FCHSD1

Summary

FCHSD1 (FCH and double SH3 domains 1, HGNC:25463) is a protein-coding gene on chromosome 5q31.3, encoding F-BAR and double SH3 domains protein 1 (Q86WN1). Promotes actin polymerization mediated by SNX9 and WASL.

Predicted to enable lipid binding activity. Predicted to be involved in neuromuscular synaptic transmission and positive regulation of actin filament polymerization. Predicted to act upstream of or within several processes, including import into nucleus; inflammatory response; and response to hydrogen peroxide. Predicted to be located in cuticular plate. Predicted to be part of protein-containing complex. Predicted to be active in cytosol; neuromuscular junction; and recycling endosome.

Source: NCBI Gene 89848 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 184 total
• MANE Select transcript: NM_033449

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25463
Approved symbol	FCHSD1
Name	FCH and double SH3 domains 1
Location	5q31.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ00007
Ensembl gene	ENSG00000197948
Ensembl biotype	protein_coding
OMIM	617555
Entrez	89848

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 9 protein_coding, 4 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000435817, ENST00000518160, ENST00000518499, ENST00000519800, ENST00000520747, ENST00000522126, ENST00000522386, ENST00000522763, ENST00000522783, ENST00000523856, ENST00000896537, ENST00000896538, ENST00000896539, ENST00000969297, ENST00000969298

RefSeq mRNA: 1 — MANE Select: NM_033449 NM_033449

CCDS: CCDS47295

Canonical transcript exons

ENST00000435817 — 20 exons

Exon	Start	End
ENSE00001159878	141646087	141646191
ENSE00001159881	141646603	141646722
ENSE00001159890	141648957	141649020
ENSE00001159897	141649172	141649308
ENSE00001259006	141651348	141651418
ENSE00001378790	141647398	141647520
ENSE00001382933	141647968	141648096
ENSE00001685016	141649395	141649536
ENSE00002136491	141639302	141641563
ENSE00003463904	141649887	141649954
ENSE00003480229	141647135	141647230
ENSE00003485266	141644859	141644942
ENSE00003537093	141651020	141651117
ENSE00003539026	141643001	141643088
ENSE00003586694	141644218	141644438
ENSE00003644683	141641702	141641757
ENSE00003656058	141650359	141650404
ENSE00003685115	141645020	141645148
ENSE00003691218	141645771	141645932
ENSE00003693153	141644573	141644690

Expression profiles

Bgee: expression breadth ubiquitous, 168 present calls, max score 96.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.4405 / max 151.2561, expressed in 1774 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63859	12.3865	1774
63860	0.0540	18

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	96.75	gold quality
left ovary	UBERON:0002119	93.10	gold quality
descending thoracic aorta	UBERON:0002345	92.95	gold quality
vermiform appendix	UBERON:0001154	92.85	gold quality
right ovary	UBERON:0002118	92.65	gold quality
adenohypophysis	UBERON:0002196	92.53	gold quality
ascending aorta	UBERON:0001496	92.47	gold quality
thoracic aorta	UBERON:0001515	92.42	gold quality
sural nerve	UBERON:0015488	92.30	gold quality
body of uterus	UBERON:0009853	91.75	gold quality
ectocervix	UBERON:0012249	91.72	gold quality
spleen	UBERON:0002106	91.69	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.58	gold quality
skin of leg	UBERON:0001511	91.39	gold quality
stromal cell of endometrium	CL:0002255	90.90	gold quality
endocervix	UBERON:0000458	90.85	gold quality
right uterine tube	UBERON:0001302	90.80	gold quality
skin of abdomen	UBERON:0001416	90.74	gold quality
pituitary gland	UBERON:0000007	90.37	gold quality
gall bladder	UBERON:0002110	90.36	gold quality
mucosa of stomach	UBERON:0001199	90.27	gold quality
right lobe of thyroid gland	UBERON:0001119	90.24	gold quality
aorta	UBERON:0000947	90.11	gold quality
lymph node	UBERON:0000029	89.76	gold quality
minor salivary gland	UBERON:0001830	89.58	gold quality
right coronary artery	UBERON:0001625	89.45	gold quality
left lobe of thyroid gland	UBERON:0001120	89.44	gold quality
tibial nerve	UBERON:0001323	89.05	gold quality
small intestine	UBERON:0002108	88.94	gold quality
lower esophagus mucosa	UBERON:0035834	88.81	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-GEOD-99795	no	18.98
E-ANND-3	no	2.91

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

115 targeting FCHSD1, 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-4283	100.00	66.42	2097
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-23A-5P	99.94	65.39	468
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-6756-5P	99.82	67.97	2466

