BHLHE41

Summary

BHLHE41 (basic helix-loop-helix family member e41, HGNC:16617) is a protein-coding gene on chromosome 12p12.1, encoding Class E basic helix-loop-helix protein 41 (Q9C0J9). Transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes.

This gene encodes a basic helix-loop-helix protein expressed in various tissues. The encoded protein can interact with ARNTL or compete for E-box binding sites in the promoter of PER1 and repress CLOCK/ARNTL’s transactivation of PER1. This gene is believed to be involved in the control of circadian rhythm and cell differentiation. Defects in this gene are associated with the short sleep phenotype.

Source: NCBI Gene 79365 — RefSeq curated summary.

At a glance

• Gene–disease (curated): short sleep, familial natural, 1 (Limited, GenCC)
• GWAS associations: 16
• Clinical variants (ClinVar): 106 total
• Phenotypes (HPO): 1
• Transcription factor: yes — 33 downstream targets (CollecTRI)
• MANE Select transcript: NM_030762

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16617
Approved symbol	BHLHE41
Name	basic helix-loop-helix family member e41
Location	12p12.1
Locus type	gene with protein product
Status	Approved
Aliases	DEC2, SHARP-1, SHARP1
Ensembl gene	ENSG00000123095
Ensembl biotype	protein_coding
OMIM	606200
Entrez	79365

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 2 retained_intron

ENST00000242728, ENST00000394326, ENST00000541271, ENST00000957109

RefSeq mRNA: 1 — MANE Select: NM_030762 NM_030762

CCDS: CCDS8706

Canonical transcript exons

ENST00000242728 — 5 exons

Exon	Start	End
ENSE00000835813	26123630	26123741
ENSE00000835814	26124072	26124179
ENSE00001007937	26124718	26125037
ENSE00001007938	26120030	26123168
ENSE00003584720	26124519	26124582

Expression profiles

Bgee: expression breadth ubiquitous, 282 present calls, max score 98.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.3664 / max 1411.1280, expressed in 1199 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
130208	13.6254	1094
130206	6.1452	662
130207	2.4923	629
130205	0.5314	216
130209	0.4569	275
130199	0.4196	198
130201	0.2621	130
130200	0.2018	114
130198	0.1187	66
130202	0.1130	72

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	98.37	gold quality
inferior vagus X ganglion	UBERON:0005363	98.23	gold quality
calcaneal tendon	UBERON:0003701	98.03	gold quality
cranial nerve II	UBERON:0000941	97.87	gold quality
subthalamic nucleus	UBERON:0001906	97.73	gold quality
spinal cord	UBERON:0002240	97.48	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.48	gold quality
corpus callosum	UBERON:0002336	97.40	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.25	gold quality
lateral globus pallidus	UBERON:0002476	97.11	gold quality
superior vestibular nucleus	UBERON:0007227	97.11	gold quality
caput epididymis	UBERON:0004358	96.74	gold quality
medulla oblongata	UBERON:0001896	96.73	gold quality
endothelial cell	CL:0000115	96.56	gold quality
substantia nigra pars compacta	UBERON:0001965	96.06	gold quality
biceps brachii	UBERON:0001507	95.72	gold quality
tibia	UBERON:0000979	95.66	gold quality
inferior olivary complex	UBERON:0002127	95.66	gold quality
ventral tegmental area	UBERON:0002691	95.52	gold quality
gall bladder	UBERON:0002110	95.48	gold quality
vastus lateralis	UBERON:0001379	95.41	gold quality
dorsal plus ventral thalamus	UBERON:0001897	95.39	gold quality
pigmented layer of retina	UBERON:0001782	95.09	gold quality
retina	UBERON:0000966	95.08	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	94.88	gold quality
mammary duct	UBERON:0001765	94.85	gold quality
midbrain	UBERON:0001891	94.84	gold quality
cartilage tissue	UBERON:0002418	94.82	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	94.80	gold quality
CA1 field of hippocampus	UBERON:0003881	94.77	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	25.29
E-ANND-3	yes	17.50
E-GEOD-135922	yes	12.97
E-MTAB-5061	yes	8.87
E-GEOD-81608	yes	6.30

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

33 targets.

