BTC

Summary

BTC (betacellulin, HGNC:1121) is a protein-coding gene on chromosome 4q13.3, encoding Probetacellulin (P35070). Growth factor that binds to EGFR, ERBB4 and other EGF receptor family members.

This gene encodes a member of the epidermal growth factor (EGF) family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the secreted growth factor. A secreted form and a membrane-anchored form of this protein bind to multiple different EGF receptors. This protein promotes pancreatic cell proliferation and insulin secretion, as well as retinal vascular permeability. Mutations in this gene may be associated with type 2 diabetes in human patients.

Source: NCBI Gene 685 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 53 total
• MANE Select transcript: NM_001729

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1121
Approved symbol	BTC
Name	betacellulin
Location	4q13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000174808
Ensembl biotype	protein_coding
OMIM	600345
Entrez	685

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000395743, ENST00000512743, ENST00000909121, ENST00000909122, ENST00000951965, ENST00000951966

RefSeq mRNA: 2 — MANE Select: NM_001729 NM_001316963, NM_001729

CCDS: CCDS3566

Canonical transcript exons

ENST00000395743 — 6 exons

Exon	Start	End
ENSE00001193708	74748040	74748149
ENSE00001286386	74770058	74770156
ENSE00001522677	74794262	74794523
ENSE00001774644	74744759	74746675
ENSE00002487067	74750573	74750719
ENSE00002498672	74755859	74755976

Expression profiles

Bgee: expression breadth ubiquitous, 201 present calls, max score 89.09.

FANTOM5 (CAGE): breadth broad, TPM avg 0.4315 / max 61.0669, expressed in 203 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
52573	0.3032	142
52572	0.1282	53

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
muscle layer of sigmoid colon	UBERON:0035805	89.09	gold quality
upper leg skin	UBERON:0004262	88.33	gold quality
lower esophagus muscularis layer	UBERON:0035833	88.12	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	88.12	gold quality
lower esophagus	UBERON:0013473	88.10	gold quality
skin of hip	UBERON:0001554	86.96	gold quality
mucosa of stomach	UBERON:0001199	85.78	gold quality
descending thoracic aorta	UBERON:0002345	83.77	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	83.09	gold quality
bronchial epithelial cell	CL:0002328	82.94	gold quality
mucosa of paranasal sinus	UBERON:0005030	82.82	gold quality
blood vessel layer	UBERON:0004797	81.29	gold quality
skin of leg	UBERON:0001511	81.23	gold quality
thoracic aorta	UBERON:0001515	80.33	gold quality
esophagus	UBERON:0001043	80.24	gold quality
ascending aorta	UBERON:0001496	79.93	gold quality
pigmented layer of retina	UBERON:0001782	79.84	gold quality
zone of skin	UBERON:0000014	79.77	gold quality
upper arm skin	UBERON:0004263	79.50	gold quality
aorta	UBERON:0000947	79.46	gold quality
right coronary artery	UBERON:0001625	79.16	gold quality
skin of abdomen	UBERON:0001416	79.11	gold quality
colon	UBERON:0001155	78.99	gold quality
rectum	UBERON:0001052	78.94	gold quality
popliteal artery	UBERON:0002250	78.85	gold quality
tibial artery	UBERON:0007610	78.83	gold quality
large intestine	UBERON:0000059	78.67	gold quality
transverse colon	UBERON:0001157	78.41	gold quality
gall bladder	UBERON:0002110	77.87	gold quality
right uterine tube	UBERON:0001302	77.86	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.64

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYCN, PAX6

miRNA regulators (miRDB)

106 targeting BTC, 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-3163	100.00	77.23	8605
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
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

Literature-anchored findings (GeneRIF, showing 26)

