FNIP1

Summary

FNIP1 (folliculin interacting protein 1, HGNC:29418) is a protein-coding gene on chromosome 5q31.1, encoding Folliculin-interacting protein 1 (Q8TF40). Binding partner of the GTPase-activating protein FLCN: involved in the cellular response to amino acid availability by regulating the non-canonical mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3.

This gene encodes a protein that binds to the tumor suppressor protein folliculin and to AMP-activated protein kinase (AMPK). The encoded protein participates in the regulation of cellular metabolism and nutrient sensing by modulating the AMPK and target of rapamycin signaling pathways. This gene has a closely related paralog that encodes a protein with similar binding activities. Both related proteins also associate with the molecular chaperone heat shock protein-90 (Hsp90) and negatively regulate its ATPase activity and facilitate its association with folliculin.

Source: NCBI Gene 96459 — RefSeq curated summary.

At a glance

• Gene–disease (curated): FNIP1-associated syndrome (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 20
• Clinical variants (ClinVar): 497 total — 24 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 21
• Druggable target: yes
• MANE Select transcript: NM_133372

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29418
Approved symbol	FNIP1
Name	folliculin interacting protein 1
Location	5q31.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1961
Ensembl gene	ENSG00000217128
Ensembl biotype	protein_coding
OMIM	610594
Entrez	96459

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 TEC

ENST00000307954, ENST00000307968, ENST00000510461, ENST00000511848, ENST00000623690, ENST00000934997

RefSeq mRNA: 4 — MANE Select: NM_133372 NM_001008738, NM_001346113, NM_001346114, NM_133372

CCDS: CCDS34226, CCDS34227, CCDS87320, CCDS87321

Canonical transcript exons

ENST00000510461 — 18 exons

Exon	Start	End
ENSE00000899265	131679029	131679175
ENSE00000899266	131698917	131699002
ENSE00000899267	131704065	131704266
ENSE00000899268	131706411	131706546
ENSE00001084000	131651802	131651999
ENSE00001171918	131647090	131647205
ENSE00001171934	131670463	131670631
ENSE00001171941	131671505	131672924
ENSE00001354197	131677703	131677872
ENSE00002067175	131796830	131797017
ENSE00002087554	131641714	131644763
ENSE00002467820	131710578	131710661
ENSE00002495750	131719317	131719417
ENSE00002500644	131716565	131716656
ENSE00002518147	131718986	131719060
ENSE00002519315	131709201	131709272
ENSE00002524130	131730904	131731038
ENSE00003709819	131744564	131744690

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 96.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.0298 / max 430.7187, expressed in 1813 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63273	18.9310	1813
63272	0.6093	264
63274	0.4895	220

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cardiac muscle of right atrium	UBERON:0003379	96.03	gold quality
left ventricle myocardium	UBERON:0006566	95.68	gold quality
myocardium	UBERON:0002349	94.31	gold quality
layer of synovial tissue	UBERON:0007616	94.19	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.96	gold quality
corpus callosum	UBERON:0002336	93.85	gold quality
epithelial cell of pancreas	CL:0000083	93.80	gold quality
vastus lateralis	UBERON:0001379	93.45	gold quality
pancreatic ductal cell	CL:0002079	93.22	gold quality
deltoid	UBERON:0001476	93.05	gold quality
calcaneal tendon	UBERON:0003701	92.99	gold quality
quadriceps femoris	UBERON:0001377	92.94	gold quality
subthalamic nucleus	UBERON:0001906	92.91	gold quality
substantia nigra pars reticulata	UBERON:0001966	92.71	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	92.65	gold quality
inferior vagus X ganglion	UBERON:0005363	92.55	gold quality
biceps brachii	UBERON:0001507	92.50	gold quality
synovial joint	UBERON:0002217	92.48	gold quality
tibia	UBERON:0000979	92.35	gold quality
lateral globus pallidus	UBERON:0002476	92.27	gold quality
dorsal plus ventral thalamus	UBERON:0001897	92.21	gold quality
heart right ventricle	UBERON:0002080	92.09	gold quality
substantia nigra pars compacta	UBERON:0001965	91.87	gold quality
saphenous vein	UBERON:0007318	91.73	gold quality
skeletal muscle tissue	UBERON:0001134	91.42	gold quality
medulla oblongata	UBERON:0001896	91.35	gold quality
tibialis anterior	UBERON:0001385	91.31	gold quality
penis	UBERON:0000989	91.26	gold quality
lateral nuclear group of thalamus	UBERON:0002736	91.07	gold quality
urethra	UBERON:0000057	91.02	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-124858	no	522.50
E-MTAB-10290	no	127.78
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PRKAA1, PRKAB1, PRKAG1

miRNA regulators (miRDB)