Target	Regulation
BHLHE40	Repression
BHLHE41
BMAL1
BRCA1	Repression
CCND1	Repression
CENPX
CLOCK
CYP21A1P
CYP2D6
CYP51A1
CYP7A1
DBP	Repression
GADD45A
IL13	Activation
IL2RA	Activation
IL4	Activation
IL5	Activation
MLH1	Repression
MYH14	Repression
MYOD1
MYOG
NR1D1	Repression
NR1H4	Repression
PER1	Repression
PMS2
SDC1
SLU7
SNAI2
SREBF1	Repression
TCF3

JASPAR motifs

Motif	Name	Family
MA0636.1	BHLHE41	Hairy-related factors

JASPAR matrix evidence (PMIDs): PMID:18345027

Upstream regulators (CollecTRI, top): BHLHE40, BHLHE41, BMAL1, BMAL2, CLOCK, GATA3, GLI1, GLI2, HIF1A, RORA

miRNA regulators (miRDB)

145 targeting BHLHE41, 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-3162-3P	100.00	65.37	363
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850

Literature-anchored findings (GeneRIF, showing 40)

• DEC1 and DEC2 may play a crucial role in the adaptation to hypoxia (PMID:12354771)
• Dec1 and Dec2 are regulators of the mammalian molecular clock, and form a fifth clock-gene family. [dec1] (PMID:12397359)
• DEC1-mediated repression on the expression of DEC2 (PMID:12624110)
• a corepressor complex containing CtIP/CtBP facilitates RBP-Jkappa/SHARP-mediated repression of Notch target genes (PMID:16287852)
• role of the BHLHB3 protein as a tumor suppressor for lung cancer. (PMID:18223678)
• MLH1 is transcriptionally repressed by the hypoxia-inducible transcription factors, DEC1 and DEC2. (PMID:18345027)
• DEC1, along with DEC2, plays a role in the finer regulation and robustness of the molecular clock CLOCK/BMAL1 (PMID:18411297)
• study identified a mutation, P385R, in DEC2 associated with a short sleep phenotype; activity profiles & sleep recordings of transgenic mice carrying this mutation showed increased vigilance time and less sleep time than control mice (PMID:19679812)
• demonstrated DEC2 expression in response to the treatment with polyinosinic-polycytidylic acid (poly IC), an authentic double-stranded RNA, in cultured human mesangial cells (PMID:21129405)
• DEC2 has anti-apoptotic effects on the paclitaxel-induced apoptosis in human breast cancer MCF-7 cells. (PMID:21327324)
• results suggest that DEC2 periodically represses the promoter activity of CYP2D6, resulting in its circadian expression in serum-shocked cells (PMID:22355045)
• DEC2 regulates apoptosis in oral cancer cells via regulation of pro-apoptotic factor Bim expression (PMID:22572381)
• SHARP1 is required, and sufficient, to limit expression of HIF-target genes (PMID:22801492)
• Sumoylation of Sharp-1 exerts an impact on chromatin structure and transcriptional repression of muscle gene expression through recruitment of G9a. (PMID:23637228)
• GLI1 expression was immunohistochemically related positively with BHLHE41 and inversely with MLH1 in PDAC cells and precancerous lesions of the pancreas. (PMID:24165159)
• we find high frequency of RAS mutations in t(6;11)(q27;q23) pediatric AML and are the first to report a unique and significant differential overexpression of BHLHB3 in these patients. (PMID:24561520)
• SHARP1 interacted with HIF-1alpha physically. (PMID:24918449)
• Data suggest that SHARP1 plays a critical role in tumorigenesis and acquisition of the metastatic phenotype in endometrial cancer. (PMID:24997474)
• BHLHE41 mutations reduce total sleep while maintaining NREM sleep and provide resistance to the effects of sleep loss; mutations that affect sleep also modify the normal inhibition of BHLHE41 of CLOCK/BMAL1 transactivation (PMID:25083013)
• DEC2 regulates cellular function by modulating the expression of Twist1 (PMID:25446074)
• DEC2 participates in hypoxia-induced cell proliferation by functioning as a target gene of the PI3K/Akt signaling pathway and regulating the expression of c-Myc. (PMID:25524285)
• DEC2 facilitates HIF-1alpha stabilization and promotes HIF-1 activation in osteosarcoma. (PMID:25884381)
