FAT4

Summary

FAT4 (FAT atypical cadherin 4, HGNC:23109) is a protein-coding gene on chromosome 4q28.1, encoding Protocadherin Fat 4 (Q6V0I7). Cadherins are calcium-dependent cell adhesion proteins.

The protein encoded by this gene is a member of the protocadherin family. This gene may play a role in regulating planar cell polarity (PCP). Studies in mice suggest that loss of PCP signaling may cause cystic kidney disease, and mutations in this gene have been associated with Van Maldergem Syndrome 2. Alternatively spliced transcript variants have been noted for this gene.

Source: NCBI Gene 79633 — RefSeq curated summary.

At a glance

• Gene–disease (curated): FAT4-related neurodevelopmental disorder (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 12
• Clinical variants (ClinVar): 3,573 total — 45 pathogenic, 18 likely-pathogenic
• Phenotypes (HPO): 136
• Cancer driver (intOGen): activating (oncogene-like) across 24 cancer types
• MANE Select transcript: NM_001291303

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23109
Approved symbol	FAT4
Name	FAT atypical cadherin 4
Location	4q28.1
Locus type	gene with protein product
Status	Approved
Aliases	CDHF14, FAT-J, CDHR11
Ensembl gene	ENSG00000196159
Ensembl biotype	protein_coding
OMIM	612411
Entrez	79633

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000335110, ENST00000394329, ENST00000509444, ENST00000674496, ENST00000678072

RefSeq mRNA: 3 — MANE Select: NM_001291303 NM_001291285, NM_001291303, NM_024582

CCDS: CCDS93620

Canonical transcript exons

ENST00000394329 — 18 exons

Exon	Start	End
ENSE00001240292	125414884	125415806
ENSE00001240299	125408444	125408794
ENSE00001240306	125406880	125407141
ENSE00001240320	125416448	125416622
ENSE00001283617	125468512	125468819
ENSE00001334434	125448461	125452810
ENSE00001382816	125398784	125398915
ENSE00001405529	125477155	125477334
ENSE00001407027	125476171	125476256
ENSE00001418614	125434245	125434425
ENSE00001426440	125481521	125481738
ENSE00001431205	125487345	125487606
ENSE00001518108	125479741	125479865
ENSE00001518111	125463563	125463667
ENSE00001888607	125489901	125492932
ENSE00001897051	125316400	125321586
ENSE00003898358	125446293	125446543
ENSE00003898914	125314955	125315977

Expression profiles

Bgee: expression breadth ubiquitous, 231 present calls, max score 93.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.5909 / max 194.7389, expressed in 1276 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
49590	3.8049	1006
49587	3.3720	980
49589	0.4551	260
49588	0.4276	221
49585	0.2695	126
49586	0.2620	119

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	93.32	gold quality
cortical plate	UBERON:0005343	92.56	gold quality
blood vessel layer	UBERON:0004797	90.75	gold quality
stromal cell of endometrium	CL:0002255	87.82	gold quality
periodontal ligament	UBERON:0008266	87.22	gold quality
colonic epithelium	UBERON:0000397	85.25	gold quality
tendon	UBERON:0000043	83.00	gold quality
mucosa of paranasal sinus	UBERON:0005030	82.44	silver quality
descending thoracic aorta	UBERON:0002345	82.20	gold quality
popliteal artery	UBERON:0002250	82.08	gold quality
tibial artery	UBERON:0007610	82.05	gold quality
ventricular zone	UBERON:0003053	81.86	gold quality
aorta	UBERON:0000947	81.40	gold quality
tibia	UBERON:0000979	81.30	gold quality
cardiac muscle of right atrium	UBERON:0003379	80.67	gold quality
thoracic aorta	UBERON:0001515	80.49	gold quality
ascending aorta	UBERON:0001496	80.26	gold quality
ganglionic eminence	UBERON:0004023	79.52	gold quality
left coronary artery	UBERON:0001626	79.48	gold quality
visceral pleura	UBERON:0002401	79.46	gold quality
right coronary artery	UBERON:0001625	79.28	gold quality
pleura	UBERON:0000977	79.24	gold quality
coronary artery	UBERON:0001621	78.94	gold quality
parietal pleura	UBERON:0002400	78.93	gold quality
skin of hip	UBERON:0001554	78.90	gold quality
muscle layer of sigmoid colon	UBERON:0035805	78.69	gold quality
urethra	UBERON:0000057	78.62	gold quality
lower lobe of lung	UBERON:0008949	78.50	gold quality
germinal epithelium of ovary	UBERON:0001304	78.44	gold quality
synovial joint	UBERON:0002217	78.15	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.73
E-ENAD-17	no	114.29

