FST

Summary

FST (follistatin, HGNC:3971) is a protein-coding gene on chromosome 5q11.2, encoding Follistatin (P19883). Multifunctional regulatory protein whose primary function is to antagonize members of the transforming growth factor beta (TGF-beta) superfamily including activin, myostatin, GDF11 or bone morphogenetic proteins (BMPs).

Follistatin is a single-chain gonadal protein that specifically inhibits follicle-stimulating hormone release. The single FST gene encodes two isoforms, FST317 and FST344 containing 317 and 344 amino acids respectively, resulting from alternative splicing of the precursor mRNA. In a study in which 37 candidate genes were tested for linkage and association with polycystic ovary syndrome (PCOS) or hyperandrogenemia in 150 families, evidence was found for linkage between PCOS and follistatin.

Source: NCBI Gene 10468 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cleft lip/palate (Limited, GenCC)
• GWAS associations: 18
• Clinical variants (ClinVar): 41 total
• MANE Select transcript: NM_013409

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3971
Approved symbol	FST
Name	follistatin
Location	5q11.2
Locus type	gene with protein product
Status	Approved
Aliases	FS
Ensembl gene	ENSG00000134363
Ensembl biotype	protein_coding
OMIM	136470
Entrez	10468

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 7 protein_coding, 1 retained_intron

ENST00000256759, ENST00000396947, ENST00000491717, ENST00000497789, ENST00000504226, ENST00000901914, ENST00000918518, ENST00000953332

RefSeq mRNA: 2 — MANE Select: NM_013409 NM_006350, NM_013409

CCDS: CCDS3959, CCDS43315

Canonical transcript exons

ENST00000256759 — 6 exons

Exon	Start	End
ENSE00000743379	53482880	53483071
ENSE00000743382	53484069	53484293
ENSE00000743383	53484997	53485227
ENSE00001190599	53480629	53480876
ENSE00001941684	53485951	53487134
ENSE00003581021	53483504	53483722

Expression profiles

Bgee: expression breadth ubiquitous, 222 present calls, max score 97.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.8597 / max 4451.6803, expressed in 1099 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
56425	26.8597	1099

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	97.55	gold quality
buccal mucosa cell	CL:0002336	95.72	gold quality
right lobe of liver	UBERON:0001114	93.64	gold quality
liver	UBERON:0002107	92.52	gold quality
oocyte	CL:0000023	90.68	gold quality
secondary oocyte	CL:0000655	89.94	gold quality
mucosa of urinary bladder	UBERON:0001259	89.49	gold quality
calcaneal tendon	UBERON:0003701	89.34	gold quality
pericardium	UBERON:0002407	88.55	gold quality
subcutaneous adipose tissue	UBERON:0002190	88.24	gold quality
mucosa of stomach	UBERON:0001199	87.62	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.15	gold quality
skin of leg	UBERON:0001511	86.77	gold quality
saphenous vein	UBERON:0007318	86.61	gold quality
right lung	UBERON:0002167	86.06	gold quality
skin of abdomen	UBERON:0001416	86.02	gold quality
vena cava	UBERON:0004087	85.46	silver quality
zone of skin	UBERON:0000014	85.45	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.29	gold quality
tibial nerve	UBERON:0001323	85.12	gold quality
mammary duct	UBERON:0001765	84.74	gold quality
tibial artery	UBERON:0007610	84.69	gold quality
popliteal artery	UBERON:0002250	84.64	gold quality
diaphragm	UBERON:0001103	84.33	gold quality
epithelium of mammary gland	UBERON:0003244	84.19	gold quality
embryo	UBERON:0000922	83.84	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	83.73	silver quality
adipose tissue	UBERON:0001013	83.45	gold quality
urethra	UBERON:0000057	83.05	gold quality
connective tissue	UBERON:0002384	83.04	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-86618	yes	743.86
E-MTAB-10018	yes	205.61
E-MTAB-3929	yes	59.50
E-MTAB-8271	yes	7.05
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, BRCA1, CREB1, CTNNB1, E2F4, EGR2, ESRRB, FOXL2, GDNF, GLI1, GLI2, GLI3, HNF4A, KDM5B, LEF1, MYOD1, NFATC2, PPARA, PPARG, RELA, SMAD2, SMAD3, SP1, TCF4, TCF7L2, TFAP2A

miRNA regulators (miRDB)

45 targeting FST, 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-3924	100.00	72.09	2394
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-3618	99.69	68.57	1012
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-425-5P	99.59	67.67	900
HSA-MIR-208A-5P	99.42	70.83	1913
HSA-MIR-208B-5P	99.42	70.83	1952
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-6882-5P	99.35	71.13	1206
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362