• BHLHE40/41 are promising markers to predict the aggressiveness of each Endometrial Neoplasm case and that molecular targeting strategies involving BHLHE40/41 and SP1 may effectively regulate Endometrial Neoplasm progression. (PMID:26391953)
• DEC2 is aberrantly expressed in rheumatoid arthritis tissue, it is induced by TNFalpha and not only affects the expression of genes belonging to molecular clock but also significantly impacts on the expression of IL-1beta as well as other inflammatory genes. (PMID:26710124)
• Study found that DEC2 was a direct target of miR-138. (PMID:27095063)
• the present study indicated that SHARP1 acts as a tumor suppressor in thyroid cancer and that its downregulation may contribute to the proliferation, migration and invasion of thyroid cancer cells through mechanisms possibly involving HIF1alpha (PMID:27121679)
• It has been concluded that the renal cell carcinoma risk allele at 12p12.1 maps to rs7132434, a functional variant in an enhancer that upregulates BHLHE41 expression which, in turn, induces IL-11, a member of the IL-6 cytokine family. (PMID:27384883)
• Findings suggest that basic helix-loop-helix family, member e41 protein (DEC2) suppresses cell cycle progression of the mesenchymal cells. (PMID:27430159)
• DEC1, at least partly, exerted a pro-apoptotic effect, whereas DEC2 exerted an anti-apoptotic effect in paclitaxel-induced apoptosis of human prostate cancer cells. (PMID:27840924)
• venous levels lower in preeclampsia than in normal pregnancy (PMID:27845885)
• The renal cell cancers associated polymorphic HIF-binding site at chromosome 12p12.1 regulates BHLHE41 expression. (PMID:28715484)
• Mutation in DCE2 gene is associated with short sleep behavioral trait. (PMID:29531056)
• Suppression of SHARP1 induces robust apoptosis of human MLL-AF6 Acute Myeloid Leukemia cells. (PMID:29692408)
• We validated DEC2 gene as a direct target of miR-873 which could reverse the repressive effects of miR-873 on esophageal cancer cell. (PMID:29890466)
• These results provide evidence that DEC1 and DEC2 have opposite effects on TGFbetainduced epithelialmesenchymal transition in human prostate cancer PC3 cells. (PMID:30106153)
• Knockdown of DEC2 resulted in a significant (26.7%) reduction of VEGF expression in MIO-M1 cells under hypoxia-mimicking conditions induced by DFO (P < .05). Levels of HIF1alpha protein were also reduced significantly, by 60.2%, in MIO-M1 cells treated with siRNA against the DEC2 gene (P < .05). Moreover, HIF1alpha levels showed a significant (2.5-fold) increase in MIO-M1 cells overexpressing DEC2 (P < .05). (PMID:30250985)
• The expression of BHLHE41 in clear cell renal cell carcinoma (ccRCC) was significantly increased in microarray datasets, RNA sequencing data, and in fresh ccRCC tissue samples, compared with than their adjacent nontumorous controls. BHLHE41 knockdown reduced cell proliferation and migration of A498 and CAKI1 cells. These observations demonstrated that BHLHE41 could be a biomarker and an oncogene for ccRCC. (PMID:30816499)
• BHLHE41 suppresses MCF-7 cell invasion via MAPK/JNK pathway. (PMID:32073238)
• MicroRNA-301a inhibits the progression of osteosarcoma by regulating DEC2. (PMID:32521900)
• ARID1A-dependent permissive chromatin accessibility licenses estrogen-receptor signaling to regulate circadian rhythms genes in endometrial cancer. (PMID:32858102)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	bhlhe41	ENSDARG00000041691
mus_musculus	Bhlhe41	ENSMUSG00000030256
rattus_norvegicus	Bhlhe41	ENSRNOG00000048961
drosophila_melanogaster	E(spl)m8-HLH	FBGN0000591
drosophila_melanogaster	E(spl)m3-HLH	FBGN0002609
drosophila_melanogaster	E(spl)m5-HLH	FBGN0002631
drosophila_melanogaster	E(spl)m7-HLH	FBGN0002633
drosophila_melanogaster	E(spl)mbeta-HLH	FBGN0002733
drosophila_melanogaster	E(spl)mdelta-HLH	FBGN0002734
drosophila_melanogaster	E(spl)mgamma-HLH	FBGN0002735
drosophila_melanogaster	Hesr	FBGN0030899
drosophila_melanogaster	cwo	FBGN0259938

