FGF4

Summary

FGF4 (fibroblast growth factor 4, HGNC:3682) is a protein-coding gene on chromosome 11q13.3, encoding Fibroblast growth factor 4 (P08620). Plays an important role in the regulation of embryonic development, cell proliferation, and cell differentiation.

The protein encoded by this gene is a member of the fibroblast growth factor (FGF) family. FGF family members possess broad mitogenic and cell survival activities and are involved in a variety of biological processes including embryonic development, cell growth, morphogenesis, tissue repair, tumor growth and invasion. This gene was identified by its oncogenic transforming activity. This gene and FGF3, another oncogenic growth factor, are located closely on chromosome 11. Co-amplification of both genes was found in various kinds of human tumors. Studies on the mouse homolog suggested a function in bone morphogenesis and limb development through the sonic hedgehog (SHH) signaling pathway.

Source: NCBI Gene 2249 — RefSeq curated summary.

At a glance

• Gene–disease (curated): thoracic malformation (Limited, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 33 total — 1 pathogenic
• Phenotypes (HPO): 19
• Druggable target: yes
• MANE Select transcript: NM_002007

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3682
Approved symbol	FGF4
Name	fibroblast growth factor 4
Location	11q13.3
Locus type	gene with protein product
Status	Approved
Aliases	K-FGF, HBGF-4, HST, HST-1, KFGF
Ensembl gene	ENSG00000075388
Ensembl biotype	protein_coding
OMIM	164980
Entrez	2249

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000168712, ENST00000538040

RefSeq mRNA: 1 — MANE Select: NM_002007 NM_002007

CCDS: CCDS8194

Canonical transcript exons

ENST00000168712 — 3 exons

Exon	Start	End
ENSE00000991995	69771022	69773485
ENSE00001064298	69774745	69775341
ENSE00001064299	69774024	69774127

Expression profiles

Bgee: expression breadth broad, 16 present calls, max score 82.36.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5992 / max 260.8393, expressed in 76 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
121055	0.5852	73
206362	0.0141	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.36	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.48	gold quality
olfactory bulb	UBERON:0002264	77.08	silver quality
tibialis anterior	UBERON:0001385	76.99	silver quality
upper arm skin	UBERON:0004263	74.50	gold quality
diaphragm	UBERON:0001103	72.23	gold quality
triceps brachii	UBERON:0001509	72.13	gold quality
gluteal muscle	UBERON:0002000	72.01	gold quality
deltoid	UBERON:0001476	71.59	silver quality
type B pancreatic cell	CL:0000169	69.44	gold quality
ileal mucosa	UBERON:0000331	68.17	silver quality
tibial nerve	UBERON:0001323	67.43	gold quality
myocardium	UBERON:0002349	66.94	gold quality
biceps brachii	UBERON:0001507	65.10	gold quality
cardiac muscle of right atrium	UBERON:0003379	65.09	gold quality
left ventricle myocardium	UBERON:0006566	64.91	gold quality
thymus	UBERON:0002370	64.27	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	64.16	gold quality
skeletal muscle tissue	UBERON:0001134	63.27	gold quality
choroid plexus epithelium	UBERON:0003911	63.16	gold quality
upper leg skin	UBERON:0004262	63.05	silver quality
vena cava	UBERON:0004087	62.73	gold quality
decidua	UBERON:0002450	62.52	gold quality
muscle tissue	UBERON:0002385	62.42	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	62.23	gold quality
trigeminal ganglion	UBERON:0001675	61.95	gold quality
pancreatic ductal cell	CL:0002079	61.83	silver quality
cervix squamous epithelium	UBERON:0006922	61.74	gold quality
blood vessel layer	UBERON:0004797	61.03	gold quality
mucosa of paranasal sinus	UBERON:0005030	60.18	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-109979	yes	143.00
E-MTAB-10018	yes	113.16
E-ANND-3	no	1.47

