FNDC1

Summary

FNDC1 (fibronectin type III domain containing 1, HGNC:21184) is a protein-coding gene on chromosome 6q25.3, encoding Fibronectin type III domain-containing protein 1 (Q4ZHG4). May be an activator of G protein signaling.

Predicted to act upstream of or within several processes, including cellular response to hypoxia; positive regulation of cardiac muscle cell apoptotic process; and positive regulation of protein phosphorylation. Predicted to be located in cell-cell junction; mitochondrial membrane; and plasma membrane.

Source: NCBI Gene 84624 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 401 total
• MANE Select transcript: NM_032532

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21184
Approved symbol	FNDC1
Name	fibronectin type III domain containing 1
Location	6q25.3
Locus type	gene with protein product
Status	Approved
Aliases	bA243O10.1, KIAA1866, dJ322A24.1
Ensembl gene	ENSG00000164694
Ensembl biotype	protein_coding
OMIM	609991
Entrez	84624

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000297267, ENST00000329629, ENST00000480856, ENST00000906655, ENST00000906656

RefSeq mRNA: 1 — MANE Select: NM_032532 NM_032532

CCDS: CCDS47512

Canonical transcript exons

ENST00000297267 — 23 exons

Exon	Start	End
ENSE00001086663	159231882	159234479
ENSE00001086674	159229815	159230003
ENSE00001204093	159214945	159215151
ENSE00001204099	159169400	159169705
ENSE00001311650	159251302	159251532
ENSE00001324426	159249039	159249182
ENSE00001330186	159246901	159246969
ENSE00001344839	159239517	159239957
ENSE00001421587	159236215	159236315
ENSE00001424680	159238554	159238665
ENSE00001443384	159226473	159226580
ENSE00001443388	159200513	159200581
ENSE00001443389	159199996	159200082
ENSE00001443390	159197431	159197625
ENSE00001928279	159271327	159272108
ENSE00002218469	159267804	159267926
ENSE00002234646	159256523	159256631
ENSE00002249787	159261190	159261269
ENSE00002298507	159264975	159265004
ENSE00002313353	159266084	159266245
ENSE00003473131	159221598	159221696
ENSE00003600071	159225535	159225722
ENSE00003616386	159223528	159223645

Expression profiles

Bgee: expression breadth ubiquitous, 183 present calls, max score 97.90.

FANTOM5 (CAGE): breadth broad, TPM avg 7.3488 / max 405.4181, expressed in 460 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
70932	7.3488	460

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	97.90	gold quality
synovial joint	UBERON:0002217	95.67	gold quality
cartilage tissue	UBERON:0002418	94.68	gold quality
layer of synovial tissue	UBERON:0007616	93.78	gold quality
tibia	UBERON:0000979	91.77	gold quality
tendon	UBERON:0000043	87.14	gold quality
mammalian vulva	UBERON:0000997	86.56	gold quality
urethra	UBERON:0000057	85.48	gold quality
skin of hip	UBERON:0001554	83.96	gold quality
parietal pleura	UBERON:0002400	83.81	gold quality
ileal mucosa	UBERON:0000331	83.69	gold quality
calcaneal tendon	UBERON:0003701	83.42	gold quality
thyroid gland	UBERON:0002046	82.88	gold quality
trabecular bone tissue	UBERON:0002483	82.65	gold quality
right lobe of thyroid gland	UBERON:0001119	82.51	gold quality
left lobe of thyroid gland	UBERON:0001120	82.45	gold quality
gall bladder	UBERON:0002110	81.04	gold quality
smooth muscle tissue	UBERON:0001135	80.25	gold quality
visceral pleura	UBERON:0002401	79.15	gold quality
saphenous vein	UBERON:0007318	77.73	gold quality
muscle layer of sigmoid colon	UBERON:0035805	77.61	gold quality
trigeminal ganglion	UBERON:0001675	76.35	gold quality
descending thoracic aorta	UBERON:0002345	76.02	gold quality
palpebral conjunctiva	UBERON:0001812	75.12	gold quality
sural nerve	UBERON:0015488	74.07	gold quality
mammary duct	UBERON:0001765	73.92	silver quality
epithelium of mammary gland	UBERON:0003244	73.78	silver quality
ventricular zone	UBERON:0003053	72.81	gold quality
colonic epithelium	UBERON:0000397	72.70	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	72.39	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-9906	yes	744.44
E-ANND-3	yes	6.07

