IAPP

Summary

IAPP (islet amyloid polypeptide, HGNC:5329) is a protein-coding gene on chromosome 12p12.1, encoding Islet amyloid polypeptide (P10997). Amylin/IAPP is a glucoregulatory peptide hormone that plays an important role in the regulation of energy homeostasis.

This gene encodes a member of the calcitonin family of peptide hormones. This hormone is released from pancreatic beta cells following food intake to regulate blood glucose levels and act as a satiation signal. Human patients with type 1 and advanced type 2 diabetes exhibit reduced levels of the encoded hormone in blood and pancreas. This protein also exhibits a bactericidal, antimicrobial activity.

Source: NCBI Gene 3375 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 8 total
• Druggable target: yes
• MANE Select transcript: NM_000415

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5329
Approved symbol	IAPP
Name	islet amyloid polypeptide
Location	12p12.1
Locus type	gene with protein product
Status	Approved
Aliases	AMYLIN, DAP, IAP
Ensembl gene	ENSG00000121351
Ensembl biotype	protein_coding
OMIM	147940
Entrez	3375

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000240652, ENST00000535428, ENST00000537593, ENST00000539393, ENST00000542023, ENST00000877981

RefSeq mRNA: 2 — MANE Select: NM_000415 NM_000415, NM_001329201

CCDS: CCDS8688

Canonical transcript exons

ENST00000240652 — 3 exons

Exon	Start	End
ENSE00000822246	21373337	21373431
ENSE00000994897	21372902	21373004
ENSE00003467382	21378237	21379980

Expression profiles

Bgee: expression breadth broad, 68 present calls, max score 99.74.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0391 / max 32.9224, expressed in 3 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
124661	0.0391	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
type B pancreatic cell	CL:0000169	99.74	gold quality
islet of Langerhans	UBERON:0000006	99.74	gold quality
pancreas	UBERON:0001264	91.03	gold quality
body of pancreas	UBERON:0001150	87.66	gold quality
epithelial cell of pancreas	CL:0000083	82.02	gold quality
hair follicle	UBERON:0002073	71.98	gold quality
right lobe of liver	UBERON:0001114	67.56	gold quality
olfactory bulb	UBERON:0002264	63.47	gold quality
diaphragm	UBERON:0001103	58.10	gold quality
epithelium of nasopharynx	UBERON:0001951	57.71	gold quality
thymus	UBERON:0002370	57.30	gold quality
decidua	UBERON:0002450	56.55	gold quality
superficial temporal artery	UBERON:0001614	56.36	gold quality
oocyte	CL:0000023	56.08	gold quality
liver	UBERON:0002107	56.02	gold quality
left testis	UBERON:0004533	55.37	gold quality
cerebellar vermis	UBERON:0004720	54.64	gold quality
trachea	UBERON:0003126	53.88	gold quality
testis	UBERON:0000473	53.40	gold quality
layer of synovial tissue	UBERON:0007616	53.31	gold quality
saphenous vein	UBERON:0007318	53.28	gold quality
nipple	UBERON:0002030	52.61	gold quality
urethra	UBERON:0000057	52.54	gold quality
dorsal plus ventral thalamus	UBERON:0001897	52.41	gold quality
nephron tubule	UBERON:0001231	52.28	gold quality
dorsal root ganglion	UBERON:0000044	52.27	gold quality
metanephric glomerulus	UBERON:0004736	52.21	gold quality
pericardium	UBERON:0002407	52.11	gold quality
trigeminal ganglion	UBERON:0001675	52.05	gold quality
synovial joint	UBERON:0002217	51.93	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-GEOD-81608	yes	21484.31
E-HCAD-31	yes	20293.35
E-ENAD-27	yes	15955.23
E-GEOD-81547	yes	15193.96
E-GEOD-83139	yes	14637.92
E-MTAB-5061	yes	10939.21
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
FOS	Activation

Upstream regulators (CollecTRI, top): CDX1, CDX2, FEZF2, FOXA2, FOXO1, GATA4, HNF1A, HOXB7, ISL1, KLF4, LMX1A, MAZ, NEUROD1, NFAT5, NKX6-1, NRF1, PAX6, PDX1, SSRP1, TFAP2A, ZGLP1, ZNF148

miRNA regulators (miRDB)