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BACH2, GATA3, LEF1, MYBL2, MYF5, MYOD1, NANOG, NFYA, NR6A1, PARP1, PATZ1, POU2F1, POU5F1, SHH, SOX17, SOX2, SP1, SP3, ZFP42, ZNF143

miRNA regulators (miRDB)

29 targeting FGF4, 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-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868
HSA-MIR-519C-3P	99.67	71.67	1870
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-32-3P	99.36	68.20	2517
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-511-5P	98.97	70.94	2268
HSA-MIR-367-5P	98.84	67.18	902
HSA-MIR-4671-5P	97.10	65.70	93

Literature-anchored findings (GeneRIF, showing 25)

• activation of human HST-1 gene in transgenic mice induces spermatogenesis and prevents adriamycin-induced testicular toxicity (PMID:11840335)
• possible role of fibroblast growth factors in expression of genes of the plasminogen activator system in breast fibroblasts (PMID:12008951)
• Differential effects of FGF4, EGF and TGFB1 on functional development of stromal layers (progenitor cell-outputs) in acute myeloid leukemia (PMID:12163055)
• results show that Hensen’s node and FGFs induce ectopic expression of cardiac lineage markers, and that FGF and TGFbeta family members can modulate early development of the heart (PMID:12172783)
• FGF4 is upregulated by the OCT3 transcription factor in breast cancer cells. (PMID:12841847)
• HST-1 protects male germ cells from apoptosis under heat-stress condition in a mouse model. (PMID:14980503)
• Both myeov and hst (fgf4) are normally situated approximately 475-kb apart at band 11q13, a region that is frequently amplified and overexpressed in various tumours. (PMID:17390055)
• FGF-4 increases the rate at which MSC proliferate and has no significant effect on MSC pluripotency (PMID:17852409)
• These results suggest a growth-promoting role for FGF4 in human embryonic stem cells and a putative feedback inhibition mechanism by a novel FGF4 splice isoform that may serve to promote differentiation at later stages of development. (PMID:18192227)
• Implantation of human FGF4-soaked beads is sufficient to restore expression of G1- and S-phase cell-cycle genes and S-phase progression in zebrafish sonic hedgehog (Shh) mutant fin buds. (PMID:18811955)
• The combined action of retinoic acid and FGF4 results in induction of PDX1+ foregut endoderm. (PMID:19277121)
• knockdown of FGFR4 expression led to decreased proliferation and an increased rate of apoptosis in the MKN45 and SGC7901 GC cell lines (PMID:21567388)
• Myoblasts which overexpress FGF-4 exhibit significant changes in cell cycle and pro-angiogenic potential with only slight differences in the expression of the myogenic genes. (PMID:21673370)
• In vivo stimulation of BT-474 cell growth by progesterone is associated with up-regulation of FGF4 which may promote tumor growth and maintenance. (PMID:22237711)
• Data show that the interaction between Artd1 and Sox2 is crucial for the first steps of the reprogramming process and that early expression of Fgf4 is an essential component for the successful generation of iPSCs. (PMID:23939864)
• A de novo 290 kb interstitial duplication of chromosome 11q13.3 including the FGF3 and FGF4 genes. (PMID:24120895)
• Fibroblasts induce expression of FGF4 in ovarian cancer stem-like cells/cancer-initiating cells and upregulate their tumor initiation capacity. (PMID:25329002)
• Thus, we conclude that the oncoprotein HBXIP up-regulates FGF4 through activating transcriptional factor Sp1 to promote the migration of breast cancer cells. Therapeutically, HBXIP may serve as a novel target in breast cancer. (PMID:26828265)
• our study demonstrated that FGFR4 rs2011077 and rs1966265 are associated with the progression of cervical normal tissues to precancerous lesions in Taiwanese women. Moreover, rs351855 (Gly388Arg) is the only FGFR4 genetic polymorphism that is associated with patient survival. (PMID:28378614)
• FGF4 amplification was an independent prognostic factor in esophageal squamous cell carcinoma patients (PMID:29936056)
• miR-511 inhibits proliferation and metastasis of breast cancer cells by targeting FGF4. (PMID:32023352)
• Gene duplication, rather than epigenetic changes, drives FGF4 overexpression in KIT/PDGFRA/SDH/RAS-P WT GIST. (PMID:33199729)
• FGF4 Promotes Skin Wound Repair through p38 MAPK and GSK3beta-Mediated Stabilization of Slug. (PMID:36521556)
• FGF4 improves hepatocytes ferroptosis in autoimmune hepatitis mice via activation of CISD3. (PMID:36702076)
• FGF4 ameliorates the liver inflammation by reducing M1 macrophage polarization in experimental autoimmune hepatitis. (PMID:39095789)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fgf4	ENSDARG00000105230
mus_musculus	Fgf4	ENSMUSG00000050917
rattus_norvegicus	Fgf4	ENSRNOG00000083188

