ANXA6

Summary

ANXA6 (annexin A6, HGNC:544) is a protein-coding gene on chromosome 5q33.1, encoding Annexin A6 (P08133). May associate with CD21.

Annexin VI belongs to a family of calcium-dependent membrane and phospholipid binding proteins. Several members of the annexin family have been implicated in membrane-related events along exocytotic and endocytotic pathways. The annexin VI gene is approximately 60 kbp long and contains 26 exons. It encodes a protein of about 68 kDa that consists of eight 68-amino acid repeats separated by linking sequences of variable lengths. It is highly similar to human annexins I and II sequences, each of which contain four such repeats. Annexin VI has been implicated in mediating the endosome aggregation and vesicle fusion in secreting epithelia during exocytosis. Alternatively spliced transcript variants have been described.

Source: NCBI Gene 309 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 170 total
• Druggable target: yes
• MANE Select transcript: NM_001155

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:544
Approved symbol	ANXA6
Name	annexin A6
Location	5q33.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000197043
Ensembl biotype	protein_coding
OMIM	114070
Entrez	309

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 34 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000354546, ENST00000377751, ENST00000517486, ENST00000517677, ENST00000517707, ENST00000517757, ENST00000519610, ENST00000519644, ENST00000520054, ENST00000520378, ENST00000521512, ENST00000521749, ENST00000522664, ENST00000523164, ENST00000523714, ENST00000700367, ENST00000893676, ENST00000893677, ENST00000893678, ENST00000893679, ENST00000893680, ENST00000893681, ENST00000893682, ENST00000893683, ENST00000893684, ENST00000893685, ENST00000893686, ENST00000893687, ENST00000893688, ENST00000893689, ENST00000893690, ENST00000893693, ENST00000935749, ENST00000941434, ENST00000941435, ENST00000941436, ENST00000941437, ENST00000941438, ENST00000941439, ENST00000941440

RefSeq mRNA: 3 — MANE Select: NM_001155 NM_001155, NM_001193544, NM_001363114

CCDS: CCDS47314, CCDS47315, CCDS54941

Canonical transcript exons

ENST00000354546 — 26 exons

Exon	Start	End
ENSE00000767754	151105245	151105303
ENSE00000767755	151108455	151108550
ENSE00000767756	151109753	151109846
ENSE00000767758	151117758	151117837
ENSE00000767759	151119300	151119390
ENSE00000767770	151136256	151136335
ENSE00000767771	151137231	151137321
ENSE00000767772	151138678	151138791
ENSE00000841252	151117127	151117180
ENSE00000841253	151139353	151139447
ENSE00000972889	151103570	151103692
ENSE00002093216	151157680	151157779
ENSE00002130581	151100706	151101507
ENSE00002484563	151110627	151110644
ENSE00003499983	151122147	151122260
ENSE00003502102	151122917	151123011
ENSE00003519281	151133094	151133187
ENSE00003578447	151129407	151129529
ENSE00003605571	151124286	151124367
ENSE00003631413	151140153	151140243
ENSE00003644105	151131231	151131289
ENSE00003648816	151128181	151128239
ENSE00003658508	151126402	151126480
ENSE00003673005	151147884	151147926
ENSE00003675639	151132476	151132571
ENSE00003787707	151134427	151134483

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 99.08.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 204.5445 / max 1357.8017, expressed in 1802 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
64343	202.3192	1802
64342	1.6350	758
64340	0.2264	75
64341	0.1820	57
64339	0.1819	52

