ACVR1C

Summary

ACVR1C (activin A receptor type 1C, HGNC:18123) is a protein-coding gene on chromosome 2q24.1, encoding Activin receptor type-1C (Q8NER5). Serine/threonine protein kinase which forms a receptor complex on ligand binding.

ACVR1C is a type I receptor for the TGFB (see MIM 190180) family of signaling molecules. Upon ligand binding, type I receptors phosphorylate cytoplasmic SMAD transcription factors, which then translocate to the nucleus and interact directly with DNA or in complex with other transcription factors (Bondestam et al., 2001 [PubMed 12063393]).

Source: NCBI Gene 130399 — RefSeq curated summary.

At a glance

• GWAS associations: 47
• Clinical variants (ClinVar): 79 total — 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_145259

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18123
Approved symbol	ACVR1C
Name	activin A receptor type 1C
Location	2q24.1
Locus type	gene with protein product
Status	Approved
Aliases	ALK7, ACVRLK7
Ensembl gene	ENSG00000123612
Ensembl biotype	protein_coding
OMIM	608981
Entrez	130399

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000243349, ENST00000335450, ENST00000348328, ENST00000409680, ENST00000906709, ENST00000906710, ENST00000906711

RefSeq mRNA: 4 — MANE Select: NM_145259 NM_001111031, NM_001111032, NM_001111033, NM_145259

CCDS: CCDS2205, CCDS46432, CCDS46433, CCDS46434

Canonical transcript exons

ENST00000243349 — 9 exons

Exon	Start	End
ENSE00000840656	157538573	157538703
ENSE00000840657	157541090	157541214
ENSE00000840658	157542706	157542862
ENSE00001069011	157556093	157556332
ENSE00001069015	157550162	157550392
ENSE00001419071	157628572	157628864
ENSE00001467706	157526767	157534043
ENSE00001731212	157544445	157544612
ENSE00003612897	157587187	157587417

Expression profiles

Bgee: expression breadth ubiquitous, 195 present calls, max score 84.98.

FANTOM5 (CAGE): breadth broad, TPM avg 1.5890 / max 253.2151, expressed in 284 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
31411	0.7230	198
31410	0.3686	114
31412	0.3252	121
31409	0.0982	44
31408	0.0740	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	84.98	gold quality
adipose tissue	UBERON:0001013	82.01	gold quality
secondary oocyte	CL:0000655	79.52	gold quality
endothelial cell	CL:0000115	79.25	silver quality
islet of Langerhans	UBERON:0000006	79.20	gold quality
subcutaneous adipose tissue	UBERON:0002190	79.19	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.96	silver quality
buccal mucosa cell	CL:0002336	77.42	silver quality
thoracic mammary gland	UBERON:0005200	76.92	gold quality
adipose tissue of abdominal region	UBERON:0007808	76.68	gold quality
mammary gland	UBERON:0001911	76.57	gold quality
postcentral gyrus	UBERON:0002581	76.42	gold quality
omental fat pad	UBERON:0010414	75.54	gold quality
peritoneum	UBERON:0002358	75.44	gold quality
primary visual cortex	UBERON:0002436	74.92	gold quality
mammary duct	UBERON:0001765	74.39	gold quality
parietal lobe	UBERON:0001872	74.35	gold quality
occipital lobe	UBERON:0002021	73.48	gold quality
lateral globus pallidus	UBERON:0002476	73.41	gold quality
nucleus accumbens	UBERON:0001882	73.18	gold quality
colonic mucosa	UBERON:0000317	73.12	gold quality
putamen	UBERON:0001874	73.12	gold quality
caudate nucleus	UBERON:0001873	72.64	gold quality
Brodmann (1909) area 23	UBERON:0013554	72.55	gold quality
superior frontal gyrus	UBERON:0002661	72.43	gold quality
duodenum	UBERON:0002114	72.06	gold quality
entorhinal cortex	UBERON:0002728	71.93	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	71.64	gold quality
skin of hip	UBERON:0001554	71.30	gold quality
rectum	UBERON:0001052	70.97	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.16