189 targeting FNIP1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4682	100.00	68.89	1258
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790

Literature-anchored findings (GeneRIF, showing 12)

• Results suggest that FLCN, mutated in Birt-Hogg-Dube syndrome, and its interacting partner FNIP1 may be involved in energy and/or nutrient sensing through the AMPK and mTOR signaling pathways. (PMID:17028174)
• The FLCN-FNIP complex deregulated in Birt-Hogg-Dube syndrome is absolutely required for B-cell differentiation. (PMID:22709692)
• Based on previous studies and gene ontology database, we found that POLQ encoding DNA polymerase theta enzyme and FNIP1 encoding tumor suppressor folliculin-interacting protein might have contributed to the Interdigitating dendritic cell sarcoma (IDCS). Our study provides potential causative genetic factors of IDCS and plays a role in advancing the understanding of IDCS pathogenesis (PMID:30099721)
• casein kinase-2 phosphorylation of the co-chaperone folliculin-interacting protein 1 (FNIP1) on priming serine-938 and subsequent relay phosphorylation on serine-939, 941, 946, and 948 promotes its gradual interaction with Hsp90. (PMID:30699359)
• Mutations of the gene FNIP1 associated with a syndromic autosomal recessive immunodeficiency with cardiomyopathy and pre-excitation syndrome. (PMID:32181500)
• Absent B cells, agammaglobulinemia, and hypertrophic cardiomyopathy in folliculin-interacting protein 1 deficiency. (PMID:32905580)
• A Cellular Mechanism to Detect and Alleviate Reductive Stress. (PMID:32941802)
• Loss of FLCN-FNIP1/2 induces a non-canonical interferon response in human renal tubular epithelial cells. (PMID:33459596)
• Familial multiple discoid fibromas is linked to a locus on chromosome 5 including the FNIP1 gene. (PMID:36599954)
• Induction of lysosomal and mitochondrial biogenesis by AMPK phosphorylation of FNIP1. (PMID:37079666)
• Direct regulation of FNIP1 and FNIP2 by MEF2 sustains MTORC1 activation and tumor progression in pancreatic cancer. (PMID:37772772)
• Muscle-bone cross-talk through the FNIP1-TFEB-IGF2 axis is associated with bone metabolism in human and mouse. (PMID:38838134)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	fnip1	ENSDARG00000102171
mus_musculus	Fnip1	ENSMUSG00000035992
rattus_norvegicus	Fnip1	ENSRNOG00000009104
drosophila_melanogaster	CG3764	FBGN0036684
caenorhabditis_elegans		WBGENE00020208

Paralogs (1): FNIP2 (ENSG00000052795)

Protein

Protein identifiers

Folliculin-interacting protein 1 — Q8TF40 (reviewed: Q8TF40)

All UniProt accessions (2): Q8TF40, J3KNG8

UniProt curated annotations — full annotation on UniProt →

Function. Binding partner of the GTPase-activating protein FLCN: involved in the cellular response to amino acid availability by regulating the non-canonical mTORC1 signaling cascade controlling the MiT/TFE factors TFEB and TFE3. Required to promote FLCN recruitment to lysosomes and interaction with Rag GTPases, leading to activation of the non-canonical mTORC1 signaling. In low-amino acid conditions, component of the lysosomal folliculin complex (LFC) on the membrane of lysosomes, which inhibits the GTPase-activating activity of FLCN, thereby inactivating mTORC1 and promoting nuclear translocation of TFEB and TFE3. Upon amino acid restimulation, disassembly of the LFC complex liberates the GTPase-activating activity of FLCN, leading to activation of mTORC1 and subsequent inactivation of TFEB and TFE3. Together with FLCN, regulates autophagy: following phosphorylation by ULK1, interacts with GABARAP and promotes autophagy. In addition to its role in mTORC1 signaling, also acts as a co-chaperone of HSP90AA1/Hsp90: following gradual phosphorylation by CK2, inhibits the ATPase activity of HSP90AA1/Hsp90, leading to activate both kinase and non-kinase client proteins of HSP90AA1/Hsp90. Acts as a scaffold to load client protein FLCN onto HSP90AA1/Hsp90. Competes with the activating co-chaperone AHSA1 for binding to HSP90AA1, thereby providing a reciprocal regulatory mechanism for chaperoning of client proteins. Also acts as a core component of the reductive stress response by inhibiting activation of mitochondria in normal conditions: in response to reductive stress, the conserved Cys degron is reduced, leading to recognition and polyubiquitylation by the CRL2(FEM1B) complex, followed by proteasomal. Required for B-cell development.