Literature-anchored findings (GeneRIF, showing 40)

• Transcription activation of FLRG and follistatin by activin A, through Smad proteins, participates in a negative feedback loop to modulate activin A function (PMID:11948405)
• Follistatin and FLRG proteins downmodulate the effects of activin A and BMP2 on erythroid maturation. (PMID:12531697)
• Results quantify the relative expression of inhibin alpha, inhibin/activin beta(A), beta(B), beta(C), follistatin, activin receptors and beta-glycan genes in placental tissue of term pre-eclamptic patients. (PMID:12651901)
• Circulatory concentrations of follistatin is elevated in patients diagnosed with septicemia, consistent with potential role in the systemic inflammatory response (PMID:12720540)
• A continuous sequence comprising the N-terminal domain and followed by FS domains 1 and 2 fulfills the minimum structural requirement for activin binding and FS bioactivity. (PMID:14563935)
• Blocked activin signaling and its biologic functions in vitro. Significant correlation between serum follistatin levels and liver weight. (PMID:14578849)
• follistatin is secreted by melanoma cells (PMID:15064726)
• Whilst follistatin expression is unchanged, follistatin-related gene is down-regulated in endometrial carcinoma (PMID:15296481)
• comparison of the kinetics of FST isoform and FSTL3 biosynthesis, trafficking, and secretion (PMID:16150905)
• the differential biological actions among the FST isoforms and FSTL3 are primarily dependent on their relative cell-surface binding ability and ligand specificity (PMID:16627583)
• Follistatin was overexpressed while both activin subunits were downregulated in the majority of rat and human liver tumours (PMID:16935389)
• mRNA expressed in human granulosa-luteal cells at oocyte retrieval (PMID:17053951)
• it is concluded that FST is not a susceptibility locus for polycystic ovary syndrome (PCOS); however, the SNP rs3797297 from FST gene was associated with androgenic markers for PCOS and may be of importance in the hyperandrogenaemia of the disease (PMID:17284512)
• Ovarian endometriotic lesions show a deranged expression of activin A-binding proteins FLRG and follistatin, which may result in an altered effect of activin A on angiogenesis and/or endometrial differentiation. (PMID:17296189)
• These results indicate that haplotype structure at the ACVR2B and follistatin loci may contribute to interindividual variation in skeletal muscle mass and strength, although these data indicate sex-specific relationships. (PMID:17347381)
• Endometrial expression of follistatin mRNA is lower in women with dysfunctional uterine bleeding. (PMID:17644811)
• myostatin blockade by FS I-I has a therapeutic potential for muscular dystrophy (PMID:17893249)
• Inhibin/activin BA subunit, follistatin, and activin receptor proteins and mRNAs are present in the human fetal palate. (PMID:18001154)
• intron 1 of the follistatin gene has a critical role in mediating Smad-dependent effects of activin and regulating the expression level of this gene (PMID:18184649)
• FST plays a critical role in the production of multiple-organ metastasis, predominantly by inhibiting the angiogenesis when transfected into SCID mice. (PMID:18245525)
• These results reveal a key role of GLI2 in activation of the activin/BMP antagonist FST in response to hedgehog (HH) signaling. (PMID:18319260)
• several genes that are known to be regulated by DNA methylation were up-regulated dramatically by integrin alpha6beta4 expression, including S100A4, FST, PDLIM4, CAPG, and Nkx2.2. (PMID:19011242)
• FoxL2 and Smad3 coordinately regulate follistatin gene transcription.( (PMID:19106105)
• MSTN 2379 A > G and FST -5003 A > T were associated with baseline muscle strength and size among African Americans only. (PMID:19346981)
• Follistatin is a new adipokine important for adipogenesis. (PMID:19470636)
• the overexpression of the follistatin in normal human myoblasts improved in vitro their proliferation and differentiation rate (PMID:19520047)
• Data suggest inhibition of BMP-7, by Drm (Gremlin), follistatin, and Noggin and upregulation of BMP-4 may play an integral role in the development of nonunions. (PMID:19597895)
• Follistatin was detected in the epithelial cytoplasm and nucleus in normal, benign and malignant breast tissue. (PMID:19740438)
• Follistatin seems more sensitive than high-sensitivity C-reactive protein alone to represent the aggravated low-grade inflammatory status after oral contraceptive treatment in obese and non-obese women with polycystic ovary syndrome. (PMID:20093255)
• In prostate cancer patients the serum concentrations of FLST significantly correlated with the presence of bone metastases or increased PSA levels (PMID:20623366)
• Effects of training and androgens on MYOPRO and FOLLI concentrations in blood and skeletal muscle, were investigated. (PMID:20801187)
• Nucleolar follistatin promotes cancer cell survival under glucose-deprived conditions through inhibiting cellular rRNA synthesis. (PMID:20843798)
• Protein levels of activin A and follistatin were assessed in glioblastoma and normal brain tissues in this study. (PMID:20926007)
• Changes in hepatically metabolised follistatin during and after exercise are reported. (PMID:21068158)
• analysis of candidate genes revealed four genes that influence fertility: CGB/LHB gene cluster (p = 0.0036), FSHR (p = 0.023), FST (p = 0.023), and INHB; none of the independent SNPs in these genes predicted mortality (PMID:21222045)
• increased follistatin levels occurred with inflammation, reduced muscle strength, and low bone mineral density, suggesting an involvement of a mechanism including follistatin in the uremic wasting process (PMID:21350111)
• Disturbed expression of endometrial activin A, cripto , and follistatin suggests a dysfunction of the activin pathway in endometriosis/endometrioma. (PMID:21496809)
• GDF9 decreases basal and activin A-induced FST and FSTL3 expression, and this explains, in part, its enhancing effects on activin A-induced inhibin beta(B)-subunit mRNA expression and inhibin B production in hGL cells (PMID:21829661)
• Follistatin showed highly significant positive associations to the intrafollicular concentrations of antimullerian hormone and inhibin B. (PMID:21846490)
• LIR was able to induce gains in 1RM and quadriceps CSA similar to those observed after traditional HI. These responses may be related to the concomitant decrease in MSTN and increase in FLST isoforms, GASP-1, and SMAD-7 mRNA gene expression. (PMID:21900845)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	fsta	ENSDARG00000052846
danio_rerio	fstb	ENSDARG00000057992
mus_musculus	Fst	ENSMUSG00000021765
rattus_norvegicus	Fst	ENSRNOG00000011631

