FSTL3

Summary

FSTL3 (follistatin like 3, HGNC:3973) is a protein-coding gene on chromosome 19p13.3, encoding Follistatin-related protein 3 (O95633). Isoform 1 or the secreted form is a binding and antagonizing protein for members of the TGF-beta family, such as activin, BMP2 and MSTN.

Follistatin-like 3 is a secreted glycoprotein of the follistatin-module-protein family. It may have a role in leukemogenesis.

Source: NCBI Gene 10272 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 56 total
• Expression (HPA): Low tissue specificity — highest in placenta, blood vessel, vagina
• GTEx eGene: eQTL in 13 tissues, sQTL in 2 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.60 (unconstrained)
• MANE Select transcript: NM_005860
• Notable: 56 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3973
Approved symbol	FSTL3
Name	follistatin like 3
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	FLRG, FSRP
Ensembl gene	ENSG00000070404
Ensembl biotype	protein_coding
OMIM	605343
Entrez	10272

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 12 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

MANE Select: ENST00000166139

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 3, TSL 4: 1, TSL 5: 1

ENST00000166139, ENST00000588773, ENST00000589185, ENST00000591573, ENST00000592058, ENST00000592947, ENST00000605925, ENST00000905299, ENST00000964202, ENST00001047662, ENST00001047663, ENST00001047664, ENST00001047665, ENST00001142214

RefSeq mRNA: 1 — MANE Select: NM_005860 NM_005860

CCDS: CCDS12040

Canonical transcript exons

ENST00000166139 — 5 exons

Exon	Start	End
ENSE00000655234	677792	677977
ENSE00000892310	681650	683385
ENSE00000892311	676392	676526
ENSE00003602279	680274	680489
ENSE00003684051	681333	681560

Expression profiles

Bgee: expression breadth ubiquitous, 195 present calls, max score 98.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 95.9411 / max 6089.9346, expressed in 1742 samples.

Highest expression (Bgee): coronary artery, nerve, tibial nerve, ascending aorta, thoracic aorta.

Genetic regulation across tissues (GTEx eQTL / sQTL)

FSTL3 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 13 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

15 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	sqtl	2.9e-15	-0.39	19:677646:C:T
Whole Blood	eqtl	1.8e-09	+0.18	19:663929:A:G
Artery Tibial	sqtl	2.3e-08	-0.36	19:676559:G:A
Nerve Tibial	eqtl	2.1e-03	-0.11	19:675513:T:G
Colon Sigmoid	eqtl	2.6e-03	+0.23	19:1318111:C:T
Brain Cerebellar Hemisphere	eqtl	6.2e-03	-0.30	19:680943:G:T
Cells EBV-transformed lymphocytes	eqtl	9.0e-03	-0.66	19:1601253:G:A
Minor Salivary Gland	eqtl	1.5e-02	-0.63	19:832886:T:C
Muscle Skeletal	eqtl	1.7e-02	-0.18	19:680943:G:T
Heart Left Ventricle	eqtl	2.0e-02	-0.13	19:1188408:T:A
Thyroid	eqtl	2.4e-02	+0.49	19:932981:G:A
Brain Hippocampus	eqtl	2.5e-02	-0.72	19:831815:GT:G
Spleen	eqtl	3.7e-02	+0.54	19:788740:G:A
Liver	eqtl	4.5e-02	+1.05	19:761139:G:A
Esophagus Mucosa	eqtl	4.8e-02	-0.14	19:557979:T:C

FANTOM5 promoters

8 alternative TSS:

Promoter ID	TPM avg	Samples expressed
172722	89.9461	1495
172727	3.4063	1192
172726	0.7456	362
172728	0.7304	481
172724	0.4270	190
172734	0.3200	122
172723	0.2112	95
172725	0.1545	63