Subunit / interactions. Homodimer and homomultimer. Heterodimer and heteromultimer with FNIP2. Interacts with FLCN (via C-terminus). Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RagA/RRAGA or RagB/RRAGB GDP-bound, RagC/RRAGC or RagD/RRAGD GTP-bound, and Ragulator. Interacts with HSPCA and with the PRKAA1, PRKAB1 and PRKAG1 subunits of 5’-AMP-activated protein kinase (AMPK). Phosphorylated FLCN and AMPK are preferentially bound. Interacts with HSP70, STIP1, PTGES3, CDC37, BRAF, GCR and CDK4. Interacts with HSP90AA1; the interaction inhibits HSP90AA1 ATPase activity. Interacts with ATP2A2.

Subcellular location. Lysosome membrane. Cytoplasm. Cytosol.

Tissue specificity. Strong expression is found in the heart, liver placenta, muscle, nasal mucosa, salivary gland and uvula and moderate expression in kidney and lung. Higher levels detected in clear cell renal cell carcinoma (RCC) and chromophobe RCC than in normal kidney tissue. Expressed in peripheral blood mononuclear cells.

Post-translational modifications. Phosphorylated by AMPK in response to energetic stress. Phosphorylation by AMPK in response to mitochondrial damage promotes inactivation of the non-canonical mTORC1 signaling, nuclear translocation of TFEB and TFE3, inducing transcription of lysosomal or autophagy genes. Sequential phosphorylation by CK2 promotes its gradual interaction with HSP90AA1/Hsp90. Priming phosphorylation at Ser-938 is followed by relay phosphorylation at Ser-939, Ser-941, Ser-946 and Ser-948, promoting its gradual interaction with HSP90AA1/Hsp90. This leads to incremental inhibition of HSP90AA1/Hsp90 ATPase activity and gradual activation of both kinase and non-kinase clients. Dephosphorylated by protein phosphatase 5 (PP5), promoting glycosylation by OGT. GlcNAcylation at Ser-938 by OGT following dephosphorylation by protein phosphatase 5 (PP5) promotes ubiquitination and degradation by the proteasome. Ubiquitinated through ‘Lys-11’ linkage of ubiquitin moieties at Lys-1119 following glycosylation by OGT, leading to its degradation by the proteasome. Ubiquitinated by the CRL2(FEM1B) complex in response to reductive stress: reductive stress causes reduction of the conserved Cys degron in FNIP1, followed by zinc-binding, zinc acting as a molecular glue for recognition by the CRL2(FEM1B) complex. Ubiquitination leads to FNIP1 degradation, and activation of mitochondria to recalibrate reactive oxygen species (ROS). Oxidation of the Cys degron in normal conditions promotes its stabilization by preventing recognition and ubiquitination by the CRL2(FEM1B) complex.

Disease relevance. Immunodeficiency 93 and hypertrophic cardiomyopathy (IMD93) [MIM:619705] An autosomal recessive disorder characterized by onset of recurrent viral and bacterial infections, particularly with encapsulated bacteria, and hypertrophic cardiomyopathy in the first months or years of life. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The KY-finger orients the Cys degron for ubiquitination by the CRL2(FEM1B) complex.

Similarity. Belongs to the FNIP family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8TF40-1	1	yes
Q8TF40-2	2
Q8TF40-3	3

RefSeq proteins (4): NP_001008738, NP_001333042, NP_001333043, NP_588613* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026156	FNIP_fam	Family
IPR028084	FNIP_N_dom	Domain
IPR028085	FNIP_mid_dom	Domain
IPR028086	FNIP_C_dom	Domain
IPR037545	DENN_FNIP1/2	Domain

Pfam: PF14636, PF14637, PF14638

UniProt features (53 total): modified residue 15, mutagenesis site 10, sequence variant 7, binding site 5, region of interest 4, domain 3, splice variant 3, compositionally biased region 2, chain 1, glycosylation site 1, cross-link 1, short sequence motif 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8JE2	ELECTRON MICROSCOPY	3.63