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.08	gold quality
smooth muscle tissue	UBERON:0001135	98.92	gold quality
right coronary artery	UBERON:0001625	98.89	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.89	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.86	gold quality
lower esophagus	UBERON:0013473	98.85	gold quality
apex of heart	UBERON:0002098	98.73	gold quality
stromal cell of endometrium	CL:0002255	98.69	gold quality
popliteal artery	UBERON:0002250	98.68	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.68	gold quality
tibial artery	UBERON:0007610	98.68	gold quality
mucosa of stomach	UBERON:0001199	98.67	gold quality
right ovary	UBERON:0002118	98.67	gold quality
left uterine tube	UBERON:0001303	98.66	gold quality
adenohypophysis	UBERON:0002196	98.66	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.66	gold quality
aorta	UBERON:0000947	98.65	gold quality
thoracic aorta	UBERON:0001515	98.65	gold quality
left coronary artery	UBERON:0001626	98.65	gold quality
ascending aorta	UBERON:0001496	98.64	gold quality
descending thoracic aorta	UBERON:0002345	98.62	gold quality
coronary artery	UBERON:0001621	98.59	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.57	gold quality
omental fat pad	UBERON:0010414	98.56	gold quality
peritoneum	UBERON:0002358	98.55	gold quality
pituitary gland	UBERON:0000007	98.53	gold quality
body of uterus	UBERON:0009853	98.52	gold quality
endocervix	UBERON:0000458	98.46	gold quality
left ovary	UBERON:0002119	98.45	gold quality
ventricular zone	UBERON:0003053	98.45	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	43.11
E-HCAD-10	yes	37.15
E-MTAB-8142	yes	25.99
E-HCAD-11	yes	19.29
E-ANND-3	yes	13.12
E-CURD-114	yes	11.52
E-MTAB-8498	yes	10.38
E-MTAB-6678	yes	9.72
E-GEOD-134144	yes	9.01
E-MTAB-9388	yes	8.58
E-CURD-112	yes	4.24
E-GEOD-70580	no	1834.04
E-GEOD-100618	no	247.77

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

33 targeting ANXA6, 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-432-3P	100.00	67.86	705
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-10393-3P	99.72	66.56	961
HSA-MIR-6801-5P	99.72	66.50	981
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6716-5P	99.56	68.62	1244
HSA-MIR-569	99.42	66.32	1009
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-3154	98.94	66.55	1455
HSA-MIR-181A-2-3P	98.91	67.60	1168
HSA-MIR-4436B-3P	98.25	65.26	1494
HSA-MIR-6735-5P	98.24	65.36	1488
HSA-MIR-7843-5P	98.12	65.26	1421
HSA-MIR-4483	98.09	64.12	1642
HSA-MIR-4257	97.86	68.05	1190
HSA-MIR-4632-5P	97.82	65.38	1470
HSA-MIR-6879-5P	97.77	65.52	1521
HSA-MIR-4670-3P	97.37	68.35	1378
HSA-MIR-3137	97.26	66.78	761
HSA-MIR-3674	97.01	68.86	1171
HSA-MIR-3935	96.33	66.79	797
HSA-MIR-1293	96.16	64.69	916
HSA-MIR-6753-5P	94.70	64.08	470

Literature-anchored findings (GeneRIF, showing 40)

