AOC1

Summary

AOC1 (amine oxidase copper containing 1, HGNC:80) is a protein-coding gene on chromosome 7q36.1, encoding Diamine oxidase [copper-containing] (P19801). Catalyzes the oxidative deamination of primary amines to the corresponding aldehydes with the concomitant production of hydrogen peroxide and ammonia.

This gene encodes a metal-binding membrane glycoprotein that oxidatively deaminates putrescine, histamine, and related compounds. The encoded protein is inhibited by amiloride, a diuretic that acts by closing epithelial sodium ion channels. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 26 — RefSeq curated summary.

At a glance

• Gene–disease (curated): amyotrophic lateral sclerosis (Moderate, GenCC)
• GWAS associations: 24
• Clinical variants (ClinVar): 226 total — 1 pathogenic
• Phenotypes (HPO): 1
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001091

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:80
Approved symbol	AOC1
Name	amine oxidase copper containing 1
Location	7q36.1
Locus type	gene with protein product
Status	Approved
Aliases	DAO
Ensembl gene	ENSG00000002726
Ensembl biotype	protein_coding
OMIM	104610
Entrez	26

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 11 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000360937, ENST00000416793, ENST00000460213, ENST00000467291, ENST00000480582, ENST00000483043, ENST00000493429, ENST00000863992, ENST00000863993, ENST00000863994, ENST00000941408, ENST00000941409

RefSeq mRNA: 2 — MANE Select: NM_001091 NM_001091, NM_001272072

CCDS: CCDS43679, CCDS64797

Canonical transcript exons

ENST00000360937 — 5 exons

Exon	Start	End
ENSE00001318462	150856455	150858040
ENSE00001362040	150852517	150852558
ENSE00001844752	150860943	150861504
ENSE00003663247	150860501	150860633
ENSE00003681734	150858763	150859048

Expression profiles

Bgee: expression breadth ubiquitous, 145 present calls, max score 99.59.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 10.9943 / max 3871.6664, expressed in 181 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
81991	10.9098	180
82012	0.0522	13
82013	0.0147	6
81989	0.0064	3
82011	0.0058	4
81988	0.0031	1
205004	0.0023	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	99.59	gold quality
decidua	UBERON:0002450	99.36	gold quality
mucosa of transverse colon	UBERON:0004991	99.03	gold quality
jejunal mucosa	UBERON:0000399	98.95	gold quality
colonic mucosa	UBERON:0000317	98.80	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.64	gold quality
renal medulla	UBERON:0000362	97.43	gold quality
nephron tubule	UBERON:0001231	97.01	gold quality
adult organism	UBERON:0007023	96.85	gold quality
rectum	UBERON:0001052	96.70	gold quality
kidney epithelium	UBERON:0004819	96.26	gold quality
adult mammalian kidney	UBERON:0000082	95.83	gold quality
placenta	UBERON:0001987	95.11	gold quality
duodenum	UBERON:0002114	95.00	gold quality
renal glomerulus	UBERON:0000074	94.67	gold quality
metanephric glomerulus	UBERON:0004736	94.30	gold quality
kidney	UBERON:0002113	93.37	gold quality
small intestine Peyer’s patch	UBERON:0003454	90.27	gold quality
metanephros cortex	UBERON:0010533	89.97	gold quality
small intestine	UBERON:0002108	89.91	gold quality
cortex of kidney	UBERON:0001225	89.69	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.78	gold quality
transverse colon	UBERON:0001157	88.52	gold quality
metanephros	UBERON:0000081	87.97	gold quality
vermiform appendix	UBERON:0001154	82.98	gold quality
intestine	UBERON:0000160	81.58	gold quality
caecum	UBERON:0001153	81.39	gold quality
large intestine	UBERON:0000059	78.98	gold quality
colon	UBERON:0001155	78.15	gold quality
jejunum	UBERON:0002115	77.92	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	64.77
E-MTAB-6678	yes	17.15
E-ANND-3	yes	8.89
E-MTAB-7381	no	1435.18
E-MTAB-8410	no	3.26

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 27)