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PAX6

miRNA regulators (miRDB)

119 targeting FAT4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AR-5P	99.94	71.28	3515

Literature-anchored findings (GeneRIF, showing 29)

• Fat4 may be a breast tumor suppressor gene (PMID:19048595)
• Recurrent somatic mutations in FAT4 gene is associated with gastric adenocarcinoma. (PMID:22484628)
• the nonsynonymous variants rs1014867 (Pro4972Ser) and rs1039808 (Ala807Val) of FAT4 may contribute to esophageal cancer susceptibility (PMID:23319386)
• The atypical cadherin Fat4 encodes at least part of the stromal cell differentiation signal. (PMID:23974041)
• findings show that mutations in genes encoding the receptor-ligand cadherin pair DCHS1 and FAT4 lead to a recessive syndrome in humans that includes periventricular neuronal heterotopia (PMID:24056717)
• study defined eight additional recurrently mutated genes in SMZL; these genes are CREBBP, CBFA2T3, AMOTL1, FAT4, FBXO11, PLA2G4D, TRRAP and USH2A. (PMID:24349473)
• Homozygosity mapping and whole-exome sequencing was used in the original Hennekam syndrome family with multiple affected individuals in whom no CCBE1 mutation had been detected, and identified a homozygous mutation in the FAT4 gene. (PMID:24913602)
• These findings suggest that Fat and Dachsous self-bend due to the loss of Ca(2+)-binding amino acids from specific EC-EC linkers, and can therefore adapt to confined spaces. (PMID:25355906)
• our results reveal a novel inhibitory mechanism of FAT4 gene expression through actin depolymerization during Src-induced carcinogenesis in human breast cells. (PMID:25679223)
• Study shows that when key regulators during mammalian cerebral cortical development are disrupted due to DCHS1-FAT4 mutations, functional cerebral asymmetries are stronger. (PMID:25930014)
• In conclusion, Fat4 expression is deceased in gastric cancer cells, leading to nuclear translocation of Yap and correlates with poor prognosis. (PMID:26575609)
• FAT4 has a tumour suppressor role mediated by the modulation of Wnt/beta-catenin signalling, providing potential novel targets for the treatment of gastric cancer (PMID:26633557)
• In hepatocellular carcinoma patients, both FAT4 expression and FAT4 mutational status significantly correlated with patient prognosis. FAT4 acts as a putative tumor suppressor that is frequently inactivated in human hepatocellular carcinoma. (PMID:26672766)
• Epigenetic inactivation of FAT4 contributes to gastric field cancerization. (PMID:26792292)
• The results provide direct evidence that localized feedbacks on Fat4-Ds1 complexes can give rise to planar cell polarity. (PMID:28826487)
• our findings reveal that lncRNA ZFHX4-AS1 silencing exerts an inhibitory effect on breast cancer development by suppressing the activation of the Hippo signaling pathway via FAT4. (PMID:30546116)
• the regulatory effects of FAT4 on autophagy and the EMT were partially attributed to the PI3K-AKT signaling pathway. The results in vivo also showed that FAT4 modulated CRC tumorigenesis. FAT4 can regulate the activity of PI3K to promote autophagy and inhibit the EMT in part through the PI3K/AKT/mTOR and PI3K/AKT/GSK-3b signaling pathways. (PMID:30832706)
• Fat4 and Dchs1 mutants mimic the craniofacial phenotype of the human Van Maldergem syndrome and Dchs1-Fat4 signalling is essential for osteoblast differentiation. (PMID:31358536)
• This study identifies frequent genetic alterations in cancer-related genes especially FAT4 illustrated the very high genomic complexity in HCC pathogenesis. (PMID:31395065)
• FAT4 silencing promotes epithelial-to-mesenchymal transition and invasion via regulation of YAP and beta-catenin activity in ovarian cancer. (PMID:32366234)
• MiR-106b-5p regulates the migration and invasion of colorectal cancer cells by targeting FAT4. (PMID:33063118)
• FAT4 identified as a potential modifier of orofacial cleft laterality. (PMID:34130359)
• Increased expression of FAT4 suppress metastasis of lung adenocarcinoma through regulating MAPK pathway and associated with immune cells infiltration. (PMID:35770846)
• A pan-cancer analysis of FAT atypical cadherin 4 (FAT4) in human tumors. (PMID:36051999)
• Structure of the planar cell polarity cadherins Fat4 and Dachsous1. (PMID:36797229)
• Identification of FAT4 as a positive prognostic biomarker in DLBCL by comprehensive genomic analysis. (PMID:36811800)
• Prognostic Impact of FSTL3, ADAM12, and FAT4 in Patients of Colon Cancer: Clinicopathologic Study. (PMID:37751246)
• FAT4 loss initiates hepatocarcinogenesis through the switching of canonical to noncanonical WNT signaling pathways. (PMID:38055646)
• IL-32 aggravates metabolic disturbance in human nucleus pulposus cells by activating FAT4-mediated Hippo/YAP signaling. (PMID:39178518)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	FAT4	ENSDARG00000105285
mus_musculus	Fat4	ENSMUSG00000046743
rattus_norvegicus	Fat4	ENSRNOG00000028335
drosophila_melanogaster	ft	FBGN0001075