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TF40-F1	55.41	0.16

Functional residue map

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

Ligand- & substrate-binding residues (5): 608; 610; 613; 613; 615

Post-translational modifications (16): 220, 230, 232, 261, 294, 296, 593, 594, 760, 763, 938, 939, 941, 946, 948, 1119

Glycosylation sites (1): 938

Mutagenesis-validated functional residues (10):

Position	Phenotype
220	in sa5 mutant; abolishes phosphorylation by ampk, leading to activation of the non-canonical mtorc1 signaling; when asso
230–232	in sa5 mutant; abolishes phosphorylation by ampk, leading to activation of the non-canonical mtorc1 signaling; when asso
261	in sa5 mutant; abolishes phosphorylation by ampk, leading to activation of the non-canonical mtorc1 signaling; when asso
593	in sa5 mutant; abolishes phosphorylation by ampk, leading to activation of the non-canonical mtorc1 signaling; when asso
938–948	mimics phosphorylation status; leading to inhibit atpase activity of hsp90aa1/hsp90.
938	impaired phosphorylation by ck2 and interaction with hsp90aa1/hsp90.
982	no effect on ubiquitination and protein stability.
1117	no effect on ubiquitination and protein stability.
1119	impaired ubiquitination, leading to increased stability.
1134	no effect on ubiquitination and protein stability.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9639288	Amino acids regulate mTORC1

MSigDB gene sets: 294 (showing top): GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_LYMPHOCYTE_APOPTOTIC_PROCESS, ACTACCT_MIR196A_MIR196B, GOBP_VACUOLE_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS, GOBP_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS, GOBP_B_CELL_ACTIVATION, GOCC_VACUOLAR_MEMBRANE, GOBP_POSITIVE_REGULATION_OF_TOR_SIGNALING, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_REGULATION_OF_LYMPHOCYTE_APOPTOTIC_PROCESS, TATTATA_MIR374, GOBP_REGULATION_OF_VACUOLE_ORGANIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION

GO Biological Process (20): negative regulation of transcription by RNA polymerase II (GO:0000122), B cell apoptotic process (GO:0001783), immature B cell differentiation (GO:0002327), positive regulation of B cell apoptotic process (GO:0002904), negative regulation of cell population proliferation (GO:0008285), cellular response to starvation (GO:0009267), B cell differentiation (GO:0030183), positive regulation of protein-containing complex assembly (GO:0031334), TOR signaling (GO:0031929), negative regulation of TOR signaling (GO:0032007), positive regulation of TOR signaling (GO:0032008), positive regulation of TORC1 signaling (GO:1904263), negative regulation of lysosome organization (GO:1905672), regulation of pro-B cell differentiation (GO:2000973), lysosome organization (GO:0007040), SCF-dependent proteasomal ubiquitin-dependent protein catabolic process (GO:0031146), protein destabilization (GO:0031648), cellular response to nutrient levels (GO:0031669), TORC1 signaling (GO:0038202), negative regulation of protein localization to nucleus (GO:1900181)

GO Molecular Function (6): enzyme activator activity (GO:0008047), enzyme binding (GO:0019899), ATPase inhibitor activity (GO:0042030), metal ion binding (GO:0046872), protein-folding chaperone binding (GO:0051087), protein binding (GO:0005515)

GO Cellular Component (5): cytoplasm (GO:0005737), lysosomal membrane (GO:0005765), cytosol (GO:0005829), lysosome (GO:0005764), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cellular response to starvation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
TOR signaling	3
cellular anatomical structure	3
regulation of TOR signaling	2
protein binding	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
lymphocyte apoptotic process	1
B cell differentiation	1
B cell apoptotic process	1
regulation of B cell apoptotic process	1
positive regulation of lymphocyte apoptotic process	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
cellular response to nutrient levels	1
cellular response to stress	1
response to starvation	1
lymphocyte differentiation	1
B cell activation	1
regulation of protein-containing complex assembly	1
positive regulation of cellular component biogenesis	1
positive regulation of cellular component organization	1
protein-containing complex assembly	1
intracellular signal transduction	1
negative regulation of intracellular signal transduction	1
positive regulation of intracellular signal transduction	1
positive regulation of TOR signaling	1
TORC1 signaling	1
regulation of TORC1 signaling	1
lysosome organization	1
negative regulation of organelle organization	1
regulation of lysosome organization	1
pro-B cell differentiation	1
regulation of lymphoid progenitor cell differentiation	1
lytic vacuole organization	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
regulation of protein stability	1
response to nutrient levels	1
cellular response to stimulus	1