Top tissues by expression

showing 100 of 285 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right coronary artery	UBERON:0001625	98.00	gold quality
nerve	UBERON:0001021	97.85	gold quality
tibial nerve	UBERON:0001323	97.85	gold quality
ascending aorta	UBERON:0001496	97.74	gold quality
thoracic aorta	UBERON:0001515	97.70	gold quality
left coronary artery	UBERON:0001626	97.50	gold quality
apex of heart	UBERON:0002098	97.44	gold quality
left adrenal gland cortex	UBERON:0035825	97.33	gold quality
left uterine tube	UBERON:0001303	97.30	gold quality
left adrenal gland	UBERON:0001234	97.15	gold quality
upper lobe of left lung	UBERON:0008952	97.14	gold quality
mucosa of stomach	UBERON:0001199	97.12	gold quality
right adrenal gland	UBERON:0001233	96.98	gold quality
right lung	UBERON:0002167	96.95	gold quality
aorta	UBERON:0000947	96.78	gold quality
right atrium auricular region	UBERON:0006631	96.70	gold quality
right adrenal gland cortex	UBERON:0035827	96.49	gold quality
tibial artery	UBERON:0007610	96.38	gold quality
popliteal artery	UBERON:0002250	96.37	gold quality
coronary artery	UBERON:0001621	96.21	gold quality
descending thoracic aorta	UBERON:0002345	96.17	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.16	gold quality
lower esophagus	UBERON:0013473	96.08	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	95.92	gold quality
upper lobe of lung	UBERON:0008948	95.74	gold quality
endocervix	UBERON:0000458	95.73	gold quality
adrenal cortex	UBERON:0001235	95.68	gold quality
right testis	UBERON:0004534	95.13	gold quality
left testis	UBERON:0004533	94.88	gold quality
omental fat pad	UBERON:0010414	94.81	gold quality
adrenal gland	UBERON:0002369	94.74	gold quality
peritoneum	UBERON:0002358	94.71	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.41	gold quality
right ovary	UBERON:0002118	94.38	gold quality
cardiac atrium	UBERON:0002081	94.34	gold quality
heart left ventricle	UBERON:0002084	94.26	gold quality
adipose tissue of abdominal region	UBERON:0007808	93.94	gold quality
ectocervix	UBERON:0012249	93.82	gold quality
metanephros cortex	UBERON:0010533	93.76	gold quality
cardiac ventricle	UBERON:0002082	93.57	gold quality
sural nerve	UBERON:0015488	93.41	gold quality
left ovary	UBERON:0002119	93.08	gold quality
decidua	UBERON:0002450	92.63	gold quality
heart	UBERON:0000948	92.58	gold quality
body of uterus	UBERON:0009853	92.40	gold quality
subcutaneous adipose tissue	UBERON:0002190	92.18	gold quality
stromal cell of endometrium	CL:0002255	92.04	gold quality
testis	UBERON:0000473	91.85	gold quality
left lobe of thyroid gland	UBERON:0001120	90.34	gold quality
right lobe of thyroid gland	UBERON:0001119	90.23	gold quality
adenohypophysis	UBERON:0002196	89.81	gold quality
adipose tissue	UBERON:0001013	89.70	gold quality
body of pancreas	UBERON:0001150	89.65	gold quality
placenta	UBERON:0001987	89.50	gold quality
body of stomach	UBERON:0001161	89.34	gold quality
esophagus	UBERON:0001043	89.13	gold quality
skin of leg	UBERON:0001511	89.00	gold quality
connective tissue	UBERON:0002384	88.34	gold quality
lower esophagus mucosa	UBERON:0035834	88.34	gold quality
skin of abdomen	UBERON:0001416	87.92	gold quality
thyroid gland	UBERON:0002046	87.77	gold quality
pancreas	UBERON:0001264	87.55	gold quality
small intestine Peyer’s patch	UBERON:0003454	87.50	gold quality
islet of Langerhans	UBERON:0000006	87.28	gold quality
ovary	UBERON:0000992	87.24	gold quality
transverse colon	UBERON:0001157	87.11	gold quality
vagina	UBERON:0000996	86.77	gold quality
sigmoid colon	UBERON:0001159	86.56	gold quality
prostate gland	UBERON:0002367	86.45	gold quality
minor salivary gland	UBERON:0001830	86.32	gold quality
gall bladder	UBERON:0002110	86.27	gold quality
stomach	UBERON:0000945	85.82	gold quality
endometrium epithelium	UBERON:0004811	85.60	silver quality
pituitary gland	UBERON:0000007	85.50	gold quality
lung	UBERON:0002048	85.23	gold quality
Brodmann (1909) area 10	UBERON:0013541	84.85	silver quality
fundus of stomach	UBERON:0001160	84.50	gold quality
zone of skin	UBERON:0000014	84.40	gold quality
vermiform appendix	UBERON:0001154	84.38	gold quality
middle frontal gyrus	UBERON:0002702	84.20	silver quality
right lobe of liver	UBERON:0001114	84.19	gold quality
myometrium	UBERON:0001296	83.98	gold quality
colon	UBERON:0001155	83.94	gold quality
right uterine tube	UBERON:0001302	83.94	gold quality
small intestine	UBERON:0002108	83.89	gold quality
esophagus mucosa	UBERON:0002469	83.79	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.70	gold quality
right frontal lobe	UBERON:0002810	83.69	gold quality
mouth mucosa	UBERON:0003729	83.58	gold quality
large intestine	UBERON:0000059	82.99	gold quality
intestine	UBERON:0000160	82.92	gold quality
anterior cingulate cortex	UBERON:0009835	82.73	gold quality
cingulate cortex	UBERON:0003027	82.72	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	82.72	gold quality
smooth muscle tissue	UBERON:0001135	82.60	gold quality
saliva-secreting gland	UBERON:0001044	82.52	gold quality
monocyte	CL:0000576	82.48	gold quality
spleen	UBERON:0002106	82.36	gold quality
mucosa of transverse colon	UBERON:0004991	82.21	gold quality
adult mammalian kidney	UBERON:0000082	82.18	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	3906.14
E-MTAB-6678	yes	3633.31
E-HCAD-24	yes	2834.30
E-GEOD-135922	yes	19.48
E-ANND-3	yes	10.73