• The solution structure of the EGF-like domain of betacellulin has been determined using two-dimensional nuclear magnetic resonance spectroscopy (PMID:12074582)
• The main structural properties of the model and the templates are compared and the hBTC conformation is closely similar to that of hTGFalpha. (PMID:12111392)
• Betacellulin and heregulin/NDF-alpha are involved in epidermal morphogenesis and/or in maintenance of the differentiated phenotype. (PMID:12768307)
• although BTC and EGF share overlapping signaling properties, the ability of BTC to enhance Erk activation occurs independent of Ras. (PMID:15192046)
• BTC may play a pivotal role as a local growth factor in promoting the differentiated villous trophoblastic function via ErbB-1 in early placentas and in contributing to placental growth through EVT cell function via ErbB-4 in term placentas. (PMID:15248827)
• Betacellulin is expressed in malignant fibrous histiocytoma and is a regulator of tumor growth. (PMID:15274392)
• shedding of precursor is mediated by ADAM10 (PMID:15507448)
• To determine if mutations in the betacellulin gene play a role in the development of type 2 diabetes, we screened subjects with type 2 diabetes for the presence of mutations. (PMID:15793259)
• Genetic variations in the protein-coding region of the human BTC gene are unlikely to be a major contributor to development of type 2 diabetes. (PMID:15936459)
• -226A/G polymorphism of the BTC gene may contribute to the development of diabetes. (PMID:16306376)
• intron 4 T-4 allele in the betacellulin gene is associated with lower risk of type 1 diabetes mellitus and may interact with human leukocyte antigen (PMID:16683131)
• Failure to confirm a role for nonsynonymous coding variants of betacellulin in the propensity to type 2 diabetes or to impaired insulin secretion in African American subjects. (PMID:16869959)
• Variants in the betacellulin gene do not play a major role in the development of type 2 diabetes in an Amish Caucasian populations (PMID:17479438)
• In vivo, EGFR signaling is hyperactive in tumor cells of skin SCC but not of BCC, and in nearby asymptomatic epidermis of both tumor types. Hyperactivation is due to upregulation of EGFR ligands AREG, HBEGF and TGFA, and downregulation of BTC (PMID:17525275)
• the ADAM10 prodomain inhibits betacellulin shedding, demonstrating that it could be of potential use as a therapeutic agent to treat cancer. (PMID:17895248)
• 1st report of BTC expression in breast cancer. Its expression was lower in lobular breast cancers than in ductal carcinomas. (PMID:17962208)
• These results indicate the possibility of designing BTC mutants, which have an activity of inducing differentiation only, without facilitating growth promotion. (PMID:18508082)
• These are the first data that demonstrate an influence of betacellulin upon mesenchymal stem cells and the first to implicate HIF-alpha in betacellulin-mediated proliferation. (PMID:20165885)
• Data suggest a novel receptor-independent role for betacellulin intracellular-domain fragment signaling due to its ability to inhibit cell growth in vitro. (PMID:20530572)
• BTC has properties of increasing retinal vascular leakage that could contribute to the development of diabetic retinopathy. (PMID:22183345)
• Data suggest that BTC (betacellulin), AREG (amphiregulin), and EREG (epiregulin) induced prostaglandin E2 production by induction of COX-2 (prostaglandin-endoperoxide synthase 2) through MAP kinase signaling in granulosa cells. (PMID:24092824)
• CXCL8 production from lung cancer cells could be initiated by an autocrine mechanism or external sources of BTC. (PMID:24629040)
• Our results suggest that betacellulin induces ovarian cancer migration and Slug-dependent E-cadherin down-regulation (PMID:27129169)
• Despite both ligands binding to the EGFR, BTC biases the EGFR to dimerize with ErbB3 to regulate the biologic response. (PMID:30249613)
• Betacellulin enhances ovarian cancer cell migration by up-regulating Connexin43 via MEK-ERK signaling. (PMID:31654720)
• Betacellulin regulates gap junction intercellular communication by inducing the phosphorylation of connexin 43 in human granulosa-lutein cells. (PMID:37231448)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	btc	ENSDARG00000098112
mus_musculus	Btc	ENSMUSG00000082361
rattus_norvegicus	Btc	ENSRNOG00000002728

Paralogs (5): AREG (ENSG00000109321), HBEGF (ENSG00000113070), EREG (ENSG00000124882), TGFA (ENSG00000163235), EPGN (ENSG00000182585)

Protein

Protein identifiers

Probetacellulin — P35070 (reviewed: P35070)

All UniProt accessions (4): P35070, A0A0S2Z3I5, A0A0S2Z437, H0Y8Q5

UniProt curated annotations — full annotation on UniProt →

Function. Growth factor that binds to EGFR, ERBB4 and other EGF receptor family members. Potent mitogen for retinal pigment epithelial cells and vascular smooth muscle cells.