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Fchsd1	ENSMUSG00000038524
rattus_norvegicus	Fchsd1	ENSRNOG00000039415
drosophila_melanogaster	nwk	FBGN0263456
caenorhabditis_elegans	C26C6.8	WBGENE00007742

Paralogs (1): FCHSD2 (ENSG00000137478)

Protein

Protein identifiers

F-BAR and double SH3 domains protein 1 — Q86WN1 (reviewed: Q86WN1)

Alternative names: Protein nervous wreck 2

All UniProt accessions (4): E5RGB1, E5RGT6, E5RK49, Q86WN1

UniProt curated annotations — full annotation on UniProt →

Function. Promotes actin polymerization mediated by SNX9 and WASL.

Subunit / interactions. Homodimer. Interacts (via F-BAR domain) with SNX9 (via SH3 domain). Interacts (via F-BAR domain) with SNX18 and SNX33. Interacts (via SH3 domain 1) with WASL. Interacts (via SH3 domain 2) with ITSN1.

Subcellular location. Cytoplasm. Perikaryon. Cell projection. Cytoplasmic vesicle.

Domain organisation. The F-BAR domain has an atypical, flat shape and binds preferentially to flat membranes. Upon heterologous expression, the isolated F-BAR domain is localized at the cell membrane, and causes the formation of cellular protrusions.

Isoforms (3)

UniProt ID	Names	Canonical?
Q86WN1-1	1	yes
Q86WN1-2	2
Q86WN1-3	3

RefSeq proteins (1): NP_258260* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001060	FCH_dom	Domain
IPR001452	SH3_domain	Domain
IPR027267	AH/BAR_dom_sf	Homologous_superfamily
IPR031160	F_BAR_dom	Domain
IPR035460	FCHSD_SH3_1	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily

Pfam: PF00611, PF14604

UniProt features (20 total): splice variant 6, domain 3, compositionally biased region 3, sequence variant 2, region of interest 2, coiled-coil region 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86WN1-F1	77.68	0.37

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): 444

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 132 (showing top): GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_INFLAMMATORY_RESPONSE, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_RESPONSE_TO_PEPTIDE, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GGGTGGRR_PAX4_03, GOBP_CELL_CELL_SIGNALING, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS, GOBP_NUCLEAR_TRANSPORT, AGCGCTT_MIR518F_MIR518E_MIR518A, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE, GOBP_POSITIVE_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, MODULE_205, GOBP_ACTIN_FILAMENT_ORGANIZATION

GO Biological Process (12): apoptotic process (GO:0006915), inflammatory response (GO:0006954), neuromuscular synaptic transmission (GO:0007274), gene expression (GO:0010467), regulation of actin filament polymerization (GO:0030833), positive regulation of actin filament polymerization (GO:0030838), response to hydrogen peroxide (GO:0042542), import into nucleus (GO:0051170), membrane organization (GO:0061024), response to peptide (GO:1901652), positive regulation of cytoskeleton organization (GO:0051495), positive regulation of supramolecular fiber organization (GO:1902905)

GO Molecular Function (2): lipid binding (GO:0008289), protein binding (GO:0005515)

GO Cellular Component (9): cytosol (GO:0005829), neuromuscular junction (GO:0031594), cuticular plate (GO:0032437), protein-containing complex (GO:0032991), cell projection (GO:0042995), perikaryon (GO:0043204), recycling endosome (GO:0055037), cytoplasm (GO:0005737), cytoplasmic vesicle (GO:0031410)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
actin filament polymerization	2
binding	2
cytoplasm	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
defense response	1
chemical synaptic transmission	1
macromolecule biosynthetic process	1
regulation of actin polymerization or depolymerization	1
regulation of protein polymerization	1
regulation of actin filament polymerization	1
positive regulation of protein polymerization	1
positive regulation of cytoskeleton organization	1
positive regulation of supramolecular fiber organization	1
response to reactive oxygen species	1
nucleocytoplasmic transport	1
intercellular transport	1
cellular component organization	1
response to chemical	1
cytoskeleton organization	1
positive regulation of organelle organization	1
regulation of cytoskeleton organization	1
positive regulation of cellular component organization	1
supramolecular fiber organization	1
regulation of supramolecular fiber organization	1
synapse	1
cortical actin cytoskeleton	1
cellular_component	1
neuronal cell body	1
endosome	1
intracellular anatomical structure	1
intracellular vesicle	1