Protein interactions and networks

STRING

2391 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FNIP1	FLCN	Q8NFG4	999
FNIP1	FNIP2	Q9P278	942
FNIP1	MTOR	P42345	808
FNIP1	PRKAG1	P54619	772
FNIP1	PRKAA1	Q13131	705
FNIP1	RRAGC	Q9HB90	696
FNIP1	RRAGB	Q5VZM2	691
FNIP1	PRKAB1	Q9Y478	668
FNIP1	EFNA5	P52803	641
FNIP1	SMCR8	Q8TEV9	626
FNIP1	RRAGD	Q9NQL2	622
FNIP1	MADD	Q8WXG6	609
FNIP1	TFE3	P19532	586
FNIP1	TSC2	P49815	585
FNIP1	AGRP	O00253	582

IntAct

35 interactions, top by confidence:

A	B	Type	Score
COPS5	COPS2	psi-mi:“MI:0914”(association)	0.910
FNIP2	FLCN	psi-mi:“MI:0914”(association)	0.630
FNIP1	FNIP2	psi-mi:“MI:0915”(physical association)	0.620
GABARAP	IPO5	psi-mi:“MI:0914”(association)	0.590
FLCN	FNIP1	psi-mi:“MI:0915”(physical association)	0.560
FNIP1	FLCN	psi-mi:“MI:0914”(association)	0.560
ORF	EIF3D	psi-mi:“MI:0914”(association)	0.560
FNIP1	ORF	psi-mi:“MI:0915”(physical association)	0.560
VTA1	CHMP2A	psi-mi:“MI:0914”(association)	0.530
FNIP1	GABARAP	psi-mi:“MI:0407”(direct interaction)	0.520
FNIP1	GABARAPL1	psi-mi:“MI:0407”(direct interaction)	0.520
GABARAPL2	FNIP1	psi-mi:“MI:0407”(direct interaction)	0.440
FNIP1	MAP1LC3B	psi-mi:“MI:0407”(direct interaction)	0.440
MAP1LC3C	FNIP1	psi-mi:“MI:0407”(direct interaction)	0.440
FLCN	FNIP1	psi-mi:“MI:0915”(physical association)	0.400
FNIP1	Flcn	psi-mi:“MI:0915”(physical association)	0.400
FNIP1	CFTR	psi-mi:“MI:0915”(physical association)	0.370
FNIP1	PRKAG1	psi-mi:“MI:0914”(association)	0.350
GABARAPL1		psi-mi:“MI:0914”(association)	0.350
GABARAP		psi-mi:“MI:0914”(association)	0.350
PRKAA2	DFFA	psi-mi:“MI:0914”(association)	0.350
VTA1	FLCN	psi-mi:“MI:0914”(association)	0.350

BioGRID (64): FNIP1 (Affinity Capture-MS), Flcn (Affinity Capture-Western), FNIP1 (Affinity Capture-MS), FNIP1 (Affinity Capture-MS), FNIP1 (Affinity Capture-MS), FNIP1 (Proximity Label-MS), FNIP1 (Affinity Capture-MS), FNIP1 (Affinity Capture-MS), FNIP1 (Affinity Capture-MS), FNIP1 (Affinity Capture-MS), FNIP1 (Affinity Capture-Western), HSP90AA1 (Affinity Capture-Western), HSPA1B (Affinity Capture-Western), STIP1 (Affinity Capture-Western), CDC37 (Affinity Capture-Western)

ESM2 similar proteins: A0AVK6, A5PLL1, B2GUN4, D2H3M0, D2HNW6, E1BLP6, E1BP74, E1BZ85, E2QTD3, O14607, O15550, O70546, O88850, P79457, Q5FW46, Q5VCS6, Q5W4S4, Q5ZI58, Q68FD7, Q69ZK7, Q6A098, Q6B4Z3, Q6NRE4, Q6P1H6, Q6P7W0, Q6ZPF3, Q7TP65, Q7ZVU1, Q80TD3, Q8BFU3, Q8BJ34, Q8BM75, Q8C7R7, Q8CCH7, Q8HWS3, Q8IVF5, Q8IW35, Q8NAT2, Q8ND24, Q8TF40

Diamond homologs: Q5W4S4, Q68FD7, Q80TD3, Q8TF40, Q9P278

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
FNIP1	“down-regulates activity”	HSP90AA1	binding
FNIP1	“down-regulates activity”	HSP90AB1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 25 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
Macroautophagy	8	40.1×	1e-09
Membrane Trafficking	5	8.1×	4e-03
Vesicle-mediated transport	5	7.6×	4e-03