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTCF

miRNA regulators (miRDB)

249 targeting ACVR1C, 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-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-568	99.98	69.86	2084
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790

Literature-anchored findings (GeneRIF, showing 28)

• cDNA cloning, expression studies and chromosome mapping (PMID:12063393)
• ALK7 and its isoforms are expressed in human placentae of different stages of pregnancy and that their expression is developmentally regulated (PMID:12606401)
• ALK7 induces apoptosis through activation of the traditional TGF-beta pathway components (PMID:15107418)
• the Nodal-ALK7 pathway inhibits cell proliferation by inducing G(1) cell cycle arrest (PMID:15150278)
• AB and activin B and is responsible for activin-mediated secretion of insulin from pancreatic beta cell line, MIN6. (PMID:15196700)
• ALK7-induced apoptosis is at least in part through two Smad-dependent pathways, Bax/Bcl-2 and Xiap. (PMID:16603637)
• GDF3 regulates adipose-tissue homeostasis and energy balance under nutrient overload in part by signaling through the ALK7 receptor (PMID:18480259)
• The antiproliferative effect of Nodal/ALK7 on ovarian cancer cells is in part mediated by cyclin G2. (PMID:18784254)
• One of the direct target genes in the ALK7 signaling pathway is the insulin gene in pancreatic beta-cells, and that PDX-1 is directly involved in this pathway through interaction with Smad2 and Smad3. (PMID:18951876)
• Microarray analysis showed that adipose tissue expressed activin type I and II receptors and that the expression of activin receptor-like kinase 7 was adipose tissue specific. (PMID:19275893)
• These findings suggest that the Nodal/ALK7 pathway plays important roles in human placentation and that its abnormal signaling may contribute to the development of preeclampsia. (PMID:21356369)
• reduction or lack of ALK7 expression may account for the loss of its ligand sensitivity of breast cancer cells, thereby leading to breast tumor progression. (PMID:22086737)
• Our findings suggested that the ALK7 gene polymorphism rs13010956 was significantly associated with metabolic syndrome risk in females and may be involved in cardiovascular remodeling in metabolic syndrome patients. (PMID:23765385)
• ACVR 1C is a tumor suppressor, and lowered ACVR 1C expression is an important marker for the metastasis, invasion, and prognosis of gallbladder cancer. (PMID:23793810)
• Alk7 is expressed in male germ cells and Sertoli cells. (PMID:26289399)
• Loss of ALK7 expression are associated with invasion, metastasis of the pancreatic ductal adenocarcinoma. (PMID:26406402)
• reduced expression in sensitive skin; plays crucial roles in the pathogenesis of sensitive skin (PMID:26836979)
• Taken together, our observations suggest that activin signaling mediated through ALK7 could therefore contribute to the hormonal heterogeneity and increased proliferation of prolactinomas. (PMID:30012586)
• MiR-454 binds to the 3’-UTR of ALK7 and regulates ALK7 expression in placenta.ALK7 signaling is regulated by MicroRNA-454 in the placental tissues from pre-eclampsia patients. (PMID:30367833)
• ACVR1C/SMAD2 pathway in promoting invasion and growth of retinoblastoma (PMID:30401983)
• Authors report that the TGFss superfamily receptor ALK7 is a suppressor of tumorigenesis and metastasis, as revealed by functional studies in mouse models of pancreatic neuroendocrine and luminal breast cancer, complemented by experimental metastasis assays. (PMID:31063757)
• The activin-ALK7 pathway as a mediator of endothelial ablation by PDAC. (PMID:31489365)
• Knockdown of ALK7 inhibits high glucose-induced oxidative stress and apoptosis in retinal pigment epithelial cells. (PMID:31608496)
• Control of brown adipose tissue adaptation to nutrient stress by the activin receptor ALK7. (PMID:32366358)
• UV-Induced Reduction of ACVR1C Decreases SREBP1 and ACC Expression by the Suppression of SMAD2 Phosphorylation in Normal Human Epidermal Keratinocytes. (PMID:33499275)
• Regulation of metabolic homeostasis by the TGF-beta superfamily receptor ALK7. (PMID:34173336)
• Activin receptor-like kinase 7 silencing alleviates cardiomyocyte apoptosis, cardiac fibrosis, and dysfunction in diabetic rats. (PMID:35666032)
• Human ACVR1C missense variants that correlate with altered body fat distribution produce metabolic alterations of graded severity in knock-in mutant mice. (PMID:38307384)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	acvr1c	ENSDARG00000086172
mus_musculus	Acvr1c	ENSMUSG00000026834
rattus_norvegicus	Acvr1c	ENSRNOG00000004828
drosophila_melanogaster	tkv	FBGN0003716
drosophila_melanogaster	babo	FBGN0011300
caenorhabditis_elegans		WBGENE00000897
caenorhabditis_elegans		WBGENE00004860