• Data show that annexin 6 is a candidate receptor for chondroitin sulfate chains. (PMID:12140262)
• Characterization of phosphorylation-mimicking mutant annexin VI (T356D) reveals a potential regulatory mechanism leading to a higher degree of flexibility and possibly a higher calcium binding affinity of annexin VI upon phosphorylation. (PMID:12534274)
• The nucleotide-binding site of ANXA6 is formed by the amino acid residues located in both halves of the protein, in two distinct domains. (PMID:12885247)
• cell surface annexin VI may function as an acidic pH binding site or receptor and may also function as a co-receptor with LRP-1 at neutral pH (PMID:15226301)
• endogenous annexin 6 could regulate the Maxi-chloride channel in placenta (PMID:15355961)
• TPD52 bound to annexin VI in a Ca(2+)-dependent manner suggesting that these molecules may act in concert to regulate secretory processes in plasma cells (PMID:15576473)
• Macrophage reprogramming during oxidative stress occurs through the cytosolic mobilization of annexin VI from lipid rafts. (PMID:16153422)
• It is a first report supporting the hypothesis of a direct implication of AnxA6 in vitamin A-dependent tissue mineralization. (PMID:16674946)
• Annexin A6 has roles in alterations in cholesterol transport and caveolin export from the Golgi complex (PMID:17822395)
• analysis of the pH-induced membrane binding of annexins A6 and A2-S100A10 (PMID:17824845)
• analysis of translocation and assembly at the plasma membrane and the nuclear envelope (PMID:18164291)
• AnxA6 interferes with caveolin transport through the inhibition of cPLA(2). (PMID:18245088)
• annexin A6 contributes to the calcium-dependent cell surface exposition of the membrane associated-S100A8/A9 complex (PMID:18786929)
• Annexin A6 is highly abundant in monocytes of obese and type 2 diabetic individuals. (PMID:19322030)
• These findings indicate that the polymorphisms of ANXA6 are associated with osteonecrosis of the femoral head. (PMID:19345290)
• results implicate annexin A6 in the actin-dependent regulation of Ca(2+) entry, with consequences for the rates of cell proliferation (PMID:19386597)
• AnxA6 may participate in formation of cholesterol-rich platforms on LE and therefore may contribute to the pathology of the NPC disease. (PMID:19900398)
• Data suggests that the hydroxyl group of cholesterol and Trp 343 are involved in AnxA6-membrane interactions. (PMID:20363475)
• In addition to regulating cholesterol and caveolin distribution, AnxA6 acts as a scaffold/targeting protein for several signaling proteins. (PMID:20888375)
• High ANXA6 expression in the cytoplasm is associated with uterine cervix carcinogenesis. (PMID:21119665)
• reduced AnxA6 expression contributes to breast cancer progression by promoting the loss of functional cell-cell and/or cell-ECM contacts and anchorage-independent cell proliferation (PMID:21185831)
• In the presence of calcium, AnxA6 re-located to the fractions enriched in detergent-resistant microdomains only in the Niemann-Pick type C disease cells, suggestive of AnxA6 participation in organization of these microdomains. (PMID:21216236)
• AnxA6 is a novel receptor that mediates the endocytosis of bovine beta-glucuronidase. (PMID:21672540)
• the regulation of cell surface receptors by annexin A6 may be facilitated by its unique structure that allows recruitment of interaction partners and simultaneously bridging specialized membrane domains with cortical actin surrounding activated receptors (PMID:21990038)
• AnxA6 via its stimulatory actions on PKCalpha and its role in mediating Ca(2+) flux across membranes regulates terminal differentiation and mineralization events of chondrocytes. (PMID:22399299)
• AnxA6 is a new PKCalpha scaffold to promote PKCalpha-mediated EGFR inactivation. (PMID:22797061)
• anxA6 inhibits Drp1 activity, and Ca(2+)-binding to anxA6 relieves this inhibition to permit Drp1-mediated mitochondrial fission (PMID:23341998)
• Ca(2+) is the main factor which regulates the interaction of AnxA6 with monolayers composed of neutral lipids, determine AnxA6 localization in cholesterol and sphingomyelin enriched microdomains, thus contributing to the etiology of the NPC disease. (PMID:23360953)
• TNIP1/ANXA6 and CSMD1 variants interacting with cigarette smoking and alcohol intake affect risk of psoriasis. (PMID:23541940)
• Influence of the 524-VAAEIL-529 sequence of annexins A6 in their interfacial behavior and interaction with lipid monolayers. (PMID:23683957)
• These results show that influenza A virus replication depends on maintenance of the cellular cholesterol balance and identify AnxA6 as a critical factor in linking the virus to cellular cholesterol homeostasis. (PMID:24194536)
• The rapid degradation of activated EGFR in AnxA6-depleted invasive tumor cells underlies their sensitivity to EGFR-targeted inhibitors. (PMID:24354805)
• Evidence for annexin A6-dependent plasma membrane remodelling of lipid domains (PMID:25409976)
• ANXA6 is a EZH2 target gene involving gastric cellular proliferation. (PMID:25947258)
• ANXA6 was detected as a novel systemic lupus erythematosus susceptibility gene, with several single-nucleotide polymorphisms (SNPs) contributing independently to the association with disease (PMID:26202167)
• Data suggest that reduced ability of AnxA6-expressing cells to migrate is associated with decreased cell surface expression of integrins alphaVbeta3 and alpha5beta1. (PMID:26578516)
• The current study shows that AnxA6 is specifically reduced in human hepatocellular carcinoma suggesting a role of this protein in hepatocarcinogenesis. (PMID:27334756)
• These findings suggest that cancer-associated fibroblasts -tumor cell crosstalk supported by ANXA6+ EVs is predictive of pancreatic ductal adenocarcinoma aggressiveness, highlighting a therapeutic target and potential biomarker for pancreatic ductal adenocarcinoma. (PMID:27701147)
• AnxA6 protein in adipocytes was upregulated by oxidative stress which might trigger AnxA6 induction in adipose tissues and contribute to impaired fat storage and adiponectin release. (PMID:27702590)
• Immunoprecipitation of the products obtained from the transcription/translation system using various anti-annexin A6 antibodies confirmed the presence of several isoforms and suggested that this protein might be present in different configurations. (PMID:27743858)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	anxa6	ENSDARG00000013335
mus_musculus	Anxa6	ENSMUSG00000018340
rattus_norvegicus	Anxa6	ENSRNOG00000010668
drosophila_melanogaster	AnxB9	FBGN0000083
drosophila_melanogaster	AnxB11	FBGN0030749