Paralogs (21): FGF10 (ENSG00000070193), FGF22 (ENSG00000070388), FGF20 (ENSG00000078579), FGF14 (ENSG00000102466), FGF9 (ENSG00000102678), FGF21 (ENSG00000105550), FGF8 (ENSG00000107831), FGF6 (ENSG00000111241), FGF1 (ENSG00000113578), FGF12 (ENSG00000114279), FGF23 (ENSG00000118972), FGF13 (ENSG00000129682), FGF5 (ENSG00000138675), FGF2 (ENSG00000138685), FGF7 (ENSG00000140285), FGF18 (ENSG00000156427), FGF17 (ENSG00000158815), FGF11 (ENSG00000161958), FGF19 (ENSG00000162344), FGF3 (ENSG00000186895), FGF16 (ENSG00000196468)

Protein

Protein identifiers

Fibroblast growth factor 4 — P08620 (reviewed: P08620)

Alternative names: Heparin secretory-transforming protein 1, Heparin-binding growth factor 4, Transforming protein KS3

All UniProt accessions (2): P08620, A0A7U3JW12

UniProt curated annotations — full annotation on UniProt →

Function. Plays an important role in the regulation of embryonic development, cell proliferation, and cell differentiation. Required for normal limb and cardiac valve development during embryogenesis. May play a role in embryonic molar tooth bud development via inducing the expression of MSX1, MSX2 and MSX1-mediated expression of SDC1 in dental mesenchyme cells.

Subunit / interactions. Interacts with FGFR1, FGFR2, FGFR3 and FGFR4. Affinity between fibroblast growth factors (FGFs) and their receptors is increased by heparan sulfate glycosaminoglycans that function as coreceptors.

Subcellular location. Secreted.

Disease relevance. Short-rib thoracic dysplasia 22 without polydactyly (SRTD22) [MIM:621260] A form of short-rib thoracic dysplasia, a group of autosomal recessive ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a ’trident’ appearance of the acetabular roof. Polydactyly is variably present. Non-skeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of the disease are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life. Disease spectrum encompasses Ellis-van Creveld syndrome, asphyxiating thoracic dystrophy (Jeune syndrome), Mainzer-Saldino syndrome, and short rib-polydactyly syndrome. SRTD22 is a form characterized by short ribs, abnormally narrow chest, and respiratory insufficiency, without other diagnostic clinical or radiological signs. The disease may be caused by variants affecting the gene represented in this entry.

Miscellaneous. Antagonist of isoform 1, shutting down FGF4-induced Erk1/2 phosphorylation.

Similarity. Belongs to the heparin-binding growth factors family.

