BMAL2

Summary

BMAL2 (basic helix-loop-helix ARNT like 2, HGNC:18984) is a protein-coding gene on chromosome 12p11.23, encoding Basic helix-loop-helix ARNT-like protein 2 (Q8WYA1). Transcriptional activator which forms a core component of the circadian clock.

This gene encodes a basic helix-loop-helix transcription factor belonging to the PAS (PER, ARNT, SIM) superfamily. The PAS proteins play important roles in adaptation to low atmospheric and cellular oxygen levels, exposure to certain environmental pollutants, and diurnal oscillations in light and temperature. This protein forms a transcriptionally active heterodimer with the circadian CLOCK protein, the structurally related MOP4, and hypoxia-inducible factors, such as HIF1alpha. Consistent with its role as a biologically relevant partner of circadian and hypoxia factors, this protein is coexpressed in regions of the brain such as the thalamus, hypothalamus, and amygdala. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 56938 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 124 total — 1 pathogenic, 1 likely-pathogenic
• MANE Select transcript: NM_020183

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18984
Approved symbol	BMAL2
Name	basic helix-loop-helix ARNT like 2
Location	12p11.23
Locus type	gene with protein product
Status	Approved
Aliases	MOP9, CLIF, PASD9, bHLHe6
Ensembl gene	ENSG00000029153
Ensembl biotype	protein_coding
OMIM	614517
Entrez	56938

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 12 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000261178, ENST00000266503, ENST00000311001, ENST00000395901, ENST00000457040, ENST00000539558, ENST00000542388, ENST00000544915, ENST00000546179, ENST00000929515, ENST00000929516, ENST00000959850, ENST00000959851

RefSeq mRNA: 11 — MANE Select: NM_020183 NM_001248002, NM_001248003, NM_001248004, NM_001248005, NM_001394524, NM_001394525, NM_001394526, NM_001394527, NM_001394528, NM_001394529, NM_020183

CCDS: CCDS58219, CCDS58220, CCDS58221, CCDS58222, CCDS8712, CCDS91666

Canonical transcript exons

ENST00000266503 — 17 exons

Exon	Start	End
ENSE00000835928	27418088	27418196
ENSE00000936653	27385481	27385560
ENSE00000936654	27387228	27387320
ENSE00000936656	27389179	27389296
ENSE00000936658	27390096	27390239
ENSE00000936665	27415869	27415947
ENSE00001007997	27380247	27380404
ENSE00001098214	27401524	27401674
ENSE00001098216	27403433	27403541
ENSE00001098221	27402619	27402677
ENSE00001098222	27400534	27400774
ENSE00001098224	27401257	27401363
ENSE00001600104	27368262	27368412
ENSE00002224670	27420396	27425286
ENSE00003681246	27376346	27376387
ENSE00003693240	27370129	27370230
ENSE00003930765	27332836	27333103

Expression profiles

Bgee: expression breadth ubiquitous, 200 present calls, max score 93.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.9428 / max 371.8653, expressed in 1652 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
124835	10.0138	1556
124836	4.6340	1339
124834	3.3494	1079
124837	0.6669	346
124833	0.2787	128

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	93.51	gold quality
esophagus squamous epithelium	UBERON:0006920	90.98	gold quality
amniotic fluid	UBERON:0000173	90.14	gold quality
esophagus mucosa	UBERON:0002469	89.54	gold quality
oral cavity	UBERON:0000167	89.36	gold quality
epithelium of esophagus	UBERON:0001976	88.67	gold quality
buccal mucosa cell	CL:0002336	87.04	gold quality
squamous epithelium	UBERON:0006914	83.61	gold quality
islet of Langerhans	UBERON:0000006	83.34	gold quality
pharyngeal mucosa	UBERON:0000355	83.19	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.99	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.08	gold quality
gingiva	UBERON:0001828	79.66	gold quality
vagina	UBERON:0000996	79.45	gold quality
stromal cell of endometrium	CL:0002255	78.99	gold quality
esophagus	UBERON:0001043	78.99	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	77.52	gold quality
gingival epithelium	UBERON:0001949	77.35	gold quality
cervix epithelium	UBERON:0004801	77.20	gold quality
tonsil	UBERON:0002372	76.95	gold quality
middle temporal gyrus	UBERON:0002771	76.48	silver quality
skin of leg	UBERON:0001511	76.21	gold quality
mouth mucosa	UBERON:0003729	76.11	gold quality
body of tongue	UBERON:0011876	76.10	gold quality
calcaneal tendon	UBERON:0003701	75.78	gold quality
vermiform appendix	UBERON:0001154	75.73	gold quality
skin of abdomen	UBERON:0001416	75.63	gold quality
minor salivary gland	UBERON:0001830	74.93	gold quality
oviduct epithelium	UBERON:0004804	74.86	gold quality
sperm	CL:0000019	74.68	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-11	yes	191.05
E-ANND-3	yes	6.12