Paralogs (12): ANXA13 (ENSG00000104537), ANXA10 (ENSG00000109511), ANXA11 (ENSG00000122359), ANXA1 (ENSG00000135046), ANXA7 (ENSG00000138279), ANXA3 (ENSG00000138772), ANXA9 (ENSG00000143412), ANXA5 (ENSG00000164111), ANXA2 (ENSG00000182718), ANXA4 (ENSG00000196975), ANXA8L1 (ENSG00000264230), ANXA8 (ENSG00000265190)

Protein

Protein identifiers

Annexin A6 — P08133 (reviewed: P08133)

Alternative names: 67 kDa calelectrin, Annexin VI, Annexin-6, Calphobindin-II, Chromobindin-20, Lipocortin VI, Protein III, p68, p70

All UniProt accessions (12): A0A0S2Z2Z6, A0A0S2Z377, E5RFF0, E5RI05, E5RIU8, E5RJF5, E5RJR0, E5RK63, E5RK69, E7EMC6, P08133, H0YC77

UniProt curated annotations — full annotation on UniProt →

Function. May associate with CD21. May regulate the release of Ca(2+) from intracellular stores.

Subcellular location. Cytoplasm. Melanosome.

Post-translational modifications. Phosphorylated in response to growth factor stimulation.

Domain organisation. A pair of annexin repeats may form one binding site for calcium and phospholipid.

Induction. By Epstein-Barr virus (EBV).

Miscellaneous. Seems to bind one calcium ion with high affinity.

Similarity. Belongs to the annexin family.

Isoforms (2)

UniProt ID	Names	Canonical?
P08133-1	1	yes
P08133-2	2

RefSeq proteins (3): NP_001146, NP_001180473, NP_001350043 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001464	Annexin	Family
IPR002393	ANX6	Family
IPR018252	Annexin_repeat_CS	Conserved_site
IPR018502	Annexin_repeat	Repeat
IPR037104	Annexin_sf	Homologous_superfamily

Pfam: PF00191

UniProt features (85 total): helix 40, modified residue 15, strand 10, repeat 8, sequence conflict 5, turn 4, initiator methionine 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
1M9I	X-RAY DIFFRACTION	2.65

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08133-F1	94.73	0.88

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 (15): 2, 13, 30, 63, 68, 75, 81, 201, 306, 370, 418, 422, 483, 537, 620

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-445355	Smooth Muscle Contraction
R-HSA-397014	Muscle contraction

MSigDB gene sets: 272 (showing top): BASSO_B_LYMPHOCYTE_NETWORK, GOCC_VACUOLAR_MEMBRANE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, CACCAGC_MIR138, USF_C, CAGCTG_AP4_Q5, GOBP_MONOATOMIC_CATION_TRANSPORT, SRF_Q5_01, GOBP_MITOCHONDRIAL_CALCIUM_ION_HOMEOSTASIS, SRF_01, SRF_C, GOBP_REGULATION_OF_MUSCLE_CONTRACTION, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_MUSCLE_CONTRACTION, GOBP_APOPTOTIC_SIGNALING_PATHWAY

GO Biological Process (6): calcium ion transport (GO:0006816), regulation of muscle contraction (GO:0006937), monoatomic ion transmembrane transport (GO:0034220), obsolete negative regulation of sequestering of calcium ion (GO:0051283), mitochondrial calcium ion homeostasis (GO:0051560), apoptotic signaling pathway (GO:0097190)

