VWA2

Summary

VWA2 (von Willebrand factor A domain containing 2, HGNC:24709) is a protein-coding gene on chromosome 10q25.3, encoding von Willebrand factor A domain-containing protein 2 (Q5GFL6).

This gene encodes a member of the von Willebrand factor A-like domain protein superfamily. The encoded protein is localized to the extracellular matrix and may serve as a structural component in basement membranes or in anchoring structures on scaffolds of collagen VII or fibrillin. This gene has been linked to type 1A diabetes and is a candidate serological marker for colon cancer.

Source: NCBI Gene 340706 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital anomaly of kidney and urinary tract (Limited, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 30 total — 1 pathogenic
• MANE Select transcript: NM_001272046

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24709
Approved symbol	VWA2
Name	von Willebrand factor A domain containing 2
Location	10q25.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ45857, FLJ16213, CCSP-2, AMACO, NET42
Ensembl gene	ENSG00000165816
Ensembl biotype	protein_coding
OMIM	618281
Entrez	340706

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 retained_intron

ENST00000298715, ENST00000392982, ENST00000603594, ENST00000892505, ENST00000942547

RefSeq mRNA: 2 — MANE Select: NM_001272046 NM_001272046, NM_001320804

CCDS: CCDS7589

Canonical transcript exons

ENST00000392982 — 14 exons

Exon	Start	End
ENSE00001449371	114290240	114290365
ENSE00001449373	114288938	114289489
ENSE00001613715	114291218	114294489
ENSE00003473205	114282516	114282571
ENSE00003514201	114285939	114286511
ENSE00003516409	114272740	114272934
ENSE00003521910	114254915	114255048
ENSE00003543392	114284863	114284970
ENSE00003550071	114253651	114253725
ENSE00003631480	114278719	114278851
ENSE00003663321	114248704	114248765
ENSE00003672089	114261186	114261295
ENSE00003686850	114277914	114278047
ENSE00003848363	114239254	114239569

Expression profiles

Bgee: expression breadth ubiquitous, 122 present calls, max score 91.44.

FANTOM5 (CAGE): breadth broad, TPM avg 0.7111 / max 254.3284, expressed in 233 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
107155	0.3369	104
107159	0.2637	108
107156	0.0349	11
107160	0.0329	12
107158	0.0173	7
107157	0.0128	6
107161	0.0125	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
thymus	UBERON:0002370	91.44	gold quality
right uterine tube	UBERON:0001302	79.71	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	78.69	gold quality
sural nerve	UBERON:0015488	76.99	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.06	gold quality
body of stomach	UBERON:0001161	74.54	gold quality
stomach	UBERON:0000945	74.03	gold quality
fundus of stomach	UBERON:0001160	72.12	gold quality
skin of abdomen	UBERON:0001416	71.75	gold quality
zone of skin	UBERON:0000014	70.25	gold quality
body of pancreas	UBERON:0001150	69.72	gold quality
quadriceps femoris	UBERON:0001377	69.42	gold quality
skin of leg	UBERON:0001511	69.03	gold quality
pancreas	UBERON:0001264	68.22	gold quality
fallopian tube	UBERON:0003889	67.87	gold quality
cerebellar vermis	UBERON:0004720	67.75	gold quality
prostate gland	UBERON:0002367	67.71	gold quality
duodenum	UBERON:0002114	66.43	gold quality
saliva-secreting gland	UBERON:0001044	66.09	gold quality
lung	UBERON:0002048	65.88	gold quality
islet of Langerhans	UBERON:0000006	65.72	gold quality
tibial nerve	UBERON:0001323	65.67	gold quality
esophagus mucosa	UBERON:0002469	65.30	gold quality
minor salivary gland	UBERON:0001830	65.28	gold quality
tonsil	UBERON:0002372	64.98	gold quality
upper lobe of left lung	UBERON:0008952	63.89	gold quality
vagina	UBERON:0000996	63.39	gold quality
right lung	UBERON:0002167	63.12	gold quality
prefrontal cortex	UBERON:0000451	62.38	gold quality
primary visual cortex	UBERON:0002436	62.05	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7249	yes	27.62
E-ANND-3	yes	5.70

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 8)

• AMACO is a new member of the von Willebrand factor A-like domain protein superfamily with a regulated expression in the kidney (PMID:14506275)
• CCSP-2 is a novel candidate for development as a diagnostic serum marker of early stage colon cancer (PMID:15580307)
• Single nucleotide polymorphisms in the AMACO gene are associated with dominant protection against Type 1A diabetes in an Arab family. (PMID:15699509)
• O-glucosylation and O-fucosylation occur together in close proximity on the first epidermal growth factor repeat of AMACO (PMID:18434322)
• By kinetic analysis of recombinant ADAMTS13 constructs, we show that the first thrombospondin-1, Cys-rich, and spacer domains of ADAMTS13 interact with segments of VWF domain A2 between Gln(1624) and Arg(1668). (PMID:18492952)
• We have revealed a novel Ca((2)+)-binding site at the A2 domain of VWF and demonstrated a relationship between Ca((2)+) and force in the regulation of VWF and primary hemostasis (PMID:21385852)
• VWA2 might be a constituent of a larger oncogenic transcriptional program regulated by c-Myc. (PMID:30038405)
• Contribution of homozygous and compound heterozygous missense mutations in VWA2 to Alzheimer’s disease. (PMID:33023779)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	vwa2	ENSDARG00000075441
mus_musculus	Vwa2	ENSMUSG00000025082
rattus_norvegicus	Vwa2	ENSRNOG00000025581

Paralogs (12): COCH (ENSG00000100473), COL12A1 (ENSG00000111799), MATN4 (ENSG00000124159), MATN3 (ENSG00000132031), MATN2 (ENSG00000132561), MATN1 (ENSG00000162510), COL6A3 (ENSG00000163359), COL6A5 (ENSG00000172752), VWA1 (ENSG00000179403), COL14A1 (ENSG00000187955), VIT (ENSG00000205221), COL6A6 (ENSG00000206384)

Protein

Protein identifiers

von Willebrand factor A domain-containing protein 2 — Q5GFL6 (reviewed: Q5GFL6)

Alternative names: A domain-containing protein similar to matrilin and collagen, Colon cancer secreted protein 2

All UniProt accessions (1): Q5GFL6

UniProt curated annotations — full annotation on UniProt →

Subunit / interactions. Forms monomers and multimers.

Subcellular location. Secreted.

Tissue specificity. Expression is generally absent in normal colon and other normal body tissues, but it is induced an average of 78-fold in Stage II, III, and IV colon cancers, as well as in colon adenomas and colon cancer cell lines.

Post-translational modifications. A 55 kDa form is produced by proteolytic cleavage.

Miscellaneous. May be used as a serological marker for colon neoplasia.

Isoforms (3)

UniProt ID	Names	Canonical?
Q5GFL6-1	1	yes
Q5GFL6-2	2
Q5GFL6-3	3

RefSeq proteins (2): NP_001258975, NP_001307733 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR002035	VWF_A	Domain
IPR036465	vWFA_dom_sf	Homologous_superfamily
IPR050525	ECM_Assembly_Org	Family

Pfam: PF00008, PF00092

UniProt features (23 total): disulfide bond 6, domain 5, splice variant 3, sequence variant 3, sequence conflict 2, signal peptide 1, chain 1, site 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5GFL6-F1	86.02	0.47

Functional residue map

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

Catalytic / active sites (1): 267–268 (cleavage)

Disulfide bonds (6): 304–320, 322–332, 716–727, 721–736, 738–747, 299–310

Glycosylation sites (1): 147

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 76 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_INSULIN_STIMULUS, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, GOBP_RESPONSE_TO_INSULIN, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_HORMONE, LEF1_Q6, E12_Q6, GOCC_BASEMENT_MEMBRANE, GOBP_CELL_SUBSTRATE_ADHESION, GOBP_CELL_MATRIX_ADHESION, TGGAAA_NFAT_Q4_01, chr10q25

GO Biological Process (2): calcium-independent cell-matrix adhesion (GO:0007161), regulation of insulin receptor signaling pathway (GO:0046626)

GO Molecular Function (3): calcium ion binding (GO:0005509), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (4): basement membrane (GO:0005604), obsolete extracellular space (GO:0005615), extracellular exosome (GO:0070062), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell-matrix adhesion	1
insulin receptor signaling pathway	1
regulation of signal transduction	1
metal ion binding	1
protein binding	1
binding	1
extracellular matrix	1
extracellular vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

809 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VWA2	FREM1	Q5H8C1	594
VWA2	NHLRC2	Q8NBF2	561
VWA2	CEMIP	Q8WUJ3	484
VWA2	FREM2	Q5SZK8	476
VWA2	SPATA31D3	P0C874	446
VWA2	LRRC30	A6NM36	430
VWA2	ABLIM1	O14639	422
VWA2	FRAS1	Q86XX4	403
VWA2	SPATA31D4	Q6ZUB0	397
VWA2	AFAP1	Q8N556	394
VWA2	ADRB1	P08588	391
VWA2	GAGE12J	A6NER3	370
VWA2	TDRD1	Q9BXT4	369
VWA2	CDADC1	Q9BWV3	360
VWA2	FANK1	Q8TC84	355

IntAct

7 interactions, top by confidence:

A	B	Type	Score
TRAF2	VWA2	psi-mi:“MI:0915”(physical association)	0.560
VWA2	TRAF2	psi-mi:“MI:0915”(physical association)	0.560
KLF15	PPP2R5E	psi-mi:“MI:0914”(association)	0.530
VWA2	WDR47	psi-mi:“MI:0914”(association)	0.350
VWA2	RECQL4	psi-mi:“MI:0914”(association)	0.350

BioGRID (41): VWA2 (Two-hybrid), TUBB7P (Affinity Capture-MS), TCTEX1D2 (Affinity Capture-MS), UBB (Affinity Capture-MS), VWA2 (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), WDR47 (Affinity Capture-MS), HSPA2 (Affinity Capture-MS), VWA2 (Two-hybrid), DDX19B (Affinity Capture-MS), TUBB7P (Affinity Capture-MS), TCTEX1D2 (Affinity Capture-MS), HSPA8 (Affinity Capture-MS), VWA2 (Affinity Capture-MS), UBB (Affinity Capture-MS)

ESM2 similar proteins: A2AX52, A6H584, A6NMZ7, A6X935, A8TX70, E1BMV3, E7FF10, O00339, O02668, O08746, O55123, O89029, P05099, P06681, P12111, P15989, P19823, P19827, P21180, P21941, P51942, P79263, P97278, P97279, Q0IIH7, Q0V8T0, Q0V8T5, Q0V8T6, Q0V8T7, Q0VCM5, Q14624, Q21540, Q29052, Q3SYW2, Q3T052, Q5GFL6, Q61702, Q61703, Q6DCQ6, Q70UZ7

Diamond homologs: A2AX52, A6QLN9, E1BMV3, E7FF10, O00339, O08746, O15232, O35701, O42163, O42401, O43405, O75578, O89029, O95460, P05099, P12111, P13944, P15989, P17301, P18614, P21941, P24063, P32018, P51942, P53710, P56199, P84552, Q02388, Q21540, Q3V3R4, Q5EA64, Q5GFL6, Q60847, Q62507, Q63870, Q642A6, Q6DCQ6, Q6PCB0, Q6UXI7, Q70UZ7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	2
Likely benign	10
Benign	12

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
443323	GRCh37/hg19 10q23.32-26.3(chr10:93283493-135427143)x3	Pathogenic

SpliceAI

2516 predictions. Top by Δscore:

Variant	Effect	Δscore
10:114248691:T:TA	acceptor_gain	1.0000
10:114248693:T:TA	acceptor_gain	1.0000
10:114248699:TGTA:T	acceptor_loss	1.0000
10:114248701:TAG:T	acceptor_loss	1.0000
10:114248702:A:AC	acceptor_loss	1.0000
10:114248702:A:AG	acceptor_gain	1.0000
10:114248703:G:GG	acceptor_gain	1.0000
10:114248703:GT:G	acceptor_gain	1.0000
10:114248703:GTT:G	acceptor_gain	1.0000
10:114248703:GTTA:G	acceptor_gain	1.0000
10:114248703:GTTAT:G	acceptor_gain	1.0000
10:114248763:GAG:G	donor_gain	1.0000
10:114248766:G:GC	donor_loss	1.0000
10:114248767:T:A	donor_loss	1.0000
10:114253726:G:GG	donor_gain	1.0000
10:114261261:G:GT	donor_gain	1.0000
10:114272727:T:TA	acceptor_gain	1.0000
10:114272728:G:A	acceptor_gain	1.0000
10:114289462:G:GT	donor_gain	1.0000
10:114289487:GAGGT:G	donor_loss	1.0000
10:114289490:G:GC	donor_loss	1.0000
10:114289491:T:A	donor_loss	1.0000
10:114253649:A:AG	acceptor_gain	0.9900
10:114253650:G:GG	acceptor_gain	0.9900
10:114253650:GT:G	acceptor_gain	0.9900
10:114254913:A:AG	acceptor_gain	0.9900
10:114254914:G:GG	acceptor_gain	0.9900
10:114255047:GG:G	donor_gain	0.9900
10:114255048:GG:G	donor_gain	0.9900
10:114261271:C:T	donor_gain	0.9900