• GAGA factor and the TFIID complex collaborate in generating an open chromatin structure at the Drosophila melanogaster hsp26 promoter. (PMID:12167709)
• Data show that overexpression of either heat-shock proteins 26 or 27 extended the mean lifespan by 30%, and the flies also displayed increased stress resistance. (PMID:15308776)
• Hsp26 overexpression in larva had only a small thermoprotective effect on locomotion and no effect on neural function. (PMID:18347945)
• The functional similarities and differences of neuronal expression of hsp26 and hsp27 in adult Drosophila were demonstrated. (PMID:18796296)
• The study provides evidence for the attenuation of cellular and functional decline in aged Drosophila after prolonged DCA exposure and the effect of hsp27 modulation which further incites studies towards the therapeutic application of DCA. (PMID:24535708)
• Small heat shock proteins determine synapse number and neuronal activity during development. (PMID:32437379)
• could be detected at the feto-maternal interface of human (PMID:11603849)
• for the diamine oxidase gene differences in allele distribution were found in patients with food allergy and sprue compared to controls (PMID:12755416)
• newly identified DAO gene polymorphisms (PMID:15928835)
• Individuals carrying the 645Asp amino acid displayed lower serum diamine oxidase activity as compared with noncarriers (P<0.001) with a significant gene-dose effect (P<0.05). (PMID:17700358)
• An association of the HNMT Thr105Ile polymorphism, but not of the ABP1 His645Asp polymorphism, with PD was observed. Patients with PD showed a higher frequency of homozygous HNMT genotypes (PMID:17985251)
• The study of a non-synonymous single nucleotide polymorphisms(rs1049793) of diamine oxidase gene does not seem to be of use in assessing susceptibility to CD (PMID:19670078)
• Results examine the levels of serum soluble intercellular adhesion molecule-1 (sICAM-1), plasma D-lactate and diamine oxidase (DAO) in patients with inflammatory bowel disease. (PMID:19701972)
• An aspartic acid residue, conserved in all diamine oxidases, is responsible for the diamine specificity by interacting with the second amino group of preferred diamine substrates. (PMID:19764817)
• structure of human DAO refined to 2.1 A resolution in space group C222(1) with one molecule in the asymmetric unit is reported. (PMID:20124708)
• Low serum diamine oxidase activity in inflammatory bowel disease. (PMID:21225906)
• Diamine oxidase (DAO) variants were not associated with the histamine intolerance (HIT) phenotype per se, only with DAO activity alone and the subgroup of HIT patients displaying a reduced DAO activity. (PMID:21488903)
• Low diamine oxidase activity is associated with gastrointestinal tract toxicities during chemotherapy with oral fluorouracil anti-cancer drugs in patients with gastric cancer.( (PMID:22433290)
• Serum diamine oxidase levels were influenced by the menstrual cycle. (PMID:23099198)
• This study findings suggest that DAO genotypes and allelic variants are associated with the risk for migraine in Caucasian Spanish people, especially in women. (PMID:25612138)
• HRH1-17 TT and HNMT-1639 TT genotypes were associated with the allergic asthma phenotype among African-American children and that the ABP 4107 GG genotype was associated with nonallergic asthma among white children. (PMID:25909280)
• The T allele of rs3787429 exhibited protective effect against CHF under the dominant and additive models , while, for SNPs in HRH2, DAO, and HNMT, no significant associations were observed in the present study (PMID:26989676)
• this study shows that single nucleotide polymorphism is associated with the severity of allergic rhinitis in a group of Mexican children (PMID:27255477)
• DAO levels were higher in atopic asthma and allergic rhinitis patients compared to controls. DAO had a high sensitivity and negative predictive value. There was a positive correlation between severity of diseases and DAO. DAO may be helpful in the assessment of severity and in ruling out respiratory allergy. (PMID:31532921)
• Plasma diamine oxidase level > 19.7 ng/mL predicts high rate of 6-month readmission in patients with HBV-related decompensated cirrhosis. (PMID:31533748)
• m6A-enriched lncRNA LINC00839 promotes tumor progression by enhancing TAF15-mediated transcription of amine oxidase AOC1 in nasopharyngeal carcinoma. (PMID:37257820)
• METTL14 contributes to the progression of nasopharyngeal carcinoma through regulating the stability of AOC1 mRNA. (PMID:38956710)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	aoc1	ENSDARG00000061355
mus_musculus	Aoc1	ENSMUSG00000029811
mus_musculus	Aoc1l2	ENSMUSG00000029813
mus_musculus	Aoc1l3	ENSMUSG00000039215
mus_musculus	Aoc1l1	ENSMUSG00000068536
rattus_norvegicus	Aoc1	ENSRNOG00000008575
rattus_norvegicus	Svs1	ENSRNOG00000008714
rattus_norvegicus	Doxl1	ENSRNOG00000023612
rattus_norvegicus	Doxl2	ENSRNOG00000032432