Paralogs (12): HES2 (ENSG00000069812), HES1 (ENSG00000114315), BHLHE40 (ENSG00000134107), HEY2 (ENSG00000135547), HES6 (ENSG00000144485), HEYL (ENSG00000163909), HEY1 (ENSG00000164683), HES3 (ENSG00000173673), HES7 (ENSG00000179111), HELT (ENSG00000187821), HES4 (ENSG00000188290), HES5 (ENSG00000197921)

Protein

Protein identifiers

Class E basic helix-loop-helix protein 41 — Q9C0J9 (reviewed: Q9C0J9)

Alternative names: Class B basic helix-loop-helix protein 3, Differentially expressed in chondrocytes protein 2, Enhancer-of-split and hairy-related protein 1

All UniProt accessions (1): Q9C0J9

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional repressor involved in the regulation of the circadian rhythm by negatively regulating the activity of the clock genes and clock-controlled genes. Acts as the negative limb of a novel autoregulatory feedback loop (DEC loop) which differs from the one formed by the PER and CRY transcriptional repressors (PER/CRY loop). Both these loops are interlocked as it represses the expression of PER1 and in turn is repressed by PER1/2 and CRY1/2. Represses the activity of the circadian transcriptional activator: CLOCK-BMAL1 heterodimer by competing for the binding to E-box elements (5’-CACGTG-3’) found within the promoters of its target genes. Negatively regulates its own expression and the expression of DBP and BHLHE41/DEC2. Acts as a corepressor of RXR and the RXR-LXR heterodimers and represses the ligand-induced RXRA/B/G, NR1H3/LXRA, NR1H4 and VDR transactivation activity. Inhibits HNF1A-mediated transactivation of CYP1A2, CYP2E1 AND CYP3A11.

Subunit / interactions. Homodimer. Heterodimer with BHLHE40/DEC1. Interacts with CIART and BMAL1. Interacts with RXRA. Interacts with NR0B2 and HNF1A.

Subcellular location. Nucleus.

Tissue specificity. Highly expressed in skeletal muscle and brain, moderately expressed in pancreas and heart, weakly expressed in placenta, lung, liver and kidney.

Polymorphism. Genetic variations in BHLHE41 are associated with the familial natural short sleep 1 (FNSS1) phenotype, an autosomal dominant trait [MIM:612975]. Individuals with this trait require less sleep in any 24-hour period than is typical for their age group.

RefSeq proteins (1): NP_110389* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003650	Orange_dom	Domain
IPR011598	bHLH_dom	Domain
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR050370	HES_HEY	Family

Pfam: PF00010, PF07527

UniProt features (16 total): cross-link 4, sequence variant 3, region of interest 3, domain 2, compositionally biased region 2, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9C0J9-F1	56.72	0.14

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 (4): 210, 266, 31, 121

Mutagenesis-validated functional residues (1):

Position	Phenotype
70–71	abolishes rxra repression.

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: 286 (showing top): GOBP_CIRCADIAN_RHYTHM, AHRARNT_01, YAATNRNNNYNATT_UNKNOWN, TAATAAT_MIR126, BENPORATH_ES_WITH_H3K27ME3, GOBP_NEGATIVE_REGULATION_OF_STRIATED_MUSCLE_CELL_DIFFERENTIATION, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_NEGATIVE_REGULATION_OF_MUSCLE_CELL_DIFFERENTIATION, TGCACTT_MIR519C_MIR519B_MIR519A, TTTGTAG_MIR520D, MENSE_HYPOXIA_UP, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_STRIATED_MUSCLE_CELL_DIFFERENTIATION, AREB6_01, GOBP_NEGATIVE_REGULATION_OF_MYOTUBE_DIFFERENTIATION