62 targeting IAPP, 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-3613-3P	100.00	76.36	7965
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-548AZ-5P	99.83	69.94	3230
HSA-MIR-548T-5P	99.83	69.91	3220
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4658	99.77	64.94	514
HSA-MIR-6790-5P	99.77	65.24	505
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-548AU-3P	99.70	68.22	1373
HSA-MIR-1208	99.70	68.28	1533
HSA-MIR-4804-3P	99.65	67.78	866
HSA-MIR-6757-3P	99.63	66.88	1089
HSA-MIR-4743-3P	99.62	68.12	2095
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-5584-5P	99.49	68.22	2814

Literature-anchored findings (GeneRIF, showing 40)

• structure-based design and study of non-amyloidogenic, double N-methylated IAPP amyloid core sequences as inhibitors of IAPP amyloid formation and cytotoxicity (PMID:11786016)
• progressive intermittent exercise protocol of moderate to maximum exercise intensities stimulates increases in amylin levels (PMID:11979402)
• estrogen prevents or reverses obesity and diabetes in transgenic mice expressing the human gene (PMID:12086946)
• The presence of amylin-derived islet amyloid is felt to play a significant role in the remodeling of the endocrine pancreas as well as the natural progressive history of type 2 diabetes mellitus. (PMID:12221327)
• Inhibition of amyloid fibril formation of human amylin by N-alkylated amino acid and alpha-hydroxy acid residue containing peptides (PMID:12298020)
• Results describe a novel molecular recognition motif within the human islet amyloid polypeptide (hIAPP) molecule. (PMID:12367525)
• results suggest strongly that human amylin induces apoptosis in pancreatic islet beta-cells through stimulation of expression and activation of c-Jun (PMID:12441106)
• Increased dietary fat promotes islet cell formation and dysfunction in transgenic mice models. (PMID:12540610)
• polymorphism of IAPP gene in nondiabetic subjects and type 2 diabetes is associated with lower levels of LDL cholesterol; abnormalities of coding regions or 5’-UTR not associated with type 2 diabetes or gestational diabetes mellitus in Spanish population. (PMID:12588049)
• Data show that the three specific proline residues in human and rat amylin play a dominant negative role in fibril formation. (PMID:12589759)
• Human amylin, like beta-Amyloid, is capable of modulating ion channel function in rat cholinergic basal forebrain neurons. The hAmylin effects could be occluded by beta-amyloid and vice versa. (PMID:12611974)
• IAPP is found in 90% of patients with NIDDM at post-mortem. More extensive amyloidosis is associated with decreased islet function and requirement for insulin therapy. (PMID:12706318)
• The frequency of the S20G mutation in the amylin gene is 1.92% in unrelated Korean type 2 diabetic patients and this mutation is associated with a lower BMI and a higher HbA(1c) level. (PMID:12706321)
• DAP 12 gene of chromosome 19q13.1 is implicated in Nasu Hakola disease (PMID:12717671)
• conformational preferences of hIAPP(20-29) in membrane-mimicking environments (PMID:12717720)
• role played by the hydrophobic and aromatic residues in inter-sheet association and fibril formation (PMID:12767835)
• amylin has a role in evoking a JNK1-mediated apoptotic pathway, which is partially dependent and partially independent of caspase-8, and in which caspase-3 acts as a common downstream effector (PMID:14532296)
• Islet amyloid deposits were identified using Congo red staining in islets of patients with NIDDM. (PMID:14578294)
• Amylin is widely expressed in non-tumorous pancreatic islets and in one insulin producing beta cell tumor (PMID:14656003)
• the dominant effect of insulin is to act on the elongation portion of the fiber formation reaction (PMID:14659752)
• this study reports the expression, purification and characterization of the amyloidogenicity and cytotoxicity of recombinant human mature IAPP (PMID:15292167)
• Results describe the interactions of islet amyloid polypeptide (IAPP) with phospholipid bilayers and the morphological effects of membranes on IAPP fibers. (PMID:15321714)
• interaction between lipid bilayers and the 37 amino acid residue polypeptide amylin, which is the primary constituent of the pancreatic amyloid associated with type 2 diabetes (PMID:15342243)
• Data are consistent with a parallel arrangement of islet amyloid polypeptide (IAPP) peptides within the amyloid fibril. (PMID:15358791)
• process of hIAPP amyloid formation is accompanied by a loss of barrier function, whereby lipids are extracted from the membrane and taken up in the forming amyloid deposits (PMID:15527771)
• Structure of the amylin fibrils was studied using atomic force microscopy. (PMID:15638806)
• findings are consistent with the hypothesis that membrane-active pre-fibrillar hIAPP oligomers insert into beta cell membranes in NIDDM (PMID:15710403)
• Structural analysis of the clusters clearly suggested the formation of “flat” ellipsoid-shaped clusters through a preferred locally parallel alignment of the peptides in water. (PMID:15778964)
• protein structure of amylin (as a model for amyloid fibrils) (PMID:15811365)
• Genetic polymorphism of the islet amyloid polypeptide gene promoter region is not associated with type 2 diabetes or islet amyloidosis. (PMID:15878744)
• Oligomeric IAPP assemblies exert toxic effects on beta cells that die, leading to reduced beta-cell mass. (review) (PMID:15929864)
• Rosiglitazone and metformin protect beta-cells from the deleterious effects of islet amyloid, and this effect may contribute to the ability of these treatments to alleviate the progressive loss of beta-cell mass and function in type 2 diabetes. (PMID:15983227)
• conditions that promote weakly stable alpha-helical conformations may promote IAPP aggregation (PMID:16142909)
• In human islets, activation of PPAR-gamma inhibits h-IAPP-induced islet cell apoptosis, and this action is at least in part mediated through activation of the phosphatidylinositol 3’-kinase-Akt cascade. (PMID:16204373)
• The amino acid residues 20-29 region of IAPP was tested for amyloidogenic domain. (PMID:16303136)
• Results describe the role of Histidine-18 in amyloid formation by human islet amyloid polypeptide. (PMID:16331989)
• IAPP monomers might insert with high efficiency in biological membranes in vivo; this process could play an important role as a first step in IAPP-induced membrane damage in type 2 diabetes. (PMID:16403520)
• The HIP rat, a human IAPP transgenic rat model that develops islet pathology comparable to humans with type 2 diabetes. (PMID:16804082)
• The heparin binding site in the N-terminus of IAPP precursor is characterized in detail, and an important role for the IAPP Cys-13/Cys-18 disulfide bridge in heparin binding is demonstrated. (PMID:16866369)
• No mutation in IAPP was found in the Mexican Mestizo population. (PMID:16950544)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000105976
mus_musculus	Iapp	ENSMUSG00000041681
rattus_norvegicus	Iapp	ENSRNOG00000082704