Paralogs (6): FSTL4 (ENSG00000053108), FSTL3 (ENSG00000070404), SPINK5 (ENSG00000133710), FSTL1 (ENSG00000163430), FSTL5 (ENSG00000168843), SPINK6 (ENSG00000178172)

Protein

Protein identifiers

Follistatin — P19883 (reviewed: P19883)

Alternative names: Activin-binding protein

All UniProt accessions (3): P19883, H0YA75, H0YAF9

UniProt curated annotations — full annotation on UniProt →

Function. Multifunctional regulatory protein whose primary function is to antagonize members of the transforming growth factor beta (TGF-beta) superfamily including activin, myostatin, GDF11 or bone morphogenetic proteins (BMPs). Mechanistically, binds to these ligands in the extracellular space, blocking their type II receptor-binding site to inhibit downstream signaling. Plays an essential role in muscle fiber formation and growth both by preventing the repressive effects of myostatin and through SMAD3/AKT/mTOR signaling independently of myostatin. Also promotes neural differentiation by antagonizing the action BMP4. Acts as a specific inhibitor of the biosynthesis and secretion of pituitary follicle stimulating hormone (FSH) by sequestering activin A/INHBA. On the other hand, translocates into the nucleus where it down-regulates rRNA synthesis and ribosome biogenesis to maintain cellular energy homeostasis by binding to rDNA.

Subunit / interactions. Interacts with GDF11. Interacts with activin A/INHBA. Interacts with MYOSTATIN/MSTN.

Subcellular location. Secreted. Nucleus. Nucleolus.

Tissue specificity. Isoform 1 is the predominant isoform in serum but is undetectable in follicular fluid. In the embryo, strong expression is seen in the palatal epithelia, including the medial edge epithelial and midline epithelial seam of the palatal shelves. Less pronounced expression is also seen throughout the palatal shelf and tongue mesenchyme.

Induction. By glucose deprivation.

Isoforms (2)

UniProt ID	Names	Canonical?
P19883-1	1, FS315, FS-315	yes
P19883-2	2, FS288, FS-288

RefSeq proteins (2): NP_006341, NP_037541* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002350	Kazal_dom	Domain
IPR003645	Fol_N	Domain
IPR015369	Follistatin/Osteonectin_EGF	Domain
IPR017878	TB_dom	Domain
IPR036058	Kazal_dom_sf	Homologous_superfamily
IPR036773	TB_dom_sf	Homologous_superfamily
IPR050653	Prot_Inhib_GrowthFact_Antg	Family

Pfam: PF07648, PF09289, PF21333

UniProt features (72 total): strand 23, disulfide bond 18, domain 7, helix 7, mutagenesis site 5, turn 3, glycosylation site 2, sequence variant 2, signal peptide 1, chain 1, compositionally biased region 1, splice variant 1, region of interest 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
3HH2	X-RAY DIFFRACTION	2.15
5JHW	X-RAY DIFFRACTION	2.35
2B0U	X-RAY DIFFRACTION	2.8
2P6A	X-RAY DIFFRACTION	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P19883-F1	87.83	0.77