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

59 targeting FNDC1, 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-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-1179	99.71	68.70	1040
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-1287-3P	99.63	66.93	492
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-190A-5P	99.54	71.45	933
HSA-MIR-190B-5P	99.54	71.40	925
HSA-MIR-5689	99.50	71.26	1154
HSA-MIR-217-5P	99.49	69.93	1419
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-12131	99.48	68.72	1673

Literature-anchored findings (GeneRIF, showing 10)

• mechanical stretching of FN-III1 may induce fibrillogenesis through a partially unfolded intermediate (PMID:14657397)
• MEL4B3 is a novel mRNA induced in skin tumors and regulated by TGF-beta and pro-inflammatory cytokines (PMID:16098131)
• Knockdown of AGS8 inhibited vascular endothelial growth factor (VEGF)-induced tube formation, as well as VEGF-stimulated cell growth and migration. (PMID:26826188)
• these studies have revealed a novel microRNA-1207-3p/FNDC1/FN1/AR regulatory pathway in prostate cancer. (PMID:27693493)
• activator of G-protein signaling 8 regulated the trafficking of VEGFR-3 to the plasma membrane (PMID:29649427)
• The findings elaborated the biological role of fibronectin type III domain containing 1 in gastric cancer and potential mechanism of action, possibly providing a new insight for future clinical diagnosis or even molecular therapy (PMID:31530096)
• The silencing of FNDC1 inhibits the tumorigenesis of breast cancer cells via modulation of the PI3K/Akt signaling pathway. (PMID:33899120)
• Up-regulated FNDC1 accelerates stemness and chemoradiation resistance in colorectal cancer cells. (PMID:35255438)
• [FNDC1 is highly expressed in lung adenocarcinoma and closely related with poor prognosis]. (PMID:36073217)
• The role of miR-143-3p/FNDC1 axis on the progression of non-small cell lung cancer. (PMID:37132497)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	fndc1	ENSDARG00000002847
mus_musculus	Fndc1	ENSMUSG00000071984
rattus_norvegicus	Fndc1	ENSRNOG00000030210

Paralogs (1): ABI3BP (ENSG00000154175)

Protein

Protein identifiers

Fibronectin type III domain-containing protein 1 — Q4ZHG4 (reviewed: Q4ZHG4)

Alternative names: Activation-associated cDNA protein, Expressed in synovial lining protein

All UniProt accessions (2): Q4ZHG4, J3KNQ2

UniProt curated annotations — full annotation on UniProt →

Function. May be an activator of G protein signaling.

Subcellular location. Secreted.

Tissue specificity. Almost absent from healthy skin; especially in epidermal keratinocytes, skin fibroblasts or endothelial cells and is barely detectable in benign melanocytic naevi. Expressed in the stroma close to skin tumors, in the tumor cells themselves and in the epidermis of psoriasis.

Induction. By TGFB1 present in the melanoma cell conditioned medium (MCCM).

Isoforms (2)

UniProt ID	Names	Canonical?
Q4ZHG4-1	1	yes
Q4ZHG4-2	2

RefSeq proteins (1): NP_115921* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003961	FN3_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036116	FN3_sf	Homologous_superfamily
IPR049109	TARSH/FNDC1_C	Domain

Pfam: PF00041, PF21731

UniProt features (43 total): compositionally biased region 13, sequence variant 9, sequence conflict 6, domain 5, region of interest 4, glycosylation site 2, signal peptide 1, chain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q4ZHG4-F1	54.19	0.16

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): 717

Glycosylation sites (2): 149, 1661

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 83 (showing top): TURASHVILI_BREAST_LOBULAR_CARCINOMA_VS_DUCTAL_NORMAL_UP, BENPORATH_ES_WITH_H3K27ME3, chr6q25, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_UP, TURASHVILI_BREAST_LOBULAR_CARCINOMA_VS_LOBULAR_NORMAL_DN, AAAGACA_MIR511, LINDVALL_IMMORTALIZED_BY_TERT_DN, MCCLUNG_COCAIN_REWARD_4WK, VECCHI_GASTRIC_CANCER_ADVANCED_VS_EARLY_UP, WANG_SMARCE1_TARGETS_UP, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_DN, YANG_BCL3_TARGETS_UP, ZWANG_TRANSIENTLY_UP_BY_2ND_EGF_PULSE_ONLY, SNF5_DN.V1_UP, NABA_ECM_GLYCOPROTEINS

GO Biological Process (0):

