FAT1

Summary

FAT1 (FAT atypical cadherin 1, HGNC:3595) is a protein-coding gene on chromosome 4q35.2, encoding Protocadherin Fat 1 (Q14517). Plays an essential role for cellular polarization, directed cell migration and modulating cell-cell contact.

This gene is an ortholog of the Drosophila fat gene, which encodes a tumor suppressor essential for controlling cell proliferation during Drosophila development. The gene product is a member of the cadherin superfamily, a group of integral membrane proteins characterized by the presence of cadherin-type repeats. In addition to containing 34 tandem cadherin-type repeats, the gene product has five epidermal growth factor (EGF)-like repeats and one laminin A-G domain. This gene is expressed at high levels in a number of fetal epithelia. Its product probably functions as an adhesion molecule and/or signaling receptor, and is likely to be important in developmental processes and cell communication. Transcript variants derived from alternative splicing and/or alternative promoter usage exist, but they have not been fully described.

Source: NCBI Gene 2195 — RefSeq curated summary.

At a glance

• Gene–disease (curated): focal segmental glomerulosclerosis (Strong, ClinGen) — +1 more curated relationship
• GWAS associations: 17
• Clinical variants (ClinVar): 1,824 total — 24 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 2
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 28 cancer types
• MANE Select transcript: NM_005245

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3595
Approved symbol	FAT1
Name	FAT atypical cadherin 1
Location	4q35.2
Locus type	gene with protein product
Status	Approved
Aliases	CDHF7, CDHR8
Ensembl gene	ENSG00000083857
Ensembl biotype	protein_coding
OMIM	600976
Entrez	2195

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000441802, ENST00000500085, ENST00000503253, ENST00000507105, ENST00000507662, ENST00000508035, ENST00000509537, ENST00000509647, ENST00000509927, ENST00000512347, ENST00000512772, ENST00000917424, ENST00000917425

RefSeq mRNA: 1 — MANE Select: NM_005245 NM_005245

CCDS: CCDS47177

Canonical transcript exons

ENST00000441802 — 27 exons

Exon	Start	End
ENSE00001016636	186617708	186621775
ENSE00001016638	186596540	186597171
ENSE00001016640	186636585	186636914
ENSE00001016642	186603176	186603977
ENSE00001016643	186633684	186633823
ENSE00001016644	186614191	186614344
ENSE00001016648	186628488	186628763
ENSE00001016649	186613109	186613342
ENSE00001016652	186636025	186636235
ENSE00001016653	186604377	186604574
ENSE00001170861	186599898	186600360
ENSE00001170870	186601269	186601426
ENSE00001170880	186602903	186603034
ENSE00001170912	186609183	186609320
ENSE00001170919	186609801	186610015
ENSE00001170927	186611386	186611775
ENSE00001198148	186617005	186617201
ENSE00001198187	186639722	186639783
ENSE00001271118	186606070	186606213
ENSE00001271227	186663299	186663613
ENSE00001271254	186706563	186709845
ENSE00001672978	186628154	186628364
ENSE00002028444	186587794	186589220
ENSE00002032048	186723664	186723856
ENSE00003473665	186597972	186598125
ENSE00003637797	186595689	186595826
ENSE00003666327	186597682	186597792

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 63.4034 / max 1520.2959, expressed in 1465 samples.

FANTOM5 promoters (23 alternative TSS)

Promoter ID	TPM avg	Samples expressed
55381	53.6748	1434
55375	6.1282	1252
55380	1.1107	434
55379	0.5498	284
55377	0.4495	169
55376	0.3358	106
55382	0.2893	140
55347	0.2411	110
55362	0.2059	74
55346	0.1184	49

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
choroid plexus epithelium	UBERON:0003911	99.04	gold quality
tibia	UBERON:0000979	98.91	gold quality
metanephric glomerulus	UBERON:0004736	98.41	gold quality
renal glomerulus	UBERON:0000074	98.25	gold quality
periodontal ligament	UBERON:0008266	98.07	gold quality
ventricular zone	UBERON:0003053	98.04	gold quality
stromal cell of endometrium	CL:0002255	97.99	gold quality
cartilage tissue	UBERON:0002418	97.99	gold quality
jejunal mucosa	UBERON:0000399	97.54	gold quality
metanephros	UBERON:0000081	97.35	gold quality
colonic mucosa	UBERON:0000317	97.33	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.29	gold quality
pancreatic ductal cell	CL:0002079	97.10	gold quality
kidney epithelium	UBERON:0004819	96.95	gold quality
hair follicle	UBERON:0002073	96.93	gold quality
renal medulla	UBERON:0000362	96.85	gold quality
transverse colon	UBERON:0001157	96.83	gold quality
duodenum	UBERON:0002114	96.40	gold quality
epithelial cell of pancreas	CL:0000083	96.32	gold quality
metanephros cortex	UBERON:0010533	96.29	gold quality
adrenal tissue	UBERON:0018303	96.21	gold quality
colon	UBERON:0001155	96.17	gold quality
cortex of kidney	UBERON:0001225	96.17	gold quality
sigmoid colon	UBERON:0001159	96.16	gold quality
large intestine	UBERON:0000059	96.14	gold quality
tibial artery	UBERON:0007610	96.09	gold quality
popliteal artery	UBERON:0002250	96.08	gold quality
intestine	UBERON:0000160	96.03	gold quality
mucosa of transverse colon	UBERON:0004991	95.99	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.91	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	19.42
E-CURD-112	yes	15.85
E-GEOD-81608	yes	15.71
E-GEOD-93593	yes	14.21
E-ANND-3	yes	9.44

