BEST3

Summary

BEST3 (bestrophin 3, HGNC:17105) is a protein-coding gene on chromosome 12q15, encoding Bestrophin-3 (Q8N1M1). Ligand-gated anion channel that allows the movement of chloride monoatomic anions across cell membranes when activated by calcium (Ca2+).

BEST3 belongs to the bestrophin family of anion channels, which includes BEST1 (MIM 607854), the gene mutant in vitelliform macular dystrophy (VMD; MIM 153700), and 2 other BEST1-like genes, BEST2 (MIM 607335) and BEST4 (MIM 607336). Bestrophins are transmembrane (TM) proteins that share a homology region containing a high content of aromatic residues, including an invariant arg-phe-pro (RFP) motif. The bestrophin genes share a conserved gene structure, with almost identical sizes of the 8 RFP-TM domain-encoding exons and highly conserved exon-intron boundaries. Each of the 4 bestrophin genes has a unique 3-prime end of variable length (Stohr et al., 2002 [PubMed 12032738]; Tsunenari et al., 2003 [PubMed 12907679]).

Source: NCBI Gene 144453 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 103 total — 2 pathogenic, 1 likely-pathogenic
• GTEx eGene: eQTL in 17 tissues, sQTL in 5 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.27 (unconstrained)
• MANE Select transcript: NM_032735
• Notable: 103 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17105
Approved symbol	BEST3
Name	bestrophin 3
Location	12q15
Locus type	gene with protein product
Status	Approved
Aliases	MGC40411, MGC13168
Ensembl gene	ENSG00000127325
Ensembl biotype	protein_coding
OMIM	607337
Entrez	144453

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 15 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

MANE Select: ENST00000330891

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 4, TSL 3: 4, TSL 5: 4

ENST00000330891, ENST00000266661, ENST00000331471, ENST00000476098, ENST00000488961, ENST00000529843, ENST00000533674, ENST00000547208, ENST00000548658, ENST00000551160, ENST00000552295, ENST00000553096, ENST00000944745, ENST00001025894, ENST00001025895, ENST00001025896, ENST00001113534, ENST00001139930

RefSeq mRNA: 6 — MANE Select: NM_032735 NM_001282613, NM_001282614, NM_001282615, NM_001282616, NM_032735, NM_152439

CCDS: CCDS41810, CCDS61192, CCDS61193, CCDS73496, CCDS8992

Canonical transcript exons

ENST00000330891 — 10 exons

Exon	Start	End
ENSE00001294773	69671428	69671579
ENSE00001319593	69676916	69677068
ENSE00001423775	69699205	69699303
ENSE00001910204	69653609	69655813
ENSE00003251214	69677180	69677257
ENSE00003318513	69672885	69672965
ENSE00003494773	69678739	69678893
ENSE00003500049	69694370	69694464
ENSE00003569612	69693674	69693907
ENSE00003572303	69697647	69697813

Expression profiles

Bgee: expression breadth ubiquitous, 174 present calls, max score 96.96.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.7485 / max 431.2756, expressed in 168 samples.

Highest expression (Bgee): tibialis anterior, gastrocnemius, muscle of leg, deltoid, sperm.

Genetic regulation across tissues (GTEx eQTL / sQTL)

BEST3 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 17 tissues and its splicing (sQTL) in 5 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 22 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Muscle Skeletal	sqtl	2.8e-79	-1.19	12:69695285:G:A
Muscle Skeletal	eqtl	1.1e-64	-0.51	12:69688577:G:A
Testis	eqtl	2.3e-19	-0.37	12:69813575:C:T
Heart Left Ventricle	eqtl	1.6e-17	-0.56	12:69688577:G:A
Brain Cerebellar Hemisphere	eqtl	2.2e-12	+0.39	12:69691664:C:T
Pancreas	eqtl	2.0e-11	-0.49	12:69699426:G:C
Pituitary	eqtl	3.8e-11	-0.33	12:69688577:G:A
Adrenal Gland	eqtl	3.0e-10	-0.52	12:69632285:T:C
Brain Cerebellum	eqtl	4.7e-10	-0.39	12:69691015:G:A
Brain Frontal Cortex BA9	eqtl	4.8e-07	-0.32	12:69689434:G:T
Brain Cerebellum	sqtl	1.6e-06	-0.69	12:69691664:C:T
Brain Cerebellar Hemisphere	sqtl	3.5e-05	-0.62	12:69691664:C:T
Testis	sqtl	4.0e-05	-0.55	12:69687841:C:T
Brain Nucleus accumbens basal ganglia	eqtl	5.9e-05	-0.39	12:69689434:G:T
Brain Caudate basal ganglia	eqtl	8.4e-05	-0.50	12:69673743:C:T
Brain Cortex	eqtl	1.5e-03	+0.34	12:69644502:T:G
Brain Hippocampus	eqtl	8.1e-03	-0.31	12:69694352:C:T
Brain Cortex	sqtl	9.7e-03	+1.06	12:69141274:G:A
Brain Hypothalamus	eqtl	1.6e-02	-0.24	12:69650398:A:G
Skin Sun Exposed Lower leg	eqtl	1.8e-02	-0.19	12:69649823:G:C