Paralogs (6): CELSR3 (ENSG00000008300), CELSR1 (ENSG00000075275), FAT1 (ENSG00000083857), FAT2 (ENSG00000086570), CELSR2 (ENSG00000143126), FAT3 (ENSG00000165323)

Protein

Protein identifiers

Protocadherin Fat 4 — Q6V0I7 (reviewed: Q6V0I7)

Alternative names: Cadherin family member 14, FAT tumor suppressor homolog 4, Fat-like cadherin protein FAT-J

All UniProt accessions (3): Q6V0I7, A0A6Q8JR05, A0A7P0T1I0

UniProt curated annotations — full annotation on UniProt →

Function. Cadherins are calcium-dependent cell adhesion proteins. FAT4 plays a role in the maintenance of planar cell polarity as well as in inhibition of YAP1-mediated neuroprogenitor cell proliferation and differentiation.

Subunit / interactions. Heterophilic interaction with DCHS1; this interaction affects their respective protein levels. Interacts (via cytoplasmic domain) with MPDZ. Forms a complex with PALS1 and MPDZ.

Subcellular location. Membrane.

Tissue specificity. Widely expressed. Expressed in fetal brain, infant brain, brain tumor and colorectal cancer.

Disease relevance. Van Maldergem syndrome 2 (VMLDS2) [MIM:615546] An autosomal recessive disorder characterized by intellectual disability, typical craniofacial features, auditory malformations resulting in hearing loss, and skeletal and limb malformations. Some patients have renal hypoplasia. Brain MRI typically shows periventricular nodular heterotopia. The disease is caused by variants affecting the gene represented in this entry. Hennekam lymphangiectasia-lymphedema syndrome 2 (HKLLS2) [MIM:616006] A form of Hennekam lymphangiectasia-lymphedema syndrome, a generalized lymph-vessels dysplasia characterized by intestinal lymphangiectasia with severe lymphedema of the limbs, genitalia and face. In addition, affected individuals have unusual facies and some manifest intellectual disability. HKLLS2 individuals have lymphangiectasia variably affecting the gut, pericardium, lungs, kidneys, and genitalia. Other features include camptodactyly and rare syndactyly. HKLLS2 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
Q6V0I7-1	1	yes
Q6V0I7-2	2
Q6V0I7-3	3

RefSeq proteins (3): NP_001278214, NP_001278232, NP_078858 (=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
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR013032	EGF-like_CS	Conserved_site
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
IPR039808	Cadherin	Family
IPR049883	NOTCH1_EGF-like	Domain

Pfam: PF00008, PF00028, PF02210, PF07645, PF12661, PF25374

UniProt features (178 total): domain 42, glycosylation site 38, strand 32, disulfide bond 20, sequence variant 15, region of interest 6, splice variant 5, turn 5, helix 4, compositionally biased region 3, sequence conflict 2, topological domain 2, signal peptide 1, chain 1, transmembrane region 1, modified residue 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
8EGW	X-RAY DIFFRACTION	2.3
8EGX	X-RAY DIFFRACTION	3.69

Predicted structure (AlphaFold)

No AlphaFold model available for Q6V0I7 — 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.