Isoforms (2)

UniProt ID	Names	Canonical?
P08620-1	1	yes
P08620-2	2, FGF4si

RefSeq proteins (1): NP_001998* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002209	Fibroblast_GF_fam	Family
IPR008996	IL1/FGF	Homologous_superfamily

Pfam: PF00167

UniProt features (21 total): strand 11, helix 4, sequence variant 2, signal peptide 1, chain 1, turn 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1IJT	X-RAY DIFFRACTION	1.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08620-F1	83.06	0.62

Function

Pathways and Gene Ontology

Reactome pathways

39 pathways

ID	Pathway
R-HSA-109704	PI3K Cascade
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1839122	Signaling by activated point mutants of FGFR1
R-HSA-1839130	Signaling by activated point mutants of FGFR3
R-HSA-190322	FGFR4 ligand binding and activation
R-HSA-190372	FGFR3c ligand binding and activation
R-HSA-190373	FGFR1c ligand binding and activation
R-HSA-190375	FGFR2c ligand binding and activation
R-HSA-2033519	Activated point mutants of FGFR2
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-5654219	Phospholipase C-mediated cascade: FGFR1
R-HSA-5654221	Phospholipase C-mediated cascade; FGFR2
R-HSA-5654227	Phospholipase C-mediated cascade; FGFR3
R-HSA-5654228	Phospholipase C-mediated cascade; FGFR4
R-HSA-5654687	Downstream signaling of activated FGFR1
R-HSA-5654688	SHC-mediated cascade:FGFR1
R-HSA-5654689	PI-3K cascade:FGFR1
R-HSA-5654693	FRS-mediated FGFR1 signaling
R-HSA-5654695	PI-3K cascade:FGFR2
R-HSA-5654699	SHC-mediated cascade:FGFR2
R-HSA-5654700	FRS-mediated FGFR2 signaling
R-HSA-5654704	SHC-mediated cascade:FGFR3
R-HSA-5654706	FRS-mediated FGFR3 signaling
R-HSA-5654710	PI-3K cascade:FGFR3
R-HSA-5654712	FRS-mediated FGFR4 signaling
R-HSA-5654719	SHC-mediated cascade:FGFR4
R-HSA-5654720	PI-3K cascade:FGFR4
R-HSA-5654726	Negative regulation of FGFR1 signaling
R-HSA-5654727	Negative regulation of FGFR2 signaling
R-HSA-5654732	Negative regulation of FGFR3 signaling

MSigDB gene sets: 237 (showing top): MODULE_92, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_CARTILAGE_DEVELOPMENT, GOBP_CELL_CHEMOTAXIS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_RESPONSE_TO_PEPTIDE, GOBP_HINDLIMB_MORPHOGENESIS, KEGG_MAPK_SIGNALING_PATHWAY, REACTOME_FGFR2C_LIGAND_BINDING_AND_ACTIVATION, REACTOME_SIGNALING_BY_FGFR, REACTOME_FGFR1_LIGAND_BINDING_AND_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_NEUROGENESIS, GOMF_GROWTH_FACTOR_ACTIVITY

GO Biological Process (31): cartilage condensation (GO:0001502), signal transduction (GO:0007165), cell-cell signaling (GO:0007267), positive regulation of cell population proliferation (GO:0008284), fibroblast growth factor receptor signaling pathway (GO:0008543), mesenchymal cell proliferation (GO:0010463), positive regulation of gene expression (GO:0010628), neurogenesis (GO:0022008), regulation of cell migration (GO:0030334), somatic stem cell population maintenance (GO:0035019), embryonic hindlimb morphogenesis (GO:0035116), odontogenesis of dentin-containing tooth (GO:0042475), negative regulation of apoptotic process (GO:0043066), positive regulation of MAPK cascade (GO:0043410), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of cell division (GO:0051781), cranial suture morphogenesis (GO:0060363), apoptotic process involved in morphogenesis (GO:0060561), chondroblast differentiation (GO:0060591), positive regulation of ERK1 and ERK2 cascade (GO:0070374), stem cell proliferation (GO:0072089), epithelial cell apoptotic process (GO:1904019), cellular response to leukemia inhibitory factor (GO:1990830), regulation of endothelial cell chemotaxis to fibroblast growth factor (GO:2000544), positive regulation of stem cell proliferation (GO:2000648), apoptotic process (GO:0006915), cell population proliferation (GO:0008283), regulation of gene expression (GO:0010468), stem cell population maintenance (GO:0019827), cell differentiation (GO:0030154), embryonic limb morphogenesis (GO:0030326)