GO Molecular Function (10): phosphatidylserine binding (GO:0001786), calcium ion binding (GO:0005509), GTP binding (GO:0005525), calcium-dependent phospholipid binding (GO:0005544), lipid binding (GO:0008289), ligand-gated monoatomic ion channel activity (GO:0015276), cholesterol binding (GO:0015485), identical protein binding (GO:0042802), calcium-dependent protein binding (GO:0048306), protein binding (GO:0005515)

GO Cellular Component (15): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), focal adhesion (GO:0005925), vesicle membrane (GO:0012506), membrane (GO:0016020), extracellular matrix (GO:0031012), late endosome membrane (GO:0031902), melanosome (GO:0042470), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), cytoplasmic vesicle (GO:0031410), zymogen granule membrane (GO:0042589)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cytoplasm	3
phospholipid binding	2
binding	2
protein binding	2
intracellular membrane-bounded organelle	2
metal ion transport	1
muscle contraction	1
regulation of muscle system process	1
monoatomic ion transport	1
transmembrane transport	1
mitochondrion	1
intracellular calcium ion homeostasis	1
apoptotic process	1
signal transduction	1
anion binding	1
modified amino acid binding	1
metal ion binding	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
monoatomic ion channel activity	1
ligand-gated channel activity	1
sterol binding	1
alcohol binding	1
calcium ion binding	1
intracellular anatomical structure	1
lysosome	1
lytic vacuole membrane	1
membrane	1
cell periphery	1
cell-substrate junction	1
organelle membrane	1
vesicle	1
external encapsulating structure	1
late endosome	1
endosome membrane	1
pigment granule	1
extracellular vesicle	1
intracellular vesicle	1
secretory granule membrane	1

Protein interactions and networks

STRING

1422 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANXA6	LRP1	Q07954	931
ANXA6	RELA	Q04206	773
ANXA6	PRKCA	P17252	720
ANXA6	ANXA4	P09525	686
ANXA6	NDST1	P52848	679
ANXA6	S100A11	P31949	677
ANXA6	POLD1	P28340	660
ANXA6	CDX1	P47902	639
ANXA6	RPS14	P06366	623
ANXA6	AHNAK	Q09666	617
ANXA6	AHSG	P02765	598
ANXA6	S100A6	P06703	597
ANXA6	TCOF1	Q13428	592
ANXA6	RASA1	P20936	583
ANXA6	SLC26A2	P50443	580

IntAct

68 interactions, top by confidence:

A	B	Type	Score
CD9	ADAM10	psi-mi:“MI:0914”(association)	0.750
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
TJP1	ACTN4	psi-mi:“MI:0914”(association)	0.600
MAPT	ANXA6	psi-mi:“MI:0915”(physical association)	0.560
ANXA6	IL16	psi-mi:“MI:0915”(physical association)	0.560
NAPA	NBAS	psi-mi:“MI:0914”(association)	0.530
ATP6V0A2	B4GALT3	psi-mi:“MI:0914”(association)	0.530
	AP3D1	psi-mi:“MI:0914”(association)	0.460
	MYL12B	psi-mi:“MI:0914”(association)	0.460
LRRC45	ANXA6	psi-mi:“MI:0915”(physical association)	0.400
ANXA6	RPL7A	psi-mi:“MI:0915”(physical association)	0.400
CPNE6	ANXA6	psi-mi:“MI:0915”(physical association)	0.400
CHST11	ANXA6	psi-mi:“MI:0915”(physical association)	0.400
ACTB	DDX3X	psi-mi:“MI:0915”(physical association)	0.400
ANXA6	PAK6	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
ANXA6	MLH1	psi-mi:“MI:0915”(physical association)	0.370
ANXA6	ERBB2	psi-mi:“MI:0915”(physical association)	0.370
SF1	U2SURP	psi-mi:“MI:0914”(association)	0.350
	SNAP23	psi-mi:“MI:0914”(association)	0.350
METTL14	HMGB1P1	psi-mi:“MI:0914”(association)	0.350
PRNP	CARNS1	psi-mi:“MI:0914”(association)	0.350
PRNP	WDR91	psi-mi:“MI:0914”(association)	0.350
CUL5	DDX3X	psi-mi:“MI:0914”(association)	0.350
SHOC2	IDH1	psi-mi:“MI:0914”(association)	0.350
CAV1	ACOT7	psi-mi:“MI:0914”(association)	0.350