Post-translational modifications (1): 4876

Disulfide bonds (20): 3888–3897, 3904–3915, 3909–3924, 3926–3935, 3942–3953, 3947–3962, 3964–3973, 4133–4159, 4166–4177, 4171–4186, 4188–4197, 4365–4398, 4430–4441, 4435–4451, 4453–4462, 3806–3817, 3811–3848, 3850–3859, 3866–3877, 3871–3886

Glycosylation sites (38): 84, 237, 393, 416, 435, 483, 551, 615, 676, 721, 825, 880, 946, 1085, 1101, 1104, 1225, 1296, 1389, 1514 …

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 428 (showing top): CLAUS_PGR_POSITIVE_MENINGIOMA_UP, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_HETEROPHILIC_CELL_CELL_ADHESION, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_UP, GOBP_NEUROGENESIS, GOBP_HIPPO_SIGNALING, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_CELL_CELL_ADHESION, CAIRO_HEPATOBLASTOMA_CLASSES_DN, GOBP_CEREBRAL_CORTEX_DEVELOPMENT, GOBP_PALLIUM_DEVELOPMENT, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, ONDER_CDH1_TARGETS_2_UP, GOBP_HEAD_DEVELOPMENT, GOBP_CELL_PROJECTION_ORGANIZATION

GO Biological Process (26): homophilic cell-cell adhesion (GO:0007156), heterophilic cell-cell adhesion (GO:0007157), axonogenesis (GO:0007409), cerebral cortex development (GO:0021987), neurogenesis (GO:0022008), epithelial cell differentiation (GO:0030855), hippo signaling (GO:0035329), cell-cell adhesion mediated by cadherin (GO:0044331), branching involved in ureteric bud morphogenesis (GO:0001658), kidney development (GO:0001822), heart morphogenesis (GO:0003007), plasma membrane organization (GO:0007009), cell adhesion (GO:0007155), Notch signaling pathway (GO:0007219), fibroblast growth factor receptor signaling pathway (GO:0008543), anatomical structure morphogenesis (GO:0009653), cell differentiation (GO:0030154), ossification involved in bone maturation (GO:0043931), digestive tract development (GO:0048565), generation of neurons (GO:0048699), inner ear receptor cell stereocilium organization (GO:0060122), epithelium development (GO:0060429), nephron development (GO:0072006), condensed mesenchymal cell proliferation (GO:0072137), regulation of metanephric nephron tubule epithelial cell differentiation (GO:0072307), cell-cell adhesion (GO:0098609)

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

GO Cellular Component (5): plasma membrane (GO:0005886), adherens junction (GO:0005912), extracellular exosome (GO:0070062), membrane (GO:0016020), apical part of cell (GO:0045177)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell-cell adhesion	3
anatomical structure development	2
cell differentiation	2
cellular anatomical structure	2
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
pallium development	1
nervous system development	1
epithelium development	1
intracellular signal transduction	1
branching morphogenesis of an epithelial tube	1
ureteric bud morphogenesis	1
animal organ development	1
renal system development	1
heart development	1
animal organ morphogenesis	1
endomembrane system organization	1
membrane organization	1
cellular process	1
cell surface receptor signaling pathway	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to fibroblast growth factor stimulus	1
developmental process	1
cellular developmental process	1
ossification	1
bone maturation	1
tube development	1
digestive system development	1
neurogenesis	1
metal ion binding	1
binding	1
membrane	1
cell periphery	1
cell-cell junction	1
extracellular vesicle	1

Protein interactions and networks

STRING

1774 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FAT4	FJX1	Q86VR8	909
FAT4	VANGL2	Q9ULK5	864
FAT4	LAMC1	P11047	668
FAT4	TP53	P04637	658
FAT4	CTNNB1	P35222	645
FAT4	ARID1A	O14497	625
FAT4	FAT1	Q14517	617
FAT4	SAV1	Q9H4B6	593
FAT4	AMOTL1	Q8IY63	593
FAT4	SYNE1	Q8NF91	588
FAT4	FAT2	Q9NYQ8	582
FAT4	CSMD3	Q7Z407	570
FAT4	MUC16	Q8WXI7	570
FAT4	CCBE1	Q6UXH8	569
FAT4	DCHS1	Q96JQ0	556

IntAct

61 interactions, top by confidence:

A	B	Type	Score
DKKL1	DENND11	psi-mi:“MI:0914”(association)	0.640
PCDHGB1	FAM171A2	psi-mi:“MI:0914”(association)	0.530
CMA1	MANBA	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	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
DCDC2B	HSPA8	psi-mi:“MI:0914”(association)	0.530
PPIAL4G	ACTB	psi-mi:“MI:0914”(association)	0.530
IFNE	FAT1	psi-mi:“MI:0914”(association)	0.530
DNA2	CIAO1	psi-mi:“MI:0914”(association)	0.530
SPSB2	ARHGEF10	psi-mi:“MI:0914”(association)	0.530
SPSB4	ARHGEF10	psi-mi:“MI:0914”(association)	0.530
AP2B1	FAT4	psi-mi:“MI:0407”(direct interaction)	0.440
TNKS2	FAT4	psi-mi:“MI:0407”(direct interaction)	0.440
FAT4	H1-2	psi-mi:“MI:0915”(physical association)	0.400
RPS15A	FAT4	psi-mi:“MI:0915”(physical association)	0.400
NS1	SAC3D1	psi-mi:“MI:0914”(association)	0.350
NEK4	E2F8	psi-mi:“MI:0914”(association)	0.350
SHANK3	IGKV3D-15	psi-mi:“MI:0914”(association)	0.350
DNA2	TARS3	psi-mi:“MI:0914”(association)	0.350
DKKL1	VWA8	psi-mi:“MI:0914”(association)	0.350
CSTL1	DENND11	psi-mi:“MI:0914”(association)	0.350
LLCFC1	POTEF	psi-mi:“MI:0914”(association)	0.350
NPPB	TCAF2	psi-mi:“MI:0914”(association)	0.350
FBXO45	METTL15	psi-mi:“MI:0914”(association)	0.350
SPSB4	CCDC85C	psi-mi:“MI:0914”(association)	0.350
ADAMTS13	C2CD4B	psi-mi:“MI:0914”(association)	0.350

BioGRID (97): FAT4 (Affinity Capture-RNA), FAT4 (Affinity Capture-RNA), FAT4 (Affinity Capture-RNA), FAT4 (Affinity Capture-MS), FAT4 (Affinity Capture-MS), FAT4 (Affinity Capture-MS), FAT4 (Affinity Capture-MS), FAT4 (Affinity Capture-MS), FAT4 (Affinity Capture-MS), FAT4 (Affinity Capture-MS), FAT4 (Affinity Capture-MS), FAT4 (Affinity Capture-MS), FAT4 (Affinity Capture-MS), FAT4 (Affinity Capture-MS), FAT4 (Affinity Capture-MS)

ESM2 similar proteins: D4ACX8, E9PVD3, O35161, O60500, P33146, P55291, Q2PZL6, Q5DRA2, Q5DRA3, Q5DRA4, Q5DRC3, Q5DRC4, Q5DRC6, Q5DRC7, Q5DRC8, Q5DRC9, Q5DRD1, Q5DRD2, Q5DRD3, Q5DRD6, Q5DRD9, Q5DRF1, Q5SZK8, Q6PFX6, Q6V0I7, Q6V1P9, Q86UP0, Q91XZ2, Q91XZ4, Q96JQ0, Q96MS0, Q96TA0, Q9HCU4, Q9NRJ7, Q9NYQ6, Q9QYP2, Q9R0M0, Q9UN66, Q9UN67, Q9UN70

Diamond homologs: A2RUV0, A4FV93, B2LW77, B8JI71, D3ZHH1, D3ZUK3, O35474, O70534, O88277, P10041, P21783, P31695, P78504, P80370, P97607, Q09163, Q2PZL6, Q5IJ48, Q5R6R1, Q5ZQU0, Q63722, Q6DCQ6, Q6QNF4, Q6UY11, Q6V0I7, Q70E20, Q8JZM4, Q8K1E3, Q8NFT8, Q8TER0, Q8VHS2, Q90Y54, Q90Y57, Q9JI71, Q9QXX0, Q9QYE5, Q9Y219, A0A8M9PFP2, B0S5G3, F1R520

SIGNOR signaling

0 interactions.

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 24 cancer types — ACC, ALL, AML, ANSC, BCC, BRCA, CLLSLL, COADREAD, DLBCLNOS, ESCA, GBM, HCC…(+12 more).