Paralogs (2): CALCA (ENSG00000110680), CALCB (ENSG00000175868)

Protein

Protein identifiers

Islet amyloid polypeptide — P10997 (reviewed: P10997)

Alternative names: Amylin, Diabetes-associated peptide, Insulinoma amyloid peptide

All UniProt accessions (4): F5H0S1, F5H1F0, P10997, H0YF85

UniProt curated annotations — full annotation on UniProt →

Function. Amylin/IAPP is a glucoregulatory peptide hormone that plays an important role in the regulation of energy homeostasis. Selectively inhibits insulin-stimulated glucose utilization and glycogen deposition in muscle, while not affecting adipocyte glucose metabolism. IAPP function is mediated by the CALCR-RAMPs (AMYRs) receptor complexes. Amylin can also bind CALCR receptor in the absence of RAMPs, although it is more selective for AMYRs.

Subunit / interactions. Can form homodimers. Interacts with IDE and INS. Interaction with INS inhibits homodimerization and fibril formation.

Subcellular location. Secreted.

Post-translational modifications. Amyloid fibrils are degraded by insulin-degrading enzyme IDE.

Domain organisation. The mature protein is largely unstructured in the absence of a cognate ligand, and has a strong tendency to form fibrillar aggregates. Homodimerization may be the first step of amyloid formation.

Miscellaneous. IAPP is the peptide subunit of amyloid found in pancreatic islets of type 2 diabetic patients and in insulinomas.