Paralogs (11): TGFBR1 (ENSG00000106799), BMPR1A (ENSG00000107779), ACVR2B (ENSG00000114739), ACVR1 (ENSG00000115170), ACVR2A (ENSG00000121989), AMHR2 (ENSG00000135409), ACVR1B (ENSG00000135503), BMPR1B (ENSG00000138696), ACVRL1 (ENSG00000139567), TGFBR2 (ENSG00000163513), BMPR2 (ENSG00000204217)

Protein

Protein identifiers

Activin receptor type-1C — Q8NER5 (reviewed: Q8NER5)

Alternative names: Activin receptor type IC, Activin receptor-like kinase 7

All UniProt accessions (1): Q8NER5

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine protein kinase which forms a receptor complex on ligand binding. The receptor complex consists of 2 type II and 2 type I transmembrane serine/threonine kinases. Type II receptors phosphorylate and activate type I receptors which autophosphorylate, then bind and activate SMAD transcriptional regulators, SMAD2 and SMAD3. Receptor for activin AB, activin B, activin E and NODAL. Upon NODAL binding, activation results in increased apoptosis and reduced proliferation through suppression of AKT signaling and the activation of Smad2-dependent signaling pathway in pancreatic beta-cells, trophoblasts, epithelial or neuronal cells. Acts as a positive regulator for macrophage activation partially through down-regulation of PPARG expression.

Subunit / interactions. Binds the type 2 receptor protein ACVR2A.

Subcellular location. Membrane.

Tissue specificity. Present in pancreas, heart, colon, small intestine, ovary and the hippocampus, medulla oblongata and putamen of the brain. Isoform 1, isoform 2, isoform 3 and isoform 4 are all expressed in the placenta throughout pregnancy.

Similarity. Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. TGFB receptor subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8NER5-1	1	yes
Q8NER5-2	2, B, soluble B
Q8NER5-3	3, A, soluble A
Q8NER5-4	4, Truncated

RefSeq proteins (4): NP_001104501, NP_001104502, NP_001104503, NP_660302* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000333	TGFB_receptor	Family
IPR000472	Activin_recp	Domain
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR003605	GS_dom	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR045860	Snake_toxin-like_sf	Homologous_superfamily

Pfam: PF01064, PF07714, PF08515

Enzyme classification (BRENDA):

• EC 2.7.11.30 — receptor protein serine/threonine kinase (BRENDA: 8 organisms, 67 substrates, 81 inhibitors, 4 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

3 substrates with measured Km, best-characterized 3. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0057–0.0088	2
KKVLTQMGSPSIRCS(P)SVS	0.26	1
KVLTQMGSPSVRCS(P)SMS	0.331	1

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[receptor-protein] + ATP = O-phospho-L-seryl-[receptor-protein] + ADP + H(+) (RHEA:18673)
• L-threonyl-[receptor-protein] + ATP = O-phospho-L-threonyl-[receptor-protein] + ADP + H(+) (RHEA:44880)

