCT05721326	Not specified	COMPLETED	Sequential EHR Based Interventions to Increase Genetic Testing for Breast and Ovarian Cancer Predisposition
NCT06096688	Not specified	RECRUITING	Discovering New Targets for Colorectal and Endometrial Cancer Risk Reduction
NCT06654466	Not specified	RECRUITING	Closing the GAPS: Guideline Adherence, Prevention and Surveillance in Hereditary Cancer
NCT06708429	Not specified	RECRUITING	Lynch Syndrome X-Talk of Enteral Mucosa With Immune System
NCT06726642	Not specified	RECRUITING	CfDNA in Hereditary And High-risk Malignancies 2
NCT06914726	Not specified	ENROLLING_BY_INVITATION	Patient Centered Clinical Decision Support for Hereditary Cancer Syndromes
NCT06927947	Not specified	RECRUITING	Navigation Interventions to Improve Cascade Genetic Testing Among Relatives of Patients With Hereditary Cancer Syndromes
NCT06999954	Not specified	RECRUITING	Shwachman-Diamond Syndrome Global Patient Survey and Partnering Platform
NCT07052266	Not specified	RECRUITING	Trial of Combined Obstetric Carrier Screening and Hereditary Cancer Screening