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 (18): 32–55, 42–88, 56–91, 95–106, 100–116, 118–150, 122–143, 132–164, 168–179, 173–189, 192–225, 196–218, 207–239, 245–256, 250–267, 270–302, 274–295, 284–316

Glycosylation sites (2): 124, 288

Mutagenesis-validated functional residues (5):

Position	Phenotype
33	more than 90% loss of binding to activin a/inhba and fsh secretion inhibition.
52	about 30% of binding to activin a/inhba.
55	more than 95% loss of binding to activin a/inhba and fsh secretion inhibition; when associated with a-56.
56	more than 95% loss of binding to activin a/inhba and fsh secretion inhibition; when associated with a-55.
163	complete loss of binding to activin a/inhba.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2473224	Antagonism of Activin by Follistatin

MSigDB gene sets: 354 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, RNGTGGGC_UNKNOWN, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, MODULE_52, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_EPIDERMIS_MORPHOGENESIS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, FISCHER_G1_S_CELL_CYCLE, JAEGER_METASTASIS_DN, GOBP_KERATINOCYTE_PROLIFERATION, CMYB_01, SHEPARD_CRASH_AND_BURN_MUTANT_UP

GO Biological Process (17): negative regulation of transcription by RNA polymerase II (GO:0000122), skeletal system development (GO:0001501), hematopoietic progenitor cell differentiation (GO:0002244), gamete generation (GO:0007276), pattern specification process (GO:0007389), female gonad development (GO:0008585), cell differentiation (GO:0030154), BMP signaling pathway (GO:0030509), regulation of BMP signaling pathway (GO:0030510), negative regulation of epithelial cell differentiation (GO:0030857), hair follicle morphogenesis (GO:0031069), negative regulation of activin receptor signaling pathway (GO:0032926), ameloblast differentiation (GO:0036305), odontogenesis of dentin-containing tooth (GO:0042475), keratinocyte proliferation (GO:0043616), positive regulation of hair follicle development (GO:0051798), cellular response to growth factor stimulus (GO:0071363)

GO Molecular Function (4): activin receptor antagonist activity (GO:0038102), heparan sulfate proteoglycan binding (GO:0043395), activin binding (GO:0048185), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleolus (GO:0005730), cytoplasm (GO:0005737), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Signaling by Activin	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
hair follicle development	2
cellular anatomical structure	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
system development	1
hemopoiesis	1
cell differentiation	1
sexual reproduction	1
multicellular organismal reproductive process	1
multicellular organism development	1
multicellular organismal process	1
gonad development	1
development of primary female sexual characteristics	1
cellular developmental process	1
cellular response to BMP stimulus	1
transforming growth factor beta receptor superfamily signaling pathway	1
BMP signaling pathway	1
regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
regulation of cellular response to growth factor stimulus	1
epithelial cell differentiation	1
regulation of epithelial cell differentiation	1
negative regulation of cell differentiation	1
anatomical structure morphogenesis	1
hair cycle process	1
epidermis morphogenesis	1
activin receptor signaling pathway	1
regulation of activin receptor signaling pathway	1
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
columnar/cuboidal epithelial cell differentiation	1
odontogenesis	1
epithelial cell proliferation	1
positive regulation of developmental process	1
positive regulation of multicellular organismal process	1
regulation of hair follicle development	1
response to growth factor	1
cellular response to endogenous stimulus	1
negative regulation of activin receptor signaling pathway	1
receptor antagonist activity	1
proteoglycan binding	1

Protein interactions and networks

STRING

2028 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FST	MSTN	O14793	997
FST	BMP7	P18075	989
FST	BMP4	P12644	918
FST	GDF11	O95390	915
FST	INHBA	P08476	899
FST	BMP15	O95972	885
FST	WFIKKN1	Q96NZ8	871
FST	ACVR2B	Q13705	858
FST	CHRD	Q9H2X0	846
FST	WFIKKN2	Q8TEU8	845
FST	ACVR2A	P27037	818
FST	BMP5	P22003	811
FST	GDF9	O60383	806
FST	BMP2	P12643	803
FST	BMP6	P22004	800

IntAct

45 interactions, top by confidence:

A	B	Type	Score
FST	ANG	psi-mi:“MI:0915”(physical association)	0.570
FST	ANG	psi-mi:“MI:0403”(colocalization)	0.570
FST	ANG	psi-mi:“MI:0407”(direct interaction)	0.570
ZNF417	FST	psi-mi:“MI:0915”(physical association)	0.560
FST	ZNF417	psi-mi:“MI:0915”(physical association)	0.560
FST	CREB5	psi-mi:“MI:0915”(physical association)	0.560
TXN	FST	psi-mi:“MI:0915”(physical association)	0.560
FST	ZNF587	psi-mi:“MI:0915”(physical association)	0.560
FST	BEX2	psi-mi:“MI:0915”(physical association)	0.560
FST	HOXA1	psi-mi:“MI:0915”(physical association)	0.560
FST	CATSPER1	psi-mi:“MI:0915”(physical association)	0.560
FST	DIP2A	psi-mi:“MI:0407”(direct interaction)	0.540
DIP2A	FST	psi-mi:“MI:0915”(physical association)	0.540
GPIHBP1	ADAM10	psi-mi:“MI:0914”(association)	0.530
NOTCH2	ZNF316	psi-mi:“MI:0914”(association)	0.530
FST	ADAM12	psi-mi:“MI:0407”(direct interaction)	0.440
ADAM8	FST	psi-mi:“MI:0407”(direct interaction)	0.440
FST	Mstn	psi-mi:“MI:0407”(direct interaction)	0.440
FST	FSTL1	psi-mi:“MI:0407”(direct interaction)	0.440
FST	HIST2H2BF	psi-mi:“MI:0915”(physical association)	0.400
FST	NPM1	psi-mi:“MI:0915”(physical association)	0.400
C8orf33	FST	psi-mi:“MI:0915”(physical association)	0.370
FST	MEST	psi-mi:“MI:0915”(physical association)	0.370
TK1	FST	psi-mi:“MI:0915”(physical association)	0.370
FOXA1	AREG	psi-mi:“MI:0914”(association)	0.350
FST	ZZEF1	psi-mi:“MI:0914”(association)	0.350
EAF1	C1orf226	psi-mi:“MI:0914”(association)	0.350
ELSPBP1	ADAM10	psi-mi:“MI:0914”(association)	0.350
ZCCHC10	ARHGAP10	psi-mi:“MI:0914”(association)	0.350

BioGRID (28): FST (Two-hybrid), FST (Two-hybrid), TXN (Two-hybrid), CREB5 (Two-hybrid), CATSPER1 (Two-hybrid), ZNF587 (Two-hybrid), FST (Proximity Label-MS), HIST2H2BF (Proximity Label-MS), FST (Two-hybrid), FST (Reconstituted Complex), ZZEF1 (Affinity Capture-MS), ZNF696 (Affinity Capture-MS), CERK (Affinity Capture-MS), ZNF146 (Affinity Capture-MS), SORL1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D5PUP4, A5YT95, O35757, O62650, O75882, O95980, P07225, P09858, P10669, P17247, P19883, P21214, P21674, P26012, P26013, P27090, P30371, P31514, P31515, P47931, P49767, P50291, P61811, P61812, P97299, P97953, Q07257, Q0VBD0, Q17QD6, Q38L25, Q5RA73, Q6NW40, Q6V9H4, Q6ZQ11, Q863H1, Q86X52, Q8BFR2, Q8CI19, Q8JG54, Q8N475

Diamond homologs: A0A1D5PUP4, A0JP86, A2ASQ1, A3KN33, A5YT95, E9Q7X7, G4V4G1, G5ECE3, O00468, O00634, O09118, O15230, O62650, O75094, O75445, O88280, O94813, O95631, O95633, O95980, P02468, P02469, P07942, P0DKM7, P0DKM8, P0DKM9, P10184, P10669, P11046, P11047, P15215, P15800, P16895, P19883, P21674, P25304, P31514, P31515, P31696, P47931

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
FST	“down-regulates activity”	INHBA	binding
FST	“down-regulates activity”	MSTN	binding
CREB1	“up-regulates quantity by expression”	FST	“transcriptional regulation”
FST	“down-regulates activity”	GDF11	binding
LEF1	“up-regulates quantity by expression”	FST	“transcriptional regulation”
MYOD1	“up-regulates quantity by expression”	FST	“transcriptional regulation”
NFATC2	“up-regulates quantity by expression”	FST	“transcriptional regulation”
GDNF	“up-regulates quantity by expression”	FST	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	28
Likely benign	1
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

842 predictions. Top by Δscore:

Variant	Effect	Δscore
5:53480874:AGGG:A	donor_loss	1.0000
5:53480875:GG:G	donor_gain	1.0000
5:53480875:GGGTA:G	donor_loss	1.0000
5:53480876:GG:G	donor_gain	1.0000
5:53480876:GGT:G	donor_loss	1.0000
5:53482875:CACA:C	acceptor_loss	1.0000
5:53482876:A:AG	acceptor_gain	1.0000
5:53482877:C:G	acceptor_gain	1.0000
5:53482878:A:AG	acceptor_gain	1.0000
5:53482878:AGCT:A	acceptor_gain	1.0000
5:53482878:AGCTG:A	acceptor_gain	1.0000
5:53482879:G:GT	acceptor_gain	1.0000
5:53482879:GC:G	acceptor_gain	1.0000
5:53482879:GCT:G	acceptor_gain	1.0000
5:53482879:GCTG:G	acceptor_gain	1.0000
5:53482879:GCTGG:G	acceptor_gain	1.0000
5:53483069:AAG:A	donor_gain	1.0000
5:53483070:AGGTA:A	donor_loss	1.0000
5:53483072:G:GG	donor_gain	1.0000
5:53483502:A:AG	acceptor_gain	1.0000
5:53483503:G:GG	acceptor_gain	1.0000
5:53483503:GAAAC:G	acceptor_gain	1.0000
5:53483607:G:GT	donor_gain	1.0000
5:53483695:G:GT	donor_gain	1.0000
5:53483723:G:GG	donor_gain	1.0000
5:53480873:CAGG:C	donor_gain	0.9900
5:53480874:AGG:A	donor_gain	0.9900
5:53480875:GGG:G	donor_gain	0.9900
5:53480877:G:GG	donor_gain	0.9900
5:53480878:T:G	donor_loss	0.9900

AlphaMissense

2267 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:53482888:T:A	C32S	1.000
5:53482889:G:C	C32S	1.000
5:53482891:T:A	W33R	1.000
5:53482891:T:C	W33R	1.000
5:53482893:G:C	W33C	1.000
5:53482893:G:T	W33C	1.000
5:53482918:T:A	C42S	1.000
5:53482918:T:C	C42R	1.000
5:53482919:G:C	C42S	1.000
5:53482957:T:A	C55S	1.000
5:53482958:G:C	C55S	1.000
5:53482989:G:C	W65C	1.000
5:53482989:G:T	W65C	1.000
5:53483028:G:C	W78C	1.000
5:53483028:G:T	W78C	1.000
5:53483056:T:A	C88S	1.000
5:53483056:T:C	C88R	1.000
5:53483057:G:A	C88Y	1.000
5:53483057:G:C	C88S	1.000
5:53483058:C:G	C88W	1.000
5:53483065:T:A	C91S	1.000
5:53483066:G:A	C91Y	1.000
5:53483066:G:C	C91S	1.000
5:53483524:T:A	C100S	1.000
5:53483524:T:C	C100R	1.000
5:53483525:G:A	C100Y	1.000
5:53483525:G:C	C100S	1.000
5:53483542:T:A	C106S	1.000
5:53483542:T:C	C106R	1.000
5:53483543:G:C	C106S	1.000

dbSNP variants (sampled 300 via entrez): RS1000150126 (5:53485305 G>A,T), RS1000552658 (5:53487245 G>A), RS1000875144 (5:53486832 T>C), RS1001673381 (5:53481756 C>T), RS1002057780 (5:53482531 G>A), RS1002754615 (5:53479692 G>A,C,T), RS1003215242 (5:53479417 G>C), RS1003582169 (5:53478670 G>A,C), RS1003698041 (5:53486435 C>G), RS1003969940 (5:53482307 CTT>C), RS1004367581 (5:53482484 A>C), RS1004667714 (5:53479709 A>T), RS1005574333 (5:53484428 GTGT>G), RS1005843699 (5:53479812 A>T), RS1005906908 (5:53486115 A>G)

Disease associations

OMIM: gene MIM:136470 | disease phenotypes: MIM:119530

GenCC curated gene-disease

Disease	Classification	Inheritance
cleft lip/palate	Limited	Autosomal dominant

Mondo (2): orofacial cleft (MONDO:0000358), cleft lip/palate (MONDO:0016044)

Orphanet (0):

HPO phenotypes

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

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST002481_13	Acne (severe)	5.000000e-09
GCST004283_25	Midgestational circulating levels of PCBs	8.000000e-08
GCST005170_47	Intraocular pressure	1.000000e-16
GCST005580_200	Intraocular pressure	2.000000e-26
GCST005580_210	Intraocular pressure	7.000000e-24
GCST007234_11	Acne (severe)	2.000000e-15
GCST007511_12	Alzheimer’s disease (late onset)	3.000000e-07
GCST008058_209	Estimated glomerular filtration rate	8.000000e-13
GCST008059_179	Estimated glomerular filtration rate	6.000000e-13
GCST008839_399	Height	5.000000e-08
GCST009007_1	High-grade serous ovarian cancer	6.000000e-08
GCST009462_58	Optic disc size	4.000000e-10
GCST010002_26	Refractive error	6.000000e-12
GCST010242_105	HDL cholesterol levels	2.000000e-08
GCST011384_2	Vaginal microbiome composition (community state type)	1.000000e-05
GCST90000654_18	Central corneal thickness	1.000000e-08
GCST90013407_168	Liver enzyme levels (gamma-glutamyl transferase)	1.000000e-13
GCST90013442_6	Keratoconus	3.000000e-18