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

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

872 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FNDC1	GNG2	P59768	650
FNDC1	GNB1	P04697	649
FNDC1	GNAS	Q5JWF2	497
FNDC1	COL10A1	Q03692	436
FNDC1	ELFN1	P0C7U0	399
FNDC1	MXRA5	Q9NR99	393
FNDC1	IGSF10	Q6WRI0	364
FNDC1	ARL11	Q969Q4	346
FNDC1	TRRAP	Q9Y4A5	338
FNDC1	AP5B1	Q2VPB7	329
FNDC1	FNDC10	F2Z333	321
FNDC1	CTHRC1	Q96CG8	321
FNDC1	NDUFAF6	Q330K2	313
FNDC1	MCRIP2	Q9BUT9	310
FNDC1	AZI2	Q9H6S1	310

IntAct

2 interactions, top by confidence:

A	B	Type	Score
FNDC1	IGLL5	psi-mi:“MI:0914”(association)	0.350

BioGRID (23): FNDC1 (Affinity Capture-MS), ATP6V0C (Affinity Capture-MS), IGHG2 (Affinity Capture-MS), CRYAB (Affinity Capture-MS), TF (Affinity Capture-MS), IGHG1 (Affinity Capture-MS), LGALS7B (Affinity Capture-MS), FGB (Affinity Capture-MS), SERPINB5 (Affinity Capture-MS), SERPINA1 (Affinity Capture-MS), EVPL (Affinity Capture-MS), IGKC (Affinity Capture-MS), HP (Affinity Capture-MS), FGG (Affinity Capture-MS), C3 (Affinity Capture-MS)

ESM2 similar proteins: A2BDC9, A6NM62, E9Q793, O08999, O35806, O55233, O95813, P13207, P22389, P23499, P23943, P24054, P29560, P35054, P70041, P86275, Q07G34, Q14515, Q17R60, Q2Q0I9, Q3UU94, Q3V1M1, Q4V9H3, Q4ZHG4, Q5K027, Q5NRP8, Q5NRP9, Q5NRQ1, Q5QQ37, Q68CR7, Q6WRH9, Q6WRI0, Q701R2, Q701R3, Q701R4, Q76K27, Q8CG19, Q8JIR8, Q8JZQ0, Q8R1W8

Diamond homologs: G5EF96, O09127, O15197, O42422, P0C0K6, P16144, P29320, P29322, P43146, P54759, P70211, P97603, P97798, Q15375, Q24372, Q4ZHG4, Q61772, Q63155, Q8C310, Q90610, Q91736, Q91845, Q92859, A4IFW2, P22063, P97686, Q2Q0I9, Q589G5, Q7Z7G0, Q810U4, Q9HCK4, Q8BZ52

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	337
Likely benign	23
Benign	9

Top pathogenic / likely-pathogenic (0)

SpliceAI

4491 predictions. Top by Δscore:

Variant	Effect	Δscore
6:159214942:A:AG	acceptor_gain	1.0000
6:159214943:A:G	acceptor_gain	1.0000
6:159215148:C:G	donor_gain	1.0000
6:159223526:A:AG	acceptor_gain	1.0000
6:159223527:G:GA	acceptor_gain	1.0000
6:159223527:GAA:G	acceptor_gain	1.0000
6:159223641:TCAAG:T	donor_loss	1.0000
6:159223642:CAAGG:C	donor_loss	1.0000
6:159223643:AAGGT:A	donor_loss	1.0000
6:159223644:AGGTA:A	donor_loss	1.0000
6:159223646:GT:G	donor_loss	1.0000
6:159223647:T:G	donor_loss	1.0000
6:159226464:A:AG	acceptor_gain	1.0000
6:159226468:T:TA	acceptor_gain	1.0000
6:159226471:A:AG	acceptor_gain	1.0000
6:159226472:G:GG	acceptor_gain	1.0000
6:159226472:GC:G	acceptor_gain	1.0000
6:159226472:GCC:G	acceptor_gain	1.0000
6:159226472:GCCC:G	acceptor_gain	1.0000
6:159226472:GCCCC:G	acceptor_gain	1.0000
6:159226571:A:T	donor_gain	1.0000
6:159226578:AAGG:A	donor_loss	1.0000
6:159226579:AGGT:A	donor_loss	1.0000
6:159226580:GG:G	donor_loss	1.0000
6:159226581:G:C	donor_loss	1.0000
6:159226582:T:G	donor_loss	1.0000
6:159230678:G:GT	donor_gain	1.0000
6:159236312:GTGG:G	donor_gain	1.0000
6:159249033:TTTCA:T	acceptor_loss	1.0000
6:159249035:TCAGA:T	acceptor_loss	1.0000