Subunit / interactions. Monomer. Interacts with EGFR and ERBB4.

Subcellular location. Secreted. Extracellular space Cell membrane.

Tissue specificity. Synthesized in several tissues and tumor cells. Predominantly expressed in pancreas and small intestine.

RefSeq proteins (2): NP_001303892, NP_001720* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain

UniProt features (22 total): strand 4, disulfide bond 3, sequence variant 3, chain 2, turn 2, topological domain 2, signal peptide 1, helix 1, propeptide 1, transmembrane region 1, domain 1, glycosylation site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
8U4J	ELECTRON MICROSCOPY	3.7
8U4K	ELECTRON MICROSCOPY	4.27
1IOX	SOLUTION NMR
1IP0	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P35070-F1	72.51	0.11

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (3): 77–93, 95–104, 69–82

Glycosylation sites (1): 34

Function

Pathways and Gene Ontology

Reactome pathways

46 pathways

ID	Pathway
R-HSA-1227986	Signaling by ERBB2
R-HSA-1236394	Signaling by ERBB4
R-HSA-1250196	SHC1 events in ERBB2 signaling
R-HSA-1250342	PI3K events in ERBB4 signaling
R-HSA-1250347	SHC1 events in ERBB4 signaling
R-HSA-1251985	Nuclear signaling by ERBB4
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-177929	Signaling by EGFR
R-HSA-179812	GRB2 events in EGFR signaling
R-HSA-180292	GAB1 signalosome
R-HSA-180336	SHC1 events in EGFR signaling
R-HSA-182971	EGFR downregulation
R-HSA-1963640	GRB2 events in ERBB2 signaling
R-HSA-1963642	PI3K events in ERBB2 signaling
R-HSA-212718	EGFR interacts with phospholipase C-gamma
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-5638303	Inhibition of Signaling by Overexpressed EGFR
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6785631	ERBB2 Regulates Cell Motility
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-8847993	ERBB2 Activates PTK6 Signaling
R-HSA-8856825	Cargo recognition for clathrin-mediated endocytosis
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-8863795	Downregulation of ERBB2 signaling
R-HSA-9009391	Extra-nuclear estrogen signaling
R-HSA-9634638	Estrogen-dependent nuclear events downstream of ESR-membrane signaling
R-HSA-9664565	Signaling by ERBB2 KD Mutants
R-HSA-9665686	Signaling by ERBB2 TMD/JMD mutants
R-HSA-1227990	Signaling by ERBB2 in Cancer
R-HSA-162582	Signal Transduction

MSigDB gene sets: 199 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, GOBP_POSITIVE_REGULATION_OF_MITOTIC_NUCLEAR_DIVISION, REACTOME_GAB1_SIGNALOSOME, GOBP_REGULATION_OF_NUCLEAR_DIVISION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOMF_GROWTH_FACTOR_ACTIVITY, REACTOME_MEMBRANE_TRAFFICKING, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_ERBB2_SIGNALING_PATHWAY, chr4q13, GOMF_KINASE_ACTIVATOR_ACTIVITY, MARTINEZ_RB1_TARGETS_UP, KEGG_ERBB_SIGNALING_PATHWAY, GOBP_ORGANELLE_FISSION