Protein interactions and networks

STRING

462 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FCHSD1	SNX9	Q9Y5X1	728
FCHSD1	FNBP1	Q96RU3	670
FCHSD1	TRIP10	Q15642	643
FCHSD1	FCHO1	O14526	608
FCHSD1	SNX16	P57768	576
FCHSD1	ARHGAP4	P98171	567
FCHSD1	ITSN1	Q15811	535
FCHSD1	PACSIN3	Q9UKS6	529
FCHSD1	ARHGEF37	A1IGU5	516
FCHSD1	DDIT4	Q9NX09	513
FCHSD1	AMPH	P49418	504
FCHSD1	RPTOR	Q8N122	494
FCHSD1	SNX18	Q96RF0	493
FCHSD1	PACSIN1	Q9BY11	492
FCHSD1	PACSIN2	Q9UNF0	464
FCHSD1	DNMBP	Q6XZF7	464

IntAct

26 interactions, top by confidence:

A	B	Type	Score
SNX9	SYNJ1	psi-mi:“MI:0914”(association)	0.790
NCKIPSD	GEMIN2	psi-mi:“MI:0914”(association)	0.640
SNX9	WASL	psi-mi:“MI:0914”(association)	0.640
FCHSD1	LRRK2	psi-mi:“MI:0407”(direct interaction)	0.440
Dlg4	FCHSD1	psi-mi:“MI:0407”(direct interaction)	0.440
FCHSD1	EBNA2	psi-mi:“MI:0915”(physical association)	0.370
CDK15	A2ML1	psi-mi:“MI:0914”(association)	0.350
NCKIPSD	USP9Y	psi-mi:“MI:0914”(association)	0.350
SNX33	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.350
STX17	A2ML1	psi-mi:“MI:0914”(association)	0.350
OR2A4	A2ML1	psi-mi:“MI:0914”(association)	0.350
GOT1	A2ML1	psi-mi:“MI:0914”(association)	0.350
CCR1	UBA6	psi-mi:“MI:0914”(association)	0.350
SSUH2	IGLC7	psi-mi:“MI:0914”(association)	0.350
RNF115	IGLC7	psi-mi:“MI:0914”(association)	0.350
MBNL1	A2ML1	psi-mi:“MI:0914”(association)	0.350
NCKIPSD	GAS7	psi-mi:“MI:0914”(association)	0.350
SNX33	FCHSD2	psi-mi:“MI:0914”(association)	0.350
SMPD2	A2ML1	psi-mi:“MI:0914”(association)	0.350
prlC	FCHSD1	psi-mi:“MI:0915”(physical association)	0.000
hemC	FCHSD1	psi-mi:“MI:0915”(physical association)	0.000
FCHSD1	degQ	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (26): FCHSD1 (Affinity Capture-RNA), FCHSD1 (Reconstituted Complex), FCHSD1 (Affinity Capture-MS), FCHSD1 (Affinity Capture-MS), FCHSD1 (Affinity Capture-MS), FCHSD1 (Reconstituted Complex), FCHSD1 (Affinity Capture-MS), FCHSD1 (Affinity Capture-MS), FCHSD1 (Affinity Capture-MS), FCHSD1 (Affinity Capture-MS), FCHSD1 (Affinity Capture-MS), FCHSD1 (Affinity Capture-MS), FCHSD1 (Affinity Capture-MS), FCHSD1 (Affinity Capture-MS), FCHSD1 (Affinity Capture-MS)

ESM2 similar proteins: A1IGU3, A1IGU4, A1IGU5, A6QP29, B1AVH7, B2RUP2, B5DFA1, D2H0G5, D3ZFJ3, O15068, O55043, P00530, P07332, P14238, P16879, P55194, P98171, Q0GNC1, Q14155, Q15052, Q27J81, Q3U5C8, Q3UMR0, Q58EX7, Q5VV41, Q5XXR3, Q5ZLR6, Q60I26, Q63406, Q64096, Q6PFY1, Q6PGG2, Q70J99, Q7TNH6, Q80TT2, Q80VK6, Q86WN1, Q8C2K1, Q8C6B2, Q8CJ00

Diamond homologs: A4RF61, A6ZKU1, A7E8B6, D3ZG83, O74749, P10569, P32790, P35991, P42683, P42686, P42690, Q02779, Q06187, Q5ALV2, Q66L42, Q6CHN0, Q6PFY1, Q7T2V3, Q86WN1, Q8IPW2, Q9P7E8, A0A0K3AV08, A4FU49, A6QLK6, A7A261, B1V8A0, F1LRS8, G5EC32, O00160, O13154, O35413, O42287, O43639, O55033, O55043, O75563, O75791, O77775, O94868, O94875

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	148
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3591 predictions. Top by Δscore:

Variant	Effect	Δscore
5:141639623:G:T	donor_gain	1.0000
5:141641559:CGCAT:C	acceptor_gain	1.0000
5:141641695:CCCTT:C	donor_loss	1.0000
5:141641697:CTTAC:C	donor_loss	1.0000
5:141641698:TTA:T	donor_loss	1.0000
5:141641699:TAC:T	donor_loss	1.0000
5:141641700:A:AC	donor_gain	1.0000
5:141641700:A:G	donor_loss	1.0000
5:141641700:ACCGG:A	donor_gain	1.0000
5:141641701:C:CC	donor_gain	1.0000
5:141641701:CC:C	donor_loss	1.0000
5:141641701:CCGG:C	donor_gain	1.0000
5:141641701:CCGGC:C	donor_gain	1.0000
5:141641753:TTTGT:T	acceptor_gain	1.0000
5:141641754:TTGT:T	acceptor_gain	1.0000
5:141641755:TGT:T	acceptor_gain	1.0000
5:141641756:GTCTG:G	acceptor_loss	1.0000
5:141641757:TCTGG:T	acceptor_loss	1.0000
5:141641758:C:CA	acceptor_loss	1.0000
5:141641758:C:CC	acceptor_gain	1.0000
5:141641759:T:A	acceptor_loss	1.0000
5:141644434:GAATG:G	acceptor_gain	1.0000
5:141644437:TG:T	acceptor_gain	1.0000
5:141644439:C:CC	acceptor_gain	1.0000
5:141644450:C:CT	acceptor_gain	1.0000
5:141644450:C:T	acceptor_gain	1.0000
5:141644451:A:T	acceptor_gain	1.0000
5:141644703:CAA:C	acceptor_gain	1.0000
5:141644705:A:AC	acceptor_gain	1.0000
5:141645034:C:CT	donor_gain	1.0000

AlphaMissense

4443 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:141644659:A:T	V519D	0.997
5:141644285:A:G	F599S	0.996
5:141644320:G:C	F587L	0.996
5:141644320:G:T	F587L	0.996
5:141644322:A:G	F587L	0.996
5:141644363:A:G	I573T	0.996
5:141644381:A:G	F567S	0.995
5:141644284:G:C	F599L	0.994
5:141644284:G:T	F599L	0.994
5:141644286:A:G	F599L	0.994
5:141644363:A:C	I573S	0.992
5:141644363:A:T	I573N	0.992
5:141649514:A:G	W86R	0.992
5:141649514:A:T	W86R	0.992
5:141650386:C:A	R46S	0.992
5:141650386:C:G	R46S	0.992
5:141650385:C:G	A47P	0.991
5:141644381:A:C	F567C	0.989
5:141650392:C:A	K44N	0.989
5:141650392:C:G	K44N	0.989
5:141650400:A:C	Y42D	0.989
5:141644285:A:C	F599C	0.988
5:141644387:A:G	L565P	0.987
5:141644923:A:G	L487P	0.987
5:141649950:A:G	L57P	0.987
5:141650363:C:T	G54E	0.987
5:141649954:C:G	A56P	0.986
5:141650372:C:G	R51P	0.986
5:141644321:A:G	F587S	0.985
5:141650395:G:C	S43R	0.985

dbSNP variants (sampled 300 via entrez): RS1000317841 (5:141653364 C>T), RS1000830589 (5:141642670 T>C), RS1001048209 (5:141644790 A>C,G), RS1001425408 (5:141645093 A>G), RS1001725897 (5:141640771 G>A), RS1002417698 (5:141650415 T>A,C,G), RS1002461059 (5:141639398 C>A,T), RS1002504731 (5:141643668 G>C), RS1002655990 (5:141649112 C>CTAGCCA), RS1002710648 (5:141642976 A>G), RS1002773433 (5:141650689 G>A), RS1003949336 (5:141640457 T>C,G), RS1004085355 (5:141640764 A>C,G), RS1004127358 (5:141644070 GC>G,GCC), RS1004318349 (5:141648960 G>A,C)

Disease associations

OMIM: gene MIM:617555 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010002_39	Refractive error	2.000000e-14

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, increases abundance, increases expression	3
Arsenic	increases expression, increases abundance	2
Valproic Acid	increases expression	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
titanium dioxide	increases expression	1
arsenite	affects binding, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Cisplatin	decreases expression	1
Estradiol	affects expression	1
Lead	decreases expression	1
Ozone	affects expression, increases abundance	1
Phthalic Acids	affects methylation	1
Plant Extracts	affects cotreatment, increases expression	1
Quercetin	decreases phosphorylation	1
Smoke	decreases expression	1
Thiram	increases expression	1
Triclosan	increases expression	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

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