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ING1

miRNA regulators (miRDB)

112 targeting FAT1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-223-3P	99.99	70.14	1140
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-548D-3P	99.87	70.67	4362

Literature-anchored findings (GeneRIF, showing 40)

• Processing of FAT1 and the translocation of its cytoplasmic domain to the nucleus were studied. (PMID:15922730)
• A cadherin gene, FAT, confers susceptibility to bipolar disorder in four independent cohorts. In mice, Fat was shown to be significantly downregulated and Catnb and Enah were significantly upregulated in response to therapeutic doses of lithium. (PMID:16402135)
• Fat1 exhibit co-localisation with Homer-3 in cellular protrusions and at the plasma membrane of HeLa cells (PMID:16979624)
• results identify mutations in FAT as an important factor in the development of oral cancer and indicate the importance of FATs function in some squamous cell carcinomas (PMID:17325662)
• FAT1(WT) is up-regulated in migration, induces cellular process formation when overexpressed, and is necessary for efficient wound healing (PMID:17500054)
• This study did not support the two FAT polymorphism in the affectve disorder. (PMID:17895925)
• The results of this study supports an involvement of variation at the FAT gene in the etiology of BPAD. (PMID:17938632)
• Results point to a role of the FAT in astrocytic tumorigenesis and demonstrate the use of RAPD analysis in identifying specific alterations in astrocytic tumors. (PMID:19126244)
• FAT1 may be involved in the migration and invasion mechanisms of oral squamous cell carcinoma cells (PMID:21617878)
• In vitro localization studies of FAT1 showed that melanoma cells display high levels of cytosolic FAT1 protein, whereas keratinocytes, despite comparable FAT1 expression levels, exhibited mainly cell-cell junctional staining (PMID:21680732)
• data presented demonstrate that Fat1 expression in preB-ALL has a role in the emergence of relapse and could provide a suitable therapeutic target in high-risk preB-ALL (PMID:22116550)
• Lipid accumulation in myotubes derived from obese type 2 diabetic patients arises from abnormal FAT/CD36 cycling. (PMID:22194967)
• FAT1 suppression in activated hepatic stellate cells caused a downregulation of NFkappaB activity (PMID:22959770)
• this study identifies a novel signaling mechanism mediated by FAT1 in regulating the activity of PDCD4 in gliomas. (PMID:22986533)
• Taken together, these data strongly point to FAT1 as a tumor suppressor gene driving loss of chromosome 4q35, a prevalent region of deletion in cancer (PMID:23354438)
• Fat1 may therefore provide a new marker of MRD for patients with ALL lacking known genomic aberrations or within a multiplex approach to MRD detection. (PMID:23433465)
• Our study identifies FAT1 as a critical determinant of muscle form, misregulation of which associates with facioscapulohumeral dystrophy . (PMID:23785297)
• There is a mechanism to regulate death receptor-mediated apoptosis via an interaction between FAT1 and procaspase-8. (PMID:24442637)
• frequency of FAT1-mutated cases was significantly higher in drug resistant chronic lymphocytic leukemia than in unselected chronic lymphocytic leukemia (PMID:24550227)
• This work establishes S1-processing as a clear functional prerequisite for ectodomain shedding of FAT1 with general implications for the shedding of other transmembrane receptors. (PMID:24560745)
• FAT1 expression in HCC is regulated via promotor methylation. (PMID:24590895)
• Fat1 is released from pancreatic cancer cells in its soluble form by ADAM10 mediated ectodomain shedding (PMID:24625754)
• Analysis revealed an aberrant expression of FAT1 predominantly in mature BCP-ALL and thymic T-ALL and a high rate of FAT1 mutations. (PMID:24972153)
• FJX1 does not influence the levels of FAT1 ectodomain phosphorylation. (PMID:25150169)
• our data suggest that defective FAT1 is associated with an FSHD-like phenotype. (PMID:25615407)
• FAT1 is expressed at lower levels in muscles that are affected at early stages of facioscapulohumeral muscular dystrophy progression. (PMID:26018399)
• FAT1 protein acts upstream of Hippo signalling through TAZ protein to regulate neuronal differentiation. (PMID:26104008)
• that loss of FAT1 and beta-catenin are associated with breast cancer progression, aggressive behavior, and poor prognosis (PMID:26721716)
• FAT1 mutational status is a strong independent prognostic factor in patients with HPV-negative head and neck squamous cell carcinoma; FAT1 mutation was significantly associated with better overall survival (PMID:26876381)
• Recessive mutations in FAT1 cause a distinct renal disease entity in four families with a combination of steroid-resistance nephrotic syndrome, tubular ectasia, haematuria and facultative neurological involvement. (PMID:26905694)
• We identified recurrent mutations in the novel penile cancer tumor suppressor genes CSN1(GPS1) and FAT1 (PMID:27325650)
• FAT1 and mAb198.3 may offer new therapeutic opportunities for CRC. (PMID:27328312)
• At the molecular level, under hypoxia the FAT1 depletion-associated reduction in HIF1alpha was due to compromised EGFR-Akt signaling as well as increased VHL-dependent proteasomal degradation of HIF1alpha. (PMID:27536856)
• Loss of function mutations in FAT1 and CASP8 prevent cell adhesion and promote cell migration and proliferation in oral squamous cell carcinoma cell lines. (PMID:27693639)
• Low FAT1 expression was associated with poor prognosis in children with medulloblastoma. Furthermore, FAT1 may act on Wnt signaling pathway to exert its antitumor effect (PMID:27834469)
• Data show that the two N-terminal SH3 domains of SH3 domain containing ring finger 1 (SH3RF1) protein interact with FAT1 protein. (PMID:28129444)
• Disruption of MAPK/ERK pathway by FAT1 contributes the epithelial mesenchymal transformation in esophageal squamous cell carcinomas. (PMID:28366557)
• FAT1 has a novel regulatory effect on EMT/stemness markers both via or independent of HIF-1alpha. The functional relevance of this study was corroborated by significant reduction in the number of soft-agar colonies formed in hypoxic-siFAT1 treated U87MG cells. (PMID:28994107)
• Study showed that FAT1 exhibits a high frequency of mutations and a downregulated expression in esophageal squamous cell carcinoma (ESCC) leading to cell migration and invasion by affecting the cellular mechanical properties of ESCC cells. (PMID:29565465)
• Fat1 functional loss results in YAP1 activation and is associated with human malignancies. (PMID:29985391)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	fat1a	ENSDARG00000017591
danio_rerio	fat1b	ENSDARG00000019063
mus_musculus	Fat1	ENSMUSG00000070047
rattus_norvegicus	Fat1	ENSRNOG00000030954
drosophila_melanogaster	stan	FBGN0024836
caenorhabditis_elegans		WBGENE00001475
caenorhabditis_elegans	hmr-1	WBGENE00001980
caenorhabditis_elegans	Y52B11A.11	WBGENE00014914