GO biological processes:

GO term	Partners	Fold	FDR
autophagosome maturation	6	91.6×	4e-09
mitophagy	5	69.1×	6e-07
autophagosome assembly	5	48.9×	3e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	3
Uncertain significance	197
Likely benign	224
Benign	24

Top pathogenic / likely-pathogenic (27)

Variant ID	HGVS	Classification
1335870	NM_133372.3(FNIP1):c.3353G>A (p.Ser1118Asn)	Pathogenic
1335871	NM_133372.3(FNIP1):c.1289del (p.His430fs)	Pathogenic
1335872	NM_133372.3(FNIP1):c.3218del (p.Leu1073fs)	Pathogenic
1335873	NM_133372.3(FNIP1):c.868C>T (p.Arg290Ter)	Pathogenic
1335874	NM_133372.3(FNIP1):c.3306+1G>A	Pathogenic
1928651	NM_133372.3(FNIP1):c.157C>T (p.Arg53Ter)	Pathogenic
2025700	NM_133372.3(FNIP1):c.2922dup (p.Glu975Ter)	Pathogenic
2031591	NM_133372.3(FNIP1):c.2833dup (p.Asp945fs)	Pathogenic
2114300	NM_133372.3(FNIP1):c.1243_1250del (p.Glu415fs)	Pathogenic
2804561	NM_133372.3(FNIP1):c.2108_2109del (p.Glu703fs)	Pathogenic
2809950	NM_133372.3(FNIP1):c.1666_1676dup (p.Asp559fs)	Pathogenic
2839600	NM_133372.3(FNIP1):c.1174C>T (p.Arg392Ter)	Pathogenic
3246564	NC_000005.9:g.(?131066577)(131132614_?)del	Pathogenic
3246566	NC_000005.9:g.(?130980378)(131080403_?)del	Pathogenic
3246567	NC_000005.9:g.(?131066624)(131187096_?)del	Pathogenic
3651218	NM_133372.3(FNIP1):c.1234C>T (p.Arg412Ter)	Pathogenic
3653139	NM_133372.3(FNIP1):c.2889dup (p.Gly964fs)	Pathogenic
3663844	NM_133372.3(FNIP1):c.225_226del (p.Gly76fs)	Pathogenic
3669058	NM_133372.3(FNIP1):c.859C>T (p.Arg287Ter)	Pathogenic
3670425	NM_133372.3(FNIP1):c.3372C>A (p.Tyr1124Ter)	Pathogenic
3711756	NM_133372.3(FNIP1):c.2047del (p.Cys683fs)	Pathogenic
4279469	GRCh37/hg19 5q31.1(chr5:130986596-131146993)x1	Pathogenic
4698435	NM_133372.3(FNIP1):c.2302C>T (p.Arg768Ter)	Pathogenic
4712358	NM_133372.3(FNIP1):c.2550_2551insTT (p.Asp851fs)	Pathogenic
2750318	NM_133372.3(FNIP1):c.1520-2A>G	Likely pathogenic
3065520	NM_133372.3(FNIP1):c.454C>G (p.Arg152Gly)	Likely pathogenic
4703701	NM_133372.3(FNIP1):c.220-1G>C	Likely pathogenic

SpliceAI

3578 predictions. Top by Δscore:

Variant	Effect	Δscore
5:131647212:T:TC	acceptor_gain	1.0000
5:131651800:A:AC	donor_gain	1.0000
5:131651801:C:CC	donor_gain	1.0000
5:131651801:CAA:C	donor_gain	1.0000
5:131651801:CAAA:C	donor_gain	1.0000
5:131651801:CAAAA:C	donor_gain	1.0000
5:131651881:T:TA	donor_gain	1.0000
5:131651882:C:A	donor_gain	1.0000
5:131651886:T:A	donor_gain	1.0000
5:131651899:T:C	donor_gain	1.0000
5:131651998:TG:T	acceptor_gain	1.0000
5:131670458:CTCA:C	donor_loss	1.0000
5:131670459:TCA:T	donor_loss	1.0000
5:131670460:CA:C	donor_loss	1.0000
5:131670460:CACCT:C	donor_loss	1.0000
5:131670461:A:AC	donor_gain	1.0000
5:131670461:A:AT	donor_loss	1.0000
5:131670462:C:CC	donor_gain	1.0000
5:131670462:C:CG	donor_loss	1.0000
5:131670462:CCTG:C	donor_gain	1.0000
5:131670627:TTGAC:T	acceptor_gain	1.0000
5:131670629:GAC:G	acceptor_gain	1.0000
5:131670630:ACCTG:A	acceptor_loss	1.0000
5:131670631:CCTGG:C	acceptor_loss	1.0000
5:131670632:C:CA	acceptor_loss	1.0000
5:131670632:C:CC	acceptor_gain	1.0000
5:131670632:CT:C	acceptor_loss	1.0000
5:131670633:T:C	acceptor_loss	1.0000
5:131679027:A:AC	donor_gain	1.0000
5:131679028:C:CC	donor_gain	1.0000