Similarity. Belongs to the calcitonin family.

RefSeq proteins (2): NP_000406, NP_001316130 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000443	IAPP	Family
IPR001693	Calcitonin_peptide-like	Domain
IPR018360	Calcitonin_CS	Conserved_site
IPR021116	Calcitonin/adrenomedullin	Family
IPR021117	Calcitonin-like	Family

Pfam: PF00214

UniProt features (17 total): helix 4, strand 4, propeptide 2, signal peptide 1, peptide 1, modified residue 1, disulfide bond 1, sequence variant 1, mutagenesis site 1, sequence conflict 1

Structure

Experimental structures (PDB)

76 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
8YG2	X-RAY DIFFRACTION	1.25
5KO0	ELECTRON CRYSTALLOGRAPHY	1.4
3FPO	X-RAY DIFFRACTION	1.5
3FTK	X-RAY DIFFRACTION	1.5
3FTL	X-RAY DIFFRACTION	1.6
3FTR	X-RAY DIFFRACTION	1.61
3DG1	X-RAY DIFFRACTION	1.66
3G7W	X-RAY DIFFRACTION	1.75
3FTH	X-RAY DIFFRACTION	1.84
3FR1	X-RAY DIFFRACTION	1.85
3G7V	X-RAY DIFFRACTION	1.86
9CC5	X-RAY DIFFRACTION	1.87
5KNZ	ELECTRON CRYSTALLOGRAPHY	1.9
8F0K	ELECTRON MICROSCOPY	1.9
8F0J	ELECTRON MICROSCOPY	2
8F2B	ELECTRON MICROSCOPY	2
9NZH	X-RAY DIFFRACTION	2.03
8AZ4	ELECTRON MICROSCOPY	2.2
8F2A	ELECTRON MICROSCOPY	2.2
9BP3	ELECTRON MICROSCOPY	2.2
8AZ5	ELECTRON MICROSCOPY	2.3
9BUB	ELECTRON MICROSCOPY	2.3
9BUD	ELECTRON MICROSCOPY	2.5
2G48	X-RAY DIFFRACTION	2.6
9BQ3	ELECTRON MICROSCOPY	2.8
7BG0	X-RAY DIFFRACTION	2.89
8AZ7	ELECTRON MICROSCOPY	2.9
9GZP	ELECTRON MICROSCOPY	2.9
9GZT	ELECTRON MICROSCOPY	2.9
9GZW	ELECTRON MICROSCOPY	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10997-F1	78.59	0.09

Antibody-complex structures (SAbDab): 9 — 8F0J, 8F0K, 8F2A, 8F2B, 9BLB, 9BLC, 9BLW, 9BTW, 9BUE

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 (1): 70

Disulfide bonds (1): 35–40

Mutagenesis-validated functional residues (1):

Position	Phenotype
48	promotes formation of fibrillar aggregates.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-210745	Regulation of gene expression in beta cells
R-HSA-418555	G alpha (s) signalling events
R-HSA-419812	Calcitonin-like ligand receptors
R-HSA-977225	Amyloid fiber formation

MSigDB gene sets: 158 (showing top): GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_BEHAVIOR, GOBP_REGULATION_OF_CALCIUM_MEDIATED_SIGNALING, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GAUSSMANN_MLL_AF4_FUSION_TARGETS_C_DN, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_CELL_CELL_SIGNALING, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_TISSUE_REMODELING, MARTINEZ_RB1_TARGETS_UP, GOBP_SENSORY_PERCEPTION_OF_PAIN

GO Biological Process (21): apoptotic process (GO:0006915), signal transduction (GO:0007165), cell-cell signaling (GO:0007267), sensory perception of pain (GO:0019233), osteoclast differentiation (GO:0030316), negative regulation of protein-containing complex assembly (GO:0031333), eating behavior (GO:0042755), positive regulation of apoptotic process (GO:0043065), positive regulation of MAPK cascade (GO:0043410), bone resorption (GO:0045453), negative regulation of osteoclast differentiation (GO:0045671), negative regulation of bone resorption (GO:0045779), positive regulation of calcium-mediated signaling (GO:0050850), amylin receptor signaling pathway (GO:0097647), positive regulation of cAMP/PKA signal transduction (GO:0141163), amylin receptor 1 signaling pathway (GO:0150059), amylin receptor 2 signaling pathway (GO:0150060), amylin receptor 3 signaling pathway (GO:0150061), negative regulation of amyloid fibril formation (GO:1905907), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), calcitonin family receptor signaling pathway (GO:0097646)