Paralogs (6): CELSR3 (ENSG00000008300), CELSR1 (ENSG00000075275), FAT2 (ENSG00000086570), CELSR2 (ENSG00000143126), FAT3 (ENSG00000165323), FAT4 (ENSG00000196159)

Protein

Protein identifiers

Protocadherin Fat 1 — Q14517 (reviewed: Q14517)

Alternative names: Cadherin family member 7, Cadherin-related tumor suppressor homolog, Protein fat homolog

All UniProt accessions (6): Q14517, D6RCE4, D6RHE6, H0Y8F5, H0Y9C8, H0Y9H4

UniProt curated annotations — full annotation on UniProt →

Function. Plays an essential role for cellular polarization, directed cell migration and modulating cell-cell contact.

Subunit / interactions. Interacts (via the C-terminus 4300-4400 AA) with ATN1. Interacts with RERE.

Subcellular location. Cell membrane Nucleus.

Tissue specificity. Expressed in many epithelial and some endothelial and smooth muscle cells.

Post-translational modifications. Undergoes proteolytic cleavage. The extracellular domain is cleaved off and the cytoplasmic domain (about 400 AA) shuttles to the nucleus.

Domain organisation. A PTB-like motif (DNXYH sequence) is required for the targeting to the leading edge. This motif represents a minimal protein-protein interaction core motif that is not regulated by tyrosine phosphorylation.

RefSeq proteins (1): NP_005236* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR001791	Laminin_G	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR002126	Cadherin-like_dom	Domain
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR015919	Cadherin-like_sf	Homologous_superfamily
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR020894	Cadherin_CS	Conserved_site

Pfam: PF00008, PF00028, PF02210

UniProt features (121 total): domain 39, glycosylation site 22, sequence conflict 17, disulfide bond 16, sequence variant 12, region of interest 5, chain 2, topological domain 2, short sequence motif 2, compositionally biased region 2, signal peptide 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

No AlphaFold model available for Q14517 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

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

Disulfide bonds (16): 3794–3805, 3799–3816, 3818–3826, 3976–4009, 4017–4028, 4022–4038, 4040–4049, 4056–4067, 4061–4076, 4078–4087, 4093–4104, 4098–4113, 4115–4124, 4131–4142, 4136–4151, 4153–4162

Glycosylation sites (22): 40, 333, 660, 740, 791, 998, 1426, 1551, 1748, 1864, 1902, 1940, 1991, 2325, 2464, 3324, 3422, 3444, 3613, 3640 …

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 178 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, MODULE_52, MODULE_92, MODULE_64, GOZGIT_ESR1_TARGETS_DN, DITTMER_PTHLH_TARGETS_UP, GOBP_CELL_CELL_SIGNALING, MODULE_66, GOBP_CELL_CELL_ADHESION, DAVIES_MULTIPLE_MYELOMA_VS_MGUS_UP, ENGELMANN_CANCER_PROGENITORS_UP, chr4q35, DACOSTA_UV_RESPONSE_VIA_ERCC3_COMMON_DN, WEST_ADRENOCORTICAL_CARCINOMA_VS_ADENOMA_UP, MODULE_88