UniProt features (22 total): sequence variant 5, splice variant 3, mutagenesis site 2, topological domain 2, sequence conflict 2, domain 2, binding site 2, signal peptide 1, chain 1, transmembrane region 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NER5-F1	85.35	0.61

Functional residue map

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

Catalytic / active sites (1): 323 (proton acceptor)

Ligand- & substrate-binding residues (2): 201–209; 222

Mutagenesis-validated functional residues (2):

Position	Phenotype
194	pro-apoptotic.
222	loss of response to nodal and smad2 phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-1181150	Signaling by NODAL
R-HSA-1433617	Regulation of signaling by NODAL
R-HSA-1502540	Signaling by Activin
R-HSA-1266738	Developmental Biology
R-HSA-162582	Signal Transduction
R-HSA-9006936	Signaling by TGFB family members

MSigDB gene sets: 256 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GSE45365_NK_CELL_VS_BCELL_DN, GOBP_NEGATIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, PEREZ_TP63_TARGETS, LFA1_Q6, GOBP_RESPONSE_TO_DIETARY_EXCESS, GOBP_INSULIN_SECRETION, GOBP_GROWTH, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_NEGATIVE_REGULATION_OF_PEPTIDE_SECRETION, GOBP_HORMONE_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_AMEBOIDAL_TYPE_CELL_MIGRATION

GO Biological Process (23): trophectodermal cell proliferation (GO:0001834), response to dietary excess (GO:0002021), protein phosphorylation (GO:0006468), nervous system development (GO:0007399), response to glucose (GO:0009749), lipid storage (GO:0019915), insulin secretion (GO:0030073), cell differentiation (GO:0030154), apoptotic nuclear changes (GO:0030262), response to insulin (GO:0032868), activin receptor signaling pathway (GO:0032924), nodal signaling pathway (GO:0038092), positive regulation of apoptotic process (GO:0043065), negative regulation of insulin secretion (GO:0046676), cellular response to growth factor stimulus (GO:0071363), apoptotic signaling pathway (GO:0097190), negative regulation of trophoblast cell migration (GO:1901164), negative regulation of chorionic trophoblast cell proliferation (GO:1901383), apoptotic process (GO:0006915), cell surface receptor protein serine/threonine kinase signaling pathway (GO:0007178), regulation of cell migration (GO:0030334), regulation of multicellular organismal process (GO:0051239), transforming growth factor beta receptor superfamily signaling pathway (GO:0141091)

GO Molecular Function (12): protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), activin receptor activity, type I (GO:0016361), activin receptor activity (GO:0017002), growth factor binding (GO:0019838), nodal binding (GO:0038100), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), transmembrane receptor protein serine/threonine kinase activity (GO:0004675), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (4): plasma membrane (GO:0005886), activin receptor complex (GO:0048179), membrane (GO:0016020), serine/threonine protein kinase complex (GO:1902554)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Developmental Biology	1
Signaling by NODAL	1
Signaling by TGFB family members	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
activin receptor signaling pathway	2
apoptotic process	2
protein binding	2
blastocyst growth	1
cell population proliferation	1
response to nutrient levels	1
energy homeostasis	1
phosphorylation	1
protein modification process	1
system development	1
response to hexose	1
nutrient storage	1
protein secretion	1
peptide hormone secretion	1
cellular developmental process	1
cellular component disassembly involved in execution phase of apoptosis	1
response to peptide hormone	1
transforming growth factor beta receptor superfamily signaling pathway	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
insulin secretion	1
negative regulation of protein secretion	1
regulation of insulin secretion	1
negative regulation of peptide hormone secretion	1
response to growth factor	1
cellular response to endogenous stimulus	1
signal transduction	1
negative regulation of cell migration	1
negative regulation of multicellular organismal process	1
trophoblast cell migration	1
regulation of trophoblast cell migration	1
negative regulation of reproductive process	1
negative regulation of cell population proliferation	1
chorionic trophoblast cell proliferation	1
regulation of chorionic trophoblast cell proliferation	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
enzyme-linked receptor protein signaling pathway	1
protein kinase activity	1