GO Molecular Function (3): fibroblast growth factor receptor binding (GO:0005104), growth factor activity (GO:0008083), heparin binding (GO:0008201)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-15 pathways:

Category	Pathways
Downstream signaling of activated FGFR1	4
Downstream signaling of activated FGFR2	3
IRS-mediated signalling	1
Intracellular signaling by second messengers	1
FGFR1 mutant receptor activation	1
FGFR3 mutant receptor activation	1
Signaling by FGFR4	1
FGFR3 ligand binding and activation	1
FGFR1 ligand binding and activation	1
FGFR2 ligand binding and activation	1
FGFR2 mutant receptor activation	1
PI3K/AKT Signaling in Cancer	1
Downstream signaling of activated FGFR3	1
Downstream signaling of activated FGFR4	1
Signaling by FGFR1	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cartilage development	2
cell communication	2
signaling	2
cell population proliferation	2
positive regulation of cellular process	2
cell differentiation	2
cellular anatomical structure	2
skeletal system morphogenesis	1
cell aggregation	1
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
regulation of cell population proliferation	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to fibroblast growth factor stimulus	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
nervous system development	1
cell migration	1
regulation of cell motility	1
stem cell population maintenance	1
embryonic limb morphogenesis	1
hindlimb morphogenesis	1
odontogenesis	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
MAPK cascade	1
regulation of MAPK cascade	1
positive regulation of intracellular signal transduction	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
cell division	1
regulation of cell division	1
craniofacial suture morphogenesis	1
anatomical structure morphogenesis	1
apoptotic process involved in development	1
positive regulation of MAPK cascade	1

Protein interactions and networks

STRING

3974 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FGF4	FGFR1	P11362	998
FGF4	FGFR2	P18443	995
FGF4	FGFR4	P22455	992
FGF4	EGF	P01133	989
FGF4	KL	Q9UEF7	986
FGF4	HSPG2	P98160	948
FGF4	FGFBP1	Q14512	938
FGF4	DCN	P07585	936
FGF4	SHH	Q15465	927
FGF4	CD44	P16070	923
FGF4	KLB	Q86Z14	922
FGF4	HGF	P14210	884
FGF4	CDH2	P19022	879
FGF4	FGFR3	P22607	869
FGF4	SOX2	P48431	860

IntAct

6 interactions, top by confidence:

A	B	Type	Score
FGFR2	FGF4	psi-mi:“MI:0407”(direct interaction)	0.440
FGFR1	FGF4	psi-mi:“MI:0407”(direct interaction)	0.440
FGF4	AGRN	psi-mi:“MI:0914”(association)	0.350
FGF4	QSOX1	psi-mi:“MI:0914”(association)	0.350
FGF4	PEX14	psi-mi:“MI:0914”(association)	0.350

BioGRID (39): FGF4 (Reconstituted Complex), GRN (Affinity Capture-MS), SDC4 (Affinity Capture-MS), NID2 (Affinity Capture-MS), PEX14 (Affinity Capture-MS), LAMA5 (Affinity Capture-MS), SDC1 (Affinity Capture-MS), ITIH2 (Affinity Capture-MS), GPC4 (Affinity Capture-MS), N4BP3 (Affinity Capture-MS), UACA (Affinity Capture-MS), CETN2 (Affinity Capture-MS), GPC3 (Affinity Capture-MS), FARP1 (Affinity Capture-MS), GPC1 (Affinity Capture-MS)

ESM2 similar proteins: A0MTF4, A4Q9F4, M3X9S6, O15520, O35565, O43189, O43320, O54693, O54769, O73754, O95750, P05524, P08620, P11487, P12034, P15656, P31371, P36364, P36386, P48801, P48802, P48803, P48804, P48807, P54130, P70492, P97401, P98172, Q20FD0, Q2HXK8, Q3ZFI5, Q5RF67, Q5T6S3, Q5XI70, Q91875, Q92765, Q92838, Q95117, Q95L12, Q96GD3