Clinical variants and AI predictions

ClinVar

3573 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	45
Likely pathogenic	18
Uncertain significance	1951
Likely benign	1225
Benign	108

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1453459	NM_001291303.3(FAT4):c.2921del (p.Pro974fs)	Pathogenic
1457692	NM_001291303.3(FAT4):c.835G>T (p.Glu279Ter)	Pathogenic
156109	NM_001291303.3(FAT4):c.7035TGGAAC[3] (p.2346GT[3])	Pathogenic
156110	NM_001291303.3(FAT4):c.1195del (p.Leu399fs)	Pathogenic
156112	NM_001291303.3(FAT4):c.7204A>C (p.Arg2402=)	Pathogenic
1913238	NM_001291303.3(FAT4):c.8573_8574del (p.Thr2858fs)	Pathogenic
2020328	NM_001291303.3(FAT4):c.2632_2633del (p.Met878fs)	Pathogenic
2026850	NM_001291303.3(FAT4):c.1599del (p.Thr534fs)	Pathogenic
2028545	NM_001291303.3(FAT4):c.12686_12687dup (p.Leu4230fs)	Pathogenic
2033900	NM_001291303.3(FAT4):c.8536C>T (p.Arg2846Ter)	Pathogenic
2041878	NM_001291303.3(FAT4):c.4480_4481insG (p.Leu1494fs)	Pathogenic
2100536	NM_001291303.3(FAT4):c.12240_12244del (p.Cys4080_Glu4082delinsTer)	Pathogenic
2106120	NM_001291303.3(FAT4):c.10011T>G (p.Tyr3337Ter)	Pathogenic
2118255	NM_001291303.3(FAT4):c.9125G>A (p.Trp3042Ter)	Pathogenic
2151990	NM_001291303.3(FAT4):c.5768del (p.Gly1923fs)	Pathogenic
2700383	NM_001291303.3(FAT4):c.952C>T (p.Gln318Ter)	Pathogenic
2768836	NM_001291303.3(FAT4):c.5261del (p.Gly1754fs)	Pathogenic
2809746	NM_001291303.3(FAT4):c.7670del (p.Thr2557fs)	Pathogenic
2813871	NM_001291303.3(FAT4):c.10339G>T (p.Gly3447Ter)	Pathogenic
2818444	NM_001291303.3(FAT4):c.3922G>T (p.Glu1308Ter)	Pathogenic
2820515	NM_001291303.3(FAT4):c.3040C>T (p.Arg1014Ter)	Pathogenic
2843978	NM_001291303.3(FAT4):c.7919G>A (p.Trp2640Ter)	Pathogenic
2847475	NM_001291303.3(FAT4):c.10030C>T (p.Arg3344Ter)	Pathogenic
3684535	NM_001291303.3(FAT4):c.6771del (p.Val2258fs)	Pathogenic
3687827	NM_001291303.3(FAT4):c.7542del (p.Lys2514fs)	Pathogenic
3694574	NM_001291303.3(FAT4):c.8059C>T (p.Arg2687Ter)	Pathogenic
3721840	NM_001291303.3(FAT4):c.4154del (p.Leu1385fs)	Pathogenic
3727775	NM_001291303.3(FAT4):c.8211dup (p.Val2738fs)	Pathogenic
4714111	NM_001291303.3(FAT4):c.3926del (p.Asn1309fs)	Pathogenic
4720398	NM_001291303.3(FAT4):c.8357dup (p.Asn2786fs)	Pathogenic

SpliceAI

2582 predictions. Top by Δscore:

Variant	Effect	Δscore
4:125398779:T:TA	acceptor_gain	1.0000
4:125398782:A:AG	acceptor_gain	1.0000
4:125398782:AG:A	acceptor_gain	1.0000
4:125398783:G:GT	acceptor_gain	1.0000
4:125398783:GG:G	acceptor_gain	1.0000
4:125398783:GGT:G	acceptor_gain	1.0000
4:125398783:GGTA:G	acceptor_gain	1.0000
4:125398911:ATGAG:A	donor_loss	1.0000
4:125398912:TGAG:T	donor_loss	1.0000
4:125398913:GAGG:G	donor_loss	1.0000
4:125398914:AGGTA:A	donor_loss	1.0000
4:125398915:GG:G	donor_loss	1.0000
4:125398917:T:G	donor_loss	1.0000
4:125406875:TTTA:T	acceptor_loss	1.0000
4:125406876:TTA:T	acceptor_loss	1.0000
4:125406877:TAGG:T	acceptor_loss	1.0000
4:125406878:AG:A	acceptor_gain	1.0000
4:125406879:G:A	acceptor_loss	1.0000
4:125406879:GG:G	acceptor_gain	1.0000
4:125407141:GGTA:G	donor_loss	1.0000
4:125407142:G:C	donor_loss	1.0000
4:125407142:G:GG	donor_gain	1.0000
4:125407143:T:G	donor_loss	1.0000
4:125408593:G:GT	donor_gain	1.0000
4:125416618:TTCAG:T	donor_gain	1.0000
4:125416619:TCAGG:T	donor_loss	1.0000
4:125416621:AGGT:A	donor_loss	1.0000
4:125416622:GGT:G	donor_loss	1.0000
4:125416623:G:GG	donor_gain	1.0000
4:125416623:GTAA:G	donor_loss	1.0000