Protein interactions and networks

STRING

1496 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACVR1C	GDF3	Q9NR23	979
ACVR1C	ACVR2B	Q13705	967
ACVR1C	CRIPTO	P13385	958
ACVR1C	ACVR2A	P27037	953
ACVR1C	GDF11	O95390	897
ACVR1C	TGFBR1	P36897	892
ACVR1C	GDF1	P27539	883
ACVR1C	ACVR1B	P36896	872
ACVR1C	INHBB	P09529	851
ACVR1C	SMAD2	Q15796	808
ACVR1C	INHBA	P08476	804
ACVR1C	GDF2	Q9UK05	756
ACVR1C	MSTN	O14793	706
ACVR1C	NODAL	Q96S42	664
ACVR1C	ALK	Q9UM73	657

IntAct

6 interactions, top by confidence:

A	B	Type	Score
HSP90AB1	ACVR1C	psi-mi:“MI:0915”(physical association)	0.400
ACVR1C		psi-mi:“MI:0915”(physical association)	0.400
GTF2IRD2B	PRMT3	psi-mi:“MI:0914”(association)	0.350
ACVR1C	DNAJB5	psi-mi:“MI:0914”(association)	0.350
INHBB	ACVR1C	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (13): ACVR1C (Synthetic Growth Defect), ACVR1C (Co-localization), SUN2 (Affinity Capture-MS), C1orf43 (Affinity Capture-MS), ACVR1B (Affinity Capture-MS), ATP2A3 (Affinity Capture-MS), ACVR1C (Affinity Capture-MS), TYW1 (Affinity Capture-MS), HMGCR (Affinity Capture-MS), DNAJB5 (Affinity Capture-MS), DAGLB (Affinity Capture-MS), TGFBR1 (Affinity Capture-MS), ACVR1C (Affinity Capture-Luminescence)

ESM2 similar proteins: O00238, O08680, O42127, O42422, O46680, O73875, P09759, P22182, P29318, P29319, P29320, P29323, P36894, P36895, P36896, P36897, P36898, P37023, P37172, P54755, P54756, P54757, P54758, P54759, P54762, P70539, P80201, P80202, P80203, P80204, Q04771, Q05438, Q09488, Q15375, Q28041, Q5CD18, Q5RAN0, Q60629, Q61271, Q61288

Diamond homologs: A0A0P0XII1, A0A0R0HPY5, A7J1T2, C0LGD6, C0LGD8, C0LGD9, C0LGG3, C0LGR6, C0LGV0, O00238, O00506, O04086, O35607, O46680, O64556, O65440, P04627, P09560, P0C5E2, P10398, P10533, P14056, P15056, P18161, P20792, P27037, P27038, P27039, P27040, P27041, P27966, P28028, P34908, P36894, P36895, P36896, P36897, P36898, P37023, P37172

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
“SB 505124”	down-regulates	ACVR1C	“chemical inhibition”
NODAL	“up-regulates activity”	ACVR1C	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	38
Likely benign	3
Benign	31

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
980600	GRCh37/hg19 2q24.1(chr2:156696086-159450561)x1	Likely pathogenic

SpliceAI

1768 predictions. Top by Δscore:

Variant	Effect	Δscore
2:157533912:T:C	donor_gain	1.0000
2:157538571:A:AC	donor_gain	1.0000
2:157538572:C:CC	donor_gain	1.0000
2:157538572:CTT:C	donor_gain	1.0000
2:157538572:CTTCA:C	donor_gain	1.0000
2:157538574:T:TA	donor_gain	1.0000
2:157538574:TCACA:T	donor_gain	1.0000
2:157541091:T:TA	donor_gain	1.0000
2:157542702:TTA:T	donor_loss	1.0000
2:157542703:TACCT:T	donor_loss	1.0000
2:157542705:C:CG	donor_loss	1.0000
2:157542705:CCT:C	donor_gain	1.0000
2:157542861:ACCTA:A	acceptor_loss	1.0000
2:157544441:ATAC:A	donor_loss	1.0000
2:157544442:TACCT:T	donor_loss	1.0000
2:157544443:A:AC	donor_gain	1.0000
2:157544444:C:CC	donor_gain	1.0000
2:157544609:TTAT:T	acceptor_gain	1.0000
2:157544613:C:CC	acceptor_gain	1.0000
2:157628567:CGTAC:C	donor_loss	1.0000
2:157628569:TA:T	donor_loss	1.0000
2:157628571:C:CG	donor_loss	1.0000
2:157533898:TTTTA:T	donor_gain	0.9900
2:157538574:TC:T	donor_gain	0.9900
2:157538700:ATTCC:A	acceptor_loss	0.9900
2:157538702:TCCTG:T	acceptor_loss	0.9900
2:157538703:CCTGT:C	acceptor_loss	0.9900
2:157538704:C:CC	acceptor_gain	0.9900
2:157538704:C:T	acceptor_loss	0.9900
2:157538705:T:G	acceptor_loss	0.9900

AlphaMissense

3203 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:157542784:T:A	D341V	1.000
2:157542784:T:G	D341A	1.000
2:157542833:T:C	K325E	1.000
2:157542838:T:G	D323A	1.000
2:157542841:C:G	R322P	1.000
2:157542847:G:T	A320D	1.000
2:157544471:A:G	L306P	1.000
2:157544585:A:G	L268P	1.000
2:157544589:A:G	W267R	1.000
2:157544589:A:T	W267R	1.000
2:157544591:A:G	L266P	1.000
2:157550181:G:C	F252L	1.000
2:157550181:G:T	F252L	1.000
2:157550183:A:G	F252L	1.000
2:157550243:A:G	W232R	1.000
2:157550243:A:T	W232R	1.000
2:157550265:G:C	F224L	1.000
2:157550265:G:T	F224L	1.000
2:157550267:A:G	F224L	1.000
2:157550271:T:A	K222N	1.000
2:157550271:T:G	K222N	1.000
2:157550272:T:A	K222I	1.000
2:157550273:T:C	K222E	1.000
2:157550319:A:C	F206L	1.000
2:157550319:A:T	F206L	1.000
2:157550321:A:G	F206L	1.000
2:157550327:C:G	G204R	1.000
2:157533986:G:T	R472S	0.999
2:157534007:A:G	W465R	0.999
2:157534007:A:T	W465R	0.999

dbSNP variants (sampled 300 via entrez): RS1000002620 (2:157629513 G>A), RS1000036700 (2:157589818 T>A), RS1000075866 (2:157591022 T>C), RS1000141623 (2:157539012 G>A), RS1000354788 (2:157596358 C>G), RS1000358684 (2:157603427 T>C), RS1000389889 (2:157603044 A>G), RS1000393336 (2:157604373 C>A,G), RS1000455908 (2:157554847 T>G), RS1000463690 (2:157602710 T>C), RS1000494016 (2:157539222 G>A), RS1000510091 (2:157561203 GT>G,GTT), RS1000551223 (2:157541555 T>C,G), RS1000564450 (2:157623308 T>C), RS1000640527 (2:157616549 C>T)

Disease associations

OMIM: gene MIM:608981 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

47 associations (top):