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

9 targets.

Target	Regulation
BHLHE40	Activation
BHLHE41	Activation
IL21
MCL1
PER1
PER2
SERPINE1	Activation
SGCA
TSPOAP1

miRNA regulators (miRDB)

206 targeting BMAL2, 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-3163	100.00	77.23	8605
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-6778-3P	99.96	67.29	2693

Literature-anchored findings (GeneRIF, showing 14)

• Alternative splicing yields novel BMAL2 variants: tissue distribution and functional characterization. (PMID:12055078)
• Several new polymorphisms in ARNTL2 are reported. (PMID:18663240)
• PER2 is inhibited by BMAL2-CLOCK, which reemphasizes its negative role and a positive role of BMAL2 in circadian transcription (PMID:19605937)
• results show a difference in the expression pattern of Bmal2, but not Clock and Dec1 in PD. (PMID:21658431)
• ARNTL2 expression is increased in colorectal cancer and in a highly proliferative colon cancer cell line and is related to tumor invasiveness and aggressiveness. (PMID:22198637)
• there is significant association between diurnal preference and a polymorphism in PER3 and a novel nominally significant association between diurnal preference and a polymorphism in ARNTL2 (PMID:24635757)
• The prevalence of C carriers in BMAL2 gene rs2306074 T/C in Alzheimer disease patients was significantly higher than that of control subjects (PMID:24847962)
• BMAL2 rs7958822 genotype is associated with type 2 diabetes in obese men and women; an interaction between BMAL2 rs7958822 genotype and obesity was observed in men (PMID:26497775)
• Data indicate that high transcription factor ARNTL2 is a top predictor of lung adenocarcinoma patient outcome. (PMID:27150038)
• ARNTL2 promotes pancreatic ductal adenocarcinoma progression through TGF/BETA pathway and is regulated by miR-26a-5p. (PMID:32826856)
• [Effects of BMAL2 on Aerobic Glycolysis and Cell Proliferation in Acute Myeloid Leukemia Cells]. (PMID:38660843)
• BMAL2 promotes eCIRP-induced macrophage endotoxin tolerance. (PMID:38938563)
• The circadian gene ARNTL2 promotes nasopharyngeal carcinoma invasiveness and metastasis through suppressing AMOTL2-LATS-YAP pathway. (PMID:38956029)
• ARNTL2 facilitates bladder cancer progression through potentiating ENO1-mediated glycolysis in a SLC31A1-independent and -dependent manner. (PMID:39147318)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	bmal2	ENSDARG00000041381
mus_musculus	Bmal2	ENSMUSG00000040187
rattus_norvegicus	Bmal2	ENSRNOG00000001830
drosophila_melanogaster	Met	FBGN0002723
drosophila_melanogaster	Clk	FBGN0023076
drosophila_melanogaster	gce	FBGN0261703
drosophila_melanogaster	tgo	FBGN0264075
caenorhabditis_elegans	aha-1	WBGENE00000095

Paralogs (6): BMAL1 (ENSG00000133794), CLOCK (ENSG00000134852), ARNT (ENSG00000143437), PASD1 (ENSG00000166049), NPAS2 (ENSG00000170485), ARNT2 (ENSG00000172379)

Protein

Protein identifiers

Basic helix-loop-helix ARNT-like protein 2 — Q8WYA1 (reviewed: Q8WYA1)

Alternative names: Aryl hydrocarbon receptor nuclear translocator-like protein 2, Basic-helix-loop-helix-PAS protein MOP9, Brain and muscle ARNT-like 2, CYCLE-like factor, Class E basic helix-loop-helix protein 6, Member of PAS protein 9, PAS domain-containing protein 9