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0007042	polychlorinated biphenyls measurement
EFO:0007964	gestational serum measurement
EFO:0004695	intraocular pressure measurement
EFO:1001870	late-onset Alzheimers disease
EFO:1001516	ovarian serous carcinoma
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0011013	vaginal microbiome measurement
EFO:0005213	central corneal thickness
EFO:0004532	serum gamma-glutamyl transferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, decreases expression, affects expression, affects cotreatment	8
Benzo(a)pyrene	decreases expression, increases expression	7
methylmercuric chloride	increases expression, affects cotreatment	5
Asbestos, Crocidolite	decreases expression, increases expression	5
bisphenol A	increases expression, affects expression, decreases expression, affects cotreatment	4
Tetrachlorodibenzodioxin	decreases reaction, increases expression, decreases expression	4
trichostatin A	affects cotreatment, decreases expression	3
sodium arsenite	decreases expression, increases abundance, increases expression	3
Cisplatin	affects reaction, decreases expression, affects cotreatment, increases expression	3
Estradiol	affects expression, decreases reaction, increases expression, decreases expression	3
Oxygen	decreases expression, affects reaction, increases expression	3
Tamoxifen	decreases expression, affects expression, affects cotreatment	3
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	3
Aflatoxin B1	decreases methylation, increases expression	3
Particulate Matter	decreases expression, increases abundance, affects cotreatment, increases expression	3
arsenite	decreases reaction, increases expression, decreases expression, increases methylation	2
chloropicrin	affects expression, decreases expression	2
Resveratrol	increases expression	2
Fulvestrant	decreases reaction, increases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Cadmium	decreases expression, increases expression	2
Dust	increases abundance, increases expression, decreases expression	2
Polycyclic Aromatic Hydrocarbons	increases expression, affects cotreatment, increases abundance	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	2
Cyclosporine	decreases expression	2
Raloxifene Hydrochloride	affects expression, affects cotreatment, decreases expression	2
2-methoxy-6-undecyl-1,4-benzoquinone	decreases expression	1
bisphenol F	affects cotreatment, increases expression	1
TAK-243	increases sumoylation	1
dicrotophos	increases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B7XD	Abcam Raji FST KO	Cancer cell line	Male
CVCL_B9Y2	Abcam THP-1 FST KO	Cancer cell line	Male
CVCL_C6ZW	Abcam PC-3 FST KO	Cancer cell line	Male
CVCL_E0DD	Ubigene HeLa FST KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04234971	PHASE4	RECRUITING	Cost Effectiveness in Alveolar Bone Grafting in Patients With Cleft Lip and Palate
NCT04771156	PHASE4	RECRUITING	Ketorolac in Palatoplasty
NCT03766217	PHASE3	COMPLETED	Bone Tissue Engineering With Dental Pulp Stem Cells for Alveolar Cleft Repair
NCT06284434	PHASE3	RECRUITING	Liposomal Bupivacaine Use in Alveolar Bone Graft Patients
NCT00930124	PHASE2	COMPLETED	Cleft Orthognathic Surgery Versus Distraction Osteogenesis - Which is Better?
NCT06408337	PHASE1/PHASE2	RECRUITING	Phase I-IIa, to Evaluate the Safety, Feasibility, and Efficacy of the Use of BIOCLEFT in the Treatment of Cleft Palate.
NCT00070811	Not specified	COMPLETED	Assessing the Results of Lip Surgery in Patients With Cleft Lip and Palate
NCT00156442	Not specified	COMPLETED	A Study to Examine the Relationship Between Sleep Apnea and Cleft Lip/Palate
NCT01601171	Not specified	RECRUITING	Genetics of Reproductive Disorders (Including Kallmann Syndrome) and Cleft Lip and/or Palate
NCT01871623	Not specified	UNKNOWN	One-Piece Le Fort I Osteotomy Versus Segmental Le Fort I Osteotomy
NCT01932164	Not specified	COMPLETED	Use of Mesenchymal Stem Cells for Alveolar Bone Tissue Engineering for Cleft Lip and Palate Patients