BioGRID (140): ANXA6 (Affinity Capture-MS), ANXA6 (Co-fractionation), ANXA6 (Co-fractionation), ANXA6 (Co-fractionation), ANXA6 (Affinity Capture-MS), ANXA6 (Two-hybrid), ANXA6 (Affinity Capture-MS), ANXA6 (Affinity Capture-MS), ANXA6 (Reconstituted Complex), ANXA6 (Affinity Capture-MS), ANXA6 (Biochemical Activity), ANXA6 (Affinity Capture-MS), ANXA6 (Two-hybrid), ANXA6 (Affinity Capture-RNA), ANXA6 (Affinity Capture-MS)

ESM2 similar proteins: A2SW69, A5A6L7, A6NMY6, C1L7Y4, C4QH88, O35639, O35640, O97529, P04272, P07355, P07356, P08133, P08758, P12429, P13928, P14668, P14669, P14824, P14950, P17153, P17785, P19620, P22464, P22465, P24551, P24801, P26256, P27006, P27216, P48036, P48037, P50994, P51074, P51901, P70075, P79134, P81287, Q07936, Q29471, Q2Q1M6

Diamond homologs: A2SW69, A5A6L7, A5A6M2, A6NMY6, C0HJG9, C1L7Y4, C4QH88, O35639, O35640, O76027, O97529, P04083, P04272, P07150, P07355, P07356, P08132, P08133, P08758, P09525, P10107, P12429, P13214, P13928, P14087, P14668, P14669, P14824, P14950, P17153, P17785, P19619, P19620, P20072, P20073, P22464, P22465, P24551, P24639, P24801

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SMURF1	unknown	ANXA6	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	115
Likely benign	9
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

3855 predictions. Top by Δscore:

Variant	Effect	Δscore
5:151101506:CC:C	acceptor_gain	1.0000
5:151101507:CC:C	acceptor_gain	1.0000
5:151103563:CCCTT:C	donor_gain	1.0000
5:151103565:CTTA:C	donor_loss	1.0000
5:151103566:TTA:T	donor_loss	1.0000
5:151103566:TTACC:T	donor_gain	1.0000
5:151103567:TACC:T	donor_loss	1.0000
5:151103567:TACCT:T	donor_gain	1.0000
5:151103568:ACCT:A	donor_loss	1.0000
5:151103569:C:CT	donor_loss	1.0000
5:151103688:GCACC:G	acceptor_gain	1.0000
5:151103689:CACC:C	acceptor_gain	1.0000
5:151103689:CACCC:C	acceptor_gain	1.0000
5:151103690:ACC:A	acceptor_gain	1.0000
5:151103691:CCC:C	acceptor_gain	1.0000
5:151103692:CCTGG:C	acceptor_gain	1.0000
5:151103693:C:CC	acceptor_gain	1.0000
5:151103703:C:CT	acceptor_gain	1.0000
5:151103703:C:T	acceptor_gain	1.0000
5:151103704:A:T	acceptor_gain	1.0000
5:151103707:C:CT	acceptor_gain	1.0000
5:151103708:A:T	acceptor_gain	1.0000
5:151103718:C:CT	acceptor_gain	1.0000
5:151103721:A:T	acceptor_gain	1.0000
5:151103724:C:CT	acceptor_gain	1.0000
5:151105317:C:CT	acceptor_gain	1.0000
5:151108439:AGTC:A	donor_gain	1.0000
5:151108473:C:A	donor_gain	1.0000
5:151109874:T:C	acceptor_gain	1.0000
5:151117752:ACTC:A	donor_loss	1.0000