GO Biological Process (17): lens development in camera-type eye (GO:0002088), epithelial cell morphogenesis (GO:0003382), establishment of epithelial cell apical/basal polarity involved in camera-type eye morphogenesis (GO:0003412), actin filament organization (GO:0007015), cell adhesion (GO:0007155), homophilic cell-cell adhesion (GO:0007156), cell-cell signaling (GO:0007267), anatomical structure morphogenesis (GO:0009653), cell migration (GO:0016477), cell-cell adhesion mediated by cadherin (GO:0044331), cellular response to angiotensin (GO:1904385), positive regulation of vascular associated smooth muscle cell migration (GO:1904754), establishment or maintenance of cell polarity (GO:0007163), camera-type eye development (GO:0043010), establishment or maintenance of epithelial cell apical/basal polarity (GO:0045197), camera-type eye morphogenesis (GO:0048593), cell-cell adhesion (GO:0098609)

GO Molecular Function (2): calcium ion binding (GO:0005509), protein binding (GO:0005515)

GO Cellular Component (13): nucleus (GO:0005634), cytosol (GO:0005829), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), adherens junction (GO:0005912), focal adhesion (GO:0005925), apical plasma membrane (GO:0016324), lamellipodium (GO:0030027), filopodium (GO:0030175), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), membrane (GO:0016020), cell junction (GO:0030054)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
camera-type eye development	2
anatomical structure development	2
cellular process	2
cell-cell adhesion	2
cytoplasm	2
cell morphogenesis	1
epithelial cell development	1
establishment of epithelial cell apical/basal polarity	1
camera-type eye morphogenesis	1
actin cytoskeleton organization	1
supramolecular fiber organization	1
cell communication	1
signaling	1
developmental process	1
cell motility	1
cellular response to peptide hormone stimulus	1
response to angiotensin	1
positive regulation of smooth muscle cell migration	1
vascular associated smooth muscle cell migration	1
regulation of vascular associated smooth muscle cell migration	1
eye development	1
establishment or maintenance of apical/basal cell polarity	1
eye morphogenesis	1
cell adhesion	1
metal ion binding	1
binding	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
anchoring junction	1
cell-cell junction	1
cell-substrate junction	1
apical part of cell	1
plasma membrane region	1
cell leading edge	1
plasma membrane bounded cell projection	1
actin-based cell projection	1
extracellular vesicle	1

Protein interactions and networks

STRING

2060 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FAT1	VASP	P50552	934
FAT1	CTNNB1	P35222	929
FAT1	NPHS1	O60500	928
FAT1	NPHS2	Q9NP85	926
FAT1	SCRIB	Q14160	908
FAT1	KIRREL1	Q96J84	906
FAT1	MTNR1A	P48039	871
FAT1	LAMC1	P11047	774
FAT1	FJX1	Q86VR8	763
FAT1	MTNR1B	P49286	720
FAT1	TP53	P04637	698
FAT1	CD2AP	Q9Y5K6	676
FAT1	KRAS	P01116	666
FAT1	PIK3CA	P42336	653
FAT1	KMT2D	O14686	647

IntAct

233 interactions, top by confidence:

A	B	Type	Score
RPS6KA2	MAPK1	psi-mi:“MI:0914”(association)	0.910
EZH2	EPOP	psi-mi:“MI:0914”(association)	0.730
CFTR	XPO1	psi-mi:“MI:0914”(association)	0.710
ARL4C	RGS12	psi-mi:“MI:0914”(association)	0.640
DKKL1	DENND11	psi-mi:“MI:0914”(association)	0.640
INAVA	CYTH3	psi-mi:“MI:0914”(association)	0.640
KLK5	DENND11	psi-mi:“MI:0914”(association)	0.640
ILK	HAX1	psi-mi:“MI:0914”(association)	0.530
PSG8	PEX7	psi-mi:“MI:0914”(association)	0.530
XAGE1A	THAP12	psi-mi:“MI:0914”(association)	0.530
BRINP3	BUB1	psi-mi:“MI:0914”(association)	0.530
PDGFB	DKC1	psi-mi:“MI:0914”(association)	0.530
CBX1	KPNA3	psi-mi:“MI:0914”(association)	0.530
FGF3	GTPBP10	psi-mi:“MI:0914”(association)	0.530
CMA1	MANBA	psi-mi:“MI:0914”(association)	0.530
PRSS37	MANBA	psi-mi:“MI:0914”(association)	0.530
IFNE	FAT1	psi-mi:“MI:0914”(association)	0.530
CTSG	MANBA	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
GPIHBP1	ADAM10	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
MRPS17	MRPS22	psi-mi:“MI:0914”(association)	0.530
SPSB4	ARHGEF10	psi-mi:“MI:0914”(association)	0.530
MAST2	FAT1	psi-mi:“MI:0407”(direct interaction)	0.440
FAT1	DLG1	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (153): FAT1 (Affinity Capture-MS), FAT1 (Affinity Capture-MS), FAT1 (Affinity Capture-MS), FAT1 (Affinity Capture-MS), FAT1 (Affinity Capture-MS), FAT1 (Affinity Capture-MS), FAT1 (Affinity Capture-MS), FAT1 (Affinity Capture-MS), FAT1 (Affinity Capture-MS), FAT1 (Affinity Capture-MS), FAT1 (Affinity Capture-MS), FAT1 (Affinity Capture-MS), FAT1 (Affinity Capture-MS), FAT1 (Affinity Capture-MS), FAT1 (Biochemical Activity)