All UniProt accessions (2): Q8WYA1, H0Y5R1

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional activator which forms a core component of the circadian clock. The circadian clock, an internal time-keeping system, regulates various physiological processes through the generation of approximately 24 hour circadian rhythms in gene expression, which are translated into rhythms in metabolism and behavior. It is derived from the Latin roots ‘circa’ (about) and ‘diem’ (day) and acts as an important regulator of a wide array of physiological functions including metabolism, sleep, body temperature, blood pressure, endocrine, immune, cardiovascular, and renal function. Consists of two major components: the central clock, residing in the suprachiasmatic nucleus (SCN) of the brain, and the peripheral clocks that are present in nearly every tissue and organ system. Both the central and peripheral clocks can be reset by environmental cues, also known as Zeitgebers (German for ’timegivers’). The predominant Zeitgeber for the central clock is light, which is sensed by retina and signals directly to the SCN. The central clock entrains the peripheral clocks through neuronal and hormonal signals, body temperature and feeding-related cues, aligning all clocks with the external light/dark cycle. Circadian rhythms allow an organism to achieve temporal homeostasis with its environment at the molecular level by regulating gene expression to create a peak of protein expression once every 24 hours to control when a particular physiological process is most active with respect to the solar day. Transcription and translation of core clock components (CLOCK, NPAS2, BMAL1, BMAL2, PER1, PER2, PER3, CRY1 and CRY2) plays a critical role in rhythm generation, whereas delays imposed by post-translational modifications (PTMs) are important for determining the period (tau) of the rhythms (tau refers to the period of a rhythm and is the length, in time, of one complete cycle). A diurnal rhythm is synchronized with the day/night cycle, while the ultradian and infradian rhythms have a period shorter and longer than 24 hours, respectively. Disruptions in the circadian rhythms contribute to the pathology of cardiovascular diseases, cancer, metabolic syndromes and aging. A transcription/translation feedback loop (TTFL) forms the core of the molecular circadian clock mechanism. Transcription factors, CLOCK or NPAS2 and BMAL1 or BMAL2, form the positive limb of the feedback loop, act in the form of a heterodimer and activate the transcription of core clock genes and clock-controlled genes (involved in key metabolic processes), harboring E-box elements (5’-CACGTG-3’) within their promoters. The core clock genes: PER1/2/3 and CRY1/2 which are transcriptional repressors form the negative limb of the feedback loop and interact with the CLOCK|NPAS2-BMAL1|BMAL2 heterodimer inhibiting its activity and thereby negatively regulating their own expression. This heterodimer also activates nuclear receptors NR1D1/2 and RORA/B/G, which form a second feedback loop and which activate and repress BMAL1 transcription, respectively. The CLOCK-BMAL2 heterodimer activates the transcription of SERPINE1/PAI1 and BHLHE40/DEC1.

Subunit / interactions. Component of the circadian core oscillator, which includes the CRY proteins, CLOCK, or NPAS2, BMAL1 or BMAL2, CSNK1D and/or CSNK1E, TIMELESS and the PER proteins. Interacts directly with CLOCK to form the BMAL2-CLOCK transactivator. Can form heterodimers or homodimers which interact directly with CLOCK to form the transcription activator. Interacts with NPAS2 and HIF1A. Interacts with PER2.

Subcellular location. Nucleus.

Tissue specificity. Expressed in fetal brain. Highly expressed in brain and placenta. Lower levels in heart, liver, thymus, kidney and lung. Located to endothelial cells and neuronal cells of the suprachiasmatic nucleus (SCN). Also detected in endothelial cells of the heart, lung and kidney. In the brain, specifically expressed in the thalamus, hippocampus and amygdala.

Induction. Constitutively expressed. Has no circadian rhythm expression pattern.

