FSTL5

Summary

FSTL5 (follistatin like 5, HGNC:21386) is a protein-coding gene on chromosome 4q32.2, encoding Follistatin-related protein 5 (Q8N475).

Predicted to enable calcium ion binding activity. Predicted to be involved in cell differentiation and regulation of BMP signaling pathway. Predicted to be active in extracellular region.

Source: NCBI Gene 56884 — RefSeq curated summary.

At a glance

• GWAS associations: 21
• Clinical variants (ClinVar): 171 total
• MANE Select transcript: NM_020116

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21386
Approved symbol	FSTL5
Name	follistatin like 5
Location	4q32.2
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp566D234, KIAA1263
Ensembl gene	ENSG00000168843
Ensembl biotype	protein_coding
OMIM	620128
Entrez	56884

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000306100, ENST00000379164, ENST00000427802, ENST00000511170, ENST00000511999, ENST00000864344

RefSeq mRNA: 3 — MANE Select: NM_020116 NM_001128427, NM_001128428, NM_020116

CCDS: CCDS3802, CCDS47157, CCDS47158

Canonical transcript exons

ENST00000306100 — 16 exons

Exon	Start	End
ENSE00001134159	161455004	161455128
ENSE00001134165	161459212	161459319
ENSE00001134175	161481020	161481169
ENSE00001134181	161500016	161500134
ENSE00001134188	161510398	161510424
ENSE00001134204	161542532	161542693
ENSE00001134224	161759411	161759531
ENSE00001134234	161775878	161776074
ENSE00001196394	162033625	162033658
ENSE00001196404	162111271	162111412
ENSE00001319185	161920404	161920652
ENSE00001404185	162163615	162164000
ENSE00002062542	161383897	161386449
ENSE00002499559	161538166	161538300
ENSE00003466274	161587455	161587575
ENSE00003507186	161656328	161656494

Expression profiles

Bgee: expression breadth ubiquitous, 126 present calls, max score 99.04.

FANTOM5 (CAGE): breadth broad, TPM avg 3.3511 / max 956.7408, expressed in 223 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
54658	2.8953	191
54657	0.2617	64
54655	0.0932	41
54656	0.0510	15
54652	0.0499	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar vermis	UBERON:0004720	99.04	gold quality
endothelial cell	CL:0000115	96.77	gold quality
pons	UBERON:0000988	95.10	gold quality
ventricular zone	UBERON:0003053	92.64	gold quality
cerebellum	UBERON:0002037	92.50	gold quality
cerebellar cortex	UBERON:0002129	92.10	gold quality
cerebellar hemisphere	UBERON:0002245	91.91	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.43	gold quality
superior vestibular nucleus	UBERON:0007227	87.04	gold quality
cortical plate	UBERON:0005343	86.68	gold quality
Brodmann (1909) area 23	UBERON:0013554	85.30	gold quality
ganglionic eminence	UBERON:0004023	84.86	gold quality
Brodmann (1909) area 46	UBERON:0006483	84.68	gold quality
islet of Langerhans	UBERON:0000006	82.64	gold quality
medulla oblongata	UBERON:0001896	82.01	gold quality
middle temporal gyrus	UBERON:0002771	80.86	gold quality
prefrontal cortex	UBERON:0000451	79.66	gold quality
superior frontal gyrus	UBERON:0002661	79.17	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.29	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	77.80	gold quality
hypothalamus	UBERON:0001898	77.38	gold quality
lateral nuclear group of thalamus	UBERON:0002736	77.27	gold quality
nucleus accumbens	UBERON:0001882	77.00	gold quality
entorhinal cortex	UBERON:0002728	76.98	gold quality
frontal cortex	UBERON:0001870	76.43	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	76.18	gold quality
caudate nucleus	UBERON:0001873	76.17	gold quality
neocortex	UBERON:0001950	76.14	gold quality
substantia nigra pars compacta	UBERON:0001965	75.69	gold quality
Brodmann (1909) area 9	UBERON:0013540	75.46	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	1984.13
E-MTAB-11121	yes	1397.67
E-ENAD-27	yes	186.48
E-MTAB-7316	yes	41.92
E-MTAB-5061	yes	26.16
E-GEOD-81608	yes	20.63
E-GEOD-137537	yes	18.54
E-GEOD-83139	yes	11.56
E-ANND-3	yes	5.39

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

143 targeting FSTL5, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-548J-3P	99.94	72.61	4881