ESM2 similar proteins: E9Q7P9, O88277, O93319, P55280, P55281, P55285, P55289, P70408, P79995, P97326, Q08DJ5, Q12864, Q13634, Q14517, Q24298, Q2PZL6, Q3SWX5, Q5DWV1, Q5DWV2, Q5F226, Q63315, Q6B3P0, Q6KEQ9, Q6V0I7, Q6WXV7, Q6WYY1, Q6X862, Q6ZTQ4, Q71M42, Q8BIZ0, Q8BL00, Q8BM92, Q8BNA6, Q8N6Y1, Q8QGH3, Q8R508, Q8TDW7, Q90762, Q90763, Q91838

Diamond homologs: A0A8M9PFP2, B0S5G3, F1R520, O02840, O55111, O88278, O94985, P30944, P33151, P55287, P55288, Q0VCN6, Q14517, Q5DRC8, Q5R9Q9, Q63418, Q6Q0N0, Q6URK6, Q6V1P9, Q86UP0, Q8BNA6, Q8R553, Q8VDA1, Q96JQ0, Q99JH7, Q9BQT9, Q9EPL2, Q9ER65, Q9H4D0, Q9HCU4, Q9NYQ6, Q9R0M0, A0A1F4, A2RUV0, A4FV93, A8X481, B2LW77, B8JI71, D3ZHH1, D3ZUK3

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 220 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
Ras activation upon Ca2+ influx through NMDA receptor	5	19.7×	8e-04
Unblocking of NMDA receptors, glutamate binding and activation	5	18.8×	8e-04
Negative regulation of NMDA receptor-mediated neuronal transmission	5	18.8×	8e-04
Long-term potentiation	5	16.4×	1e-03
Assembly and cell surface presentation of NMDA receptors	9	15.8×	1e-06
Neurexins and neuroligins	10	13.6×	1e-06
Protein-protein interactions at synapses	6	11.0×	2e-03
Interleukin-17 signaling	5	8.8×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	12	35.2×	3e-13
receptor clustering	8	25.2×	5e-07
protein localization to synapse	6	23.2×	6e-05
regulation of postsynaptic membrane neurotransmitter receptor levels	6	15.0×	5e-04
establishment of cell polarity	6	11.6×	2e-03
Wnt signaling pathway, planar cell polarity pathway	5	11.5×	8e-03
establishment of protein localization	5	10.9×	8e-03
cell-cell adhesion	12	6.2×	2e-04

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 28 cancer types — AML, ANGS, ANSC, BCC, BL, BLADDER, BLCA, BRCA, CCRCC, CESC, CSCC, ESCA…(+16 more).

Clinical variants and AI predictions

ClinVar

1824 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	24
Likely pathogenic	15
Uncertain significance	960
Likely benign	506
Benign	159

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1527141	GRCh37/hg19 4q35.1-35.2(chr4:183221828-190957473)	Pathogenic
152922	GRCh38/hg38 4q35.2(chr4:186625270-190018185)x1	Pathogenic
1937208	NM_005245.4(FAT1):c.7789C>T (p.Arg2597Ter)	Pathogenic
2025904	NM_005245.4(FAT1):c.12110_12111del (p.Tyr4037fs)	Pathogenic
2043616	NM_005245.4(FAT1):c.12680_12683delinsGAA (p.Phe4227_Leu4228delinsTer)	Pathogenic
2072092	NM_005245.4(FAT1):c.6437T>G (p.Leu2146Ter)	Pathogenic
2745261	NM_005245.4(FAT1):c.4609dup (p.Gln1537fs)	Pathogenic
2810148	NM_005245.4(FAT1):c.4603C>T (p.Arg1535Ter)	Pathogenic
2849893	NM_005245.4(FAT1):c.377dup (p.Asn126fs)	Pathogenic
2875385	NM_005245.4(FAT1):c.10993C>T (p.Arg3665Ter)	Pathogenic
3277784	NM_005245.4(FAT1):c.2839_2840del (p.Met947fs)	Pathogenic
3657083	NM_005245.4(FAT1):c.5402_5403del (p.Lys1801fs)	Pathogenic
3720075	NM_005245.4(FAT1):c.11256_11257del (p.Ser3753fs)	Pathogenic
3723085	NM_005245.4(FAT1):c.6717del (p.Ile2239fs)	Pathogenic
3724013	NM_005245.4(FAT1):c.8548C>T (p.Gln2850Ter)	Pathogenic
3729124	NM_005245.4(FAT1):c.10551_10552del (p.Ala3518fs)	Pathogenic
4023102	NM_005245.4(FAT1):c.2959C>T (p.Gln987Ter)	Pathogenic
4716102	NM_005245.4(FAT1):c.11549_11553del (p.Lys3850fs)	Pathogenic
4720809	NM_005245.4(FAT1):c.9120del (p.Lys3040fs)	Pathogenic
4724533	NM_005245.4(FAT1):c.11764dup (p.Tyr3922fs)	Pathogenic
4725633	NM_005245.4(FAT1):c.7950del (p.Lys2650fs)	Pathogenic
4735781	NM_005245.4(FAT1):c.5522del (p.Ser1841fs)	Pathogenic
4761728	NM_005245.4(FAT1):c.7666C>T (p.Arg2556Ter)	Pathogenic
940489	NM_005245.4(FAT1):c.2844G>A (p.Trp948Ter)	Pathogenic
1301307	NM_005245.4(FAT1):c.12820G>T (p.Glu4274Ter)	Likely pathogenic
1333197	NM_005245.4(FAT1):c.4552G>T (p.Glu1518Ter)	Likely pathogenic
226216	GRCh37/hg19 4q35.2(chr4:187540292-187849681)	Likely pathogenic
2629321	NM_005245.4(FAT1):c.8749C>T (p.Arg2917Ter)	Likely pathogenic
2833820	NM_005245.4(FAT1):c.10351-597_10412del	Likely pathogenic
4718427	NM_005245.4(FAT1):c.12369-2A>G	Likely pathogenic