AlphaMissense

4467 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:151133102:A:G	L211P	0.998
5:151133175:C:G	A187P	0.998
5:151133183:A:G	L184P	0.998
5:151109761:A:G	L559P	0.996
5:151132511:A:G	L234P	0.996
5:151105261:A:G	L608P	0.995
5:151132523:A:T	I230N	0.995
5:151133117:C:G	R206P	0.995
5:151133138:A:G	F199S	0.995
5:151136272:A:G	L158P	0.995
5:151105270:G:T	A605D	0.994
5:151126429:C:A	W343C	0.994
5:151126429:C:G	W343C	0.994
5:151126431:A:G	W343R	0.994
5:151126431:A:T	W343R	0.994
5:151133183:A:T	L184Q	0.994
5:151105303:A:T	V594D	0.993
5:151122244:A:G	L417P	0.993
5:151132560:A:C	Y218D	0.993
5:151139392:C:A	R55S	0.993
5:151139392:C:G	R55S	0.993
5:151122957:C:G	R398P	0.992
5:151124309:A:G	L372P	0.992
5:151132490:A:G	L241P	0.992
5:151132535:A:T	I226N	0.992
5:151133123:C:T	G204E	0.992
5:151133137:G:C	F199L	0.992
5:151133137:G:T	F199L	0.992
5:151133139:A:G	F199L	0.992
5:151136263:A:G	L161P	0.992

dbSNP variants (sampled 300 via entrez): RS1000099685 (5:151139946 C>A,G), RS1000127004 (5:151159614 C>A,T), RS1000141413 (5:151128293 A>T), RS1000199162 (5:151133665 G>T), RS1000243665 (5:151114214 T>C), RS1000326522 (5:151125520 A>G), RS1000393011 (5:151107179 G>A,C), RS1000413852 (5:151131122 C>A,T), RS1000438607 (5:151139875 C>T), RS1000542223 (5:151150714 C>A,T), RS1000574229 (5:151103559 C>T), RS1000589476 (5:151105624 T>C), RS1000655828 (5:151125778 C>T), RS1000684120 (5:151149434 A>G), RS1000725128 (5:151139071 G>C)

Disease associations

OMIM: gene MIM:114070 | 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
GCST002738_13	Psoriasis	1.000000e-18
GCST002740_12	Inflammatory skin disease	4.000000e-38
GCST002874_4	Psoriasis	3.000000e-07
GCST002874_41	Psoriasis	4.000000e-14
GCST002874_6	Psoriasis	6.000000e-20
GCST003270_6	Psoriatic arthritis	3.000000e-23
GCST004131_47	Inflammatory bowel disease	3.000000e-15
GCST004132_24	Crohn’s disease	2.000000e-19
GCST90002388_328	Lymphocyte count	3.000000e-18

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004587	lymphocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066974 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.49	Kd	32.59	nM	CHEMBL5653589
7.49	ED50	32.59	nM	CHEMBL5653589
5.05	Kd	9002	nM	CHEMBL3752910
5.05	ED50	9002	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147859: Binding affinity to human ANXA6 incubated for 45 mins by Kinobead based pull down assay	kd	0.0326	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147859: Binding affinity to human ANXA6 incubated for 45 mins by Kinobead based pull down assay	kd	9.0024	uM

CTD chemical–gene interactions

69 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression, affects cotreatment	7
Valproic Acid	affects cotreatment, increases expression, affects expression	6
Tobacco Smoke Pollution	affects expression, decreases expression	3
Aflatoxin B1	decreases expression, increases methylation	3
Particulate Matter	decreases expression, increases abundance, increases expression	3
methylmercuric chloride	decreases expression	2
sodium arsenite	affects binding, increases reaction, affects cotreatment, decreases expression, increases abundance	2
Vorinostat	affects cotreatment, affects expression, increases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Dexamethasone	increases expression, affects cotreatment	2
Smoke	increases expression, decreases expression	2
GSK-J4	decreases expression	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
deoxynivalenol	decreases expression	1
sodium arsenate	decreases expression	1
arsenite	decreases expression, increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
periodate-oxidized adenosine	affects expression	1
pentanal	increases expression	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	decreases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5650901	Binding	Binding affinity to human ANXA6 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

2 cell lines: 1 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1JM	Abcam HeLa ANXA6 KO	Cancer cell line	Female
CVCL_D8Z6	Ubigene HEK293 ANXA6 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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