GO Molecular Function (7): amyloid-beta binding (GO:0001540), signaling receptor binding (GO:0005102), hormone activity (GO:0005179), lipid binding (GO:0008289), identical protein binding (GO:0042802), receptor ligand activity (GO:0048018), protein binding (GO:0005515)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), neuronal cell body (GO:0043025)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Regulation of beta-cell development	1
GPCR downstream signalling	1
Class B/2 (Secretin family receptors)	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
positive regulation of intracellular signal transduction	3
amylin receptor signaling pathway	3
cell communication	2
signaling	2
protein binding	2
binding	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
sensory perception	1
myeloid leukocyte differentiation	1
regulation of protein-containing complex assembly	1
negative regulation of cellular component organization	1
protein-containing complex assembly	1
feeding behavior	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
MAPK cascade	1
regulation of MAPK cascade	1
tissue homeostasis	1
bone remodeling	1
negative regulation of myeloid leukocyte differentiation	1
osteoclast differentiation	1
regulation of osteoclast differentiation	1
regulation of bone resorption	1
bone resorption	1
negative regulation of bone remodeling	1
calcium-mediated signaling	1
regulation of calcium-mediated signaling	1
calcitonin family receptor signaling pathway	1
cAMP/PKA signal transduction	1
regulation of cAMP/PKA signal transduction	1
negative regulation of protein metabolic process	1
negative regulation of supramolecular fiber organization	1
regulation of amyloid fibril formation	1
amyloid fibril formation	1

Protein interactions and networks

STRING

1186 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IAPP	CALCR	P30988	991
IAPP	RAMP1	O60894	980
IAPP	RAMP3	O60896	970
IAPP	INS	P01308	970
IAPP	RAMP2	O60895	949
IAPP	CALCB	P10092	949
IAPP	ADM	P35318	946
IAPP	CALCRL	Q16602	937
IAPP	GCG	P01275	933
IAPP	APP	P05067	902
IAPP	PRNP	P04156	890
IAPP	SNCA	P37840	870
IAPP	CALCA	P01258	866
IAPP	PYY	P10082	854
IAPP	IDE	P14735	845

IntAct

24 interactions, top by confidence:

A	B	Type	Score
IAPP	IAPP	psi-mi:“MI:0407”(direct interaction)	0.950
IAPP	IAPP	psi-mi:“MI:0915”(physical association)	0.950
IDE	IAPP	psi-mi:“MI:0407”(direct interaction)	0.620
IDE	IAPP	psi-mi:“MI:0570”(protein cleavage)	0.620
IAPP	BACE2	psi-mi:“MI:0570”(protein cleavage)	0.560
IAPP	BACE1	psi-mi:“MI:0570”(protein cleavage)	0.560
BACE1	IAPP	psi-mi:“MI:0407”(direct interaction)	0.560
BACE2	IAPP	psi-mi:“MI:0407”(direct interaction)	0.560
BACE2	INS	psi-mi:“MI:0570”(protein cleavage)	0.440
IAPP	TRIP6	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (4): P4HB (Affinity Capture-Western), IAPP (Synthetic Lethality), SNCA (Co-localization), TRIP6 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L2F565, B3IWF7, B3IWF8, B3IWF9, O46540, O62647, P01161, P01257, P01258, P01261, P01263, P05125, P07500, P07501, P07660, P10093, P10997, P12966, P12968, P12969, P15743, P18908, P22889, P23442, P24259, P27104, P41547, P70160, P81564, P81872, Q07334, Q0VBW8, Q0VC44, Q1HA20, Q28207, Q4QXT8, Q5H8A1, Q5H8A2, Q5H8A3, Q64387