AlphaMissense

32865 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:125316965:T:C	F185S	1.000
4:125317505:C:A	A365D	1.000
4:125317517:A:T	E369V	1.000
4:125317544:C:A	A378D	1.000
4:125317547:T:C	L379P	1.000
4:125317550:T:C	L380P	1.000
4:125317630:T:C	F407L	1.000
4:125317631:T:C	F407S	1.000
4:125317631:T:G	F407C	1.000
4:125317632:T:A	F407L	1.000
4:125317632:T:G	F407L	1.000
4:125317718:T:C	L436P	1.000
4:125317793:T:C	L461P	1.000
4:125317805:T:A	V465D	1.000
4:125316740:T:A	V110D	0.999
4:125316809:C:A	P133H	0.999
4:125316814:T:C	F135L	0.999
4:125316815:T:G	F135C	0.999
4:125316816:C:A	F135L	0.999
4:125316816:C:G	F135L	0.999
4:125316887:C:A	A159D	0.999
4:125316965:T:G	F185C	0.999
4:125317016:T:C	L202P	0.999
4:125317064:T:C	L218P	0.999
4:125317081:G:C	D224H	0.999
4:125317112:T:C	L234P	0.999
4:125317135:G:C	D242H	0.999
4:125317142:A:T	N244I	0.999
4:125317143:T:A	N244K	0.999
4:125317143:T:G	N244K	0.999

dbSNP variants (sampled 300 via entrez): RS1000004474 (4:125475563 T>C), RS1000019422 (4:125453931 C>A,T), RS1000021146 (4:125368521 T>C), RS1000029811 (4:125343333 G>A), RS10000328 (4:125403785 T>C), RS1000068806 (4:125433891 C>T), RS1000069747 (4:125478400 AT>A,ATT), RS1000079196 (4:125478609 G>A), RS1000085345 (4:125392222 A>C), RS1000107227 (4:125386042 A>G), RS1000135486 (4:125424261 T>C), RS1000147150 (4:125376373 A>C,G), RS1000155761 (4:125436807 T>A), RS1000188699 (4:125343523 A>G), RS1000192822 (4:125417856 T>C)

Disease associations

OMIM: gene MIM:612411 | disease phenotypes: MIM:615546, MIM:616006, MIM:602089, MIM:235510, MIM:601390, MIM:604229, MIM:610805

GenCC curated gene-disease

Disease	Classification	Inheritance
Hennekam lymphangiectasia-lymphedema syndrome 2	Definitive	Autosomal recessive
van Maldergem syndrome 2	Definitive	Autosomal recessive
multiple congenital anomalies/dysmorphic syndrome-intellectual disability	Strong	Autosomal recessive
FAT4-related neurodevelopmental disorder	Strong	Autosomal recessive
Hennekam syndrome	Supportive	Autosomal recessive
van Maldergem syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
FAT4-related neurodevelopmental disorder	Definitive	AR

Mondo (15): van Maldergem syndrome 2 (MONDO:0014242), Hennekam lymphangiectasia-lymphedema syndrome 2 (MONDO:0014454), intellectual disability (MONDO:0001071), chromosomal disorder (MONDO:0019040), capillary infantile hemangioma (MONDO:0011191), Hennekam lymphangiectasia-lymphedema syndrome 1 (MONDO:0009337), van Maldergem syndrome 1 (MONDO:0011070), Peters anomaly (MONDO:0011414), lymphedema (MONDO:0019297), van Maldergem syndrome (MONDO:0017813), microcephaly (MONDO:0001149), congenital anomaly of kidney and urinary tract (MONDO:0019719), multiple congenital anomalies/dysmorphic syndrome-intellectual disability (MONDO:0015159), Hennekam syndrome (MONDO:0016256), FAT4-related neurodevelopmental disorder (MONDO:0100603)