Literature-anchored findings (GeneRIF, showing 5)

• FSTL5 expression denoted a dismal prognosis both within and across medulloblastoma subgroups. (PMID:21911727)
• FSTL5 plays a suppressive role in hepatocellular carcinoma. Down-regulation of FSTL5 could promote growth and survival of HCC cells by activation of Wnt/beta-catenin signaling. (PMID:26045876)
• Mechanistic investigation demonstrated that FSTL5 promoted Hepatocellular carcinoma (HCC) cell apoptosis in a caspase-dependent manner and regulated Bcl-2 family proteins. These results indicate that FSTL5 may be a potential novel target for HCC treatment, and a biomarker for tumor prognosis. (PMID:30255547)
• Follistatin Like 5 (FSTL5) inhibits epithelial to mesenchymal transition in hepatocellular carcinoma. (PMID:32740091)
• Genetic association and characterization of FSTL5 in isolated clubfoot. (PMID:33105483)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fstl5	ENSDARG00000040198
mus_musculus	Fstl5	ENSMUSG00000034098
rattus_norvegicus	Fstl5	ENSRNOG00000047002

Paralogs (6): FSTL4 (ENSG00000053108), FSTL3 (ENSG00000070404), SPINK5 (ENSG00000133710), FST (ENSG00000134363), FSTL1 (ENSG00000163430), SPINK6 (ENSG00000178172)

Protein

Protein identifiers

Follistatin-related protein 5 — Q8N475 (reviewed: Q8N475)

Alternative names: Follistatin-like protein 5

All UniProt accessions (1): Q8N475

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Secreted.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8N475-1	1	yes
Q8N475-2	2
Q8N475-3	3

RefSeq proteins (3): NP_001121899, NP_001121900, NP_064501* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR002350	Kazal_dom	Domain
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR036058	Kazal_dom_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050653	Prot_Inhib_GrowthFact_Antg	Family

Pfam: PF07648, PF13927

UniProt features (36 total): binding site 9, sequence conflict 8, disulfide bond 5, domain 5, sequence variant 3, glycosylation site 2, splice variant 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N475-F1	83.57	0.58

Functional residue map

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

Ligand- & substrate-binding residues (9): 199; 226; 228; 230; 232; 237; 188; 190; 192

Disulfide bonds (5): 89–119, 93–112, 101–133, 270–321, 362–413

Glycosylation sites (2): 318, 394

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 152 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, chr4q32, TGCACTT_MIR519C_MIR519B_MIR519A, ACTGCAG_MIR173P, SP1_Q2_01, GTGCCTT_MIR506, MARTORIATI_MDM4_TARGETS_NEUROEPITHELIUM_DN, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY, E4F1_Q6, TGACATY_UNKNOWN, GOBP_RESPONSE_TO_BMP, GOBP_RESPONSE_TO_GROWTH_FACTOR, GOBP_REGULATION_OF_BMP_SIGNALING_PATHWAY, WHN_B

GO Biological Process (2): cell differentiation (GO:0030154), regulation of BMP signaling pathway (GO:0030510)

GO Molecular Function (3): calcium ion binding (GO:0005509), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (1): extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular developmental process	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
metal ion binding	1
binding	1
cation binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1524 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FSTL5	FSTL3	O95633	571
FSTL5	ZBBX	A8MT70	472
FSTL5	BMPER	Q8N8U9	457
FSTL5	NKAIN3	Q8N8D7	454
FSTL5	CHRDL2	Q6WN34	449
FSTL5	GJD4	Q96KN9	449
FSTL5	WDR49	Q8IV35	439
FSTL5	NRSN2	Q9GZP1	431
FSTL5	FST	P19883	430
FSTL5	CHRDL1	Q9BU40	418
FSTL5	MOGAT1	Q96PD6	413
FSTL5	SNX16	P57768	386
FSTL5	SLC26A3	P40879	383
FSTL5	SLC25A29	Q8N8R3	380
FSTL5	TBL2	Q9Y4P3	379

IntAct

19 interactions, top by confidence:

A	B	Type	Score
FSTL5	CD86	psi-mi:“MI:0915”(physical association)	0.400
CNTN5	FSTL5	psi-mi:“MI:0915”(physical association)	0.400
FSTL5	LILRB2	psi-mi:“MI:0915”(physical association)	0.400
FSTL5	CEACAM19	psi-mi:“MI:0915”(physical association)	0.400
FSTL5	GP6	psi-mi:“MI:0915”(physical association)	0.400
FSTL5	IL6R	psi-mi:“MI:0915”(physical association)	0.400
LILRA1	FSTL5	psi-mi:“MI:0915”(physical association)	0.400
FSTL5	CHL1	psi-mi:“MI:0915”(physical association)	0.400
FSTL5	SDK2	psi-mi:“MI:0915”(physical association)	0.400
SIGLEC6	FSTL5	psi-mi:“MI:0915”(physical association)	0.400
PYCARD	MYO1C	psi-mi:“MI:0914”(association)	0.350
WBP4	RBM45	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
WBP4	SNRPD3	psi-mi:“MI:0914”(association)	0.350

BioGRID (4): FSTL5 (Affinity Capture-MS), FSTL5 (Affinity Capture-MS), FSTL5 (Affinity Capture-MS), FSTL5 (Affinity Capture-RNA)

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: A0N0X6, A2AJ76, A2CG49, A4IGL7, A4IIW9, B3NS99, B4GBH0, B4HNW4, B4KPU0, B4MR28, B4P5Q9, B4QC63, G5EBF1, O75325, O95428, P0C6S8, P11627, P12960, P22063, P28685, P32004, P97924, Q02246, Q07409, Q09024, Q12860, Q290N5, Q32Q07, Q3UQ28, Q3URE9, Q3V1M1, Q5R482, Q61330, Q61809, Q62682, Q62845, Q63198, Q66HV9, Q69Z26, Q6AWJ9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	136
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

5514 predictions. Top by Δscore:

Variant	Effect	Δscore
4:161454999:CTTA:C	donor_loss	1.0000
4:161455000:TTAC:T	donor_loss	1.0000
4:161455001:TA:T	donor_loss	1.0000
4:161455002:A:AC	donor_gain	1.0000
4:161455003:C:CC	donor_gain	1.0000
4:161455003:CCT:C	donor_gain	1.0000
4:161455125:TTAC:T	acceptor_gain	1.0000
4:161455127:ACC:A	acceptor_loss	1.0000
4:161455129:CTAA:C	acceptor_loss	1.0000
4:161481014:TCATA:T	donor_loss	1.0000
4:161481015:CATA:C	donor_loss	1.0000
4:161481016:ATACC:A	donor_loss	1.0000
4:161481017:TA:T	donor_loss	1.0000
4:161481018:ACCTG:A	donor_loss	1.0000
4:161481019:C:CA	donor_loss	1.0000
4:161481168:TC:T	acceptor_gain	1.0000
4:161481168:TCC:T	acceptor_loss	1.0000
4:161481169:CC:C	acceptor_gain	1.0000
4:161481170:C:CC	acceptor_gain	1.0000
4:161481170:CTGT:C	acceptor_loss	1.0000
4:161481171:T:A	acceptor_loss	1.0000
4:161481177:T:C	acceptor_gain	1.0000
4:161481177:T:TC	acceptor_gain	1.0000
4:161538164:A:AC	donor_gain	1.0000
4:161538165:C:CC	donor_gain	1.0000
4:161538165:CGG:C	donor_gain	1.0000
4:161538165:CGGGT:C	donor_gain	1.0000
4:161538186:T:TA	donor_gain	1.0000
4:161538297:TTTG:T	acceptor_gain	1.0000
4:161538298:TTG:T	acceptor_gain	1.0000

AlphaMissense

5639 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:161542587:C:A	W374C	1.000
4:161542587:C:G	W374C	1.000
4:161542589:A:G	W374R	1.000
4:161542589:A:T	W374R	1.000
4:161481119:C:A	W503C	0.999
4:161481119:C:G	W503C	0.999
4:161481121:A:G	W503R	0.999
4:161481121:A:T	W503R	0.999
4:161500065:C:G	C470S	0.999
4:161500066:A:G	C470R	0.999
4:161500066:A:T	C470S	0.999
4:161538195:A:G	L428P	0.999
4:161538239:A:C	C413W	0.999
4:161538240:C:G	C413S	0.999
4:161538240:C:T	C413Y	0.999
4:161538241:A:G	C413R	0.999
4:161538241:A:T	C413S	0.999
4:161538247:A:C	Y411D	0.999
4:161542625:A:G	C362R	0.999
4:161542630:A:G	L360P	0.999
4:161656376:C:A	W282C	0.999
4:161656376:C:G	W282C	0.999
4:161656378:A:G	W282R	0.999
4:161656378:A:T	W282R	0.999
4:161385802:C:G	C830S	0.998
4:161385802:C:T	C830Y	0.998
4:161385803:A:G	C830R	0.998
4:161385803:A:T	C830S	0.998
4:161459259:A:G	W557R	0.998
4:161459259:A:T	W557R	0.998