FANTOM5 promoters

6 alternative TSS:

Promoter ID	TPM avg	Samples expressed
132028	0.6810	92
132030	0.6561	120
132029	0.2573	53
132031	0.0711	28
132032	0.0465	22
132033	0.0365	12

Top tissues by expression

showing 100 of 246 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
tibialis anterior	UBERON:0001385	96.96	gold quality
gastrocnemius	UBERON:0001388	95.40	gold quality
muscle of leg	UBERON:0001383	93.66	gold quality
deltoid	UBERON:0001476	91.48	gold quality
sperm	CL:0000019	91.05	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.38	gold quality
skeletal muscle tissue	UBERON:0001134	88.08	gold quality
quadriceps femoris	UBERON:0001377	88.04	gold quality
vastus lateralis	UBERON:0001379	86.99	gold quality
biceps brachii	UBERON:0001507	85.87	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	84.61	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	82.68	gold quality
muscle tissue	UBERON:0002385	81.49	gold quality
cerebellar hemisphere	UBERON:0002245	77.01	gold quality
pancreatic ductal cell	CL:0002079	76.95	gold quality
cerebellar cortex	UBERON:0002129	76.92	gold quality
right hemisphere of cerebellum	UBERON:0014890	76.39	gold quality
islet of Langerhans	UBERON:0000006	75.69	gold quality
cerebellum	UBERON:0002037	75.47	gold quality
bone marrow cell	CL:0002092	73.54	gold quality
body of tongue	UBERON:0011876	72.78	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.32	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	69.28	gold quality
amygdala	UBERON:0001876	68.83	gold quality
adrenal tissue	UBERON:0018303	67.91	gold quality
bone marrow	UBERON:0002371	66.89	gold quality
cerebellar vermis	UBERON:0004720	66.79	gold quality
spinal cord	UBERON:0002240	66.69	gold quality
anterior cingulate cortex	UBERON:0009835	65.73	gold quality
tongue	UBERON:0001723	65.17	gold quality
substantia nigra	UBERON:0002038	64.15	gold quality
right frontal lobe	UBERON:0002810	63.62	gold quality
corpus callosum	UBERON:0002336	62.56	gold quality
left adrenal gland	UBERON:0001234	62.29	gold quality
minor salivary gland	UBERON:0001830	62.13	gold quality
Brodmann (1909) area 9	UBERON:0013540	62.07	gold quality
right adrenal gland	UBERON:0001233	62.04	gold quality
monocyte	CL:0000576	61.81	gold quality
Ammon’s horn	UBERON:0001954	61.69	gold quality
midbrain	UBERON:0001891	61.47	gold quality
right testis	UBERON:0004534	61.34	gold quality
leukocyte	CL:0000738	61.26	gold quality
pancreas	UBERON:0001264	61.03	gold quality
nucleus accumbens	UBERON:0001882	61.03	gold quality
left testis	UBERON:0004533	60.89	gold quality
apex of heart	UBERON:0002098	60.62	gold quality
brain	UBERON:0000955	60.55	gold quality
caudate nucleus	UBERON:0001873	60.27	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	60.17	gold quality
heart left ventricle	UBERON:0002084	60.15	gold quality
left adrenal gland cortex	UBERON:0035825	59.97	gold quality
mouth mucosa	UBERON:0003729	59.96	gold quality
adrenal gland	UBERON:0002369	59.93	gold quality
hypothalamus	UBERON:0001898	59.81	gold quality
testis	UBERON:0000473	59.63	gold quality
prefrontal cortex	UBERON:0000451	59.55	gold quality
cardiac ventricle	UBERON:0002082	59.53	gold quality
putamen	UBERON:0001874	59.39	gold quality
right adrenal gland cortex	UBERON:0035827	59.21	gold quality
adenohypophysis	UBERON:0002196	59.16	gold quality
stromal cell of endometrium	CL:0002255	58.99	gold quality
neocortex	UBERON:0001950	58.80	gold quality
forebrain	UBERON:0001890	58.74	gold quality
pituitary gland	UBERON:0000007	58.56	gold quality
adrenal cortex	UBERON:0001235	58.44	gold quality
ileal mucosa	UBERON:0000331	58.39	gold quality
cerebral cortex	UBERON:0000956	58.39	gold quality
trabecular bone tissue	UBERON:0002483	58.27	silver quality
temporal lobe	UBERON:0001871	58.03	gold quality
frontal cortex	UBERON:0001870	58.02	gold quality
saliva-secreting gland	UBERON:0001044	57.44	gold quality
epithelial cell of pancreas	CL:0000083	56.71	silver quality
left ventricle myocardium	UBERON:0006566	56.67	gold quality
prostate gland	UBERON:0002367	55.43	gold quality
vena cava	UBERON:0004087	54.70	gold quality
heart	UBERON:0000948	54.64	gold quality
calcaneal tendon	UBERON:0003701	54.57	gold quality
endothelial cell	CL:0000115	54.55	gold quality
lower lobe of lung	UBERON:0008949	54.51	silver quality
cardiac muscle of right atrium	UBERON:0003379	54.34	gold quality
body of pancreas	UBERON:0001150	54.31	gold quality
superior surface of tongue	UBERON:0007371	54.31	gold quality
jejunum	UBERON:0002115	54.05	gold quality
kidney epithelium	UBERON:0004819	53.93	gold quality
gall bladder	UBERON:0002110	53.86	gold quality
upper arm skin	UBERON:0004263	53.52	gold quality
tendon	UBERON:0000043	53.28	gold quality
smooth muscle tissue	UBERON:0001135	53.26	gold quality
medial globus pallidus	UBERON:0002477	53.14	silver quality
skin of leg	UBERON:0001511	52.81	gold quality
primary visual cortex	UBERON:0002436	52.68	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	52.23	gold quality
buccal mucosa cell	CL:0002336	52.08	gold quality
pons	UBERON:0000988	52.00	gold quality
anatomical system	UBERON:0000467	51.79	gold quality
blood	UBERON:0000178	51.77	gold quality
material anatomical entity	UBERON:0000465	51.62	gold quality
multicellular organism	UBERON:0000468	51.60	gold quality
myocardium	UBERON:0002349	51.50	gold quality
Brodmann (1909) area 46	UBERON:0006483	51.10	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.97
E-GEOD-93593	yes	4.05
E-MTAB-9801	no	2.97

HPA expression

RNA tissue specificity: Group enriched

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Tongue	tissue	52.0
Skeletal muscle	tissue	32.4	medium
Postcentral gyrus	tissue	15.1
Hippocampus	tissue	12.7	low
Nucleus accumbens	tissue	12.3
Locus coeruleus	tissue	9.8
Choroid plexus	tissue	9.3
Testis	tissue	2.9	low
Bone marrow	tissue	2.7	not detected
Retina	tissue	2.4
Corpus callosum	tissue	2.3
Amygdala	tissue	2.2
Cerebellum	tissue	2.2	low
Olfactory bulb	tissue	2.2
Cerebral cortex	tissue	2.1	medium
Insular cortex	tissue	2.1
Retrosplenial and cingulate cortex	tissue	1.9
Prefrontal cortex	tissue	1.8
Esophagus	tissue	1.8	low
Prostate	tissue	1.8	low
Ventral forebrain	tissue	1.8
Retrosplenial cortex	tissue	1.8
Basal ganglia	tissue	1.7	low
Hippocampal formation	tissue	1.7
Entorhinal cortex	tissue	1.7
Septum	tissue	1.7
Temporal cortex	tissue	1.7
Motor cortex	tissue	1.6
Periaqueductal gray	tissue	1.6
Occipital cortex	tissue	1.6
Putamen	tissue	1.5
Hypothalamus	tissue	1.5
Midbrain	tissue	1.4
Medulla oblongata	tissue	1.4
Substantia nigra	tissue	1.4
Somatosensory cortex	tissue	1.4
Spinal cord	tissue	1.3
Thymus	tissue	1.3
Pons	tissue	1.1
Thalamus	tissue	1.1
Superior colliculi	tissue	1.1
Pituitary gland	tissue	1.0
Pancreas	tissue	1.0	low
Skin 1	tissue	0.9	low
Breast	tissue	0.6	low
Epididymis	tissue	0.6	low
Adrenal gland	tissue	0.5	low
Heart muscle	tissue	0.4	low
Kidney	tissue	0.4	medium
Placenta	tissue	0.3	low
Lymph node	tissue	0.2	low
Rectum	tissue	0.2	low
Colon	tissue	0.2	low
Liver	tissue	0.2	low
Gallbladder	tissue	0.2	low
Tonsil	tissue	0.2	low
Cervix	tissue	0.1	low
Stomach 1	tissue	0.1	low
Ovary	tissue	0.1	low
Seminal vesicle	tissue	0.1	low

Brain sub-regions (HPA Brain Atlas): detected in 190; highest nTPM — Flocculonodular lobe (39.7), Vermis (38.0), Cerebellar cortex (32.7), Occipital cortex (white matter) (23.3), Somatosensory cortex, postcentral gyrus, ventral (white matter) (20.2).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting BEST3 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 90 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509

Functional genomics

gnomAD constraint: pLI 1.75e-12, LOEUF 1.27, missense Z 1.07 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000330891 — one region, missense o/e 0.94.

Literature-anchored findings (GeneRIF, showing 5)

• identified three novel VMD2-related human genes demonstrating a high degree of conservation in their respective RFP-TM domains [VMD2L1, VMD2L2, VMD2L3] (PMID:12032738)
• These results suggest that an auto-inhibitory mechanism in C termini of bestrophin 3 may be universal among bestrophins investigated in the study. (PMID:17442670)
• Results provide evidence that the bestrophins are expressed in pancreatic duct cells and, more specifically, that hBest1 plays a role in the calcium activated chloride channels found in these cells. (PMID:19237432)
• results demonstrated that Best-3 is an endogenous inhibitor of NF-kappaB signaling pathway in endothelial cells, suggesting that forced Best-3 expression may be a novel approach for the treatment of vascular inflammatory diseases. (PMID:25329324)
• whole-exome sequencing implicates a rare non-synonymous single-nucleotide variants of BEST3 as a candidate for mandibular prognathism in the Japanese pedigree. (PMID:30849546)

Cross-species orthologs

22 orthologs

Organism	Symbol	Gene ID
mus_musculus	Best3	ENSMUSG00000020169
rattus_norvegicus	Best3	ENSRNOG00000005491
drosophila_melanogaster	Best4	FBGN0036491
drosophila_melanogaster	Best3	FBGN0036492
drosophila_melanogaster	Best1	FBGN0040238
caenorhabditis_elegans		WBGENE00007203
caenorhabditis_elegans		WBGENE00007204
caenorhabditis_elegans		WBGENE00007404
caenorhabditis_elegans		WBGENE00007808
caenorhabditis_elegans	best-8	WBGENE00007988
caenorhabditis_elegans	best-10	WBGENE00008185
caenorhabditis_elegans	best-11	WBGENE00008186
caenorhabditis_elegans		WBGENE00008821
caenorhabditis_elegans		WBGENE00013520
caenorhabditis_elegans	best-25	WBGENE00014102
caenorhabditis_elegans	best-26	WBGENE00014103
caenorhabditis_elegans		WBGENE00015628
caenorhabditis_elegans		WBGENE00020046
caenorhabditis_elegans		WBGENE00021368
caenorhabditis_elegans		WBGENE00022797
caenorhabditis_elegans		WBGENE00206487
caenorhabditis_elegans		WBGENE00220250

Paralogs (3): BEST2 (ENSG00000039987), BEST4 (ENSG00000142959), BEST1 (ENSG00000167995)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:3580298) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 17 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal aorta morphology	1
internal hemorrhage	1
premature death	1
aortic dissection	1
abnormal vascular smooth muscle physiology	1
increased apoptosis	1
aortic aneurysm	1
increased susceptibility to induced morbidity/mortality	1
abnormal aorta elastic tissue morphology	1
abnormal aorta wall morphology	1
abnormal aorta tunica media morphology	1
aortitis	1
dilated ascending aorta	1
descending aorta dilation	1
thoracic aorta aneurysm	1
abdominal aorta aneurysm	1
decreased aorta wall thickness	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Macaca fascicularis	Q6UY87	96.8%	Diamond
Bos taurus	E1BF86	85.7%	Diamond
Sus scrofa	Q8WMR7	79.7%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
RAB3IP	protein-coding	117177
LINC03241	ncRNA	124902959
MYRFL	protein-coding	196446
LRRC10	protein-coding	376132
RAB3IP-DT	ncRNA	101928002
CCT2	protein-coding	10576
MIR3913-2	ncRNA	100500868
MIR3913-1	ncRNA	100500903
FRS2	protein-coding	10818
SNORA113	snoRNA	109623461

Protein

Protein identifiers

Bestrophin-3 — Q8N1M1 (reviewed: Q8N1M1)

Alternative names: Vitelliform macular dystrophy 2-like protein 3

All UniProt accessions (5): E9PNM2, F8VR37, F8VVX2, F8VZR0, Q8N1M1

UniProt curated annotations — full annotation on UniProt →

Function. Ligand-gated anion channel that allows the movement of chloride monoatomic anions across cell membranes when activated by calcium (Ca2+).

Subcellular location. Cell membrane.

Tissue specificity. Present in skeletal muscle and weakly in brain, spinal cord, bone marrow and retina.

Similarity. Belongs to the anion channel-forming bestrophin (TC 1.A.46) family. Calcium-sensitive chloride channel subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
Q8N1M1-2	2	yes
Q8N1M1-1	1
Q8N1M1-4	4
Q8N1M1-5	5
Q8N1M1-6	6

RefSeq proteins (6): NP_001269542, NP_001269543, NP_001269544, NP_001269545, NP_116124, NP_689652 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000615	Bestrophin	Family
IPR021134	Bestrophin-like	Family

Pfam: PF01062

Catalyzed reactions (Rhea)

• chloride(in) = chloride(out) (RHEA:29823)

UniProt features (30 total): splice variant 7, topological domain 5, binding site 5, transmembrane region 4, region of interest 3, compositionally biased region 3, sequence variant 2, chain 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N1M1-F1	67.66	0.50

Human Protein Atlas

Protein class: Transporters, Transporter channels and pores, Predicted membrane proteins, Predicted intracellular proteins

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH approved

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 (5)

Position	Role
10	Ca(2+)
293	Ca(2+)
296	Ca(2+)
301	Ca(2+)
304	Ca(2+)

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-2672351	Stimuli-sensing channels	curated
R-HSA-983712	Ion channel transport	—
R-HSA-382551	Transport of small molecules	—

MSigDB gene sets: 115 (showing top): MYOGENIN_Q6, GCANCTGNY_MYOD_Q6, GOBP_INORGANIC_ANION_TRANSPORT, TGACCTY_ERR1_Q2, CAGCTG_AP4_Q5, TCF4_Q5, CAGCAGG_MIR370, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, GOBP_CHLORIDE_TRANSPORT, TGCTGAY_UNKNOWN, WTGAAAT_UNKNOWN, TCF11_01, NIKOLSKY_BREAST_CANCER_12Q13_Q21_AMPLICON, MYOD_Q6, NKX25_01

GO Biological Process (4): chloride transmembrane transport (GO:1902476), monoatomic ion transport (GO:0006811), chloride transport (GO:0006821), monoatomic ion transmembrane transport (GO:0034220)

GO Molecular Function (6): intracellularly calcium-gated chloride channel activity (GO:0005229), chloride channel activity (GO:0005254), metal ion binding (GO:0046872), ligand-gated monoatomic anion channel activity (GO:0099095), protein binding (GO:0005515), channel activity (GO:0015267)

GO Cellular Component (3): plasma membrane (GO:0005886), chloride channel complex (GO:0034707), membrane (GO:0016020)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Ion channel transport	1
Transport of small molecules	1

GO top-level categories

20 GO namespaces:

Category	Terms
monoatomic anion channel activity	2
chloride transport	1
monoatomic anion transmembrane transport	1
transport	1
monoatomic anion transport	1
inorganic anion transport	1
monoatomic ion transport	1
transmembrane transport	1
chloride channel activity	1
ligand-gated monoatomic anion channel activity	1
intracellularly calcium-gated channel activity	1
chloride transmembrane transporter activity	1
cation binding	1
ligand-gated monoatomic ion channel activity	1
binding	1
passive transmembrane transporter activity	1
membrane	1
cell periphery	1
monoatomic ion channel complex	1
cellular anatomical structure	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 1 of 13 annotations. The rest are phylogenetic / computational / electronic (IEA).

1 experimentally-supported GO terms:

GO term	NS	Evidence
intracellularly calcium-gated chloride channel activity	MF	direct assay

Protein interactions and networks

STRING

showing 16 of 446 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BEST3	LRRC10	Q5BKY1	623
BEST3	CCT2	P78371	576
BEST3	FRS2	Q8WU20	537
BEST3	TSPAN31	Q12999	513
BEST3	LRRC8A	Q8IWT6	463
BEST3	ANO1	Q5XXA6	458
BEST3	CLCN3	P51790	442
BEST3	CNGA2	Q16280	427
BEST3	TFF3	Q07654	425
BEST3	DDIT3	P0DPQ6	419
BEST3	LRRC8B	Q6P9F7	415
BEST3	ATP23	Q9Y6H3	413
BEST3	PIGU	Q9H490	401
BEST3	CLCN1	P35523	395
BEST3	ANO10	Q9NW15	385
BEST3	SLC35E3	Q7Z769	385

IntAct

BioGRID (1 interactions; top human partners by supporting records): GSC2 (Two-hybrid)

Disease & clinical

Genetic variants

Variant evidence for BEST3: 103 ClinVar records (3 pathogenic / likely pathogenic); 4 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	86
Likely benign	6
Benign	2

Top pathogenic / likely-pathogenic (3)

Showing all 3 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
4682805	GRCh37/hg19 12q15-21.1(chr12:68168330-72795051)x1	Pathogenic	criteria provided, single submitter	1
3063262	GRCh37/hg19 12q15-21.1(chr12:69498859-74073631)x1	Likely pathogenic	criteria provided, single submitter	1
980441	GRCh37/hg19 12q15(chr12:68572386-70833868)x1	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore BEST3’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 31 predictions of 1,125):

Position(s)	Effect	Δscore	Sites
12:69671426–69671427	donor_loss	1.0000	3
12:69671427	donor_loss	0.9900
12:69672883–69672884	donor_loss	0.9900	5
12:69672972	acceptor_gain	0.9900
12:69676984	donor_gain	0.9900
12:69677069–69677070	acceptor_loss	0.9900	6
12:69677265	acceptor_gain	0.9900
12:69678737–69678738	donor_loss	0.9900	6
12:69678894–69678895	acceptor_loss	0.9900	6
12:69678896	acceptor_gain	0.9900

AlphaMissense

1,605 missense substitutions predicted likely pathogenic (of 4,396 scored), across 332 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M107	9	0.907	0.994
D304	8	0.998	0.999
D301	8	0.997	0.999
F80	8	0.994	1.000
F84	8	0.991	1.000
D303	8	0.991	0.999
D335	8	0.991	0.998
D104	8	0.989	0.997
D323	8	0.987	0.997
F151	8	0.985	0.999
D302	8	0.985	0.998
F305	8	0.985	0.999
F17	8	0.984	0.998
D312	8	0.984	0.996
F283	8	0.983	0.997
F298	8	0.980	0.997
D228	8	0.978	0.995
S27	8	0.969	0.999
F276	8	0.963	0.991
F188	8	0.959	0.997

HPA cancer prognostics

RNA cancer specificity: Cancer enriched (Glioblastoma Multiforme)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Glioblastoma Multiforme (validation)	favorable	0.000485
Glioblastoma Multiforme (TCGA)	favorable	0.000533

Disease associations

OMIM: gene MIM:607337 | disease phenotypes:

GWAS associations

4 associations:

Study	Trait	p-value
GCST006061_98	Atrial fibrillation	8e-13
GCST006061_97	Atrial fibrillation	9e-13
GCST007006_11	Logical memory (delayed recall) in normal cognition	4e-7
GCST004766_14	Triglyceride change in response to fenofibrate in statin-treated type 2 diabetes	9e-7

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0007681	triglyceride change measurement
EFO:0004874	memory performance

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

1 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs61747221	hydrochlorothiazide	Efficacy	Genotypes AA + AG is associated with increased response to hydrochlorothiazide in people with Hypertension as compared to genotype GG.	PMID:30289819

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, affects methylation, decreases methylation	3
perfluorooctanoic acid	decreases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
incobotulinumtoxinA	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Atrazine	increases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Silicon Dioxide	increases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	increases expression	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.