Orphanet (10): Hennekam syndrome (Orphanet:2136), Cerebrofacioarticular syndrome (Orphanet:314679), Rare chromosomal anomaly (Orphanet:68335), Microphthalmia-anophthalmia-coloboma (Orphanet:98555), Peters anomaly (Orphanet:708), Renal or urinary tract malformation (Orphanet:93545), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), NON RARE IN EUROPE: Infantile capillary hemangioma (Orphanet:464293), OBSOLETE: Familial capillary hemangioma (Orphanet:91415), OBSOLETE: Lymphedema (Orphanet:79383)

HPO phenotypes

136 total (30 of 136 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000048	Bifid scrotum
HP:0000054	Micropenis
HP:0000085	Horseshoe kidney
HP:0000086	Ectopic kidney
HP:0000089	Renal hypoplasia
HP:0000160	Narrow mouth
HP:0000212	Gingival overgrowth
HP:0000218	High palate
HP:0000239	Large fontanelles
HP:0000252	Microcephaly
HP:0000260	Wide anterior fontanel
HP:0000272	Malar flattening
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000293	Full cheeks
HP:0000316	Hypertelorism
HP:0000322	Short philtrum
HP:0000327	Hypoplasia of the maxilla
HP:0000337	Broad forehead
HP:0000341	Narrow forehead
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000402	Stenosis of the external auditory canal
HP:0000405	Conductive hearing impairment

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST000477_48	Cognitive performance	6.000000e-06
GCST000641_1	Bipolar disorder or major depressive disorder	8.000000e-06
GCST003072_2	Cerebrospinal fluid AB1-42 levels	6.000000e-07
GCST003380_2	Bone mineral density (spine)	3.000000e-07
GCST003989_45	Chin dimples	1.000000e-08
GCST005057_4	Small vessel stroke	8.000000e-06
GCST006151_6	Memory dysfunction in frontotemporal lobe dementia	9.000000e-06
GCST009723_85	Vertical cup-disc ratio (adjusted for vertical disc diameter)	2.000000e-07
GCST009724_38	Vertical cup-disc ratio (multi-trait analysis)	3.000000e-10
GCST010174_3	Pelvic organ prolapse	5.000000e-16
GCST011742_15	Triglyceride levels in HIV infection	5.000000e-06
GCST011742_2	Triglyceride levels in HIV infection	5.000000e-06

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0003926	neuropsychological test
EFO:0004670	beta-amyloid 1-42 measurement
EFO:0007701	spine bone mineral density
EFO:1001504	small vessel stroke
EFO:0001072	memory impairment
EFO:0006939	cup-to-disc ratio measurement
EFO:0004530	triglyceride measurement

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D025063	Chromosome Disorders	C16.131.260; C16.320.180
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008209	Lymphedema	C15.604.496
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C566906	Cakut (supp.)
C535860	Hemangioma, capillary infantile (supp.)
C537884	Peters anomaly (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	6
sodium arsenite	decreases expression, affects cotreatment, increases abundance	2
potassium chromate(VI)	affects cotreatment, decreases expression	2
chromium hexavalent ion	decreases expression, increases abundance, increases expression	2
Arsenic	increases abundance, affects methylation, affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
aristolochic acid I	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	decreases expression	1
decabromobiphenyl ether	decreases expression	1
trichostatin A	decreases expression, increases expression	1
arsenite	affects binding, decreases reaction	1
tetrabromobisphenol A	decreases expression	1
zinc chromate	increases abundance, increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
coumarin	decreases phosphorylation	1
S-(1,2-dichlorovinyl)cysteine	decreases expression	1
epigallocatechin gallate	increases expression, affects cotreatment, decreases expression	1
pentanal	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	decreases expression	1
incobotulinumtoxinA	increases expression	1
Sunitinib	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Diethylhexyl Phthalate	decreases expression	1

Cellosaurus cell lines

2 cell lines: 1 induced pluripotent stem cell, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C1G3	ISFi004-A	Induced pluripotent stem cell	Male
CVCL_D7PR	Ubigene A-549 FAT4 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders