FSD2

Summary

FSD2 (fibronectin type III and SPRY domain containing 2, HGNC:18024) is a protein-coding gene on chromosome 15q25.2, encoding Fibronectin type III and SPRY domain-containing protein 2 (A1L4K1).

This gene encodes a protein that belongs to the FN3/SPRY family of proteins. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 123722 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 105 total — 1 pathogenic
• MANE Select transcript: NM_001007122

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18024
Approved symbol	FSD2
Name	fibronectin type III and SPRY domain containing 2
Location	15q25.2
Locus type	gene with protein product
Status	Approved
Aliases	RP11-127F21
Ensembl gene	ENSG00000186628
Ensembl biotype	protein_coding
Entrez	123722

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 16 protein_coding

ENST00000334574, ENST00000541889, ENST00000561368, ENST00000878624, ENST00000878625, ENST00000878626, ENST00000878627, ENST00000961198, ENST00000961199, ENST00000961200, ENST00000961201, ENST00000961202, ENST00000961203, ENST00000961204, ENST00000961205, ENST00000961206

RefSeq mRNA: 3 — MANE Select: NM_001007122 NM_001007122, NM_001281805, NM_001281806

CCDS: CCDS45332, CCDS61738

Canonical transcript exons

ENST00000334574 — 13 exons

Exon	Start	End
ENSE00001338923	82762102	82762278
ENSE00001338924	82765166	82765298
ENSE00001338925	82765898	82766031
ENSE00001338926	82768880	82769030
ENSE00001338927	82769750	82769884
ENSE00001338929	82772073	82772228
ENSE00001338932	82778766	82778887
ENSE00001338935	82782795	82783025
ENSE00001338936	82786511	82786606
ENSE00001338938	82786752	82787468
ENSE00001725715	82780245	82780267
ENSE00002290085	82755362	82759600
ENSE00002555053	82805966	82806069

Expression profiles

Bgee: expression breadth ubiquitous, 137 present calls, max score 96.65.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3978 / max 99.3942, expressed in 64 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
151277	0.2931	50
151276	0.0735	29
151278	0.0171	13
151279	0.0141	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	96.65	silver quality
cardiac muscle of right atrium	UBERON:0003379	95.22	silver quality
quadriceps femoris	UBERON:0001377	94.49	gold quality
vastus lateralis	UBERON:0001379	94.46	gold quality
biceps brachii	UBERON:0001507	94.38	gold quality
deltoid	UBERON:0001476	93.58	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.49	gold quality
skeletal muscle tissue	UBERON:0001134	93.17	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.04	gold quality
tibialis anterior	UBERON:0001385	92.88	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	92.03	gold quality
myocardium	UBERON:0002349	90.98	silver quality
muscle tissue	UBERON:0002385	88.37	gold quality
muscle of leg	UBERON:0001383	88.22	gold quality
gastrocnemius	UBERON:0001388	88.15	gold quality
apex of heart	UBERON:0002098	87.65	gold quality
cardiac atrium	UBERON:0002081	87.07	gold quality
right atrium auricular region	UBERON:0006631	86.71	gold quality
cardiac ventricle	UBERON:0002082	86.31	gold quality
heart left ventricle	UBERON:0002084	86.29	gold quality
heart right ventricle	UBERON:0002080	84.97	gold quality
heart	UBERON:0000948	82.10	gold quality
vena cava	UBERON:0004087	77.03	silver quality
body of tongue	UBERON:0011876	74.68	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	74.32	gold quality
ileal mucosa	UBERON:0000331	71.74	silver quality
pancreatic ductal cell	CL:0002079	57.16	silver quality
jejunum	UBERON:0002115	55.04	silver quality
epithelial cell of pancreas	CL:0000083	54.31	gold quality
kidney epithelium	UBERON:0004819	53.93	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.16

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

148 targeting FSD2, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917

Literature-anchored findings (GeneRIF, showing 1)