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Placenta	tissue	168.6	high
Vagina	tissue	59.3	low
Heart muscle	tissue	56.9	medium
Adrenal gland	tissue	56.9	medium
Adipose tissue	tissue	40.6	not detected
Smooth muscle	tissue	39.6	medium
Testis	tissue	35.1	medium
Pituitary gland	tissue	29.2
Lung	tissue	28.8	low
Choroid plexus	tissue	26.6
Hippocampus	tissue	25.2	medium
Pancreas	tissue	23.9	medium
Appendix	tissue	22.8	low
Urinary bladder	tissue	21.8	medium
Locus coeruleus	tissue	21.3
Seminal vesicle	tissue	20.8	medium
Cervix	tissue	18.3	medium
Postcentral gyrus	tissue	18.3
Nucleus accumbens	tissue	17.6
Spinal cord	tissue	17.2
Ovary	tissue	16.4	low
Prostate	tissue	15.8	low
Gallbladder	tissue	15.5	medium
Bone marrow	tissue	12.6	not detected
Esophagus	tissue	11.0	medium
Superior colliculi	tissue	10.7
Endometrium 1	tissue	9.9	medium
Colon	tissue	9.7	low
Small intestine	tissue	9.7	medium
Liver	tissue	9.3	medium
Kidney	tissue	9.2	high
Substantia nigra	tissue	8.5
Fallopian tube	tissue	8.4	low
Breast	tissue	7.7	medium
Stomach 1	tissue	7.6	medium
Medulla oblongata	tissue	7.3
Duodenum	tissue	7.2	medium
Salivary gland	tissue	7.1	low
Spleen	tissue	6.9	not detected
Pons	tissue	6.7
Midbrain	tissue	6.3
Hypothalamus	tissue	6.2
Corpus callosum	tissue	6.0
Skin 1	tissue	5.9	not detected
Thalamus	tissue	5.9
Epididymis	tissue	5.8	medium
Rectum	tissue	5.5	low
Periaqueductal gray	tissue	5.3
Lymph node	tissue	5.1	low
Skeletal muscle	tissue	4.7	not detected
Tongue	tissue	4.6
Thyroid gland	tissue	4.5	medium
Septum	tissue	4.5
Hippocampal formation	tissue	4.3
Cerebral cortex	tissue	4.0	medium
Motor cortex	tissue	4.0
Entorhinal cortex	tissue	3.9
Putamen	tissue	3.8
Temporal cortex	tissue	3.8
Cerebellum	tissue	3.7	medium