Diamond homologs: B3IWF7, B3IWF8, B3IWF9, P01256, P01257, P01258, P01261, P01263, P06881, P07660, P10092, P10093, P10286, P10997, P12966, P12967, P12968, P12969, P17716, P19890, P22889, P23442, P30880, P30881, P31888, P41547, P70160, P81564, Q28207, Q75V93, Q75V94, Q75V95, Q766Y6, Q766Y7, Q862B1, Q99JA0, Q99MP3, Q9MYV1, Q9N0T2, Q9N0T3

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
IAPP	“up-regulates activity”	“Amylin receptor 1 complex”	binding
IAPP	“up-regulates activity”	“Amylin receptor 2 complex”	binding
IAPP	“up-regulates activity”	“Amylin receptor 3 complex”	binding
PCSK1	“up-regulates activity”	IAPP	cleavage
PCSK2	“up-regulates activity”	IAPP	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	5
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

867 predictions. Top by Δscore:

Variant	Effect	Δscore
12:21373336:GAAA:G	acceptor_gain	0.9900
12:21373429:AAGG:A	donor_loss	0.9900
12:21373433:T:G	donor_loss	0.9900
12:21374524:ACCTA:A	acceptor_loss	0.9900
12:21374525:CCTA:C	acceptor_loss	0.9900
12:21374526:C:CC	acceptor_gain	0.9900
12:21374526:C:T	acceptor_loss	0.9900
12:21375625:AGATG:A	donor_gain	0.9900
12:21378228:T:G	acceptor_gain	0.9900
12:21373333:GCAGA:G	acceptor_loss	0.9800
12:21373334:CA:C	acceptor_loss	0.9800
12:21373335:A:AG	acceptor_gain	0.9800
12:21373336:G:A	acceptor_loss	0.9800
12:21373336:G:GG	acceptor_gain	0.9800
12:21373336:GA:G	acceptor_gain	0.9800
12:21373336:GAA:G	acceptor_gain	0.9800
12:21373710:A:C	acceptor_gain	0.9800
12:21374523:CAC:C	acceptor_gain	0.9800
12:21374530:G:C	acceptor_gain	0.9800
12:21376925:T:A	donor_gain	0.9800
12:21373315:A:AG	acceptor_gain	0.9700
12:21373316:G:GG	acceptor_gain	0.9700
12:21373430:AGGTT:A	donor_gain	0.9700
12:21374393:GTTTA:G	donor_loss	0.9700
12:21374394:TTTAC:T	donor_loss	0.9700
12:21374396:TACCT:T	donor_loss	0.9700
12:21374397:A:G	donor_loss	0.9700
12:21374398:C:CA	donor_loss	0.9700
12:21375618:A:C	donor_gain	0.9700
12:21375623:A:C	donor_gain	0.9600

AlphaMissense

571 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:21378298:T:C	F48L	0.779
12:21378300:T:A	F48L	0.779
12:21378300:T:G	F48L	0.779
12:21378287:G:C	R44P	0.741
12:21378290:T:C	L45P	0.729
12:21378259:T:A	C35S	0.726
12:21378260:G:C	C35S	0.726
12:21378375:G:C	R73S	0.722
12:21378375:G:T	R73S	0.722
12:21378372:G:C	K72N	0.721
12:21378372:G:T	K72N	0.721
12:21378368:G:A	G71D	0.713
12:21378274:T:C	C40R	0.684
12:21378276:T:G	C40W	0.666
12:21378368:G:T	G71V	0.664
12:21378290:T:A	L45Q	0.659
12:21378254:G:C	R33P	0.654
12:21378302:T:C	L49S	0.654
12:21378274:T:A	C40S	0.651
12:21378275:G:C	C40S	0.651
12:21378367:G:T	G71C	0.639
12:21378259:T:C	C35R	0.630
12:21378290:T:G	L45R	0.605
12:21378292:G:C	A46P	0.591
12:21378261:C:G	C35W	0.578
12:21378299:T:G	F48C	0.571
12:21378299:T:C	F48S	0.570
12:21378269:C:A	A38D	0.568
12:21378260:G:T	C35F	0.566

dbSNP variants (sampled 300 via entrez): RS1000045618 (12:21375788 C>T), RS1000069224 (12:21355596 T>A,C), RS1000079821 (12:21371814 C>T), RS1000122890 (12:21379213 T>A,C), RS1000208737 (12:21372086 C>T), RS1000234453 (12:21378649 T>C), RS1000267075 (12:21379014 G>A), RS1000331907 (12:21355433 G>T), RS1000405889 (12:21368131 C>T), RS1000418169 (12:21375209 A>G), RS1000459597 (12:21368387 G>A), RS1000581173 (12:21366352 G>A,T), RS1000667436 (12:21363926 G>A,T), RS1000715124 (12:21366100 G>A,C), RS1001131113 (12:21371496 T>C)