GO Biological Process (11): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), anterior/posterior pattern specification (GO:0009952), negative regulation of myotube differentiation (GO:0010832), obsolete negative regulation of transcription by competitive promoter binding (GO:0010944), circadian regulation of gene expression (GO:0032922), negative regulation of DNA-templated transcription (GO:0045892), regulation of neurogenesis (GO:0050767), regulation of DNA-templated transcription (GO:0006355), circadian rhythm (GO:0007623), rhythmic process (GO:0048511)

GO Molecular Function (14): 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 repressor activity, RNA polymerase II-specific (GO:0001227), protein homodimerization activity (GO:0042803), histone deacetylase binding (GO:0042826), bHLH transcription factor binding (GO:0043425), MRF binding (GO:0043426), protein heterodimerization activity (GO:0046982), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), E-box binding (GO:0070888), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515), protein dimerization activity (GO:0046983)

GO Cellular Component (2): chromatin (GO:0000785), nucleus (GO:0005634)

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
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
regulation of DNA-templated transcription	2
regulation of gene expression	2
DNA-templated transcription	2
protein dimerization activity	2
DNA-binding transcription factor binding	2
negative regulation of DNA-templated transcription	1
regionalization	1
regulation of myotube differentiation	1
myotube differentiation	1
negative regulation of striated muscle cell differentiation	1
circadian rhythm	1
negative regulation of RNA biosynthetic process	1
neurogenesis	1
regulation of nervous system development	1
regulation of cell development	1
regulation of RNA biosynthetic process	1
rhythmic process	1
biological_process	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
negative regulation of transcription by RNA polymerase II	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription repressor activity	1
identical protein binding	1
enzyme binding	1
bHLH transcription factor binding	1
RNA polymerase II cis-regulatory region sequence-specific DNA binding	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
protein binding	1
chromosome	1
cellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

948 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BHLHE41	BMAL1	O00327	979
BHLHE41	CRY1	Q16526	958
BHLHE41	PER2	O15055	952
BHLHE41	NR1D1	P20393	933
BHLHE41	NPAS2	Q99743	929
BHLHE41	PER3	P56645	928
BHLHE41	NR1D2	Q14995	918
BHLHE41	CRY2	Q49AN0	916
BHLHE41	CLOCK	O15516	915
BHLHE41	NFIL3	Q16649	893
BHLHE41	RORA	P35397	871
BHLHE41	RORB	Q92753	856
BHLHE41	RORC	P51449	812
BHLHE41	CSNK1E	P49674	801
BHLHE41	TIMELESS	Q9UNS1	745

IntAct

13 interactions, top by confidence:

A	B	Type	Score
HIF1A	PSMA4	psi-mi:“MI:0914”(association)	0.580
BHLHE41	HIF1A	psi-mi:“MI:0915”(physical association)	0.500
ATM	RBM47	psi-mi:“MI:0914”(association)	0.350
LLGL2	RBBP6	psi-mi:“MI:0914”(association)	0.350
CDCA5	BDP1	psi-mi:“MI:0914”(association)	0.350
Rtf2	UBE2V2	psi-mi:“MI:0914”(association)	0.350
MKNK2	WWP2	psi-mi:“MI:0914”(association)	0.350
MKNK2	WDR46	psi-mi:“MI:0914”(association)	0.350
KLC3	KLC1	psi-mi:“MI:0914”(association)	0.350
MYH13	C1orf226	psi-mi:“MI:0914”(association)	0.350
VPS26A	LCMT2	psi-mi:“MI:0914”(association)	0.350
POLK	TIA1	psi-mi:“MI:0914”(association)	0.350

BioGRID (50): BHLHE41 (Two-hybrid), BHLHE41 (Two-hybrid), BHLHE41 (Two-hybrid), BHLHE41 (Two-hybrid), BHLHE41 (Two-hybrid), BHLHE41 (Two-hybrid), BHLHE41 (Two-hybrid), BHLHE41 (Two-hybrid), FBXW11 (Two-hybrid), GSK3B (Two-hybrid), NONO (Two-hybrid), PPP2R5E (Two-hybrid), RORC (Two-hybrid), BHLHE41 (Two-hybrid), WDR5 (Two-hybrid)