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Blood vessel (151.0), Area postrema (41.4), Nucleus ambiguus (39.4), Nucleus raphe pallidus (37.5), Nucleus raphe obscurus (33.8).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB, SMAD3, SMAD4, YAP1

miRNA regulators (miRDB)

Targeting FSTL3 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 61 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-4688	99.48	64.68	828
HSA-MIR-6743-5P	99.48	63.60	721
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-593-5P	99.34	69.50	965
HSA-MIR-3064-5P	99.26	66.13	1497
HSA-MIR-3085-3P	99.26	66.16	1490
HSA-MIR-6504-5P	99.26	65.95	1487
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-3688-5P	99.12	69.67	1091
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-485-5P	99.10	64.78	1889

Functional genomics

gnomAD constraint: pLI 6.01e-07, LOEUF 1.6, missense Z -1.23 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000166139 — one region, missense o/e 1.05.

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)
• our present data suggest that protein kinase C and A signal transduction pathways differently regulate the expression of FLRG in human ovarian granulosa-luteal cells (PMID:12397211)
• Follistatin and FLRG proteins downmodulate the effects of activin A and BMP2 on erythroid maturation. (PMID:12531697)
• likely to be a local regulator of activin action in gonadal development and gametogenesis (PMID:14739256)
• Data report the endometrial mRNA and peptide expression of follistatin-related gene (FLRG), a protein that binds activin-A, preventing its interaction. (PMID:15130517)
• review discusses differences between signal targets of follistatin and FLRG and distinct functions and mechanisms for these two proteins in the human hematopoietic system (PMID:15451575)
• comparison of the kinetics of FST isoform and FSTL3 biosynthesis, trafficking, and secretion (PMID:16150905)
• IGFBP1 and Follistatin-like 3 are highly up-regulated in intrauterine growth restriction in the placenta. (PMID:16338475)
• 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-like 3 expression was low in normal but enhanced in malignant rat liver. in human normal liver, in contrast, it was abundantly expressed but downregulated in liver cancer (PMID:16935389)
• 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)
• TNFalpha activates FLRG expression at the transcriptional level. (PMID:17395406)
• Overexpression of FLRG, an antagonist of activin is associated with increased breast tumor cell growth (PMID:17671190)
• Data show that the nuclear isoform of FLRG lacks an intrinsic transactivation domain, but enhances AF10-mediated transcription, probably through promoting the homo-oligomerization of AF10, thus facilitating the recruitment of co-activators. (PMID:17868029)
• Hypoxia enhances the expression of FSTL3 and its release from PHT cells. (PMID:17959243)
• Elevated myocardial expression of FST-like genes is a feature of heart failure, and may be linked to both disease severity and mechanisms underlying recovery. (PMID:18617621)
• analysis of the structure of the FSTL3.activin A complex (PMID:18768470)
• FLRG expression was regulated in the epithelial cytoplasm and nucleus of the malignant breast tissue. (PMID:19740438)
• First-trimester FSTL3 levels are associated with glucose intolerance and gestational diabetes later in pregnancy. (PMID:20007937)
• FLRG can be successfully detected in maternal plasma in the first trimester of pregnancy but its levels are not significantly altered in the presence of Down syndrome fetuses. (PMID:20063262)
• 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)
• Structure of myostatin.follistatin-like 3: N-terminal domains of follistatin-type molecules exhibit alternate modes of binding. (PMID:22052913)
• Maternal and placental FSTL3 concentrations were reduced in GDM women compared with normally pregnant women, suggesting FSTL3 may play an important role in the pathogenesis of gestational diabetes (PMID:22122995)
• After eccentric exercise, postmenopausal women not using hormone therapy (HT) expressed higher levels of follistatin-like protein 3 while postmenopausal women using HT showed a significant increased expression over controls. (PMID:22395277)
• Resistance exercise resulted in a significant downregulation of MSTN and FBXO32 mRNA expression and a significant upregulation in FSTL3 and SMURF1 mRNA expression, and carbohydrate and protein feeding have little influence on the these markers expression. (PMID:22476926)