AlphaMissense

7767 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:131647138:A:G	L1125P	1.000
5:131647150:A:G	L1121P	1.000
5:131647192:A:G	L1107P	1.000
5:131651932:A:T	V1059D	1.000
5:131651953:G:T	A1052D	1.000
5:131677715:A:G	W503R	1.000
5:131677715:A:T	W503R	1.000
5:131677826:A:G	W466R	1.000
5:131677826:A:T	W466R	1.000
5:131677843:A:G	L460P	1.000
5:131677858:A:G	L455P	1.000
5:131679126:A:G	W418R	1.000
5:131679126:A:T	W418R	1.000
5:131704189:G:T	A331E	1.000
5:131719036:G:C	S160R	1.000
5:131719036:G:T	S160R	1.000
5:131719038:T:G	S160R	1.000
5:131719046:A:G	L157P	1.000
5:131719327:G:C	H149D	1.000
5:131719331:T:A	K147N	1.000
5:131719331:T:G	K147N	1.000
5:131719333:T:C	K147E	1.000
5:131719368:C:T	G135D	1.000
5:131719369:C:G	G135R	1.000
5:131719370:A:C	F134L	1.000
5:131719370:A:T	F134L	1.000
5:131719372:A:G	F134L	1.000
5:131744652:A:G	L44P	1.000
5:131744655:C:G	R43P	1.000
5:131644704:A:T	V1161D	0.999

dbSNP variants (sampled 300 via entrez): RS1000029077 (5:131765953 G>A), RS1000033261 (5:131741094 A>G), RS1000044854 (5:131654866 T>C), RS1000075929 (5:131654586 C>T), RS1000091516 (5:131683771 A>G), RS1000139480 (5:131650374 G>A), RS1000170182 (5:131754488 C>T), RS1000178865 (5:131682138 T>A), RS1000199892 (5:131754759 G>A), RS1000261952 (5:131656238 A>G), RS1000270480 (5:131793536 C>T), RS1000279883 (5:131704983 A>G), RS1000289817 (5:131705238 A>G,T), RS1000301175 (5:131769029 A>T), RS1000303333 (5:131718088 A>C)

Disease associations

OMIM: gene MIM:610594 | disease phenotypes: MIM:619705, MIM:194200

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 93 and hypertrophic cardiomyopathy	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
FNIP1-associated syndrome	Definitive	AR

Mondo (2): immunodeficiency 93 and hypertrophic cardiomyopathy (MONDO:0030528), Wolff-Parkinson-White syndrome (MONDO:0008685)

Orphanet (2): Agammaglobulinemia-early-onset hypertrophic cardiomyopathy-neutropenia syndrome (Orphanet:693647), NON RARE IN EUROPE: Wolff-Parkinson-White syndrome (Orphanet:907)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001263	Global developmental delay
HP:0001639	Hypertrophic cardiomyopathy
HP:0001716	Wolff-Parkinson-White syndrome
HP:0001875	Decreased total neutrophil count
HP:0002110	Bronchiectasis
HP:0002136	Broad-based gait
HP:0002194	Delayed gross motor development
HP:0002850	Decreased circulating total IgM
HP:0003593	Infantile onset
HP:0004315	Decreased circulating IgG concentration
HP:0004432	Agammaglobulinemia
HP:0005133	Right ventricular dilatation
HP:0005180	Tricuspid regurgitation
HP:0010862	Delayed fine motor development
HP:0010976	Decreased total B cell count
HP:0012389	Appendicular hypotonia
HP:0030252	Absent circulating B cells
HP:0030388	Decreased class-switched memory B cell proportion
HP:0033542	Bronchial wall thickening
HP:0100280	Crohn’s disease