Disease associations

OMIM: gene MIM:147940 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002875_10	Diisocyanate-induced asthma	7.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006995	response to diisocyanate

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1914266 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs11045995	Dosage	3	rocuronium

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11045995	IAPP, SLCO1A2	3	0.00	1	rocuronium

ChEMBL bioactivities

18 potent at pChembl≥5 of 18 total, top 18 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.16	IC50	700	nM	CHEMBL4866117
6.10	IC50	800	nM	CHEMBL439677
6.10	IC50	800	nM	CHEMBL4877746
6.10	IC50	800	nM	CHEMBL4853313
5.92	IC50	1200	nM	CHEMBL4876955
5.50	IC50	3200	nM	CHEMBL4867746
5.48	IC50	3300	nM	CHEMBL4861462
5.47	IC50	3400	nM	CHEMBL4861649
5.46	IC50	3500	nM	CHEMBL4862006
5.46	IC50	3500	nM	CHEMBL4867456
5.46	IC50	3500	nM	CHEMBL4871404
5.43	IC50	3700	nM	CHEMBL75390
5.41	IC50	3900	nM	CHEMBL4876866
5.36	IC50	4400	nM	CHEMBL4877898
5.11	IC50	7800	nM	MORIN
5.10	IC50	8000	nM	CHEMBL5272189
5.07	IC50	8500	nM	CHEMBL4878532
5.02	IC50	9500	nM	CHEMBL4856745