• Data suggest that serum levels of FSTL3 are higher in pre-eclampsia than in controls; placental expression of FSTL3 is also increased in pre-eclampsia compared with controls; no differences were observed between mild and severe pre-eclampsia. (PMID:22568578)
• Suggest FSTL3 has a role in paracrine communication between cardiomyocytes and fibroblasts. (PMID:22915069)
• The elevation of Follistatin-like-3 was demonstrated in late second trimester of pregnancy destined to developing preeclampsia, suggesting its causal role in the pathogenesis and prediction of preeclampsia. (PMID:24475769)
• Elevated FSTL-3 concentrations were attributable to preeclampsia and were associated with increased likelihood of later developing preeclampsia, suggesting further study as a biomarker prior to clinically evident disease. (PMID:24700053)
• FSTL3 is a critical mediator of exercise-dependent bone formation (PMID:25937185)
• The serum levels of IL-8, MIP-1 alpha, MIP-1 beta, MMP-8, Resistin, FLRG, and BCAM were significantly higher in breast cancer patients, but LAP and TSH-beta levels were lower. (PMID:26898119)
• first trimester maternal serum levels not altered in women who develop gestational diabetes mellitus (PMID:27623975)
• FSTL3 expression in invasive breast cancer is inversely associated with tumor size and nuclear grade but it does not predict disease relapse in the short term. (PMID:28178680)
• Human renal dysfunction is the strongest independent predictor of FSTL3 serum concentrations in multivariate analyses. (PMID:28339962)
• deficient FSTL3 expression by asthmatic Bronchial epithelial cells impairs epithelial regulation of human lung fibroblast and fibroblast-to-myofibroblast transition. (PMID:29394092)
• Aberrant expression of FSTL3 in preeclampsia led to the dysfunction of trophoblast, indicating its involvement in the pathogenesis of preeclampsia. (PMID:30454705)
• FSTL3 plays a biological role in the establishment and maintenance of normal pregnancy. (PMID:31810141)
• Alterations in activin A-myostatin-follistatin system associate with disease activity in inflammatory myopathies. (PMID:31990347)
• [Expression Level of FLRG in Colon Cancer Tissue and Its Clinical Significance]. (PMID:32543143)
• Follistatin-Like 3 Correlates With Lymph Node Metastasis and Serves as a Biomarker of Extracellular Matrix Remodeling in Colorectal Cancer. (PMID:34335633)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fstl3	ENSDARG00000025670
mus_musculus	Fstl3	ENSMUSG00000020325
rattus_norvegicus	Fstl3	ENSRNOG00000009311

Paralogs (6): FSTL4 (ENSG00000053108), SPINK5 (ENSG00000133710), FST (ENSG00000134363), FSTL1 (ENSG00000163430), FSTL5 (ENSG00000168843), SPINK6 (ENSG00000178172)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1890391) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 22 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal abdominal fat pad morphology	1
abnormal adipose tissue distribution	1
hypertension	1
abnormal liver morphology	1
abnormal testis morphology	1
enlarged testis	1
increased circulating insulin level	1
hepatic steatosis	1
increased heart weight	1
increased insulin sensitivity	1
increased pancreatic beta cell number	1
increased left ventricle systolic pressure	1
abnormal testis weight	1
abnormal pancreatic islet morphology	1
abnormal pancreatic beta cell morphology	1
improved glucose tolerance	1
increased systemic arterial systolic blood pressure	1
enlarged pancreatic islets	1
decreased liver glycogen level	1
increased liver enzyme/coenzyme level	1
macrovesicular hepatic steatosis	1
microvesicular hepatic steatosis	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bubalus bubalis	A5YT95	99.7%	Diamond
Bos taurus	P50291	99.7%	Diamond
Macaca fascicularis	Q9GKY0	99.7%	Diamond
Ovis aries	P31514	99.1%	Diamond
Pongo abelii	Q5R9Y1	99.0%	Diamond
Equus caballus	O62650	98.8%	Diamond
Sus scrofa	P10669	98.8%	Diamond
Coturnix japonica	O93390	96.6%	Diamond
Gallus gallus	P36377	96.6%	Diamond
Xenopus laevis	P31515	85.6%	Diamond
Diplobatis ommata	Q90404	63.2%	Diamond
Cairina moschata	P83039	56.0%	Diamond
Cupiennius salei	G4V4G1	50.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MISP	protein-coding	126353
PRSS57	protein-coding	400668
PALM	protein-coding	5064
RNF126	protein-coding	55658
FGF22	protein-coding	27006
POLRMT	protein-coding	5442
HCN2	protein-coding	610