GO Biological Process (13): epidermal growth factor receptor signaling pathway (GO:0007173), cell population proliferation (GO:0008283), positive regulation of cell population proliferation (GO:0008284), positive regulation of urine volume (GO:0035810), ERBB2-EGFR signaling pathway (GO:0038134), ERBB4-ERBB4 signaling pathway (GO:0038138), positive regulation of cell differentiation (GO:0045597), positive regulation of mitotic nuclear division (GO:0045840), positive regulation of fibroblast proliferation (GO:0048146), positive regulation of cell division (GO:0051781), epithelial cell apoptotic process (GO:1904019), negative regulation of epithelial cell apoptotic process (GO:1904036), apoptotic process (GO:0006915)

GO Molecular Function (5): epidermal growth factor receptor binding (GO:0005154), growth factor activity (GO:0008083), transmembrane receptor protein tyrosine kinase activator activity (GO:0030297), receptor ligand activity (GO:0048018), protein binding (GO:0005515)

GO Cellular Component (5): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), clathrin-coated endocytic vesicle membrane (GO:0030669), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Signaling by EGFR	5
Signaling by ERBB2	4
Signaling by Receptor Tyrosine Kinases	3
Signaling by ERBB4	3
Intracellular signaling by second messengers	1
PI3K/AKT Signaling in Cancer	1
Signaling by Overexpressed Wild-Type EGFR in Cancer	1
MAPK1/MAPK3 signaling	1
Negative regulation of the PI3K/AKT network	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of cellular process	3
signaling receptor activator activity	2
cellular anatomical structure	2
ERBB signaling pathway	1
cellular process	1
cell population proliferation	1
regulation of cell population proliferation	1
regulation of urine volume	1
epidermal growth factor receptor signaling pathway	1
ERBB2 signaling pathway	1
ERBB4 signaling pathway	1
cell differentiation	1
regulation of cell differentiation	1
positive regulation of developmental process	1
regulation of mitotic nuclear division	1
positive regulation of nuclear division	1
positive regulation of cell cycle process	1
mitotic nuclear division	1
positive regulation of cell population proliferation	1
fibroblast proliferation	1
regulation of fibroblast proliferation	1
cell division	1
regulation of cell division	1
apoptotic process	1
negative regulation of apoptotic process	1
epithelial cell apoptotic process	1
regulation of epithelial cell apoptotic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
growth factor receptor binding	1
receptor ligand activity	1
transmembrane receptor protein tyrosine kinase activity	1
protein tyrosine kinase activator activity	1
signaling receptor binding	1
signal transduction	1
binding	1
membrane	1
cell periphery	1
clathrin-coated vesicle membrane	1

Protein interactions and networks

STRING

798 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
BTC	EGFR	P00533	995
BTC	ERBB4	Q15303	995
BTC	AREG	P15514	986
BTC	ERBB3	P21860	960
BTC	EGF	P01133	958
BTC	EPGN	Q6UW88	924
BTC	HBEGF	Q99075	897
BTC	NRG1	P98202	855
BTC	ERBB2	P04626	808
BTC	LHCGR	P22888	780
BTC	EREG	O14944	716
BTC	NRG2	O14511	663
BTC	K7ELM3	K7ELM3	645
BTC	NRG4	Q8WWG1	644
BTC	CMBL	Q96DG6	640

IntAct

33 interactions, top by confidence:

A	B	Type	Score
KRT31	BTC	psi-mi:“MI:0915”(physical association)	0.720
GMPPA	BTC	psi-mi:“MI:0915”(physical association)	0.720
BTC	KRT31	psi-mi:“MI:0915”(physical association)	0.720
BTC	GMPPA	psi-mi:“MI:0915”(physical association)	0.720
BTC	SGTA	psi-mi:“MI:0915”(physical association)	0.720
SGTA	BTC	psi-mi:“MI:0915”(physical association)	0.720
BTC	KPRP	psi-mi:“MI:0915”(physical association)	0.560
KRTAP1-3	BTC	psi-mi:“MI:0915”(physical association)	0.560
BTC	SGTB	psi-mi:“MI:0915”(physical association)	0.560
BTC	S100A4	psi-mi:“MI:0407”(direct interaction)	0.560
BTC	VSIG8	psi-mi:“MI:0914”(association)	0.350
BTC	DNAJC5	psi-mi:“MI:2364”(proximity)	0.270
BTC	ERBB2	psi-mi:“MI:2364”(proximity)	0.270
BTC	KPRP	psi-mi:“MI:0915”(physical association)	0.000
BTC	SGTA	psi-mi:“MI:0915”(physical association)	0.000
BTC	KRTAP1-3	psi-mi:“MI:0915”(physical association)	0.000
BTC	KRT31	psi-mi:“MI:0915”(physical association)	0.000
BTC	SGTB	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (26): KRT31 (Two-hybrid), GMPPA (Two-hybrid), ERBB2 (Co-localization), SGTA (Two-hybrid), GMPPA (Two-hybrid), DNAJC5 (FRET), BTC (Two-hybrid), BTC (Two-hybrid), SGTB (Two-hybrid), KPRP (Two-hybrid), KRTAP1-3 (Two-hybrid), GALNT12 (Affinity Capture-MS), EIF2B5 (Affinity Capture-MS), EIF2B3 (Affinity Capture-MS), EIF2B4 (Affinity Capture-MS)

ESM2 similar proteins: D5K8A9, E7FEC4, O14944, O70534, O75129, O76095, O77049, O88823, O88824, O95727, P04441, P22934, P25118, P30931, P35070, P43303, P80370, Q02092, Q05928, Q09163, Q13145, Q149L7, Q3SXY7, Q5BVD1, Q60943, Q61521, Q6P9G4, Q7T2L7, Q80Z10, Q80ZD7, Q80ZD8, Q8BGE4, Q8C351, Q8C5C9, Q8HYZ0, Q8IYV9, Q8JZL1, Q8NFM7, Q8WWG1, Q90375

Diamond homologs: A0A6G9KJM3, A0A8U0LTM5, A0A8U0LTN3, A0A8U0LTT7, A0A8U0LTT9, A0A8U0LU66, P01134, P01135, P35070, P48030, P55244, P98138, Q06922, Q05928, Q9TTC5, P01133, P07522, P0DQX9, P0DSL4, P98135, Q00968, Q01580, Q06186, Q09118, Q17QD6, Q5EG71, Q6UW88, Q924X1, Q95ND4, Q99075, Q9BEA0, Q9J524, Q9QYM9, Q9UIK5, Q9W7C5, O14944, P15514, P24338, P31955, Q06175

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
BTC	up-regulates	EGFR	binding
BTC	up-regulates	ERBB4	binding
ADAM10	“up-regulates activity”	BTC	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	41
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1104 predictions. Top by Δscore:

Variant	Effect	Δscore
4:74748151:T:C	acceptor_gain	1.0000
4:74748151:T:TC	acceptor_gain	1.0000
4:74750717:CAG:C	acceptor_gain	1.0000
4:74770052:CTTTA:C	donor_loss	1.0000
4:74770053:TTTA:T	donor_loss	1.0000
4:74770054:TTACC:T	donor_loss	1.0000
4:74770055:TAC:T	donor_loss	1.0000
4:74770056:A:C	donor_loss	1.0000
4:74770157:C:CA	acceptor_loss	1.0000
4:74770158:T:G	acceptor_loss	1.0000
4:74770166:C:CT	acceptor_gain	1.0000
4:74770167:A:T	acceptor_gain	1.0000
4:74770171:C:CT	acceptor_gain	1.0000
4:74748038:A:AC	donor_gain	0.9900
4:74748039:C:CC	donor_gain	0.9900
4:74748145:GAGGG:G	acceptor_gain	0.9900
4:74748147:GGG:G	acceptor_gain	0.9900
4:74748148:GG:G	acceptor_gain	0.9900
4:74748148:GGCT:G	acceptor_loss	0.9900
4:74748149:GCT:G	acceptor_loss	0.9900
4:74748150:C:CC	acceptor_gain	0.9900
4:74748150:C:CG	acceptor_loss	0.9900
4:74748151:T:G	acceptor_loss	0.9900
4:74749663:C:CT	donor_gain	0.9900
4:74750571:A:AC	donor_gain	0.9900
4:74750572:C:CC	donor_gain	0.9900
4:74750572:CTGA:C	donor_gain	0.9900
4:74750613:C:CT	donor_gain	0.9900
4:74750614:T:TT	donor_gain	0.9900
4:74750636:A:AC	donor_gain	0.9900