Paralogs (2): AOC3 (ENSG00000131471), AOC2 (ENSG00000131480)

Protein

Protein identifiers

Diamine oxidase [copper-containing] — P19801 (reviewed: P19801)

Alternative names: Amiloride-binding protein, Amiloride-binding protein 1, Amine oxidase copper domain-containing protein 1, Histaminase, Kidney amine oxidase

All UniProt accessions (3): P19801, C9J0G8, C9J2J4

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the oxidative deamination of primary amines to the corresponding aldehydes with the concomitant production of hydrogen peroxide and ammonia. Its preferred substrates are the diamines histamine and 1-methylhistamine and it could therefore play a role in allergic and immune responses. Has a broad specificity for diamines and can also act on cadaverine and putrescine, two products of amino acid catabolism. It could also act on polyamines, like spermidine and spermine though less efficiently, and regulate various biological processes.

Subunit / interactions. Homodimer; disulfide-linked.

Subcellular location. Secreted. Extracellular space. Cell membrane.

Tissue specificity. Widely expressed with higher expression in placenta and kidney.

Post-translational modifications. N-glycosylated. Topaquinone (TPQ) is generated by copper-dependent autoxidation of a specific tyrosyl residue.

Activity regulation. Inhibited by amiloride and amiloride analogs. Inhibited by isoniazid, cimetidine, clonidine, berenil and pentamidine.

Cofactor. Binds 1 copper ion per subunit. Binds 2 calcium ions per subunit. Contains 1 topaquinone per subunit.

Miscellaneous. Originally identified as an amiloride-binding protein (ABP) that could be related to amiloride-sensitive sodium channels, but later shown to function as a diamine oxidase (DAO).

Similarity. Belongs to the copper/topaquinone oxidase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P19801-1	1, DAO1	yes
P19801-2	2, DAO2

RefSeq proteins (2): NP_001082, NP_001259001 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000269	Cu_amine_oxidase	Family
IPR015798	Cu_amine_oxidase_C	Domain
IPR015800	Cu_amine_oxidase_N2	Domain
IPR015802	Cu_amine_oxidase_N3	Domain
IPR016182	Cu_amine_oxidase_N-reg	Homologous_superfamily
IPR036460	Cu_amine_oxidase_C_sf	Homologous_superfamily
IPR049947	Cu_Am_Ox_Cu-bd	Conserved_site
IPR049948	Cu_Am_ox_TPQ-bd	Conserved_site

Pfam: PF01179, PF02727, PF02728

Enzyme classification (BRENDA):

• EC 1.4.3.22 — diamine oxidase (BRENDA: 39 organisms, 197 substrates, 239 inhibitors, 227 Km, 100 kcat entries)

Substrate kinetics (BRENDA)

58 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
PUTRESCINE	0.01–7	37
CADAVERINE	0.0146–8.1	25
SPERMIDINE	0.022–9.52	19
HISTAMINE	0.0028–2.3	18
BENZYLAMINE	0.1–4.1	11
SPERMINE	0.02–5.71	10
BENZALDEHYDE	0.12–2.2	7
PHENYLETHYLAMINE	0.0015–1.4	7
TYRAMINE	0.12–3.1	7
O2	0.0004–0.046	6
1,4-DIAMINOBUTANE	0.2–2.85	5
BUTYLAMINE	0.877–5	5
1,3-DIAMINOPROPANE	0.13–17	4
4-AMINOMETHYLPYRIDINE	0.1–0.48	4
N-METHYLPUTRESCINE	0.19–1.22	4

Catalyzed reactions (Rhea), 4 shown:

• putrescine + O2 + H2O = 4-aminobutanal + H2O2 + NH4(+) (RHEA:18273)
• histamine + O2 + H2O = imidazole-4-acetaldehyde + H2O2 + NH4(+) (RHEA:25625)
• cadaverine + O2 + H2O = 5-aminopentanal + H2O2 + NH4(+) (RHEA:69132)
• N(tau)-methylhistamine + O2 + H2O = 1-methylimidazole-4-acetaldehyde + H2O2 + NH4(+) (RHEA:78367)