Protein

Protein identifiers

Follistatin-related protein 3 — O95633 (reviewed: O95633)

Alternative names: Follistatin-like protein 3, Follistatin-related gene protein

All UniProt accessions (4): A0A087WTD3, A0A087X1Q2, O95633, K7EM71

UniProt curated annotations — full annotation on UniProt →

Function. Isoform 1 or the secreted form is a binding and antagonizing protein for members of the TGF-beta family, such as activin, BMP2 and MSTN. Inhibits activin A-, activin B-, BMP2- and MSDT-induced cellular signaling; more effective on activin A than on activin B. Involved in bone formation; inhibits osteoclast differentiation. Involved in hematopoiesis; involved in differentiation of hemopoietic progenitor cells, increases hematopoietic cell adhesion to fibronectin and seems to contribute to the adhesion of hematopoietic precursor cells to the bone marrow stroma. Isoform 2 or the nuclear form is probably involved in transcriptional regulation via interaction with MLLT10.

Subunit / interactions. Interacts with INHBA and INHBB. Interacts with FN1. Interacts with ADAM12. Isoform 2 interacts with MLLT10; the interaction enhances MLLT10 in vitro transcriptional activity and self-association. Interacts with MSTN.

Subcellular location. Secreted Nucleus.

Tissue specificity. Expressed in a wide range of tissues.

Disease relevance. A chromosomal aberration involving FSTL3 is found in a case of B-cell chronic lymphocytic leukemia. Translocation t(11;19)(q13;p13) with CCDN1.

Isoforms (2)

UniProt ID	Names	Canonical?
O95633-1	1	yes
O95633-2	2

RefSeq proteins (1): NP_005851* (*=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 (50 total): strand 19, disulfide bond 13, domain 5, helix 5, glycosylation site 2, signal peptide 1, chain 1, splice variant 1, mutagenesis site 1, region of interest 1, modified residue 1

Structure

Experimental structures (PDB)

3 structures by resolution:

PDB	Title	Method	Resolution (Å)
3SEK	Crystal Structure of the Myostatin:Follistatin-like 3 Complex	X-RAY DIFFRACTION	2.4
3B4V	X-Ray structure of Activin in complex with FSTL3	X-RAY DIFFRACTION	2.48
2KCX	Solution NMR Structure of Kazal-1 Domain of Human Follistatin-related protein 3 (FSTL-3) …	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95633-F1	86.17	0.69

Human Protein Atlas

Protein class: Predicted secreted proteins, Predicted intracellular proteins, Cancer-related genes, Disease related genes

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm

Antibody reliability (HPA): IH approved · IF supported

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)

Type	Positions
Phosphoserine	255

Disulfide bonds (13)

Type	Positions
Disulfide bond	38–61, 48–92, 62–95, 99–110, 104–119, 121–153, 125–146, 135–167, 171–182, 176–192, 195–229, 200–222, 211–243

Glycosylation sites (2)

Type	Positions
N-linked (glcnac…) asparagine	215, 73

Mutagenesis-validated functional residues (1)

Position	Phenotype
27	nuclear localization.