NCT02702869	Not specified	ENROLLING_BY_INVITATION	Allied Cleft & Craniofacial Quality-Improvement and Research Network (ACCQUIREnet)
NCT02789787	Not specified	COMPLETED	Clinical Effectiveness of Late Maxillary Protraction for Cleft Lip and Palate
NCT02845193	Not specified	COMPLETED	Effect of Novel Nasoalveolar Molding Techniques on Parents’ Satisfaction and Short Term Treatment Outcomes in Unilateral Cleft Lip and Palate Infants: A Randomized Controlled Trial
NCT02881606	Not specified	COMPLETED	Evaluation of the Clinical Effectiveness of Naso-alveolar Molding (NAM) Versus Computer Aided Design NAM (CAD/NAM) in Infants With Bilateral Cleft Lip and Palate: A Randomized Clinical Trial
NCT03011489	Not specified	UNKNOWN	Parent’s Satisfaction and Evaluation of Postsurgical Outcomes in Unilateral Cleft Lip / Palate Newly Born Infants With / Without Vacuum Formed Nasoalveolar Molding Aligners : A Controlled Clinical Trial
NCT03065686	Not specified	RECRUITING	Identification of Genetic Factors Implicated in Orofacial Cleft Using Whole Exome Sequencing
NCT03165331	Not specified	UNKNOWN	Online Psychosocial Support for Young People With a Visible Difference: A Randomised Control Study
NCT03217890	Not specified	UNKNOWN	the Relationship Between Cleft Lip and / or Palate (Different Types) and ABO Blood Groups.
NCT03308266	Not specified	COMPLETED	Electromyographic Analysis of the Masticatory Muscles in Cleft Lip and Palate Children With Temporomandibular Disorders
NCT03395015	Not specified	COMPLETED	Efficacy of Maxillo-facial Treatment on Cleft Lip and Palate Patients Faces: Aesthetic Considerations
NCT03514563	Not specified	TERMINATED	Three Dimensional Facial Growth Analysis
NCT03563495	Not specified	COMPLETED	Tissue Engineered Constructs for Alveolar Cleft Repair
NCT03582111	Not specified	COMPLETED	Ultrasound Diagnosis of Cleft Lip and Palate
NCT03686761	Not specified	COMPLETED	Periodontal Changes Following Mid Maxillary Distraction
NCT03708406	Not specified	COMPLETED	Otologic and Rhinologic Outcomes in Children With Clef Palate
NCT03740841	Not specified	TERMINATED	Evaluation of the Effects of LUNII on Pre-operative Anxiety and on the Post-operative Period in Children With Cleft Lip and Palate Admitted for Alveolar Bone Graft: Pilot Study
NCT03750708	Not specified	WITHDRAWN	Oral Hygiene and Connected Toothbrush Before Alveolar Bone Graft for Cleft Lip and Palate
NCT03839290	Not specified	UNKNOWN	Development of the Palate in Bilateral Orofacial Cleft Newborns One Year After Early Neonatal Cheiloplasty
NCT03877666	Not specified	COMPLETED	Assessment of the Influence of Cleft Repair on Microcirculation of the Palate
NCT03976609	Not specified	COMPLETED	Three Dimensional Changes on Nasal Septum and Alveolar Cleft After Maxillary Expansion
NCT04108416	Not specified	COMPLETED	Unilateral Cleft Repair in One Surgery With Pure Primary Healing
NCT04236466	Not specified	UNKNOWN	Transverse Dento-skeletal Effects of Two Rapid Palatal Expansion Appliances in Cleft Lip and Palate Patients
NCT04331379	Not specified	COMPLETED	Effectiveness of Nasal-alar Elevator Combined With Taping Vs. Taping Alone on Improving the Nose Esthetics and Maxillary Arch Dimensions in Infants With Unilateral Complete Cleft Lip and Palate
NCT04331977	Not specified	COMPLETED	Effectiveness of Two Maxillary Expanders in Improving the Transverse Skeletal and Dental Dimensions in Patients With Cleft Lip and Palate
NCT04354116	Not specified	UNKNOWN	MARPE in Patients With Cleft Lip and Palate
NCT04369638	Not specified	TERMINATED	Fabrication of Naso-alveolar Molding (NAM) Appliance in Cleft Lip and Palate (CLP) From Digital Magnetic Resonance Imaging (MRI) Face Scan
NCT04381078	Not specified	UNKNOWN	Methods of Providing Information Prior to an Alveolar Bone Graft
NCT04384276	Not specified	COMPLETED	Weigh Easy: Simplifying Home Weight Monitoring for Infants
NCT04422847	Not specified	RECRUITING	Use of Computer Aided Design and 3D Printing for Anesthesiology Management in a Pediatric Patient With Cleft Facial Defect