SpliceAI

5446 predictions. Top by Δscore:

Variant	Effect	Δscore
4:186589217:TACC:T	acceptor_gain	1.0000
4:186589219:CC:C	acceptor_gain	1.0000
4:186589219:CCCT:C	acceptor_gain	1.0000
4:186589220:CCT:C	acceptor_gain	1.0000
4:186589221:C:CC	acceptor_gain	1.0000
4:186589221:C:T	acceptor_gain	1.0000
4:186589222:T:C	acceptor_gain	1.0000
4:186592754:T:C	acceptor_gain	1.0000
4:186592754:T:TC	acceptor_gain	1.0000
4:186595683:CCTCA:C	donor_loss	1.0000
4:186595684:CTCAC:C	donor_loss	1.0000
4:186595685:TCAC:T	donor_loss	1.0000
4:186595686:CAC:C	donor_loss	1.0000
4:186595687:ACCA:A	donor_loss	1.0000
4:186595688:C:CT	donor_loss	1.0000
4:186595822:TTTTG:T	acceptor_gain	1.0000
4:186595824:TTG:T	acceptor_gain	1.0000
4:186595825:TG:T	acceptor_gain	1.0000
4:186595826:GC:G	acceptor_loss	1.0000
4:186595827:C:CC	acceptor_gain	1.0000
4:186595827:CTAAA:C	acceptor_loss	1.0000
4:186597791:ACCT:A	acceptor_loss	1.0000
4:186597793:C:T	acceptor_loss	1.0000
4:186597971:CCT:C	donor_gain	1.0000
4:186598122:TAAC:T	acceptor_gain	1.0000
4:186598126:C:CC	acceptor_gain	1.0000
4:186598127:T:G	acceptor_loss	1.0000
4:186598133:G:T	acceptor_gain	1.0000
4:186601264:CATA:C	donor_loss	1.0000
4:186601265:ATAC:A	donor_loss	1.0000

AlphaMissense

30337 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:186589210:C:A	W4383C	0.999
4:186589210:C:G	W4383C	0.999
4:186597115:C:G	C4142S	0.999
4:186597116:A:T	C4142S	0.999
4:186597148:C:G	C4131S	0.999
4:186597149:A:T	C4131S	0.999
4:186597169:C:G	C4124S	0.999
4:186597170:A:T	C4124S	0.999
4:186597712:C:G	C4113S	0.999
4:186597713:A:T	C4113S	0.999
4:186597738:G:C	C4104W	0.999
4:186597739:C:G	C4104S	0.999
4:186597740:A:G	C4104R	0.999
4:186597740:A:T	C4104S	0.999
4:186597757:C:G	C4098S	0.999
4:186597758:A:T	C4098S	0.999
4:186597789:A:C	C4087W	0.999
4:186597790:C:G	C4087S	0.999
4:186597791:A:G	C4087R	0.999
4:186597791:A:T	C4087S	0.999
4:186600268:C:A	W3911C	0.999
4:186600268:C:G	W3911C	0.999
4:186611580:A:T	V3220D	0.999
4:186617054:A:T	V3009D	0.999
4:186589212:A:G	W4383R	0.998
4:186589212:A:T	W4383R	0.998
4:186597088:C:G	C4151S	0.998
4:186597089:A:T	C4151S	0.998
4:186597115:C:T	C4142Y	0.998
4:186597170:A:G	C4124R	0.998

dbSNP variants (sampled 300 via entrez): RS1000003270 (4:186688408 T>C), RS1000007580 (4:186724267 G>A), RS1000010747 (4:186589455 G>A), RS1000011053 (4:186631148 T>C), RS1000025998 (4:186617436 T>C), RS1000026243 (4:186629191 T>C), RS1000048047 (4:186612034 C>A,G), RS1000048866 (4:186705802 A>G,T), RS1000096392 (4:186630700 A>G), RS1000133115 (4:186698214 G>A,T), RS1000133529 (4:186661028 T>C), RS10001377 (4:186639926 A>C,G), RS1000169160 (4:186677474 C>G,T), RS1000169346 (4:186665803 T>C), RS1000195563 (4:186595136 C>G)

Disease associations

OMIM: gene MIM:600976 | disease phenotypes: MIM:164400, MIM:604229, MIM:309800, MIM:254500, MIM:610542

GenCC curated gene-disease

Disease	Classification	Inheritance
syndromic disease	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
focal segmental glomerulosclerosis	Strong	AR

Mondo (10): autosomal dominant cerebellar ataxia (MONDO:0020380), nephrotic syndrome (MONDO:0005377), syndromic disease (MONDO:0002254), Peters anomaly (MONDO:0011414), hypertensive disorder (MONDO:0005044), attention deficit-hyperactivity disorder (MONDO:0007743), familial idiopathic steroid-resistant nephrotic syndrome (MONDO:0019006), syndromic microphthalmia (MONDO:0016073), plasma cell myeloma (MONDO:0009693), congenital myasthenic syndrome 12 (MONDO:0012518)