dbSNP variants (sampled 300 via entrez): RS1000000257 (4:161639523 T>G), RS1000006968 (4:161425262 G>A), RS1000011030 (4:162079269 G>A,T), RS1000011446 (4:161666599 A>G), RS1000017214 (4:162066190 A>C), RS1000021026 (4:161622025 T>C), RS1000025349 (4:161804477 T>C), RS10000255 (4:161504066 C>T), RS1000028754 (4:161749271 G>A,C), RS1000029802 (4:161581016 C>A,T), RS1000036266 (4:161902293 C>A,T), RS1000036828 (4:162156149 C>G), RS1000039259 (4:161507283 A>C,G), RS1000040112 (4:161547906 T>C), RS1000042288 (4:161581695 A>G)

Disease associations

OMIM: gene MIM:620128 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST000839_1	Height	2.000000e-06
GCST002528_1	Colorectal cancer	8.000000e-09
GCST005174_15	Coronary artery calcified atherosclerotic plaque score in type 2 diabetes	8.000000e-06
GCST006479_147	Diverticular disease	6.000000e-08
GCST006616_1	Uterine fibroid number (single vs multiple)	2.000000e-07
GCST006631_40	Nicotine dependence and major depression (severity of comorbidity)	5.000000e-06
GCST006658_14	Longevity	9.000000e-06
GCST007576_415	Chronotype	1.000000e-09
GCST007576_96	Chronotype	1.000000e-09
GCST008103_1	Bipolar disorder	2.000000e-06
GCST008103_23	Bipolar disorder	2.000000e-08
GCST008180_16	Spontaneous preterm birth with premature rupture of membranes	4.000000e-06
GCST009959_3	Retinal detachment or retinal break	1.000000e-06
GCST010146_27	Serum immune biomarker levels	3.000000e-08
GCST010724_8	HOMA-B (corrected for HOMA-IR)	3.000000e-07
GCST010988_85	Adult body size	2.000000e-10
GCST012484_24	Cerebral amyloid angiopathy x APOEe4 status interaction in Alzheimer’s disease	9.000000e-06
GCST012489_57	Heel bone mineral density x serum urate levels interaction	8.000000e-09
GCST012490_500	Femur bone mineral density x serum urate levels interaction	3.000000e-08
GCST012490_645	Femur bone mineral density x serum urate levels interaction	5.000000e-09
GCST90011894_4	Retinitis pigmentosa	8.000000e-07

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0004723	coronary artery calcification
EFO:0009959	diverticular disease
EFO:0009410	uterine fibroid measurement
EFO:0007006	depressive symptom measurement
EFO:0009262	nicotine dependence symptom count
EFO:0008328	chronotype measurement
EFO:0006917	spontaneous preterm birth
EFO:0010698	retinal break
EFO:0004872	inflammatory biomarker measurement
EFO:0004469	HOMA-B
EFO:0007659	APOE carrier status
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3749598	FSTL5		0.00	0

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	4
Benzo(a)pyrene	decreases expression, increases expression, increases methylation, affects methylation	3
Aflatoxin B1	decreases expression, decreases methylation	2
methylmercuric chloride	increases expression	1
terbufos	increases methylation	1
benzo(e)pyrene	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects cotreatment, affects response to substance	1
beta-methylcholine	affects expression	1
Arsenic Trioxide	decreases expression	1
Fulvestrant	decreases methylation	1
Acetaminophen	decreases expression	1
Air Pollutants	increases expression	1
Atrazine	increases expression	1
Cadmium	decreases expression	1
Doxorubicin	decreases expression	1
Fonofos	increases methylation	1
Fenfluramine	increases expression	1
Hydralazine	increases expression, affects cotreatment	1
Ivermectin	decreases expression	1
Lipopolysaccharides	increases expression, affects cotreatment, affects response to substance	1
Methapyrilene	decreases methylation	1
Methotrexate	increases expression	1
Oxygen	decreases expression	1
Parathion	increases methylation	1
Rotenone	decreases expression	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	increases methylation	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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