Function

Pathways and Gene Ontology

Reactome pathways

3 curated (TAS) of 8; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

8 pathways:

ID	Pathway	Evidence
R-HSA-2473224	Antagonism of Activin by Follistatin	curated
R-HSA-8957275	Post-translational protein phosphorylation	curated
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	curated
R-HSA-392499	Metabolism of proteins	—
R-HSA-597592	Post-translational protein modification	—
R-HSA-162582	Signal Transduction	—
R-HSA-1502540	Signaling by Activin	—
R-HSA-9006936	Signaling by TGFB family members	—

MSigDB gene sets: 205 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_MYELOID_CELL_DIFFERENTIATION, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_REGULATION_OF_OSTEOCLAST_DIFFERENTIATION, TGACCTY_ERR1_Q2, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, GOBP_CELL_CELL_ADHESION, GTGCCTT_MIR506, GOBP_REGULATION_OF_LEUKOCYTE_DIFFERENTIATION, CHEN_LVAD_SUPPORT_OF_FAILING_HEART_UP, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS

GO Biological Process (12): ossification (GO:0001503), hematopoietic progenitor cell differentiation (GO:0002244), DNA-templated transcription (GO:0006351), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of cell-cell adhesion (GO:0022409), cell differentiation (GO:0030154), regulation of BMP signaling pathway (GO:0030510), negative regulation of BMP signaling pathway (GO:0030514), negative regulation of activin receptor signaling pathway (GO:0032926), negative regulation of osteoclast differentiation (GO:0045671), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway (GO:0090101)

GO Molecular Function (3): fibronectin binding (GO:0001968), activin binding (GO:0048185), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), nucleus (GO:0005634), nucleoplasm (GO:0005654), endoplasmic reticulum lumen (GO:0005788)

Reactome top-level categories

5 top-level categories:

Category	Pathways
Metabolism of proteins	2
Signaling by Activin	1
Post-translational protein modification	1
Signaling by TGFB family members	1
Signal Transduction	1

GO top-level categories

34 GO namespaces:

Category	Terms
transcription by RNA polymerase II	2
BMP signaling pathway	2
regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	2
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	2
cellular anatomical structure	2
multicellular organismal process	1
hemopoiesis	1
cell differentiation	1
gene expression	1
RNA biosynthetic process	1
regulation of DNA-templated transcription	1
regulation of cell-cell adhesion	1
positive regulation of cell adhesion	1
cell-cell adhesion	1
cellular developmental process	1
regulation of cellular response to growth factor stimulus	1
regulation of BMP signaling pathway	1
negative regulation of cellular response to growth factor stimulus	1
activin receptor signaling pathway	1
regulation of activin receptor signaling pathway	1
negative regulation of myeloid leukocyte differentiation	1
osteoclast differentiation	1
regulation of osteoclast differentiation	1
regulation of transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
cell surface receptor protein serine/threonine kinase signaling pathway	1
negative regulation of signal transduction	1
protein binding	1
protein-containing complex binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
endoplasmic reticulum	1
intracellular organelle lumen	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 12 of 20 annotations. The rest are phylogenetic / computational / electronic (IEA).

12 experimentally-supported GO terms:

GO term	NS	Evidence
hematopoietic progenitor cell differentiation	BP	direct assay
negative regulation of BMP signaling pathway	BP	direct assay
negative regulation of activin receptor signaling pathway	BP	direct assay
negative regulation of osteoclast differentiation	BP	direct assay
negative regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	BP	direct assay
positive regulation of cell-cell adhesion	BP	direct assay
positive regulation of transcription by RNA polymerase II	BP	direct assay
regulation of transcription by RNA polymerase II	BP	direct assay
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
activin binding	MF	physical interaction
fibronectin binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 694 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FSTL3	MSTN	O14793	841
FSTL3	GDF11	O95390	717
FSTL3	ACVR2B	Q13705	688
FSTL3	ANG	P03950	638
FSTL3	INHBA	P08476	609
FSTL3	FSTL1	Q12841	576
FSTL3	WFIKKN2	Q8TEU8	572
FSTL3	FSTL5	Q8N475	561
FSTL3	WFIKKN1	Q96NZ8	519
FSTL3	FSD1	Q9BTV5	508
FSTL3	PAPPA	Q13219	501
FSTL3	ACVR2A	P27037	499
FSTL3	BMP2	P12643	492
FSTL3	FSTL4	Q6MZW2	492
FSTL3	ACVR1B	P36896	467

