ANO6

Summary

ANO6 (anoctamin 6, HGNC:25240) is a protein-coding gene on chromosome 12q12, encoding Anoctamin-6 (Q4KMQ2). Small-conductance calcium-activated nonselective cation (SCAN) channel which acts as a regulator of phospholipid scrambling in platelets and osteoblasts.

This gene encodes a multi-pass transmembrane protein that belongs to the anoctamin family. This protein is an essential component for the calcium-dependent exposure of phosphatidylserine on the cell surface. The scrambling of phospholipid occurs in various biological systems, such as when blood platelets are activated, they expose phosphatidylserine to trigger the clotting system. Mutations in this gene are associated with Scott syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 196527 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Scott syndrome (Strong, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 425 total — 26 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 10
• MANE Select transcript: NM_001025356

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25240
Approved symbol	ANO6
Name	anoctamin 6
Location	12q12
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp313M0720
Ensembl gene	ENSG00000177119
Ensembl biotype	protein_coding
OMIM	608663
Entrez	196527

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 10 protein_coding, 4 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000320560, ENST00000423947, ENST00000425752, ENST00000426898, ENST00000441606, ENST00000550630, ENST00000551667, ENST00000679426, ENST00000679761, ENST00000680201, ENST00000680371, ENST00000680498, ENST00000681156, ENST00000681817, ENST00000909151, ENST00000968804

RefSeq mRNA: 5 — MANE Select: NM_001025356 NM_001025356, NM_001142678, NM_001142679, NM_001204803, NM_001410973

CCDS: CCDS31782, CCDS44865, CCDS44866, CCDS55819, CCDS91686

Canonical transcript exons

ENST00000320560 — 20 exons

Exon	Start	End
ENSE00001505515	45422957	45423062
ENSE00001505516	45421071	45421273
ENSE00003466320	45347022	45347087
ENSE00003519552	45378053	45378113
ENSE00003520529	45350659	45350774
ENSE00003523571	45388161	45388303
ENSE00003534574	45302014	45302093
ENSE00003544718	45331295	45331423
ENSE00003546829	45348518	45348631
ENSE00003549425	45390421	45390498
ENSE00003565249	45348028	45348315
ENSE00003584736	45403439	45403536
ENSE00003656335	45401795	45402020
ENSE00003662046	45403072	45403241
ENSE00003670632	45357290	45357424
ENSE00003677910	45416699	45416904
ENSE00003678649	45409357	45409487
ENSE00003691788	45367688	45367793
ENSE00003848305	45429105	45432349
ENSE00003849088	45216095	45216391

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 98.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.7904 / max 847.8642, expressed in 1821 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125135	30.1772	1817
125136	8.8737	1751
125132	3.7514	1323
125137	2.6532	1411
125134	2.4007	1239
125133	1.2941	740
125129	0.2862	143
125131	0.1524	59
125130	0.0751	25
125142	0.0740	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
epithelial cell of pancreas	CL:0000083	98.95	gold quality
secondary oocyte	CL:0000655	98.58	gold quality
tibialis anterior	UBERON:0001385	98.23	gold quality
deltoid	UBERON:0001476	97.91	gold quality
jejunal mucosa	UBERON:0000399	97.70	gold quality
ileal mucosa	UBERON:0000331	97.59	gold quality
jejunum	UBERON:0002115	97.36	gold quality
quadriceps femoris	UBERON:0001377	97.23	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.21	gold quality
vastus lateralis	UBERON:0001379	97.04	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	96.95	gold quality
synovial joint	UBERON:0002217	96.84	gold quality
oocyte	CL:0000023	96.76	gold quality
pericardium	UBERON:0002407	96.75	gold quality
cardiac muscle of right atrium	UBERON:0003379	96.63	gold quality
visceral pleura	UBERON:0002401	96.60	gold quality
germinal epithelium of ovary	UBERON:0001304	96.57	gold quality
biceps brachii	UBERON:0001507	96.55	gold quality
parietal pleura	UBERON:0002400	96.42	gold quality
saphenous vein	UBERON:0007318	96.35	gold quality
cauda epididymis	UBERON:0004360	96.32	gold quality
urethra	UBERON:0000057	96.28	gold quality
skeletal muscle tissue	UBERON:0001134	96.24	gold quality
layer of synovial tissue	UBERON:0007616	96.20	gold quality
superficial temporal artery	UBERON:0001614	95.89	gold quality
seminal vesicle	UBERON:0000998	95.77	gold quality
muscle tissue	UBERON:0002385	95.71	gold quality
smooth muscle tissue	UBERON:0001135	95.68	gold quality
lower lobe of lung	UBERON:0008949	95.65	gold quality
pancreatic ductal cell	CL:0002079	95.64	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	209.10
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

174 targeting ANO6, 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-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-3686	99.90	70.53	2432

Literature-anchored findings (GeneRIF, showing 37)

• Wild-type TMEM16F was localized on the plasma membrane and conferred Ca(2+)-dependent scrambling of phospholipids (PMID:21107324)
• Study identified 2 novel mutations in the TMEM16F gene in 2 patients with Scott syndrome. (PMID:21511967)
• It scrambles phospholipids in cell membrane and its mutation leads to Scott syndrome. (review) (PMID:22256604)
• a significant association between rs17095830 and inflammatory bowel disease was observed in a Taiwanese population (PMID:23308121)
• TMEM16F is an essential component of a divalent calcium ion-activated Cl- channel with a divalent calcium ion sensitivity that is distinct from that of TMEM16A/B and not related to volume-sensitive outwardly rectifying Cl- channel (VSOR) activity. (PMID:23426967)
• Anoo6 induces a chloride ion conductance along with a smaller nonselective cation conductance that is activated either calcium ion dependently (ionomycin) or calcium independently(fas receptor), but not during mitochondrial apoptosis. (PMID:23618909)
• TMEM16A and -16F use a similar mechanism for sorting to plasma membrane and protein stabilization, but their functional domains significantly differ (PMID:24478309)
• using human osteoblasts and osteoblasts from Ano6(-/-) and WT mice, we demonstrate that NCX1 requires Ano6 to efficiently translocate Ca(2+) out of osteoblasts into the calcifying bone matrix (PMID:25589784)
• Ano6 mediates effects essential for innate immunity downstream of P2X7 receptors in macrophages. (PMID:25651887)
• Homology modeling shows that the scramblase domain forms an unusual hydrophilic cleft that faces the lipid bilayer and may function to facilitate translocation of phospholipid between membrane leaflets. (PMID:26057829)
• Ion channel and lipid scramblase activity associated with expression of TMEM16F/ANO6 isoforms (PMID:26108457)
• ANO6 is highly expressed in apoptotic cyst epithelial cells of human polycystic kidneys. (PMID:26448322)
• deficiency in Ano6 resulted in reduced viability with increased bleeding time (PMID:26481309)
• facilitates transbilayer migration of lipids [review] (PMID:26936867)
• TMEM16F modifies viability of Human Embryonic Kidney cells via its function as a phospholipid scramblase and activation of AKT signaling pathways. (PMID:27287741)
• The authorsreport the first association in two sisters of a deletion and a nonsense variation explaining the pathophysiology of Scott syndrome. (PMID:27879994)
• ICl,Swell, and cell volume are regulated by Ano6. The findings suggest a novel clinically-relevant approach for altering cell volume, and thereby outflow resistance, by targeting Ano6. (PMID:28125837)
• GD-N induced cell death in HEK293 and HAP1 cells was depending on expression of endogenous TMEM16F. (PMID:29463790)
• ANO6 current shows sluggish activation even with high [Ca2+]i, and inactivation. Actin cytoskeleton disruption accelerate both activation and inactivation of ANO6. Intracellular MgATP further delays ANO6 activation, and prevent inactivation. (PMID:29964013)
• We conclude that ANO6, by virtue of its scramblase activity, may play a role as an important regulator of the ADAM-network in the plasma membrane. (PMID:30327201)
• Both inactivating and activating mutants that elucidate the mechanism for TMEM16F activation. (PMID:30622179)
• TMEM16A and TMEM16F support membrane exocytosis and are essential for plasma membrane insertion of CFTR. (PMID:30915480)
• Study identified an inner activation gate, which is established by three hydrophobic residues, F518, Y563 and I612, in the middle of the phospholipid permeation pathway of TMEM16F-CaPLSase. Disrupting the inner gate profoundly alters TMEM16F phospholipid permeation. (PMID:31015464)
• Temperature-dependent increase in the calcium sensitivity and acceleration of activation of ANO6 chloride channel variants. (PMID:31040335)
• Lysophosphatidic acid-induced pro-thrombotic phosphatidylserine exposure and ionophore-induced microvesiculation is mediated by the scramblase TMEM16F in erythrocytes. (PMID:32222693)
• Molecular underpinning of intracellular pH regulation on TMEM16F. (PMID:33346788)
• Ca(2+) Sensitivity of Anoctamin 6/TMEM16F Is Regulated by the Putative Ca(2+)-Binding Reservoir at the N-Terminal Domain. (PMID:33658434)
• TMEM16F mediates bystander TCR-CD3 membrane dissociation at the immunological synapse and potentiates T cell activation. (PMID:33758060)
• Hyperuricemia enhances procoagulant activity of vascular endothelial cells through TMEM16F regulated phosphatidylserine exposure and microparticle release. (PMID:34390515)
• TMEM16F and dynamins control expansive plasma membrane reservoirs. (PMID:34404808)
• Supporting Cells of the Human Olfactory Epithelium Co-Express the Lipid Scramblase TMEM16F and ACE2 and May Cause Smell Loss by SARS-CoV-2 Spike-Induced Syncytia. (PMID:35670331)
• Functional coupling between TRPV4 channel and TMEM16F modulates human trophoblast fusion. (PMID:35670667)
• ANO6 is a reliable prognostic biomarker and correlates to macrophage polarization in breast cancer. (PMID:37960776)
• Deciphering and disrupting PIEZO1-TMEM16F interplay in hereditary xerocytosis. (PMID:38033286)
• TMEM16F exacerbates tau pathology and mediates phosphatidylserine exposure in phospho-tau-burdened neurons. (PMID:38941274)
• Functional Interdependence of Anoctamins May Influence Conclusions from Overexpression Studies. (PMID:39337485)
• Analysis of ANO6, HAPLN1, and EDIL3 Polymorphisms in Patients with Ankylosing Spondylitis in a Chinese Han Population: A Case-Control Study. (PMID:39358671)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ano6	ENSDARG00000061544
mus_musculus	Ano6	ENSMUSG00000064210
rattus_norvegicus	Ano6	ENSRNOG00000006995

Paralogs (10): ANO2 (ENSG00000047617), ANO8 (ENSG00000074855), PPP1R7 (ENSG00000115685), ANO1 (ENSG00000131620), ANO3 (ENSG00000134343), ANO7 (ENSG00000146205), ANO4 (ENSG00000151572), ANO10 (ENSG00000160746), ANO5 (ENSG00000171714), ANO9 (ENSG00000185101)

Protein

Protein identifiers

Anoctamin-6 — Q4KMQ2 (reviewed: Q4KMQ2)

Alternative names: Small-conductance calcium-activated nonselective cation channel, Transmembrane protein 16F

All UniProt accessions (8): Q4KMQ2, A0A7P0T8Y2, A0A7P0TAF4, A0A7P0TAW4, A0A7P0TBC5, A0A7P0TBD5, A0A7P0TBI1, F8VX71

UniProt curated annotations — full annotation on UniProt →

Function. Small-conductance calcium-activated nonselective cation (SCAN) channel which acts as a regulator of phospholipid scrambling in platelets and osteoblasts. Phospholipid scrambling results in surface exposure of phosphatidylserine which in platelets is essential to trigger the clotting system whereas in osteoblasts is essential for the deposition of hydroxyapatite during bone mineralization. Has calcium-dependent phospholipid scramblase activity; scrambles phosphatidylserine, phosphatidylcholine and galactosylceramide. Can generate outwardly rectifying chloride channel currents in airway epithelial cells and Jurkat T lymphocytes. (Microbial infection) Upon SARS coronavirus-2/SARS-CoV-2 infection, is activated by spike protein which increases the amplitude of spontaneous Ca(2+) signals and is required for spike-mediated syncytia.

Subunit / interactions. Homodimer.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in embryonic stem cell, fetal liver, retina, chronic myologenous leukemia and intestinal cancer.

Disease relevance. Scott syndrome (SCTS) [MIM:262890] A mild bleeding disorder due to impaired surface exposure of procoagulant phosphatidylserine (PS) on platelets and other blood cells, following activation with Ca(2+)-elevating agents. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Exhibits synergistic gating by Ca(2+) and voltage. Inhibited by some non-specific cation channel blockers such as: ruthenium red, 2-aminoethyl diphenylborinate (2APB), gadolinium and cadmium ions. (Microbial infection) Activated by SARS coronavirus-2/SARS-CoV-2 spike protein.

Induction. (Microbial infection) Expression is induced by SARS coronavirus-2/SARS-CoV-2 spike protein.

Miscellaneous. The term ‘anoctamin’ was coined because these channels are anion selective and are predicted to have eight (OCT) transmembrane segments. There is some dissatisfaction in the field with the Ano nomenclature because it is not certain that all the members of this family are anion channels or have the 8-transmembrane topology.

Similarity. Belongs to the anoctamin family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q4KMQ2-1	1	yes
Q4KMQ2-2	2
Q4KMQ2-3	3
Q4KMQ2-4	4

RefSeq proteins (5): NP_001020527, NP_001136150, NP_001136151, NP_001191732, NP_001397902 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007632	Anoctamin	Family
IPR032394	Anoct_dimer	Domain
IPR049452	Anoctamin_TM	Domain

Pfam: PF04547, PF16178

Catalyzed reactions (Rhea), 3 shown:

• a 1,2-diacyl-sn-glycero-3-phosphocholine(in) = a 1,2-diacyl-sn-glycero-3-phosphocholine(out) (RHEA:38571)
• a 1,2-diacyl-sn-glycero-3-phospho-L-serine(in) = a 1,2-diacyl-sn-glycero-3-phospho-L-serine(out) (RHEA:38663)
• a beta-D-galactosyl-(1<->1’)-N-acylsphing-4-enine(out) = a beta-D-galactosyl-(1<->1’)-N-acylsphing-4-enine(in) (RHEA:38899)

UniProt features (40 total): topological domain 10, transmembrane region 10, glycosylation site 6, disulfide bond 5, binding site 3, splice variant 3, chain 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q4KMQ2-F1	82.00	0.38

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 (3): 623; 666; 669

Disulfide bonds (5): 330–371, 337–364, 348–806, 351–355, 595–600

Glycosylation sites (6): 329, 361, 493, 777, 790, 802

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels
R-HSA-6798695	Neutrophil degranulation
R-HSA-9733458	Induction of Cell-Cell Fusion
R-HSA-9769739	Regulation of clotting cascade
R-HSA-9769743	Amplification and propagation of coagulation cascade
R-HSA-9853846	Defective ANO6 does not expose PS, PE on the platelet membrane
R-HSA-1643685	Disease
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-382551	Transport of small molecules
R-HSA-5663205	Infectious disease
R-HSA-9679506	SARS-CoV Infections
R-HSA-9694516	SARS-CoV-2 Infection
R-HSA-9772573	Late SARS-CoV-2 Infection Events
R-HSA-9824446	Viral Infection Pathways
R-HSA-983712	Ion channel transport

MSigDB gene sets: 331 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_CELL_CHEMOTAXIS, GOBP_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_COAGULATION, GOCC_SECRETORY_GRANULE, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, GOBP_PLASMA_MEMBRANE_ORGANIZATION, chr12q12, GOBP_POSITIVE_REGULATION_OF_COAGULATION, GOCC_CELL_SURFACE, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (24): activation of blood coagulation via clotting cascade (GO:0002543), blood coagulation (GO:0007596), plasma membrane phospholipid scrambling (GO:0017121), positive regulation of bone mineralization (GO:0030501), bleb assembly (GO:0032060), monoatomic ion transmembrane transport (GO:0034220), positive regulation of monoatomic ion transmembrane transport (GO:0034767), purinergic nucleotide receptor signaling pathway (GO:0035590), sodium ion transmembrane transport (GO:0035725), positive regulation of apoptotic process (GO:0043065), negative regulation of cell volume (GO:0045794), pore complex assembly (GO:0046931), positive regulation of phagocytosis, engulfment (GO:0060100), calcium activated phosphatidylserine scrambling (GO:0061589), calcium activated phosphatidylcholine scrambling (GO:0061590), calcium ion transmembrane transport (GO:0070588), positive regulation of monocyte chemotaxis (GO:0090026), phosphatidylserine exposure on blood platelet (GO:0097045), chloride transmembrane transport (GO:1902476), positive regulation of potassium ion export across plasma membrane (GO:1903766), monoatomic ion transport (GO:0006811), chloride transport (GO:0006821), lipid transport (GO:0006869), positive regulation of endothelial cell apoptotic process (GO:2000353)

GO Molecular Function (9): calcium-activated cation channel activity (GO:0005227), intracellularly calcium-gated chloride channel activity (GO:0005229), voltage-gated monoatomic ion channel activity (GO:0005244), voltage-gated chloride channel activity (GO:0005247), chloride channel activity (GO:0005254), phospholipid scramblase activity (GO:0017128), metal ion binding (GO:0046872), protein dimerization activity (GO:0046983), protein binding (GO:0005515)

GO Cellular Component (9): cytosol (GO:0005829), plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020), chloride channel complex (GO:0034707), specific granule membrane (GO:0035579), extracellular exosome (GO:0070062), tertiary granule membrane (GO:0070821), monoatomic ion channel complex (GO:0034702)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Coagulation pathway	2
Ion channel transport	1
Innate Immune System	1
Late SARS-CoV-2 Infection Events	1
Defects of Coagulation cascade	1
Immune System	1
Disease	1
Viral Infection Pathways	1
SARS-CoV Infections	1
SARS-CoV-2 Infection	1
Infectious disease	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
positive regulation of blood coagulation	2
monoatomic cation transmembrane transport	2
calcium activated phospholipid scrambling	2
plasma membrane phospholipid scrambling	2
chloride channel activity	2
secretory granule membrane	2
acute inflammatory response	1
hemostasis	1
wound healing	1
coagulation	1
plasma membrane organization	1
phospholipid translocation	1
bone mineralization	1
regulation of bone mineralization	1
positive regulation of ossification	1
positive regulation of biomineral tissue development	1
plasma membrane bounded cell projection assembly	1
monoatomic ion transport	1
transmembrane transport	1
monoatomic ion transmembrane transport	1
positive regulation of transmembrane transport	1
regulation of monoatomic ion transmembrane transport	1
positive regulation of monoatomic ion transport	1
cell surface receptor signaling pathway	1
sodium ion transport	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
cell volume homeostasis	1
protein-containing complex assembly	1
phagocytosis, engulfment	1
positive regulation of phagocytosis	1
regulation of phagocytosis, engulfment	1
positive regulation of membrane invagination	1
calcium ion transport	1
monocyte chemotaxis	1
positive regulation of leukocyte chemotaxis	1
positive regulation of mononuclear cell migration	1
regulation of monocyte chemotaxis	1

Protein interactions and networks

STRING

916 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANO6	SCTR	P47872	967
ANO6	NELL2	Q99435	912
ANO6	NELL1	Q92832	895
ANO6	XKR8	Q9H6D3	800
ANO6	CLCA2	Q9UQC9	657
ANO6	CLCA4	Q14CN2	655
ANO6	CLCA1	A8K7I4	608
ANO6	ATP11C	Q8NB49	605
ANO6	ANXA5	P08758	514
ANO6	PLSCR1	O15162	490
ANO6	F3	P13726	487
ANO6	PLSCR5	A0PG75	482
ANO6	CDC50A	Q9NV96	472
ANO6	LRRC8A	Q8IWT6	467
ANO6	PANX1	Q96RD7	466

IntAct

107 interactions, top by confidence:

A	B	Type	Score
ENTREP1	WWP2	psi-mi:“MI:0914”(association)	0.850
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
	DDR1	psi-mi:“MI:2364”(proximity)	0.670
	PMPCB	psi-mi:“MI:0914”(association)	0.640
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
ADGRG5	KLRG2	psi-mi:“MI:0914”(association)	0.530
DLK1	TCAF2	psi-mi:“MI:0914”(association)	0.530
ZNRF4	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
ANO6	CDC27	psi-mi:“MI:0914”(association)	0.530
LRRC8B	SLC25A17	psi-mi:“MI:0914”(association)	0.530
SLC51A	TMEM63A	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
CLGN	NPC1	psi-mi:“MI:0914”(association)	0.530
ANO4	ANO6	psi-mi:“MI:0914”(association)	0.530
HIDE1	GSDME	psi-mi:“MI:0914”(association)	0.530
LDLRAD1	ADAM10	psi-mi:“MI:0914”(association)	0.530

BioGRID (195): ANO6 (Affinity Capture-MS), ANO6 (Affinity Capture-MS), ANO6 (Affinity Capture-MS), ANO6 (Affinity Capture-MS), ANO6 (Affinity Capture-MS), ANO6 (Proximity Label-MS), ANO6 (Proximity Label-MS), ANO6 (Proximity Label-MS), ANO6 (Proximity Label-MS), CTAGE5 (Affinity Capture-MS), ANO6 (Affinity Capture-MS), ANO6 (Affinity Capture-MS), CDC16 (Affinity Capture-MS), CDC27 (Affinity Capture-MS), ANAPC4 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IQZ2, A0MFS9, A2WV32, A2YMH5, A5WVX9, A8Y2U2, F1RAX4, F4HVJ3, F4JIN3, G5ECD6, G5ED05, O13621, O17386, O18304, O45363, O48947, O62136, O74737, P0C5E7, P34319, P34389, P34577, Q0JJZ6, Q10287, Q10436, Q21412, Q22566, Q23027, Q23369, Q4KMQ2, Q4R690, Q5JN63, Q5NVB9, Q5XXA6, Q6ZF85, Q84JA6, Q8BHY3, Q8CFW1, Q8IUH4, Q8L778

Diamond homologs: A1A5B4, A2AHL1, A6QLE6, P86044, Q14AT5, Q32M45, Q4KMQ2, Q5XXA6, Q6IFT6, Q6IWH7, Q6P9J9, Q75UR0, Q75V66, Q8BHY3, Q8C5H1, Q8CFW1, Q9BYT9, Q9NQ90, Q6PB70, Q9HCE9

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
ANO6	up-regulates	Proliferation
ANO6	“up-regulates activity”	ERK1/2

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	26
Likely pathogenic	14
Uncertain significance	155
Likely benign	140
Benign	40

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1071290	NM_001025356.3(ANO6):c.2185C>T (p.Gln729Ter)	Pathogenic
1323277	NM_001025356.3(ANO6):c.1308+2T>C	Pathogenic
2584644	NM_001025356.3(ANO6):c.826C>T (p.Arg276Ter)	Pathogenic
2584645	NC_000012.12:g.(?45216094)(45367794_45378052)del	Pathogenic
2584646	NM_001025356.3(ANO6):c.747+1G>A	Pathogenic
2584647	NM_001025356.3(ANO6):c.1219dup (p.Trp407fs)	Pathogenic
2626770	NM_001025356.3(ANO6):c.1255C>T (p.Arg419Ter)	Pathogenic
2695631	NM_001025356.3(ANO6):c.2412_2413insT (p.Thr805fs)	Pathogenic
2766467	NM_001025356.3(ANO6):c.267del (p.Asn89fs)	Pathogenic
2827003	NM_001025356.3(ANO6):c.1689C>G (p.Tyr563Ter)	Pathogenic
2865427	NM_001025356.3(ANO6):c.297C>G (p.Tyr99Ter)	Pathogenic
2867447	NM_001025356.3(ANO6):c.1694C>A (p.Ser565Ter)	Pathogenic
2877884	NM_001025356.3(ANO6):c.2038_2042del (p.Phe680fs)	Pathogenic
2974435	NM_001025356.3(ANO6):c.1105A>T (p.Lys369Ter)	Pathogenic
2988767	NM_001025356.3(ANO6):c.538G>T (p.Glu180Ter)	Pathogenic
3390356	GRCh38/hg38 12q12-13.11(chr12:45299856-46290196)x1	Pathogenic
3639166	NM_001025356.3(ANO6):c.1215T>G (p.Tyr405Ter)	Pathogenic
3709177	NM_001025356.3(ANO6):c.1192C>T (p.Arg398Ter)	Pathogenic
3713303	NM_001025356.3(ANO6):c.136C>T (p.Arg46Ter)	Pathogenic
3722882	NM_001025356.3(ANO6):c.2211_2214dup (p.Asn739fs)	Pathogenic
4075857	GRCh37/hg19 12q12(chr12:45551910-45706411)x1	Pathogenic
449565	NM_001025356.3(ANO6):c.1387-1G>T	Pathogenic
4692707	NM_001025356.3(ANO6):c.1273C>T (p.Arg425Ter)	Pathogenic
4722053	NM_001025356.3(ANO6):c.238A>T (p.Arg80Ter)	Pathogenic
4748315	NM_001025356.3(ANO6):c.1912A>T (p.Arg638Ter)	Pathogenic
4775439	NM_001025356.3(ANO6):c.1903C>T (p.Arg635Ter)	Pathogenic
1323913	NM_001025356.3(ANO6):c.1914_1915del (p.Arg638fs)	Likely pathogenic
2030033	NM_001025356.3(ANO6):c.1612+1G>T	Likely pathogenic
2057277	NM_001025356.3(ANO6):c.2421-1G>C	Likely pathogenic
2632341	NM_001025356.3(ANO6):c.1874T>G (p.Leu625Ter)	Likely pathogenic

SpliceAI

3689 predictions. Top by Δscore:

Variant	Effect	Δscore
12:45216392:G:GG	donor_gain	1.0000
12:45302012:A:AG	acceptor_gain	1.0000
12:45302013:G:GG	acceptor_gain	1.0000
12:45302013:GT:G	acceptor_gain	1.0000
12:45302090:GTTT:G	donor_gain	1.0000
12:45302094:G:GG	donor_gain	1.0000
12:45331283:T:A	acceptor_gain	1.0000
12:45331289:A:AG	acceptor_gain	1.0000
12:45331290:C:G	acceptor_gain	1.0000
12:45331291:A:AG	acceptor_gain	1.0000
12:45331291:ACAG:A	acceptor_gain	1.0000
12:45331292:C:G	acceptor_gain	1.0000
12:45331292:CA:C	acceptor_loss	1.0000
12:45331293:A:AG	acceptor_gain	1.0000
12:45331293:AG:A	acceptor_gain	1.0000
12:45331294:G:GA	acceptor_gain	1.0000
12:45331294:GG:G	acceptor_gain	1.0000
12:45331294:GGA:G	acceptor_gain	1.0000
12:45331294:GGAA:G	acceptor_gain	1.0000
12:45331419:AAAGG:A	donor_gain	1.0000
12:45331420:AAGG:A	donor_gain	1.0000
12:45331421:AGG:A	donor_gain	1.0000
12:45331422:GG:G	donor_gain	1.0000
12:45331422:GGG:G	donor_gain	1.0000
12:45331423:GG:G	donor_gain	1.0000
12:45331423:GGTA:G	donor_loss	1.0000
12:45331424:G:GA	donor_loss	1.0000
12:45331424:G:GG	donor_gain	1.0000
12:45331425:T:A	donor_loss	1.0000
12:45347020:A:AG	acceptor_gain	1.0000

AlphaMissense

6051 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:45350725:T:A	W272R	1.000
12:45350725:T:C	W272R	1.000
12:45357372:G:A	G316R	1.000
12:45357372:G:C	G316R	1.000
12:45388214:T:A	W407R	1.000
12:45388214:T:C	W407R	1.000
12:45403108:T:C	L550P	1.000
12:45416857:T:A	W724R	1.000
12:45416857:T:C	W724R	1.000
12:45348092:C:A	A137D	0.999
12:45350727:G:C	W272C	0.999
12:45350727:G:T	W272C	0.999
12:45357301:G:A	G292E	0.999
12:45357301:G:T	G292V	0.999
12:45357313:G:A	G296E	0.999
12:45357327:T:A	W301R	0.999
12:45357327:T:C	W301R	0.999
12:45357331:T:C	L302P	0.999
12:45357352:T:A	L309H	0.999
12:45357352:T:C	L309P	0.999
12:45357373:G:A	G316E	0.999
12:45367731:T:A	C348S	0.999
12:45367731:T:C	C348R	0.999
12:45367732:G:C	C348S	0.999
12:45367733:T:G	C348W	0.999
12:45378093:C:A	A382E	0.999
12:45378110:T:A	W388R	0.999
12:45378110:T:C	W388R	0.999
12:45388181:T:A	W396R	0.999
12:45388181:T:C	W396R	0.999

dbSNP variants (sampled 300 via entrez): RS1000002986 (12:45229010 C>G), RS1000003878 (12:45309145 G>A,T), RS1000009690 (12:45399772 A>T), RS1000034945 (12:45309482 G>A), RS1000039654 (12:45257518 T>A), RS1000047231 (12:45315254 A>G), RS1000097475 (12:45265097 T>G), RS1000112845 (12:45258389 T>G), RS1000126248 (12:45218422 T>C), RS1000144658 (12:45346054 C>G), RS1000146285 (12:45395811 T>C), RS1000158544 (12:45300853 G>C), RS1000228525 (12:45428759 CATT>C), RS1000231904 (12:45365209 T>C), RS1000267556 (12:45302699 G>C)

Disease associations

OMIM: gene MIM:608663 | disease phenotypes: MIM:262890, MIM:617808, MIM:615219

GenCC curated gene-disease

Disease	Classification	Inheritance
Scott syndrome	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Scott syndrome	Moderate	AR

Mondo (3): Scott syndrome (MONDO:0009885), Coffin-Siris syndrome 6 (MONDO:0033492), hydrocephalus, nonsyndromic, autosomal recessive 2 (MONDO:0014085)

Orphanet (2): Scott syndrome (Orphanet:806), Congenital hydrocephalus (Orphanet:2185)

HPO phenotypes

10 total (10 of 10 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000132	Menorrhagia
HP:0000225	Gingival bleeding
HP:0000421	Epistaxis
HP:0000978	Bruising susceptibility
HP:0001892	Abnormal bleeding
HP:0004846	Prolonged bleeding after surgery
HP:0008151	Prolonged prothrombin time
HP:0008354	Factor X activation deficiency
HP:0011891	Post-partum hemorrhage

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001345_2	Ankylosing spondylitis	2.000000e-08
GCST002828_18	Urate levels in obese individuals	2.000000e-06
GCST005566_4	Insomnia	7.000000e-07
GCST008161_27	Waist circumference adjusted for body mass index	6.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C563120	Scott Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Ozone	affects cotreatment, increases expression, increases abundance, decreases reaction	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Aflatoxin B1	increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
bisphenol A	increases expression	1
arsenite	affects binding, decreases reaction	1
butyraldehyde	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	decreases expression, affects cotreatment	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
pentanal	decreases expression	1
2-palmitoylglycerol	increases 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
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Acrolein	affects cotreatment, increases expression, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases expression	1
Arsenic	affects methylation	1
Vehicle Emissions	increases abundance, increases expression	1
Benzophenoneidum	increases expression	1
Cadmium	decreases reaction, increases abundance, increases palmitoylation	1
Carbamazepine	affects expression	1
Cisplatin	affects cotreatment, decreases expression	1

Cellosaurus cell lines

8 cell lines: 6 cancer cell line, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7G4	Ubigene HEK293T ANO6 KO	Transformed cell line	Female
CVCL_D8Z5	Ubigene HEK293 ANO6 KO	Transformed cell line	Female
CVCL_DX24	HAP1 ANO6 (-) XKR8 (-) 1	Cancer cell line	Male
CVCL_DX25	HAP1 ANO6 (-) XKR8 (-) 2	Cancer cell line	Male
CVCL_DX26	HAP1 ANO6 (-) XKR8 (-) 3	Cancer cell line	Male
CVCL_DX27	HAP1 ANO6 (-) XKR8 (-) 4	Cancer cell line	Male
CVCL_RX74	HAP1 ANO6 (-) 1	Cancer cell line	Male
CVCL_SA81	HAP1 ANO6 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00617721	Not specified	TERMINATED	Markers of Defective Membrane Remodelling in Scott-like Syndromes