Diamond homologs: A0MTF4, A6P7H6, M3X9S6, O15520, O35565, O43320, O54769, P03968, P03969, P05230, P05524, P08620, P09038, P10767, P11403, P11487, P12034, P12226, P13109, P15655, P15656, P19596, P20002, P20003, P21658, P21781, P31371, P34004, P36363, P36364, P36386, P48798, P48799, P48800, P48801, P48802, P48803, P48804, P48805, P48806

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
FGF4	up-regulates	FGFR4	binding
FGF4	up-regulates	FGFR2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	28
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3911900	NM_002007.4(FGF4):c.256C>T (p.Leu86Phe)	Pathogenic

SpliceAI

601 predictions. Top by Δscore:

Variant	Effect	Δscore
11:69773481:AAGGG:A	acceptor_gain	1.0000
11:69773482:AGGG:A	acceptor_gain	1.0000
11:69773483:GGG:G	acceptor_gain	1.0000
11:69773484:GG:G	acceptor_gain	1.0000
11:69773486:C:CC	acceptor_gain	1.0000
11:69773490:A:T	acceptor_gain	1.0000
11:69773492:C:CT	acceptor_gain	1.0000
11:69774020:TCA:T	donor_loss	1.0000
11:69774021:CA:C	donor_loss	1.0000
11:69774022:A:AC	donor_gain	1.0000
11:69774023:C:CG	donor_gain	1.0000
11:69774023:CCG:C	donor_gain	1.0000
11:69774023:CCGA:C	donor_gain	1.0000
11:69774023:CCGAG:C	donor_gain	1.0000
11:69774125:GGCC:G	acceptor_loss	1.0000
11:69774127:CCTG:C	acceptor_loss	1.0000
11:69774128:C:CC	acceptor_gain	1.0000
11:69774128:CTGG:C	acceptor_loss	1.0000
11:69774129:T:G	acceptor_loss	1.0000
11:69774741:TCA:T	donor_loss	1.0000
11:69774742:CAC:C	donor_loss	1.0000
11:69774743:A:AC	donor_gain	1.0000
11:69774743:ACTGT:A	donor_gain	1.0000
11:69774744:C:CA	donor_gain	1.0000
11:69774744:CT:C	donor_gain	1.0000
11:69774744:CTG:C	donor_gain	1.0000
11:69774744:CTGT:C	donor_gain	1.0000
11:69774744:CTGTC:C	donor_gain	1.0000
11:69773489:C:CT	acceptor_gain	0.9900
11:69773493:A:T	acceptor_gain	0.9900

AlphaMissense

1309 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:69773324:G:C	F202L	0.999
11:69773324:G:T	F202L	0.999
11:69773325:A:G	F202S	0.999
11:69773326:A:G	F202L	0.999
11:69773376:C:A	G185V	0.999
11:69773376:C:T	G185E	0.999
11:69773460:A:G	F157S	0.999
11:69774803:G:C	F94L	0.999
11:69774803:G:T	F94L	0.999
11:69774805:A:G	F94L	0.999
11:69773325:A:C	F202C	0.998
11:69773366:C:A	K188N	0.998
11:69773366:C:G	K188N	0.998
11:69773465:G:C	C155W	0.998
11:69774040:C:A	G143V	0.998
11:69774821:G:C	C88W	0.998
11:69774822:C:T	C88Y	0.998
11:69773329:G:C	H201D	0.997
11:69773377:C:A	G185W	0.997
11:69773391:G:T	A180D	0.997
11:69773428:C:G	A168P	0.997
11:69773445:A:G	L162P	0.997
11:69773454:T:A	E159V	0.997
11:69773460:A:C	F157C	0.997
11:69774060:G:C	F136L	0.997
11:69774060:G:T	F136L	0.997
11:69774062:A:G	F136L	0.997
11:69774804:A:G	F94S	0.997
11:69774807:C:T	G93D	0.997
11:69773361:C:T	G190E	0.996

