ZFYVE21

Summary

ZFYVE21 (zinc finger FYVE-type containing 21, HGNC:20760) is a protein-coding gene on chromosome 14q32.33, encoding Zinc finger FYVE domain-containing protein 21 (Q9BQ24). Plays a role in cell adhesion, and thereby in cell motility which requires repeated formation and disassembly of focal adhesions.

Predicted to enable zinc ion binding activity. Predicted to be located in endosome and focal adhesion.

Source: NCBI Gene 79038 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 33 total
• MANE Select transcript: NM_024071

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20760
Approved symbol	ZFYVE21
Name	zinc finger FYVE-type containing 21
Location	14q32.33
Locus type	gene with protein product
Status	Approved
Aliases	MGC2550, ZF21
Ensembl gene	ENSG00000100711
Ensembl biotype	protein_coding
OMIM	613504
Entrez	79038

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 17 protein_coding, 7 retained_intron, 2 nonsense_mediated_decay

ENST00000216602, ENST00000311141, ENST00000553512, ENST00000553724, ENST00000554255, ENST00000554630, ENST00000554757, ENST00000555163, ENST00000555501, ENST00000556610, ENST00000556795, ENST00000602552, ENST00000892135, ENST00000892136, ENST00000892137, ENST00000892138, ENST00000892139, ENST00000892140, ENST00000935732, ENST00000935733, ENST00000935734, ENST00000935735, ENST00000944811, ENST00000944812, ENST00000944813, ENST00000944814

RefSeq mRNA: 2 — MANE Select: NM_024071 NM_001198953, NM_024071

CCDS: CCDS55948, CCDS9985

Canonical transcript exons

ENST00000311141 — 7 exons

Exon	Start	End
ENSE00002437379	103732983	103733664
ENSE00003477497	103732620	103732762
ENSE00003504542	103726792	103726842
ENSE00003509219	103729091	103729182
ENSE00003575192	103715810	103715979
ENSE00003638773	103728908	103728983
ENSE00003694378	103727746	103727914

Expression profiles

Bgee: expression breadth ubiquitous, 275 present calls, max score 98.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.1183 / max 240.1001, expressed in 1812 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
141772	28.0313	1810
141771	1.0870	626

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.99	gold quality
oocyte	CL:0000023	98.79	gold quality
mucosa of stomach	UBERON:0001199	97.80	gold quality
descending thoracic aorta	UBERON:0002345	97.71	gold quality
right coronary artery	UBERON:0001625	97.67	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.55	gold quality
esophagus squamous epithelium	UBERON:0006920	97.44	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.40	gold quality
thoracic aorta	UBERON:0001515	97.39	gold quality
ascending aorta	UBERON:0001496	97.38	gold quality
right frontal lobe	UBERON:0002810	97.36	gold quality
aorta	UBERON:0000947	97.28	gold quality
cerebellar hemisphere	UBERON:0002245	97.24	gold quality
popliteal artery	UBERON:0002250	97.22	gold quality
tibial artery	UBERON:0007610	97.22	gold quality
cerebellar cortex	UBERON:0002129	97.20	gold quality
anterior cingulate cortex	UBERON:0009835	97.13	gold quality
left uterine tube	UBERON:0001303	97.12	gold quality
ectocervix	UBERON:0012249	97.09	gold quality
body of uterus	UBERON:0009853	97.08	gold quality
endocervix	UBERON:0000458	97.07	gold quality
cingulate cortex	UBERON:0003027	96.99	gold quality
skin of leg	UBERON:0001511	96.96	gold quality
lower esophagus	UBERON:0013473	96.95	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.95	gold quality
nucleus accumbens	UBERON:0001882	96.85	gold quality
lower esophagus mucosa	UBERON:0035834	96.85	gold quality
urethra	UBERON:0000057	96.79	gold quality
amygdala	UBERON:0001876	96.77	gold quality
nipple	UBERON:0002030	96.69	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-114	yes	60.63
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

56 targeting ZFYVE21, 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-3646	100.00	73.56	5283
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-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-12117	99.50	67.57	868
HSA-MIR-203A-3P	99.49	70.56	2806

Literature-anchored findings (GeneRIF, showing 5)