ESM2 similar proteins: A0A287BDC1, A8YXY8, B1AXD8, B3F209, B3KU38, B5DF41, O00287, O14503, O15079, O35185, O54972, P03966, P04198, P12755, P18444, P26014, Q0D2I5, Q25C79, Q2KJ58, Q3MHV6, Q3UR85, Q50H33, Q53H80, Q5BL57, Q5EA15, Q5FWN7, Q5RAI7, Q60591, Q60698, Q61976, Q63379, Q68FF7, Q6GQB5, Q6ZWB6, Q7ZY70, Q8BXL9, Q8CEG5, Q8CI08, Q8N228, Q8ND83

Diamond homologs: B3F209, O14503, O35185, O35779, O35780, O57337, P13097, P35428, Q01068, Q01069, Q01070, Q04666, Q14469, Q26263, Q2KIN4, Q3ZBG4, Q5EA15, Q5PPM5, Q5RAI7, Q66KK8, Q6IRB2, Q6PBD4, Q7KM13, Q7TS99, Q8AVU4, Q8AXV5, Q8AXV6, Q90VV1, Q90Z12, Q99PV5, Q9C0J9, Q9HCC6, Q9QUS4, Q9TSZ2, Q9VGZ5, Q9WV93, Q9Y5J3, Q9UBP5, Q6QB00, Q9I8A3

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
NCOR2	up-regulates	BHLHE41	binding
CTBP1	up-regulates	BHLHE41	binding
BHLHE41	“down-regulates quantity by repression”	BHLHE40	“transcriptional regulation”
BHLHE40	“down-regulates quantity by repression”	BHLHE41	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	84
Likely benign	12
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

474 predictions. Top by Δscore:

Variant	Effect	Δscore
12:26123629:CCATT:C	donor_gain	1.0000
12:26123737:AGAGT:A	acceptor_gain	1.0000
12:26123738:GAGT:G	acceptor_gain	1.0000
12:26123740:GT:G	acceptor_gain	1.0000
12:26123741:TCTGC:T	acceptor_loss	1.0000
12:26123742:C:CC	acceptor_gain	1.0000
12:26123745:C:CT	acceptor_gain	1.0000
12:26123746:A:T	acceptor_gain	1.0000
12:26123747:G:C	acceptor_gain	1.0000
12:26123747:G:GC	acceptor_gain	1.0000
12:26123750:G:C	acceptor_gain	1.0000
12:26123750:G:GC	acceptor_gain	1.0000
12:26123753:C:CT	acceptor_gain	1.0000
12:26123754:A:T	acceptor_gain	1.0000
12:26124070:A:AC	donor_gain	1.0000
12:26124071:C:CC	donor_gain	1.0000
12:26124196:CA:C	acceptor_gain	1.0000
12:26124197:A:AC	acceptor_gain	1.0000
12:26124197:A:C	acceptor_gain	1.0000
12:26124512:CA:C	donor_gain	1.0000
12:26124517:A:AC	donor_gain	1.0000
12:26124517:AC:A	donor_gain	1.0000
12:26124518:C:CC	donor_gain	1.0000
12:26124518:CC:C	donor_gain	1.0000
12:26123164:CTCCC:C	acceptor_gain	0.9900
12:26123165:TCCC:T	acceptor_gain	0.9900
12:26123166:CCC:C	acceptor_gain	0.9900
12:26123166:CCCC:C	acceptor_gain	0.9900
12:26123167:CC:C	acceptor_gain	0.9900
12:26123167:CCC:C	acceptor_gain	0.9900