Isoforms (9)

UniProt ID	Names	Canonical?
Q8WYA1-1	1, BMAL2a	yes
Q8WYA1-2	2, BMAL2b
Q8WYA1-3	3, BMAL2c
Q8WYA1-4	4, BMAL2d
Q8WYA1-5	5, CLIF
Q8WYA1-6	6
Q8WYA1-7	7, MOP9 long form
Q8WYA1-8	8, MOP9 short form
Q8WYA1-9	9

RefSeq proteins (11): NP_001234931, NP_001234932, NP_001234933, NP_001234934, NP_001381453, NP_001381454, NP_001381455, NP_001381456, NP_001381457, NP_001381458, NP_064568* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000014	PAS	Domain
IPR001067	Nuc_translocat	Family
IPR011598	bHLH_dom	Domain
IPR013767	PAS_fold	Domain
IPR035965	PAS-like_dom_sf	Homologous_superfamily
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR050933	Circadian_TF	Family

Pfam: PF00010, PF00989, PF14598

UniProt features (41 total): strand 9, splice variant 7, sequence conflict 7, domain 4, short sequence motif 3, cross-link 2, sequence variant 2, helix 2, turn 2, region of interest 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2KDK	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WYA1-F1	61.96	0.29

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 (2): 287, 294

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1368108	BMAL1:CLOCK,NPAS2 activates circadian expression
R-HSA-400253

MSigDB gene sets: 183 (showing top): GOBP_CIRCADIAN_RHYTHM, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, HORIUCHI_WTAP_TARGETS_DN, YANG_BREAST_CANCER_ESR1_LASER_DN, GOBP_CIRCADIAN_REGULATION_OF_GENE_EXPRESSION, BILD_HRAS_ONCOGENIC_SIGNATURE, chr12p11, GOBP_REGULATION_OF_CIRCADIAN_RHYTHM, RIGGI_EWING_SARCOMA_PROGENITOR_DN, GOBP_POSITIVE_REGULATION_OF_CIRCADIAN_RHYTHM, GOBP_ENTRAINMENT_OF_CIRCADIAN_CLOCK, LIAO_METASTASIS, TGANTCA_AP1_C, CHARAFE_BREAST_CANCER_LUMINAL_VS_BASAL_DN, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_UP

GO Biological Process (9): regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), circadian rhythm (GO:0007623), entrainment of circadian clock (GO:0009649), circadian regulation of gene expression (GO:0032922), positive regulation of circadian rhythm (GO:0042753), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944), rhythmic process (GO:0048511)

GO Molecular Function (7): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription factor activity (GO:0003700), protein dimerization activity (GO:0046983), E-box binding (GO:0070888), DNA binding (GO:0003677), protein binding (GO:0005515)

GO Cellular Component (8): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), aryl hydrocarbon receptor complex (GO:0034751), CLOCK-BMAL transcription complex (GO:1990513), transcription regulator complex (GO:0005667)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Circadian clock	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
cellular anatomical structure	3
DNA-templated transcription	2
regulation of gene expression	2
transcription by RNA polymerase II	2
regulation of circadian rhythm	2
circadian rhythm	2
regulation of transcription by RNA polymerase II	2
RNA polymerase II transcription regulatory region sequence-specific DNA binding	2
nuclear lumen	2
regulation of RNA biosynthetic process	1
rhythmic process	1
response to external stimulus	1
positive regulation of biological process	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
biological_process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
protein binding	1
RNA polymerase II cis-regulatory region sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
chromosome	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
signaling receptor complex	1
intracellular protein-containing complex	1
RNA polymerase II transcription regulator complex	1
protein-containing complex	1

Protein interactions and networks

STRING

836 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BMAL2	CLOCK	O15516	962
BMAL2	NPAS2	Q99743	954
BMAL2	CRY2	Q49AN0	775
BMAL2	CRY1	Q16526	774
BMAL2	CSNK1E	P49674	743
BMAL2	TIMELESS	Q9UNS1	712
BMAL2	NR1D1	P20393	686
BMAL2	BHLHE40	O14503	683
BMAL2	SMCO2	A6NFE2	641
BMAL2	NR1D2	Q14995	633
BMAL2	PER2	O15055	608
BMAL2	NFIL3	Q16649	551
BMAL2	CSNK1D	P48730	546
BMAL2	BHLHE41	Q9C0J9	543
BMAL2	RORB	Q92753	529

IntAct

13 interactions, top by confidence:

A	B	Type	Score
OLFM1	OLFM2	psi-mi:“MI:0914”(association)	0.640
BMAL2	CLOCK	psi-mi:“MI:0915”(physical association)	0.550
BMAL2	CLOCK	psi-mi:“MI:0914”(association)	0.550
FAM200C	CRLF3	psi-mi:“MI:0914”(association)	0.530
BMAL2	USP20	psi-mi:“MI:0915”(physical association)	0.400
EPAS1	BMAL2	psi-mi:“MI:0915”(physical association)	0.370
BMAL2	EPAS1	psi-mi:“MI:0915”(physical association)	0.370
BMAL1	BCAM	psi-mi:“MI:0914”(association)	0.350
CIPC	BMAL1	psi-mi:“MI:0914”(association)	0.350
BMAL2	RORC	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (42): RORC (Two-hybrid), UBE3A (Affinity Capture-Western), ARNTL2 (Synthetic Growth Defect), ARNTL2 (Affinity Capture-MS), ARNTL2 (Affinity Capture-MS), CLOCK (Affinity Capture-MS), CIPC (Affinity Capture-MS), ARNTL2 (Affinity Capture-MS), DHTKD1 (Affinity Capture-MS), ARNTL2 (Affinity Capture-MS), NPAS2 (Affinity Capture-MS), METTL3 (Affinity Capture-MS), NSMCE4A (Affinity Capture-MS), ARNTL2 (Affinity Capture-MS), HAUS4 (Affinity Capture-MS)

ESM2 similar proteins: A0MLS5, G5EGD2, O00327, O02219, O02747, O02748, O15945, O35800, O44712, O88529, P27540, P30561, P35869, P41738, P41739, P53762, P56645, P79832, P97481, Q0PGG7, Q16665, Q17062, Q2VPD4, Q309Z6, Q5R4T2, Q61221, Q61324, Q6YGZ5, Q78E60, Q8K3T2, Q8QGQ7, Q8QGQ8, Q8R4S2, Q8R4S4, Q8R4S5, Q8R4S6, Q8R4S7, Q8WYA1, Q91YA9, Q95LD9

Diamond homologs: A0MLS5, A6NFD8, O00327, O02219, O02748, O08785, O15516, O15945, O61734, O88529, P27540, P41739, P53762, P79832, P90953, P97460, Q2NL18, Q2VPD4, Q5R4T2, Q5RAK8, Q5ZQU2, Q61324, Q6YGZ4, Q6YGZ5, Q78E60, Q7TS99, Q8BGD7, Q8IUM7, Q8QGQ6, Q8QGQ7, Q8WYA1, Q91YA8, Q91YA9, Q91YB0, Q91YB2, Q99743, Q9BE97, Q9DBX7, Q9DG12, Q9EPW1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ARNTL2	“form complex”	CLOCK/BMAL2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	88
Likely benign	7
Benign	2

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
59014	GRCh38/hg38 12p11.23-11.22(chr12:27161598-27642483)x1	Pathogenic
2685051	GRCh37/hg19 12p11.23-11.22(chr12:27514172-29338877)x4	Likely pathogenic

SpliceAI

2910 predictions. Top by Δscore:

Variant	Effect	Δscore
12:27333206:G:T	donor_gain	1.0000
12:27368391:G:GT	donor_gain	1.0000
12:27368391:G:T	donor_gain	1.0000
12:27368413:G:GG	donor_gain	1.0000
12:27380245:A:AG	acceptor_gain	1.0000
12:27380246:G:GG	acceptor_gain	1.0000
12:27380246:GA:G	acceptor_gain	1.0000
12:27380246:GAGAA:G	acceptor_gain	1.0000
12:27387290:G:GG	donor_gain	1.0000
12:27389178:GGCTA:G	acceptor_gain	1.0000
12:27390065:A:AG	acceptor_gain	1.0000
12:27390069:A:AG	acceptor_gain	1.0000
12:27390076:C:A	acceptor_gain	1.0000
12:27390086:T:TA	acceptor_gain	1.0000
12:27390094:AGCT:A	acceptor_gain	1.0000
12:27390095:GCTG:G	acceptor_gain	1.0000
12:27400563:ACT:A	acceptor_gain	1.0000
12:27401363:GGTA:G	donor_loss	1.0000
12:27401364:G:T	donor_loss	1.0000
12:27401365:T:A	donor_loss	1.0000
12:27401522:A:G	acceptor_gain	1.0000
12:27403431:A:AG	acceptor_gain	1.0000
12:27403432:G:GG	acceptor_gain	1.0000
12:27403432:GA:G	acceptor_gain	1.0000
12:27403539:GAG:G	donor_gain	1.0000
12:27415943:GGAGT:G	donor_gain	1.0000
12:27415944:GAGTG:G	donor_gain	1.0000
12:27415946:GT:G	donor_gain	1.0000
12:27418192:CCTCA:C	donor_gain	1.0000
12:27418193:CTCA:C	donor_gain	1.0000