• ZF21 is a new regulator of focal adhesion disassembly and a potential member of the spreading initiation center. We identified 45 proteins including FA-related proteins and multiple RNA binding proteins (PMID:20890123)
• the C-terminal region is important for the ability of ZF21 to induce disassembly of FAs and cell migration (PMID:21768110)
• this study demonstrates that ZF21 is a key player regulating multiple aspects of cancer cell migration and invasion. (PMID:23382803)
• ZFYVE21 is identified as a posttranslationally induced Rab5 effector that triggers phosphoinositide remodeling of early endosome membranes to mediate non-canonical NF-kappaB signal activation and tissue inflammation. (PMID:31113953)
• ZFYVE21 promotes endothelial nitric oxide signaling and vascular barrier function in the kidney during aging. (PMID:38797325)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zfyve21	ENSDARG00000027887
mus_musculus	Zfyve21	ENSMUSG00000021286
rattus_norvegicus	Zfyve21	ENSRNOG00000012185

Protein

Protein identifiers

Zinc finger FYVE domain-containing protein 21 — Q9BQ24 (reviewed: Q9BQ24)

All UniProt accessions (4): Q9BQ24, G3V2M2, G3V5D6, R4GN42

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in cell adhesion, and thereby in cell motility which requires repeated formation and disassembly of focal adhesions. Regulates microtubule-induced PTK2/FAK1 dephosphorylation, an event important for focal adhesion disassembly, as well as integrin beta-1/ITGB1 cell surface expression.

Subunit / interactions. Interacts with PTK2/FAK1.

Subcellular location. Cell junction. Focal adhesion. Cytoplasmic vesicle. Endosome.

Domain organisation. The FYVE-type zinc finger mediates interaction with PTK2/FAK1, and also interaction with PI(3)P and association with endosomes. The C-terminal region exhibits a structure similar to canonical PH domains, but lacks a positively charged interface to bind phosphatidylinositol phosphate.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BQ24-1	1	yes
Q9BQ24-2	2

RefSeq proteins (2): NP_001185882, NP_076976* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000306	Znf_FYVE	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017455	Znf_FYVE-rel	Domain
IPR032031	ZFYVE21_C	Domain
IPR038632	ZFYVE21_C_sf	Homologous_superfamily
IPR052113	FYVE-type_Zinc_Finger	Family

Pfam: PF01363, PF16696

UniProt features (24 total): binding site 8, strand 8, helix 2, chain 1, zinc finger region 1, splice variant 1, mutagenesis site 1, turn 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2RRF	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BQ24-F1	91.34	0.80

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 (8): 99; 50; 53; 66; 69; 74; 77; 96

Mutagenesis-validated functional residues (1):

Position	Phenotype
64–65	diffuse cytoplasmic localization.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 140 (showing top): GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, SENGUPTA_NASOPHARYNGEAL_CARCINOMA_DN, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, ACTTTAT_MIR1425P, chr14q32, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_DN, GOCC_ANCHORING_JUNCTION, DODD_NASOPHARYNGEAL_CARCINOMA_DN, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_DN, BRUINS_UVC_RESPONSE_MIDDLE, WAKABAYASHI_ADIPOGENESIS_PPARG_RXRA_BOUND_8D, AKT_UP.V1_DN, ASH1L_TARGET_GENES, CEBPZ_TARGET_GENES

GO Biological Process (0):

GO Molecular Function (3): zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (4): endosome (GO:0005768), focal adhesion (GO:0005925), cytoplasmic vesicle (GO:0031410), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transition metal ion binding	1
binding	1
cation binding	1
endomembrane system	1
cytoplasmic vesicle	1
cell-substrate junction	1
cytoplasm	1
intracellular vesicle	1
cell junction	1

Protein interactions and networks

STRING

554 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ZFYVE21	TLN1	Q9Y490	581
ZFYVE21	PPP1R13B	Q96KQ4	559
ZFYVE21	BAG5	Q9UL15	557
ZFYVE21	PTK2	Q05397	556
ZFYVE21	VTN	P01141	549
ZFYVE21	WDR3	Q9UNX4	460
ZFYVE21	SPAG17	Q6Q759	457
ZFYVE21	TDRD9	Q8NDG6	441
ZFYVE21	COL1A1	P02452	435
ZFYVE21	ITGB1	P05556	428
ZFYVE21	XRCC3	O43542	422
ZFYVE21	PRSS45P	Q7RTY3	421
ZFYVE21	CSDE1	O75534	415
ZFYVE21	VANGL1	Q8TAA9	411
ZFYVE21	ZNF593	O00488	409

IntAct

105 interactions, top by confidence:

A	B	Type	Score
ZFYVE21	ARL6IP1	psi-mi:“MI:0915”(physical association)	0.720
RABAC1	ZFYVE21	psi-mi:“MI:0915”(physical association)	0.720
ZFYVE21	RABAC1	psi-mi:“MI:0915”(physical association)	0.720
ARL6IP1	ZFYVE21	psi-mi:“MI:0915”(physical association)	0.720
KRT38	ZFYVE21	psi-mi:“MI:0915”(physical association)	0.560
TRIM27	ZFYVE21	psi-mi:“MI:0915”(physical association)	0.560
KRTAP5-9	ZFYVE21	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-5	ZFYVE21	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-8	ZFYVE21	psi-mi:“MI:0915”(physical association)	0.560
ZFYVE21	TRAF1	psi-mi:“MI:0915”(physical association)	0.560
ZFYVE21	KRT31	psi-mi:“MI:0915”(physical association)	0.560
MTUS2	ZFYVE21	psi-mi:“MI:0915”(physical association)	0.560
PDE4DIP	ZFYVE21	psi-mi:“MI:0915”(physical association)	0.560
KRT40	ZFYVE21	psi-mi:“MI:0915”(physical association)	0.560
ZFYVE21	AGTRAP	psi-mi:“MI:0915”(physical association)	0.560
NOTCH2NLA	ZFYVE21	psi-mi:“MI:0915”(physical association)	0.560
SIAH1	ZFYVE21	psi-mi:“MI:0915”(physical association)	0.560
REEP6	ZFYVE21	psi-mi:“MI:0915”(physical association)	0.560
ZFYVE21	RTN4	psi-mi:“MI:0915”(physical association)	0.560
ZFYVE21	MID2	psi-mi:“MI:0915”(physical association)	0.560
ZFYVE21		psi-mi:“MI:0915”(physical association)	0.560
ZFYVE21	KRT38	psi-mi:“MI:0915”(physical association)	0.560
ZFYVE21	KRTAP5-9	psi-mi:“MI:0915”(physical association)	0.560
ZFYVE21	KRTAP10-5	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (101): ZFYVE21 (Two-hybrid), ZFYVE21 (Two-hybrid), ZFYVE21 (Two-hybrid), ZFYVE21 (Two-hybrid), ZFYVE21 (Two-hybrid), ZFYVE21 (Two-hybrid), ZFYVE21 (Two-hybrid), ZFYVE21 (Two-hybrid), ZFYVE21 (Two-hybrid), ZFYVE21 (Two-hybrid), ZFYVE21 (Two-hybrid), ZFYVE21 (Two-hybrid), ZFYVE21 (Two-hybrid), REEP6 (Two-hybrid), KRT40 (Two-hybrid)

ESM2 similar proteins: D3YXJ0, D3ZVP7, E9PUQ8, M9MRI4, O00562, O14827, O35954, O70143, O75689, O76902, O95248, P08240, P11862, P34657, Q02280, Q05B78, Q15057, Q16760, Q17QP1, Q29RQ5, Q2I6J0, Q2KI13, Q38JA7, Q4R584, Q505D9, Q5F3R2, Q5RFL4, Q5U2N3, Q5W7F2, Q5ZK62, Q64398, Q68FU1, Q6NNF2, Q6NVJ5, Q6ZPE2, Q6ZTA4, Q810J8, Q86XP1, Q8C7M3, Q8VCM3

Diamond homologs: A0A0D1E015, A0JMD2, A1CEK1, A1DFP5, A2QWA2, A4QTV1, A8QCE4, A8XJZ8, B0G126, B0WAQ0, B3MT31, B3P851, B4G2G5, B4IC49, B4JHI7, B4K982, B4M140, B4NFJ7, B4PRU6, D2H5P6, D3ZVP7, D4A8G9, E1BLZ4, F1MM41, F7EP40, O13821, O14964, O59722, O76902, O95405, O96838, P0CS26, P0CS27, P34756, P40343, Q05B78, Q08CN9, Q0CJV3, Q0P4S0, Q0U4Z8

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 40 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Keratinization	6	13.9×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1693 predictions. Top by Δscore:

Variant	Effect	Δscore
14:103715976:GGAG:G	donor_gain	1.0000
14:103715977:GAGG:G	donor_gain	1.0000
14:103726790:A:AG	acceptor_gain	1.0000
14:103726791:G:GG	acceptor_gain	1.0000
14:103726791:GT:G	acceptor_gain	1.0000
14:103726838:GAAAG:G	donor_gain	1.0000
14:103726839:AAAG:A	donor_loss	1.0000
14:103726841:AGGTG:A	donor_loss	1.0000
14:103726843:GTGAG:G	donor_loss	1.0000
14:103726844:T:A	donor_loss	1.0000
14:103727739:T:TA	acceptor_gain	1.0000
14:103727910:GAGCG:G	donor_gain	1.0000
14:103727912:GCG:G	donor_gain	1.0000
14:103727913:CGGTA:C	donor_loss	1.0000
14:103727914:GGT:G	donor_loss	1.0000
14:103727915:G:C	donor_loss	1.0000
14:103727915:G:GG	donor_gain	1.0000
14:103727916:T:A	donor_loss	1.0000
14:103728904:CAA:C	acceptor_loss	1.0000
14:103728905:A:AG	acceptor_gain	1.0000
14:103728905:AAG:A	acceptor_gain	1.0000
14:103728906:A:AG	acceptor_gain	1.0000
14:103728907:G:A	acceptor_gain	1.0000
14:103728907:G:GG	acceptor_gain	1.0000
14:103728907:GGA:G	acceptor_gain	1.0000
14:103728980:AGAGG:A	donor_loss	1.0000
14:103728981:GAG:G	donor_gain	1.0000
14:103728984:GT:G	donor_loss	1.0000
14:103732615:TCCAG:T	acceptor_loss	1.0000
14:103732616:CCAG:C	acceptor_loss	1.0000

AlphaMissense

1532 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:103715964:G:C	W41C	1.000
14:103715964:G:T	W41C	1.000
14:103715962:T:A	W41R	0.999
14:103715962:T:C	W41R	0.999
14:103726822:T:C	F57L	0.999
14:103726824:T:A	F57L	0.999
14:103726824:T:G	F57L	0.999
14:103727746:C:G	H64D	0.999
14:103727749:C:G	H65D	0.999
14:103727751:C:A	H65Q	0.999
14:103727751:C:G	H65Q	0.999
14:103726838:G:C	R62T	0.998
14:103726838:G:T	R62I	0.998
14:103726839:A:C	R62S	0.998
14:103726839:A:T	R62S	0.998
14:103727748:C:A	H64Q	0.998
14:103727748:C:G	H64Q	0.998
14:103727752:T:C	C66R	0.998
14:103727754:T:G	C66W	0.998
14:103727755:C:A	R67S	0.998
14:103727765:G:A	G70E	0.998
14:103727765:G:T	G70V	0.998
14:103727821:T:C	F89L	0.998
14:103727823:T:A	F89L	0.998
14:103727823:T:G	F89L	0.998
14:103726823:T:G	F57C	0.997
14:103727752:T:A	C66S	0.997
14:103727753:G:A	C66Y	0.997
14:103727753:G:C	C66S	0.997
14:103727851:T:C	C99R	0.997

dbSNP variants (sampled 300 via entrez): RS1000145154 (14:103721485 C>T), RS1000230400 (14:103719684 C>T), RS1000291275 (14:103714925 C>A,T), RS1000321398 (14:103723974 A>G), RS1000406236 (14:103714612 A>T), RS1000504846 (14:103729594 A>G), RS1000552893 (14:103728387 C>A,T), RS1000627116 (14:103715785 C>G,T), RS1000658189 (14:103724875 T>G), RS1000732900 (14:103715575 C>T), RS1001172713 (14:103723504 C>A), RS1001333883 (14:103733103 A>G), RS1001448154 (14:103732900 C>T), RS1001642251 (14:103719501 G>C), RS1001724783 (14:103728159 G>T)

Disease associations

OMIM: gene MIM:613504 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST002539_23	Schizophrenia	1.000000e-13
GCST004521_135	Autism spectrum disorder or schizophrenia	2.000000e-09
GCST004521_15	Autism spectrum disorder or schizophrenia	2.000000e-12
GCST004521_262	Autism spectrum disorder or schizophrenia	6.000000e-09
GCST005951_9	Body mass index	4.000000e-09
GCST006803_15	Schizophrenia	3.000000e-14
GCST008103_98	Bipolar disorder	2.000000e-06
GCST009600_35	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	3.000000e-12
GCST90002384_374	Hemoglobin	9.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004509	hemoglobin measurement

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
Cyclosporine	decreases expression	2
FR900359	decreases phosphorylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	increases methylation	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
K 7174	decreases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
jinfukang	increases expression	1
Temozolomide	increases expression	1
Leflunomide	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Doxorubicin	increases expression	1
Methapyrilene	increases methylation	1
Potassium Dichromate	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases methylation	1
Tunicamycin	decreases expression	1
Valproic Acid	decreases expression	1
Antirheumatic Agents	increases expression	1
Copper Sulfate	decreases expression	1
Vitamin K 3	affects expression	1

Clinical trials (associated diseases)

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