AlphaMissense

3064 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:26122795:G:C	S240R	1.000
12:26122795:G:T	S240R	1.000
12:26122797:T:G	S240R	1.000
12:26123704:A:G	L91S	1.000
12:26123710:A:C	L89W	1.000
12:26123710:A:G	L89S	1.000
12:26123713:A:T	V88D	1.000
12:26123719:G:T	A86D	1.000
12:26123720:C:G	A86P	1.000
12:26123721:T:A	K85N	1.000
12:26123721:T:G	K85N	1.000
12:26123722:T:A	K85I	1.000
12:26123723:T:C	K85E	1.000
12:26123723:T:G	K85Q	1.000
12:26123724:C:A	E84D	1.000
12:26123724:C:G	E84D	1.000
12:26123725:T:A	E84V	1.000
12:26123725:T:C	E84G	1.000
12:26123725:T:G	E84A	1.000
12:26123726:C:T	E84K	1.000
12:26123728:A:G	L83P	1.000
12:26124082:A:G	L75P	1.000
12:26124094:A:G	L71P	1.000
12:26124106:A:C	L67R	1.000
12:26124106:A:G	L67P	1.000
12:26124106:A:T	L67Q	1.000
12:26124115:A:C	I64S	1.000
12:26124115:A:G	I64T	1.000
12:26124115:A:T	I64N	1.000
12:26124117:G:C	C63W	1.000

dbSNP variants (sampled 300 via entrez): RS1000152105 (12:26123890 A>G), RS1000264657 (12:26121140 G>C), RS1001655422 (12:26123090 ACTT>A), RS1001923651 (12:26121548 A>G), RS1002376080 (12:26121852 G>GGA), RS1002383770 (12:26126867 T>G), RS1002404821 (12:26120171 T>G), RS1002716026 (12:26125908 C>G,T), RS1002766669 (12:26126068 C>A), RS1002801009 (12:26126177 C>G,T), RS1002846119 (12:26119829 G>C,T), RS1002866959 (12:26125962 C>T), RS1003645680 (12:26120209 A>G), RS1003999698 (12:26119973 G>A), RS1004105331 (12:26125142 C>G,T)

Disease associations

OMIM: gene MIM:606200 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
short sleep, familial natural, 1	Limited	Autosomal dominant

Mondo (1): (MONDO:0020784)

Orphanet (0):

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST003806_2	Response to bupropion and depression	4.000000e-07
GCST005956_3	Waist-to-hip ratio adjusted for BMI	4.000000e-14
GCST005958_7	Waist-to-hip ratio adjusted for BMI (age >50)	4.000000e-10
GCST005962_18	Waist-to-hip ratio adjusted for BMI x sex x age interaction (4df test)	3.000000e-13
GCST90020025_659	Waist-to-hip ratio adjusted for BMI	2.000000e-15
GCST90020025_660	Waist-to-hip ratio adjusted for BMI	2.000000e-11
GCST90020025_661	Waist-to-hip ratio adjusted for BMI	3.000000e-09
GCST90020026_481	Hip index	1.000000e-08
GCST90020026_482	Hip index	1.000000e-10
GCST90020026_483	Hip index	5.000000e-13
GCST90020027_1288	Waist-hip index	3.000000e-14
GCST90020027_1289	Waist-hip index	1.000000e-10
GCST90020027_1290	Waist-hip index	3.000000e-09
GCST90020028_1904	Hip circumference adjusted for BMI	4.000000e-08
GCST90020028_1905	Hip circumference adjusted for BMI	1.000000e-10
GCST90020028_1906	Hip circumference adjusted for BMI	2.000000e-13

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008007	age at assessment
EFO:0008343	sex interaction measurement
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects cotreatment, decreases expression, increases expression	4
Oxygen	decreases reaction, increases expression	3
Silicon Dioxide	increases expression	3
Cisplatin	affects cotreatment, decreases expression, affects expression	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Progesterone	affects cotreatment, decreases expression	2
Smoke	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
1-cyclopropyl-4-(4-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-pyrazol-1-yl)methyl)pyridin-2-yl)piperazine	decreases reaction, increases expression	1
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
methylmercuric chloride	increases expression	1
methyleugenol	increases expression	1
propionaldehyde	increases expression	1
cannabidiolic acid	increases expression	1
beta-lapachone	increases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression	1
testosterone-3-carboxymethyloxime-bovine serum albumin conjugate	affects expression	1
pentanal	increases expression	1
pentabromodiphenyl ether	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
dimethylarsinous acid	decreases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
MRK 003	decreases expression	1
bisphenol S	decreases expression	1

Clinical trials (associated diseases)

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