IntAct

Human interaction partners of FSTL3 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

2 partners by confidence:

Partner	Interaction type	MIscore	Records
ADAM12	physical association	0.590	4
ADAM8	direct interaction	0.440	1

BioGRID (7 interactions; top human partners by supporting records): MSTN (Affinity Capture-MS; 3 records), HNRNPH1 (Affinity Capture-RNA), TGOLN2 (Proximity Label-MS), TRIM25 (Affinity Capture-RNA)

SIGNOR signaling

2 signaling interactions:

A	Effect	B	Mechanism
FSTL3	down-regulates	MSTN	binding
YAP1	“up-regulates quantity by expression”	FSTL3	“transcriptional regulation”

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexe by size:

Complex	Subunits	Members
★ FSTL3-MSTN complex	2	MSTN, FSTL3

Disease & clinical

Genetic variants

Variant evidence for FSTL3: 56 ClinVar records (0 pathogenic / likely pathogenic); 1 GWAS association.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	49
Likely benign	3
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 23 predictions of 534):

Position(s)	Effect	Δscore	Sites
19:676527–676528	donor_loss	0.9900	5
19:681316	acceptor_gain	0.9900
19:680491	donor_loss	0.9800	2
19:681317	acceptor_gain	0.9800
19:681332	acceptor_loss	0.9800	2
19:681553	donor_gain	0.9800
19:681879	donor_gain	0.9800
19:680490	donor_loss	0.9700
19:681331–681332	acceptor_loss	0.9700	4
19:677790–677791	acceptor_loss	0.9600	5

AlphaMissense

541 missense substitutions predicted likely pathogenic (of 1,696 scored), across 149 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D185	8	0.965	0.989
C135	7	0.991	0.997
C182	7	0.991	0.996
C211	7	0.990	0.998
C192	7	0.989	0.995
C61	7	0.988	0.997
C92	7	0.988	0.995
C222	7	0.988	0.994
C229	7	0.988	0.993
C95	7	0.986	0.995
C110	7	0.985	0.994
C38	7	0.984	0.994
C48	7	0.984	0.993
C200	7	0.984	0.990
C176	7	0.983	0.993
C167	7	0.982	0.994
C195	7	0.982	0.991
C62	7	0.980	0.992
C99	7	0.980	0.992
C171	7	0.978	0.993

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

4 prognostic cancer types:

Cancer	Prognostic	p-value
Lung Adenocarcinoma (TCGA)	unfavorable	7.46e-06
Lung Squamous Cell Carcinoma (TCGA)	unfavorable	2.97e-05
Glioblastoma Multiforme (TCGA)	unfavorable	0.000129
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	unfavorable	0.000286

Disease associations

OMIM: gene MIM:605343 | disease phenotypes:

GWAS associations

1 association:

Study	Trait	p-value
GCST002928_4	Nickel levels	2e-6

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	affects expression, increases expression	3
Cyclosporine	decreases expression, increases expression	3
sodium arsenite	decreases expression, increases expression	2
Air Pollutants	increases abundance, decreases expression	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Cisplatin	affects cotreatment, decreases expression, increases expression	2
Estradiol	affects cotreatment, increases expression	2
Smoke	decreases expression, increases abundance	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	decreases expression, increases methylation	2
Copper Sulfate	increases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment, increases expression	2
propionaldehyde	increases expression	1
bisphenol A	decreases expression	1
lead acetate	increases expression	1
diethyl maleate	increases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1
potassium chromate(VI)	decreases expression	1
cupric chloride	increases expression	1
nickel sulfate	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
chloropicrin	decreases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
MT19c compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.