Orphanet (9): Autosomal dominant cerebellar ataxia (Orphanet:99), Peters anomaly (Orphanet:708), Microphthalmia-anophthalmia-coloboma (Orphanet:98555), Hereditary steroid-resistant nephrotic syndrome (Orphanet:656), Syndromic microphthalmia-anophthalmia-coloboma (Orphanet:202948), Multiple myeloma (Orphanet:29073), AL amyloidosis (Orphanet:85443), Congenital myasthenic syndrome with glycosylation defect (Orphanet:353327), Congenital myasthenic syndrome (Orphanet:590)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0000659	Peters anomaly
HP:0000822	Hypertension

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST001057_1	Obesity	7.000000e-06
GCST003427_202	Alzheimer disease and age of onset	4.000000e-07
GCST003453_9	Chronotype	4.000000e-06
GCST003454_7	Morning vs. evening chronotype	2.000000e-08
GCST004162_12	Carotid plaque burden	9.000000e-06
GCST005231_9	Major depressive disorder	9.000000e-07
GCST006976_135	Macular thickness	4.000000e-08
GCST006979_762	Heel bone mineral density	6.000000e-09
GCST007045_27	PR interval	3.000000e-08
GCST007929_99	Medication use (calcium channel blockers)	3.000000e-08
GCST009640_22	Urinary albumin-to-creatinine ratio	6.000000e-09
GCST010321_136	PR interval	5.000000e-15
GCST011742_28	Triglyceride levels in HIV infection	8.000000e-06
GCST90002385_264	High light scatter reticulocyte count	2.000000e-10
GCST90002386_11	High light scatter reticulocyte percentage of red cells	3.000000e-11
GCST90002387_100	Immature fraction of reticulocytes	2.000000e-10
GCST90026415_13	Mild obesity-related type 2 diabetes	3.000000e-06

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004847	age at onset
EFO:0006501	carotid plaque build
EFO:0009270	heel bone mineral density
EFO:0004462	PR interval
EFO:0009930	Calcium channel blocker use measurement
EFO:0007778	urinary albumin to creatinine ratio
EFO:0004530	triglyceride measurement
EFO:0007986	reticulocyte count

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D006973	Hypertension	C14.907.489
D009101	Multiple Myeloma	C04.557.595.500; C14.907.454.460; C15.378.147.780.650; C15.378.463.515.460; C20.683.515.845; C20.683.780.650
D009404	Nephrotic Syndrome	C12.050.351.968.419.630.643; C12.200.777.419.630.643; C12.950.419.630.643
D013577	Syndrome	C23.550.288.500
C537884	Peters anomaly (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

5 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2304865	FAT1		0.00	0
rs2306987	FAT1		0.00	0
rs2306990	FAT1		0.00	0
rs2637777	FAT1		0.00	0
rs116134453	FAT1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, increases expression, decreases expression	4
bisphenol A	decreases expression, affects methylation, affects cotreatment, increases methylation, increases expression	3
sodium arsenite	affects cotreatment, decreases expression, increases abundance	3
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	3
Tetrachlorodibenzodioxin	affects expression, decreases expression	3
Particulate Matter	decreases expression, increases abundance	3
bisphenol F	decreases methylation, decreases expression, affects cotreatment	2
potassium chromate(VI)	decreases expression, affects cotreatment	2
perfluorooctane sulfonic acid	increases expression, decreases expression	2
chloropicrin	decreases expression	2
Benzo(a)pyrene	decreases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Tretinoin	decreases expression	2
Valproic Acid	increases expression, decreases expression, decreases methylation	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
securinine	increases expression	1
dicrotophos	increases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
lead acetate	affects cotreatment, decreases expression	1
beta-lapachone	decreases expression	1
chromous chloride	affects cotreatment, decreases expression	1
perfluorooctanoic acid	increases expression	1
chromic oxide	affects cotreatment, decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	1
epigallocatechin gallate	increases expression, affects cotreatment, decreases expression	1
evodiamine	increases expression	1
tamibarotene	affects expression	1
chromium hexavalent ion	decreases expression	1