dbSNP variants (sampled 300 via entrez): RS1000471491 (11:69773582 C>A,G,T), RS1001068009 (11:69774745 T>A,C), RS1001404350 (11:69774521 A>C,G), RS1001534072 (11:69777220 A>G), RS1001743591 (11:69772280 G>A), RS1002487096 (11:69776345 C>T), RS1003819673 (11:69770773 C>A,T), RS1003980612 (11:69770794 C>T), RS1004014888 (11:69771075 A>G), RS1004265476 (11:69774259 G>A,T), RS1004989633 (11:69772371 T>C), RS1005516178 (11:69775332 T>G), RS1006351256 (11:69775381 C>G,T), RS1006565783 (11:69775135 T>C,G), RS1006737567 (11:69775912 A>C)

Disease associations

OMIM: gene MIM:164980 | disease phenotypes: MIM:187750, MIM:621260

GenCC curated gene-disease

Disease	Classification	Inheritance
thoracic malformation	Limited	Autosomal recessive

Mondo (2): short-rib thoracic dysplasia 22 without polydactyly (MONDO:0979242), thoracic malformation (MONDO:0015929)

Orphanet (0):

HPO phenotypes

19 total (19 of 19 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000773	Short ribs
HP:0000774	Narrow chest
HP:0000878	11 pairs of ribs
HP:0001591	Bell-shaped thorax
HP:0001627	Abnormal heart morphology
HP:0001655	Patent foramen ovale
HP:0002021	Pyloric stenosis
HP:0002089	Pulmonary hypoplasia
HP:0002093	Respiratory insufficiency
HP:0002098	Respiratory distress
HP:0002643	Neonatal respiratory distress
HP:0003577	Congenital onset
HP:0004626	Lumbar scoliosis
HP:0005257	Thoracic hypoplasia
HP:0006644	Thoracic dysplasia
HP:0011461	Fetal onset
HP:0011471	Gastrostomy tube feeding in infancy
HP:0011947	Respiratory tract infection

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000678_13	Breast cancer	3.000000e-15
GCST002829_16	Urate levels in overweight individuals	8.000000e-07
GCST004412_6	Craniofacial microsomia	4.000000e-17
GCST008362_5	Birth weight	5.000000e-10
GCST010396_240	Gut microbiota (bacterial taxa, hurdle binary method)	5.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0004344	birth weight
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C566063	Thoracic Dysostosis, Isolated (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3286072 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, increases methylation	3
entinostat	increases expression, affects cotreatment	2
belinostat	affects cotreatment, increases expression	2
Endosulfan	decreases expression	2
bisphenol F	affects cotreatment, increases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
trichostatin A	increases expression	1
arsenite	decreases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	decreases methylation	1
MT19c compound	decreases expression	1
Resveratrol	decreases expression	1
Amphotericin B	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	increases expression	1
Carbamazepine	affects expression	1
Dexamethasone	increases expression, affects cotreatment	1
Diethylhexyl Phthalate	decreases expression	1
Estradiol	increases expression	1
Heparin	affects binding, increases activity	1
Heparan Sulfate	affects binding	1
Indomethacin	affects cotreatment, increases expression	1
Mianserin	decreases expression	1
Tretinoin	affects expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3293892	Binding	Binding affinity to human recombinant FGF4 by surface plasmon resonance assay	Synthesis and biological evaluation of a unique heparin mimetic hexasaccharide for structure-activity relationship studies. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A1T2	SEES3-1V human FGF4, clone1	Embryonic stem cell	Male
CVCL_A1T3	SEES3-1V human FGF4, clone2	Embryonic stem cell	Male
CVCL_A1T4	SEES3-1V human FGF4, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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