PubChem BioAssay actives

18 with measured affinity, of 38 total; 18 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(E)-1-(2,3-dihydroxyphenyl)hept-1-en-3-one	1775270: Inhibition of islet amyloid polypeptide (unknown origin) aggregation after 24 hrs by thioflavin T based fluorescence assay	ic50	0.7000	uM
(E)-4-(2,3-dihydroxyphenyl)but-3-en-2-one	1775270: Inhibition of islet amyloid polypeptide (unknown origin) aggregation after 24 hrs by thioflavin T based fluorescence assay	ic50	0.8000	uM
(E)-1-(2,3-dihydroxyphenyl)pent-1-en-3-one	1775270: Inhibition of islet amyloid polypeptide (unknown origin) aggregation after 24 hrs by thioflavin T based fluorescence assay	ic50	0.8000	uM
(E)-1-(2,3-dihydroxyphenyl)hex-1-en-3-one	1775270: Inhibition of islet amyloid polypeptide (unknown origin) aggregation after 24 hrs by thioflavin T based fluorescence assay	ic50	0.8000	uM
(E)-1-(3,4-dihydroxyphenyl)-7-(2-hydroxyphenyl)hept-1-en-3-one	1775270: Inhibition of islet amyloid polypeptide (unknown origin) aggregation after 24 hrs by thioflavin T based fluorescence assay	ic50	1.2000	uM
(E)-1-(3,4-dihydroxyphenyl)hept-1-en-3-one	1775270: Inhibition of islet amyloid polypeptide (unknown origin) aggregation after 24 hrs by thioflavin T based fluorescence assay	ic50	3.2000	uM
1-(2,3-dihydroxyphenyl)hexan-3-one	1775270: Inhibition of islet amyloid polypeptide (unknown origin) aggregation after 24 hrs by thioflavin T based fluorescence assay	ic50	3.3000	uM
1-(2,3-dihydroxyphenyl)heptan-3-one	1775270: Inhibition of islet amyloid polypeptide (unknown origin) aggregation after 24 hrs by thioflavin T based fluorescence assay	ic50	3.4000	uM
(E)-1-(3,4-dihydroxyphenyl)hex-1-en-3-one	1775270: Inhibition of islet amyloid polypeptide (unknown origin) aggregation after 24 hrs by thioflavin T based fluorescence assay	ic50	3.5000	uM
4-(2,3-dihydroxyphenyl)butan-2-one	1775270: Inhibition of islet amyloid polypeptide (unknown origin) aggregation after 24 hrs by thioflavin T based fluorescence assay	ic50	3.5000	uM
1-(3,4-dihydroxyphenyl)heptan-3-one	1775270: Inhibition of islet amyloid polypeptide (unknown origin) aggregation after 24 hrs by thioflavin T based fluorescence assay	ic50	3.5000	uM
(E)-4-(3,4-dihydroxyphenyl)but-3-en-2-one	1775270: Inhibition of islet amyloid polypeptide (unknown origin) aggregation after 24 hrs by thioflavin T based fluorescence assay	ic50	3.7000	uM
1-(2,3-dihydroxyphenyl)pentan-3-one	1775270: Inhibition of islet amyloid polypeptide (unknown origin) aggregation after 24 hrs by thioflavin T based fluorescence assay	ic50	3.9000	uM
(E)-1-(3,4-dihydroxyphenyl)pent-1-en-3-one	1775270: Inhibition of islet amyloid polypeptide (unknown origin) aggregation after 24 hrs by thioflavin T based fluorescence assay	ic50	4.4000	uM
2-(2,4-dihydroxyphenyl)-3,5,7-trihydroxychromen-4-one	1775270: Inhibition of islet amyloid polypeptide (unknown origin) aggregation after 24 hrs by thioflavin T based fluorescence assay	ic50	7.8000	uM
2-[[3-acetamido-6-[[2-(carboxymethoxy)-6-[[2-(carboxymethoxy)-6-[[2-(carboxymethoxy)-6-[[2-(carboxymethoxy)-6-methoxycarbonyl-3-pyridinyl]carbamoyl]-3-pyridinyl]carbamoyl]-3-pyridinyl]carbamoyl]-3-pyridinyl]carbamoyl]-2-pyridinyl]oxy]acetic acid	1937856: Inhibition of islet amyloid polypeptide (unknown origin) aggregation	ic50	8.0000	uM
1-(3,4-dihydroxyphenyl)hexan-3-one	1775270: Inhibition of islet amyloid polypeptide (unknown origin) aggregation after 24 hrs by thioflavin T based fluorescence assay	ic50	8.5000	uM
1-(3,4-dihydroxyphenyl)pentan-3-one	1775270: Inhibition of islet amyloid polypeptide (unknown origin) aggregation after 24 hrs by thioflavin T based fluorescence assay	ic50	9.5000	uM

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Copper	decreases reaction, increases chemical synthesis, increases reaction, increases abundance, increases cleavage (+6 more)	2
propionaldehyde	decreases expression	1
bisphenol A	increases methylation	1
trichostatin A	increases expression	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	affects cotreatment, decreases reaction, increases phosphorylation, increases expression, increases reaction	1
N,N’-bis(salicylideneamino)ethane-manganese(II)	decreases metabolic processing	1
kukoamine A	affects binding, decreases reaction	1
2-palmitoylglycerol	increases expression	1
EUK-134	decreases metabolic processing	1
kukoamine B	affects binding, decreases reaction	1
Rosiglitazone	increases secretion, affects cotreatment, decreases reaction, increases phosphorylation, increases expression (+1 more)	1
Glucose	decreases reaction, increases secretion	1
Glutathione	affects cotreatment, decreases reaction, increases abundance	1
Hydrogen Peroxide	decreases abundance, increases chemical synthesis, increases reaction, affects cotreatment, decreases reaction (+1 more)	1
Tretinoin	affects expression	1
Valproic Acid	decreases expression	1
Zinc	affects degradation, affects reaction	1
Aflatoxin B1	increases methylation	1

ChEMBL screening assays

21 unique, capped per target: 21 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1918760	Binding	Inhibition of IAPP fibril formation assessed as fold increase in lag time for aggregate formation at 1:10 protein to compound ratio by thioflavin T fluorescence assay relative to untreated control	Sugar-based peptidomimetics inhibit amyloid β-peptide aggregation. — Eur J Med Chem

Clinical trials (associated diseases)

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