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST002817_21	Alzheimer’s disease in APOE e4- carriers	4.000000e-07
GCST002817_22	Alzheimer’s disease in APOE e4- carriers	3.000000e-07
GCST002875_174	Diisocyanate-induced asthma	1.000000e-06
GCST004131_32	Inflammatory bowel disease	4.000000e-27
GCST004132_10	Crohn’s disease	6.000000e-36
GCST004133_36	Ulcerative colitis	2.000000e-06
GCST004606_123	Eosinophil count	4.000000e-10
GCST004624_86	Sum eosinophil basophil counts	3.000000e-10
GCST004861_65	Itch intensity from mosquito bite	1.000000e-30
GCST004862_153	Itch intensity from mosquito bite adjusted by bite size	1.000000e-17
GCST004862_225	Itch intensity from mosquito bite adjusted by bite size	3.000000e-09
GCST004862_59	Itch intensity from mosquito bite adjusted by bite size	1.000000e-09
GCST004863_102	Mosquito bite size	3.000000e-16
GCST004865_90	Itch intensity from mosquito bite adjusted by bite size	4.000000e-17
GCST010701_41	Cortical surface area (MOSTest)	1.000000e-20
GCST010702_96	Subcortical volume (MOSTest)	2.000000e-08
GCST010703_160	Brain morphology (MOSTest)	3.000000e-09
GCST011956_89	Systemic lupus erythematosus	4.000000e-08
GCST90013663_73	Alanine aminotransferase levels	2.000000e-12
GCST90013664_103	Aspartate aminotransferase levels	1.000000e-08

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0006995	response to diisocyanate
EFO:0004842	eosinophil count
EFO:0005090	basophil count
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0004346	neuroimaging measurement
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D014927	Wolff-Parkinson-White Syndrome	C14.280.067.780.977; C14.280.123.750.977; C16.131.240.400.980

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL5291519 (SINGLE PROTEIN), CHEMBL5291963 (PROTEIN-PROTEIN INTERACTION)

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

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.17	IC50	670	nM	CHEMBL5289726
5.66	IC50	2200	nM	CHEMBL5289726

PubChem BioAssay actives

3 with measured affinity, of 3 total; 1 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
2-chloro-N-(2-cyanoethyl)-N-(2,3-dihydro-1,4-benzodioxin-6-yl)acetamide	1939927: Inhibition of FNIP1 in human HEK293T cells	ic50	0.6700	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation, increases expression	2
arsenite	decreases reaction, affects expression, affects binding	2
Arsenic Trioxide	affects cotreatment, increases expression	2
Air Pollutants	decreases expression, affects cotreatment, increases abundance, increases oxidation	2
Formaldehyde	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Dronabinol	decreases expression, increases expression	2
Asbestos, Crocidolite	increases expression, affects expression	2
Cadmium Chloride	increases expression	2
Particulate Matter	affects cotreatment, decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
trichostatin A	increases expression	1
dodecyldimethylamine oxide	increases expression	1
sodium arsenite	increases expression	1
didecyldimethylammonium	increases expression	1
coumarin	decreases phosphorylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
pentabromodiphenyl ether	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
14-deoxy-11,12-didehydroandrographolide	increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5243421	Binding	Inhibition of FNIP1 in human HEK293T cells	A comprehensive review of BET-targeting PROTACs for cancer therapy. — Bioorg Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_XN86	HAP1 FNIP1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00251121	Not specified	COMPLETED	Routine Mini-invasive Electrophysiology Study for Patients Feeling Tachycardia, With a Negative Holter ECG
NCT00873470	Not specified	TERMINATED	Wolff-Parkinson-White Syndrome Anterograde Refractory Period of Accessory Duct
NCT03207373	Not specified	TERMINATED	Stress ECG Test for the Evaluation of the Risk of Sudden Cardiac Death in a Paediatric Cohort With WPW Pattern
NCT03301935	Not specified	COMPLETED	Risk Assessment in Patients With Symptomatic- and Asymptomatic Preexcitation
NCT03816033	Not specified	UNKNOWN	Cryotherapy Versus Radiofrequency Catheter Ablation Research Program
NCT04106622	Not specified	UNKNOWN	Accessory Pathway Antegrade Effective Refractory Period Among WPW Patients: the Risk in Relation to the Location
NCT06349109	Not specified	COMPLETED	Physical Activity in Children With Wolff-Parkinson-White Syndrome
NCT07435181	Not specified	NOT_YET_RECRUITING	Comparative Outcomes of Radiofrequency Ablation of Concealed and Manifest Accessory Pathways: a Single Center, Retrospective Observational Study