AlphaMissense

4207 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:27380377:G:C	A153P	0.999
12:27401601:A:C	S449R	0.999
12:27401603:C:A	S449R	0.999
12:27401603:C:G	S449R	0.999
12:27380276:G:C	R119T	0.998
12:27380277:G:C	R119S	0.998
12:27380277:G:T	R119S	0.998
12:27380280:A:C	R120S	0.998
12:27380280:A:T	R120S	0.998
12:27380309:T:C	L130P	0.998
12:27380358:A:C	K146N	0.998
12:27380358:A:T	K146N	0.998
12:27380276:G:T	R119M	0.997
12:27380279:G:C	R120T	0.997
12:27380356:A:G	K146E	0.997
12:27380357:A:T	K146I	0.997
12:27380366:T:A	V149D	0.997
12:27380369:T:C	L150S	0.997
12:27401292:T:C	L399P	0.997
12:27380279:G:T	R120I	0.996
12:27380297:T:C	L126P	0.996
12:27380354:A:T	D145V	0.996
12:27400735:G:C	R374P	0.996
12:27401616:T:C	F454L	0.996
12:27401618:C:A	F454L	0.996
12:27401618:C:G	F454L	0.996
12:27380268:A:C	E116D	0.995
12:27380268:A:T	E116D	0.995
12:27380273:G:C	R118P	0.995
12:27380354:A:C	D145A	0.995

dbSNP variants (sampled 300 via entrez): RS1000033247 (12:27393070 A>G), RS1000037848 (12:27397258 G>A), RS1000049656 (12:27404468 G>A), RS1000064966 (12:27373554 A>C,G), RS1000105850 (12:27348844 G>T), RS1000106382 (12:27392703 A>G), RS1000119445 (12:27421679 T>G), RS1000214955 (12:27353349 T>C), RS1000230419 (12:27409387 C>A,T), RS1000255963 (12:27422022 A>G), RS1000331043 (12:27339655 C>G,T), RS1000398502 (12:27414436 G>A), RS1000424448 (12:27405881 A>G), RS1000453332 (12:27419901 T>C), RS1000486214 (12:27359518 AT>A,ATT)

Disease associations

OMIM: gene MIM:614517 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): pulmonary disease, chronic obstructive, susceptibility to (MONDO:0100167)

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST009531_2	Body fat percentage	4.000000e-08
GCST90020025_18	Waist-to-hip ratio adjusted for BMI	3.000000e-08
GCST90020025_19	Waist-to-hip ratio adjusted for BMI	3.000000e-09
GCST90020027_1698	Waist-hip index	2.000000e-08
GCST90020027_1699	Waist-hip index	3.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007800	body fat percentage
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	4
bisphenol A	affects cotreatment, increases methylation, decreases expression	3
sodium arsenite	increases abundance, increases expression, increases methylation, affects cotreatment	3
Cyclosporine	increases expression	3
Cisplatin	affects cotreatment, affects expression, increases expression	2
Nickel	increases expression	2
Tobacco Smoke Pollution	increases expression	2
pirinixic acid	affects binding, decreases expression, increases activity	1
trichostatin A	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1
manganese chloride	increases expression, affects cotreatment, increases abundance	1
fumaronitrile	affects response to substance	1
cobalt oxide	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
incobotulinumtoxinA	decreases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	increases expression	1
Dasatinib	decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Panobinostat	affects cotreatment, affects expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Cadmium	increases abundance, increases expression	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Manganese	increases expression, affects cotreatment, increases abundance	1
Methyl Methanesulfonate	decreases expression	1
Quercetin	increases expression	1

Clinical trials (associated diseases)

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