AlphaMissense

4873 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:114290296:T:A	C727S	0.971
10:114290297:G:C	C727S	0.971
10:114286241:T:C	F434L	0.965
10:114286243:C:A	F434L	0.965
10:114286243:C:G	F434L	0.965
10:114254948:T:C	F54S	0.964
10:114290263:T:A	C716S	0.961
10:114290264:G:C	C716S	0.961
10:114290278:T:A	C721S	0.961
10:114290279:G:C	C721S	0.961
10:114261207:T:C	F95L	0.960
10:114261209:C:A	F95L	0.960
10:114261209:C:G	F95L	0.960
10:114255000:G:C	K71N	0.958
10:114255000:G:T	K71N	0.958
10:114272909:T:C	F181L	0.957
10:114272911:T:A	F181L	0.957
10:114272911:T:G	F181L	0.957
10:114254986:T:C	F67L	0.955
10:114254988:T:A	F67L	0.955
10:114254988:T:G	F67L	0.955
10:114290323:T:A	C736S	0.955
10:114290324:G:C	C736S	0.955
10:114261231:T:C	F103L	0.954
10:114261233:C:A	F103L	0.954
10:114261233:C:G	F103L	0.954
10:114290297:G:A	C727Y	0.953
10:114285978:T:C	F346S	0.952
10:114284883:T:A	C304S	0.950
10:114284884:G:C	C304S	0.950

dbSNP variants (sampled 300 via entrez): RS1000006452 (10:114237909 C>G,T), RS1000116339 (10:114288680 G>A,C), RS1000144058 (10:114285564 G>A), RS1000185674 (10:114247862 G>A), RS1000230255 (10:114259441 C>A,T), RS1000281733 (10:114253812 T>A,C), RS1000314984 (10:114291034 G>A,C), RS1000333797 (10:114242468 T>C), RS1000349462 (10:114280387 T>C), RS1000456119 (10:114287400 C>T), RS1000545224 (10:114275626 T>A), RS1000579825 (10:114275413 C>T), RS1000630942 (10:114263928 A>G), RS1000680917 (10:114282158 C>G), RS1000763322 (10:114242908 G>A,C)

Disease associations

OMIM: gene MIM:618281 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital anomaly of kidney and urinary tract	Limited	Autosomal recessive

Mondo (1): congenital anomaly of kidney and urinary tract (MONDO:0019719)

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006585_901	Blood protein levels	8.000000e-25
GCST90002388_526	Lymphocyte count	3.000000e-09
GCST90002393_343	Monocyte count	6.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004587	lymphocyte count
EFO:0005091	monocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C566906	Cakut (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
aristolochic acid I	increases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	affects cotreatment, decreases expression, increases abundance	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	affects methylation, decreases methylation	1
CGP 52608	increases reaction, affects binding	1
(+)-JQ1 compound	decreases expression	1
2,6-dichloro-(1,4)benzoquinone	increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Methapyrilene	decreases methylation	1
Tobacco Smoke Pollution	decreases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04115345	PHASE1	COMPLETED	A Study of a Renal Autologous Cell Therapy (REACT) in Patients With Chronic Kidney Disease (CKD) From Congenital Anomalies of the Kidney and Urinary Tract (CAKUT).
NCT05694169	PHASE1	TERMINATED	A Study of Participants With Chronic Kidney Disease Previously Treated With REACT
NCT04537364	Not specified	COMPLETED	Prediction of Renal Parenchymal Damage of CAKUT
NCT06921733	Not specified	RECRUITING	Ultrasound Localization Microscopy in Patient With Congenital Anomalies of the Kidney and Urinary Tract (CAKUT)