AlphaMissense

12127 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:159225654:T:A	V335D	1.000
6:159226546:G:C	W382C	1.000
6:159226546:G:T	W382C	1.000
6:159229932:T:C	F433S	1.000
6:159251501:G:C	W1678C	1.000
6:159251501:G:T	W1678C	1.000
6:159267851:T:A	C1832S	1.000
6:159267851:T:C	C1832R	1.000
6:159267852:G:A	C1832Y	1.000
6:159267852:G:C	C1832S	1.000
6:159267853:C:G	C1832W	1.000
6:159223599:T:A	W280R	0.999
6:159223599:T:C	W280R	0.999
6:159225555:G:C	R302P	0.999
6:159225648:T:C	F333S	0.999
6:159225686:T:A	W346R	0.999
6:159225686:T:C	W346R	0.999
6:159226503:T:A	V368D	0.999
6:159226533:T:A	V378D	0.999
6:159226544:T:A	W382R	0.999
6:159226544:T:C	W382R	0.999
6:159229824:T:C	L397P	0.999
6:159251343:T:C	C1626R	0.999
6:159251475:T:C	C1670R	0.999
6:159251476:G:A	C1670Y	0.999
6:159251477:C:G	C1670W	0.999
6:159251488:T:A	V1674D	0.999
6:159251499:T:A	W1678R	0.999
6:159251499:T:C	W1678R	0.999
6:159256532:T:A	V1692D	0.999

dbSNP variants (sampled 300 via entrez): RS1000006991 (6:159174981 A>G), RS1000038245 (6:159247441 G>A,C), RS1000061143 (6:159175378 T>A,C), RS1000066986 (6:159192413 C>A,G), RS1000094810 (6:159255501 T>G), RS1000095947 (6:159206639 A>G,T), RS1000154329 (6:159255560 G>C), RS1000164863 (6:159208041 G>A), RS1000179960 (6:159209043 C>T), RS1000194046 (6:159218011 A>G), RS1000253696 (6:159209231 A>G), RS1000264421 (6:159168949 A>G), RS1000282101 (6:159224074 G>A), RS1000315797 (6:159243581 C>G,T), RS1000366508 (6:159244009 C>T)

Disease associations

OMIM: gene MIM:609991 | disease phenotypes: MIM:616481, MIM:181800

GenCC curated gene-disease

Mondo (2): primary ciliary dyskinesia 32 (MONDO:0014657), scoliosis, isolated, susceptibility to, 1 (MONDO:0008419)

Orphanet (1): Primary ciliary dyskinesia (Orphanet:244)

HPO phenotypes

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

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST001079_2	Coronary heart disease	8.000000e-07
GCST002746_12	Lipoprotein (a) - cholesterol levels	2.000000e-11
GCST003127_12	Lipoprotein (a) levels	5.000000e-11
GCST003998_2	Joint mobility (Beighton score)	1.000000e-12
GCST004278_5	Pulse pressure	2.000000e-15
GCST005194_73	Coronary artery disease	5.000000e-06
GCST005531_95	Multiple sclerosis	6.000000e-07
GCST007096_217	Pulse pressure	1.000000e-16
GCST007269_206	Pulse pressure	4.000000e-14
GCST008644_2	Celiac disease and Rheumatoid arthritis	6.000000e-11
GCST010796_1871	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST012232_13	Lipoprotein (a) levels	1.000000e-93
GCST012490_392	Femur bone mineral density x serum urate levels interaction	4.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0006925	lipoprotein A measurement
EFO:0007905	joint hypermobility measurement
EFO:0005763	pulse pressure measurement
EFO:0004327	electrocardiography
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, affects cotreatment	8
entinostat	increases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, increases methylation	2
bisphenol A	affects cotreatment, increases methylation, decreases methylation	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
arsenite	increases methylation	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	affects methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Arsenic Trioxide	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Dexamethasone	decreases expression	1
Diethylhexyl Phthalate	increases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Lead	decreases expression	1
Lipopolysaccharides	increases expression, affects response to substance	1
Methapyrilene	increases methylation	1
Phenylmercuric Acetate	affects cotreatment, increases expression	1
Progesterone	affects cotreatment, decreases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	increases expression	1

Clinical trials (associated diseases)

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