AlphaMissense

1155 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:74750690:C:G	C104S	0.995
4:74750691:A:T	C104S	0.995
4:74755895:C:G	C82S	0.993
4:74755896:A:T	C82S	0.993
4:74755910:C:G	C77S	0.991
4:74755911:A:T	C77S	0.991
4:74750690:C:A	C104F	0.988
4:74755909:G:C	C77W	0.987
4:74755934:C:G	C69S	0.987
4:74755935:A:T	C69S	0.987
4:74750690:C:T	C104Y	0.986
4:74750691:A:G	C104R	0.986
4:74755862:C:G	C93S	0.985
4:74755863:A:T	C93S	0.985
4:74755892:C:G	R83P	0.985
4:74755894:G:C	C82W	0.985
4:74755910:C:T	C77Y	0.985
4:74750689:A:C	C104W	0.984
4:74755862:C:T	C93Y	0.984
4:74755896:A:G	C82R	0.984
4:74755942:G:C	F66L	0.984
4:74755942:G:T	F66L	0.984
4:74755944:A:G	F66L	0.984
4:74755902:C:A	G80W	0.983
4:74755943:A:C	F66C	0.983
4:74755861:A:C	C93W	0.982
4:74755895:C:T	C82Y	0.982
4:74750717:C:G	C95S	0.981
4:74750718:A:T	C95S	0.981
4:74755901:C:A	G80V	0.981

dbSNP variants (sampled 300 via entrez): RS1000057924 (4:74768937 A>C,G), RS10000837 (4:74783998 C>T), RS1000175724 (4:74785217 G>A,C), RS1000210775 (4:74768952 C>A), RS1000267510 (4:74774869 G>A,C), RS1000357012 (4:74795424 C>A), RS1000390009 (4:74752427 G>A), RS1000400286 (4:74790538 C>G), RS1000428212 (4:74770564 A>G), RS1000442251 (4:74780199 G>A), RS10005089 (4:74769396 C>T), RS10005235 (4:74772610 T>A,C), RS1000551277 (4:74748392 C>G,T), RS1000604879 (4:74790707 G>T), RS1000612282 (4:74754292 T>A)

Disease associations

OMIM: gene MIM:600345 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST002709_26	Electroencephalogram traits	7.000000e-06
GCST003985_7	Breast size	9.000000e-13
GCST006479_91	Diverticular disease	2.000000e-06
GCST007431_41	Lung function (FEV1/FVC)	2.000000e-23
GCST007432_22	FEV1	5.000000e-11
GCST007692_103	Chronic obstructive pulmonary disease	3.000000e-09
GCST011766_3	Chronic obstructive pulmonary disease	4.000000e-09
GCST90014033_30	Haemorrhoidal disease	1.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004357	electroencephalogram measurement
EFO:0006872	delta wave measurement
EFO:0009959	diverticular disease
EFO:0004713	FEV/FVC ratio
EFO:0004314	forced expiratory volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression	4
Estradiol	affects cotreatment, decreases expression, increases expression	2
Nickel	decreases expression	2
aristolochic acid I	increases expression	1
sotorasib	affects cotreatment, increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
abrine	decreases expression	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases expression	1
Cisplatin	decreases expression	1
Copper	affects cotreatment, increases expression	1
Dibutyl Phthalate	decreases expression	1
Retinaldehyde	decreases expression	1
Tretinoin	decreases expression	1
Cyclosporine	increases expression	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	decreases expression	1
Lactic Acid	decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_F0T0	MONPSYi001-A-1	Induced pluripotent stem cell	Male
CVCL_F0T1	MONPSYi001-A-2	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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