• Data identify a novel muscle-expressed TRIM-related protein minispryn, encoded by Fsd2, that has extensive sequence similarity with the C-terminus of Cmya5. They appear to have originated by a chromosomal duplication and are found within evolutionarily-conserved gene clusters on different chromosomes. Both proteins co-localize with RyR2 at the junctional sarcoplasmic reticulum of isolated cardiomyocytes. (PMID:28740084)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Fsd2	ENSMUSG00000038663
rattus_norvegicus	Fsd2	ENSRNOG00000019278

Paralogs (3): FSD1 (ENSG00000105255), FSD1L (ENSG00000106701), CMYA5 (ENSG00000164309)

Protein

Protein identifiers

Fibronectin type III and SPRY domain-containing protein 2 — A1L4K1 (reviewed: A1L4K1)

Alternative names: SPRY domain-containing protein 1

All UniProt accessions (2): A1L4K1, H0YLA8

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Interacts with CMYA5. In cardiac muscles, identified in a complex composed of FSD2, CMYA5 and RYR2.

Subcellular location. Nucleus. Sarcoplasmic reticulum. Cytoplasm. Perinuclear region.

Isoforms (2)

UniProt ID	Names	Canonical?
A1L4K1-1	1	yes
A1L4K1-2	2

RefSeq proteins (3): NP_001007123, NP_001268734, NP_001268735 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001870	B30.2/SPRY	Domain
IPR003877	SPRY_dom	Domain
IPR003879	Butyrophylin_SPRY	Domain
IPR003961	FN3_dom	Domain
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR043136	B30.2/SPRY_sf	Homologous_superfamily
IPR050617	E3_ligase_FN3/SPRY	Family

Pfam: PF00041, PF00622

UniProt features (8 total): domain 3, sequence variant 2, chain 1, coiled-coil region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A1L4K1-F1	73.39	0.34

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 83 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOCC_SARCOPLASM, WAKABAYASHI_ADIPOGENESIS_PPARG_BOUND_8D, GSE13522_CTRL_VS_T_CRUZI_Y_STRAIN_INF_SKIN_IFNAR_KO_DN, GSE14699_NAIVE_VS_ACT_CD8_TCELL_UP, CIITA_TARGET_GENES, HDAC4_TARGET_GENES, MEF2D_TARGET_GENES, SIX1_TARGET_GENES, SKIL_TARGET_GENES, MIR607, MIR6867_5P, MIR3646, MIR548E_5P

GO Biological Process (0):

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), sarcoplasmic reticulum (GO:0016529), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
binding	1
intracellular membrane-bounded organelle	1
endoplasmic reticulum	1
sarcoplasm	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

428 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FSD2	AP3B2	Q13367	575
FSD2	LRRC39	Q96DD0	537
FSD2	RNF207	Q6ZRF8	489
FSD2	MTERF3	Q96E29	455
FSD2	GSTZ1	O43708	447
FSD2	C15orf40	Q8WUR7	446
FSD2	WHAMM	Q8TF30	418
FSD2	RAMAC	Q9BTL3	380
FSD2	SIRPB2	Q5JXA9	371
FSD2	FSD1	Q9BTV5	364
FSD2	EXD2	Q9NVH0	362
FSD2	MSTN	O14793	360
FSD2	FST	P19883	342
FSD2	GDF11	O95390	323
FSD2	MFSD1	Q9H3U5	322

IntAct

356 interactions, top by confidence:

A	B	Type	Score
FSD2	ESD	psi-mi:“MI:0915”(physical association)	0.870
ESD	FSD2	psi-mi:“MI:0915”(physical association)	0.870
CORO1A	FSD2	psi-mi:“MI:0915”(physical association)	0.780
CDC73	FSD2	psi-mi:“MI:0915”(physical association)	0.780
FSD2	CORO1A	psi-mi:“MI:0915”(physical association)	0.780
FSD2	CDC73	psi-mi:“MI:0915”(physical association)	0.780
FSD2	BEX3	psi-mi:“MI:0915”(physical association)	0.720
FSD2	PPP1R18	psi-mi:“MI:0915”(physical association)	0.720
FSD2	FAM90A1	psi-mi:“MI:0915”(physical association)	0.720
FSD2	ZNF417	psi-mi:“MI:0915”(physical association)	0.720
CCHCR1	FSD2	psi-mi:“MI:0915”(physical association)	0.720
FSD2	LENG1	psi-mi:“MI:0915”(physical association)	0.720
FSD2	ZNF587	psi-mi:“MI:0915”(physical association)	0.720
BRD8	FSD2	psi-mi:“MI:0915”(physical association)	0.720
SH2D4A	FSD2	psi-mi:“MI:0915”(physical association)	0.720
FSD2	CBX8	psi-mi:“MI:0915”(physical association)	0.720
ZNF581	FSD2	psi-mi:“MI:0915”(physical association)	0.720
MRPL11	FSD2	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (136): FSD2 (Two-hybrid), FSD2 (Two-hybrid), FSD2 (Two-hybrid), FSD2 (Two-hybrid), FSD2 (Two-hybrid), FSD2 (Two-hybrid), FSD2 (Two-hybrid), FSD2 (Two-hybrid), FSD2 (Two-hybrid), FSD2 (Two-hybrid), FSD2 (Two-hybrid), FSD2 (Two-hybrid), FSD2 (Two-hybrid), FSD2 (Two-hybrid), FSD2 (Two-hybrid)

ESM2 similar proteins: A1L4K1, D4A7V9, E9QHE3, F1LW30, H0UZ81, O15344, O70583, O95361, P82457, P82458, P97573, Q14258, Q14596, Q28CB1, Q38HM4, Q3UMR0, Q3V3A7, Q58D15, Q5F479, Q5R760, Q5RC94, Q5REJ9, Q5REW9, Q5RF77, Q5XIH6, Q61510, Q6P549, Q6P6S3, Q6UXZ4, Q7T2L7, Q7TNH6, Q7Z494, Q80VK6, Q80WG7, Q8BZ52, Q8JZL1, Q8K1S2, Q8NFM7, Q91Z63, Q969Q1

Diamond homologs: A0JN74, A1L4K1, A2ABU4, A2ASS6, B1H278, H0UZ81, O00478, P18892, P82456, Q02084, Q13410, Q1XHU0, Q495X7, Q5BN31, Q5D7I0, Q5R7W8, Q5R996, Q5VTT5, Q6MFZ5, Q6UX41, Q6UXE8, Q70KF4, Q7YRV4, Q8BVW3, Q8BZ52, Q8N3K9, Q8VI40, Q8WVV5, Q8WZ42, Q91431, Q96F44, Q96KV6, Q96PL5, Q99PQ2, Q9ESN2, Q9HCM9, Q9JLN5, O00481, O00635, O75679

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	94
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
666438	GRCh37/hg19 15q25.2(chr15:83214012-84772030)x1	Pathogenic

SpliceAI

1814 predictions. Top by Δscore:

Variant	Effect	Δscore
15:82765915:G:C	donor_gain	1.0000
15:82768878:A:AC	donor_gain	1.0000
15:82768879:C:CC	donor_gain	1.0000
15:82778883:CGAGT:C	acceptor_gain	1.0000
15:82778888:C:CC	acceptor_gain	1.0000
15:82765162:GTACC:G	donor_loss	0.9900
15:82765164:A:AT	donor_loss	0.9900
15:82765165:CCTG:C	donor_loss	0.9900
15:82765931:CG:C	donor_gain	0.9900
15:82766027:CAGAC:C	acceptor_gain	0.9900
15:82766028:AGACC:A	acceptor_loss	0.9900
15:82766029:GACCT:G	acceptor_loss	0.9900
15:82766030:ACCTG:A	acceptor_loss	0.9900
15:82766032:CTGT:C	acceptor_loss	0.9900
15:82766033:T:C	acceptor_loss	0.9900
15:82768879:CT:C	donor_gain	0.9900
15:82778763:CA:C	donor_loss	0.9900
15:82778764:A:AT	donor_loss	0.9900
15:82778765:CCTG:C	donor_loss	0.9900
15:82778884:GAGT:G	acceptor_gain	0.9900
15:82778884:GAGTC:G	acceptor_loss	0.9900
15:82778886:GT:G	acceptor_gain	0.9900
15:82778886:GTC:G	acceptor_loss	0.9900
15:82778887:TCTGT:T	acceptor_loss	0.9900
15:82778888:C:A	acceptor_loss	0.9900
15:82778889:T:G	acceptor_loss	0.9900
15:82780266:TC:T	acceptor_gain	0.9900
15:82780266:TCC:T	acceptor_loss	0.9900
15:82780267:CC:C	acceptor_gain	0.9900
15:82780268:C:CC	acceptor_gain	0.9900

AlphaMissense

4965 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:82772160:A:G	W394R	0.997
15:82772160:A:T	W394R	0.997
15:82769803:G:T	A450D	0.994
15:82765932:G:C	S551R	0.993
15:82765932:G:T	S551R	0.993
15:82765934:T:G	S551R	0.993
15:82768963:C:A	W490C	0.993
15:82768963:C:G	W490C	0.993
15:82772127:A:C	Y405D	0.993
15:82765923:G:C	S554R	0.992
15:82765923:G:T	S554R	0.992
15:82765925:T:G	S554R	0.992
15:82768965:A:G	W490R	0.992
15:82768965:A:T	W490R	0.992
15:82762229:A:G	W624R	0.991
15:82762229:A:T	W624R	0.991
15:82772171:A:T	V390D	0.990
15:82769781:G:C	S457R	0.989
15:82769781:G:T	S457R	0.989
15:82769783:T:G	S457R	0.989
15:82772158:C:A	W394C	0.989
15:82772158:C:G	W394C	0.989
15:82768932:A:C	Y501D	0.988
15:82769809:A:T	V448D	0.988
15:82772216:G:T	P375Q	0.988
15:82786523:G:C	F241L	0.988
15:82786523:G:T	F241L	0.988
15:82786525:A:G	F241L	0.988
15:82769772:G:C	S460R	0.987
15:82769772:G:T	S460R	0.987

dbSNP variants (sampled 300 via entrez): RS1000100041 (15:82771924 C>T), RS1000153013 (15:82765032 C>G,T), RS1000217024 (15:82778456 A>G), RS1000220462 (15:82774418 T>A), RS1000295977 (15:82801509 C>G), RS1000319652 (15:82771080 T>C), RS1000526311 (15:82796566 T>A), RS1000580182 (15:82797019 T>A,C), RS1000584620 (15:82769553 C>T), RS1000809611 (15:82802862 C>T), RS1000819479 (15:82776013 A>G), RS1000878167 (15:82790294 G>C), RS1000886707 (15:82777753 T>C), RS1000959525 (15:82776276 A>G), RS1001071328 (15:82795720 T>C)

Disease associations

OMIM: gene `` | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST007277_21	Tourette syndrome	7.000000e-06
GCST010242_378	HDL cholesterol levels	3.000000e-10
GCST90020028_1781	Hip circumference adjusted for BMI	2.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	decreases methylation	1
S-(1,2-dichlorovinyl)cysteine	decreases expression, decreases reaction	1
Benzo(a)pyrene	increases methylation	1
Doxorubicin	decreases expression	1
Lipopolysaccharides	decreases expression, decreases reaction	1
Methapyrilene	decreases methylation	1
Triclosan	decreases expression	1

Clinical trials (associated diseases)

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