Cellosaurus cell lines

28 cell lines: 28 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0D71	FaDu 2A3	Cancer cell line	Male
CVCL_1109	CAL-39	Cancer cell line	Female
CVCL_1218	FaDu	Cancer cell line	Male
CVCL_5988	JHU-013	Cancer cell line	Male
CVCL_7712	UM-SCC-104	Cancer cell line	Male
CVCL_7746	UM-SCC-35	Cancer cell line	Male
CVCL_7749	UM-SCC-38	Cancer cell line	Male
CVCL_A4CG	FaDu-Luc2	Cancer cell line	Male
CVCL_D5YF	FaDu/DDP4	Cancer cell line	Male
CVCL_E8FQ	FaDu Fat-1	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00308321	PHASE4	UNKNOWN	Long Term Tapering or Standard Steroids for Nephrotic Syndrome
NCT01021540	PHASE4	COMPLETED	Prospective Study Evaluating the Effect of Repository Corticotropin in the Treatment of Various Nephrotic Syndromes
NCT01028287	PHASE4	COMPLETED	Adrenocorticotropic Hormone (ACTH) Treatment of Nephrotic Range Proteinuria in Diabetic Nephropathy (NRDN)
NCT01162005	PHASE4	COMPLETED	Therapeutic Effect of Tacrolimus on Primary Nephrotic Syndrome in Children
NCT01895894	PHASE4	COMPLETED	Mycophenolate Mofetil in Pediatric Steroid Dependent Nephrotic Syndrome
NCT02238418	PHASE4	COMPLETED	Efficacy of Usual Vitamin D Supplementation and Its Impact on Children and Adolescents Calciuria.
NCT02382575	PHASE4	UNKNOWN	Efficacy and Safety of Rituximab to That of Calcineurin Inhibitors in Children With Steroid Resistant Nephrotic Syndrome
NCT02427880	PHASE4	COMPLETED	Role of Acetazolamide and Hydrochlorothiazide Followed by Furosemide in Treating Nephrotic Edema
NCT03210688	PHASE4	COMPLETED	Active Vitamin D And Reduced Dose Prednisolone for Treatment in Minimal Change Nephropathy
NCT03347357	PHASE4	COMPLETED	Pharmacokinetics of Tacrolimus in Children
NCT05696977	PHASE4	UNKNOWN	Effect of Obesity on Cyclosporine Blood Trough Level in Nephrotic Syndrome Patients
NCT05966818	PHASE4	UNKNOWN	Effect of Dapagliflozin in Non-Diabetic Patients With Nephrotic Syndrome.
NCT06026787	PHASE4	COMPLETED	Clinical Value of Adding Dapagliflozin in Patients With Nephrotic Syndrome
NCT00000521	PHASE4	COMPLETED	Sodium-Potassium Blood Pressure Trial in Children
NCT00018759	PHASE4	COMPLETED	Treatment Effects on Platelet Calcium in Hypertensive and Depressed Patients
NCT00034840	PHASE4	COMPLETED	Telmisartan vs. Valsartan in Patients With Mild to Moderate Hypertension Following a Missed Dose
NCT00044265	PHASE4	COMPLETED	Treatment of Pediatric Hypertension With Altace Trial
NCT00060918	PHASE4	COMPLETED	Glycemic Control Of Carvedilol Versus Metoprolol In Patients With Type II Diabetes Mellitus And Hypertension
NCT00060931	PHASE4	COMPLETED	Effect Of Carvedilol Versus Metoprolol On Glycemic Control In Patients With Type II Diabetes And Hypertension
NCT00110422	PHASE4	COMPLETED	Irbesartan in the Treatment of Hypertensive Patients With Metabolic Syndrome
NCT00115726	PHASE4	COMPLETED	Trial Assessing the Effect of Preoperative Furosemide on Intraoperative Blood Pressure
NCT00120380	PHASE4	TERMINATED	Combination Therapy of Bosentan and Aerosolized Iloprost in Idiopathic Pulmonary Arterial Hypertension (IPAH)
NCT00122811	PHASE4	UNKNOWN	The Hypertension in the Very Elderly Trial (HYVET)
NCT00123045	PHASE4	COMPLETED	Patient-Physician Partnership to Improve High Blood Pressure Adherence
NCT00123604	PHASE4	COMPLETED	Vascular Effects of Carvedilol Versus Metoprolol in Hypertensive Patients With Type 2 Diabetes
NCT00126516	PHASE4	COMPLETED	Angiotensin II Receptor Blockers (ARB) and ACE Inhibitors (ACEI) on Silent Brain Infarction and Cognitive Decline
NCT00127348	PHASE4	COMPLETED	Effect of Continuous Positive Airway Pressure (CPAP) on Hypertension and Cardiovascular Morbidity-Mortality in Patients With Sleep Apnea and no Daytime Sleepiness
NCT00128518	PHASE4	COMPLETED	IDEAL Study: Identification of the Determinants of the Efficacy of Arterial Blood Pressure Lowering Drugs
NCT00129233	PHASE4	COMPLETED	Comparison of Valsartan With Amlodipine in Hypertensive Patients With Glucose Intolerance
NCT00129909	PHASE4	COMPLETED	STITCH (Simplified Therapeutic Intervention To Control Hypertension)
NCT00130156	PHASE4	COMPLETED	Effects of Combination Therapy With Alpha-1 Blocker (Bunazosin or Doxazosin) in the Treatment of Patients With Mild to Moderate Essential Hypertension
NCT00131846	PHASE4	COMPLETED	Diuretics In the Management of Essential Hypertension (DIME) Study
NCT00133068	PHASE4	COMPLETED	Collaboration to Reduce Disparities in Hypertension
NCT00133328	PHASE4	UNKNOWN	A Morbidity-Mortality and Remodeling Study With Valsartan
NCT00133692	PHASE4	COMPLETED	INVEST: INternational VErapamil SR Trandolapril STudy
NCT00134160	PHASE4	COMPLETED	OlmeSartan and Calcium Antagonists Randomized (OSCAR) Study
NCT00136851	PHASE4	COMPLETED	Study Comparing the Efficacy of Amlodipine Besylate/Benazepril Versus Amlodipine in the Treatment of Severe Hypertension
NCT00139386	PHASE4	COMPLETED	Candesartan for Prevention of Cardiovascular Events After Cypher or Taxus Coronary Stenting (4C) Trial
NCT00139555	PHASE4	COMPLETED	Effects of Amlodipine/Benazepril in Reducing Left Ventricular Hypertrophy in Patients With High Risk Hypertension
NCT00139984	PHASE4	COMPLETED	Ambulatory Blood Pressure Monitoring for Antihypertensive Treatment Guidance