Study	Trait	p-value
GCST006614_62	Total cholesterol levels	2.000000e-11
GCST006630_50	Diastolic blood pressure	5.000000e-16
GCST007267_178	Systolic blood pressure	2.000000e-09
GCST007483_8	Waist-to-hip ratio adjusted for BMI (additive genetic model)	5.000000e-10
GCST007487_37	Waist-to-hip ratio adjusted for BMI (additive genetic model)	2.000000e-09
GCST007500_47	Waist-to-hip ratio adjusted for BMI (additive genetic model)	2.000000e-15
GCST007502_12	Waist-to-hip ratio adjusted for BMI (additive genetic model)	3.000000e-14
GCST008362_149	Birth weight	2.000000e-08
GCST008362_204	Birth weight	1.000000e-16
GCST008363_20	Offspring birth weight	7.000000e-06
GCST008363_29	Offspring birth weight	2.000000e-07
GCST010204_150	Low density lipoprotein cholesterol levels	5.000000e-10
GCST010243_154	Apolipoprotein B levels	1.000000e-08
GCST011346_16	Total cholesterol levels	5.000000e-09
GCST011347_18	Low density lipoprotein cholesterol levels	4.000000e-09
GCST012227_1231	Hip circumference adjusted for BMI	7.000000e-09
GCST90002385_450	High light scatter reticulocyte count	2.000000e-11
GCST90002386_264	High light scatter reticulocyte percentage of red cells	2.000000e-10
GCST90002405_137	Reticulocyte count	2.000000e-10
GCST90011900_171	Serum alkaline phosphatase levels	3.000000e-12
GCST90013406_137	Liver enzyme levels (alkaline phosphatase)	3.000000e-16
GCST90020024_889	A body shape index	3.000000e-16
GCST90020024_890	A body shape index	3.000000e-21
GCST90020024_891	A body shape index	2.000000e-12
GCST90020024_892	A body shape index	3.000000e-10
GCST90020024_893	A body shape index	6.000000e-09
GCST90020024_894	A body shape index	2.000000e-08
GCST90020025_1556	Waist-to-hip ratio adjusted for BMI	6.000000e-15
GCST90020025_1557	Waist-to-hip ratio adjusted for BMI	9.000000e-19
GCST90020025_1558	Waist-to-hip ratio adjusted for BMI	6.000000e-13

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0004574	total cholesterol measurement
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004615	apolipoprotein B measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0007986	reticulocyte count
EFO:0004533	alkaline phosphatase measurement
EFO:0007789	BMI-adjusted waist circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5642 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — Type I receptor serine/threonine kinases

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.17	IC50	6.8	nM	CHEMBL6172244

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	3
Benzo(a)pyrene	decreases expression, increases methylation	2
Dexamethasone	increases expression, affects cotreatment, decreases expression	2
Aflatoxin B1	affects expression, decreases expression, decreases methylation	2
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression, affects cotreatment	1
terbufos	increases methylation	1
trichostatin A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
3,4-dichloroaniline	increases expression	1
butyraldehyde	increases expression	1
2,2-(2-chlorophenyl-4’-chlorophenyl)-1,1-dichloroethene	affects cotreatment, increases expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
bisphenol S	increases methylation	1
(+)-JQ1 compound	increases expression	1
imeglimin	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Aldrin	affects cotreatment, increases expression	1
Cisplatin	decreases reaction, decreases response to substance, increases response to substance, increases expression	1
Copper	affects cotreatment, decreases expression	1
Dichlorodiphenyldichloroethane	affects cotreatment, increases expression	1
Dichlorodiphenyl Dichloroethylene	affects cotreatment, increases expression	1
Dieldrin	affects cotreatment, increases expression	1
Diuron	increases expression	1
Fonofos	increases methylation	1
Endosulfan	increases expression	1
Estradiol	affects binding, increases expression	1
Gold	decreases expression	1
Indomethacin	affects cotreatment, decreases expression, increases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1056764	Binding	Inhibition of ALK7 expressed in baculovirus/Sf9 cells assessed as inhibition of receptor autophosphorylation at 1 uM after 3 hrs	Synthesis and biological evaluation of 1,2,4-trisubstituted imidazoles and 1,3,5-trisubstituted pyrazoles as inhibitors of transforming growth factor beta type 1 receptor (ALK5). — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8YL	Ubigene HEK293 ACVR1C KO	Transformed cell line	Female

Clinical trials (associated diseases)

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