UniProt features (103 total): strand 43, helix 21, binding site 12, sequence conflict 6, sequence variant 5, glycosylation site 4, disulfide bond 3, turn 3, active site 2, signal peptide 1, chain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
3HI7	X-RAY DIFFRACTION	1.8
3MPH	X-RAY DIFFRACTION	2.05
3HIG	X-RAY DIFFRACTION	2.09
3K5T	X-RAY DIFFRACTION	2.11
3HII	X-RAY DIFFRACTION	2.15

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P19801-F1	95.43	0.94

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 (2): 373 (proton acceptor); 461 (schiff-base intermediate with substrate; via topaquinone)

Ligand- & substrate-binding residues (12): 653; 656; 658; 664; 665; 675; 510; 512; 519; 520; 521; 562

Post-translational modifications (1): 461

Disulfide bonds (3): 177–181, 391–417, 736

Glycosylation sites (4): 110, 168, 538, 745

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-211945	Phase I - Functionalization of compounds
R-HSA-6798695	Neutrophil degranulation
R-HSA-70921	Histidine catabolism
R-HSA-1430728	Metabolism
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-211859	Biological oxidations

MSigDB gene sets: 344 (showing top): GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, MODULE_93, GOBP_DIGESTION, REACTOME_BIOLOGICAL_OXIDATIONS, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_PHENOL_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOCC_SECRETORY_GRANULE, MODULE_545, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, GOBP_GLUTAMINE_FAMILY_AMINO_ACID_METABOLIC_PROCESS, CAGCTG_AP4_Q5, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, CAIRO_HEPATOBLASTOMA_CLASSES_DN, GOBP_POLYAMINE_METABOLIC_PROCESS

GO Biological Process (2): putrescine metabolic process (GO:0009445), amine metabolic process (GO:0009308)

GO Molecular Function (12): copper ion binding (GO:0005507), calcium ion binding (GO:0005509), primary methylamine oxidase activity (GO:0008131), heparin binding (GO:0008201), protein homodimerization activity (GO:0042803), quinone binding (GO:0048038), putrescine oxidase activity (GO:0050232), diamine oxidase activity (GO:0052597), histamine oxidase activity (GO:0052598), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872)

GO Cellular Component (8): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), peroxisome (GO:0005777), plasma membrane (GO:0005886), bicellular tight junction (GO:0005923), specific granule lumen (GO:0035580), extracellular exosome (GO:0070062), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Biological oxidations	1
Innate Immune System	1
Metabolism of amino acids and derivatives	1
Immune System	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
oxidoreductase activity, acting on the CH-NH2 group of donors, oxygen as acceptor	2
diamine oxidase activity	2
cellular anatomical structure	2
polyamine metabolic process	1
metabolic process	1
transition metal ion binding	1
metal ion binding	1
glycosaminoglycan binding	1
sulfur compound binding	1
identical protein binding	1
protein dimerization activity	1
small molecule binding	1
binding	1
catalytic activity	1
cation binding	1
microbody	1
membrane	1
cell periphery	1
apical junction complex	1
tight junction	1
secretory granule lumen	1
specific granule	1
extracellular vesicle	1

Protein interactions and networks

STRING

1316 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AOC1	HNMT	P50135	891
AOC1	DDC	P20711	723
AOC1	PAOX	Q6QHF9	712
AOC1	MAOB	P27338	711
AOC1	MAOA	P21397	701
AOC1	PNMT	P11086	666
AOC1	HDC	P19113	649
AOC1	AZIN2	Q96A70	649
AOC1	ODC1	P11926	648
AOC1	OCLN	Q16625	638
AOC1	CLDN1	O95832	592
AOC1	TJP1	Q07157	583
AOC1	CLDN7	O95471	582
AOC1	FABP2	P12104	575
AOC1	RET	P07949	549

IntAct

32 interactions, top by confidence:

A	B	Type	Score
CAMKV	AP3B1	psi-mi:“MI:0914”(association)	0.640
AOC1	TIAL1	psi-mi:“MI:0915”(physical association)	0.560
AOC1	RBPMS2	psi-mi:“MI:0915”(physical association)	0.560
AOC1	KRTAP8-1	psi-mi:“MI:0915”(physical association)	0.560
FOXH1	AOC1	psi-mi:“MI:0915”(physical association)	0.560
AOC1	DAZAP2	psi-mi:“MI:0915”(physical association)	0.560
AOC1	ZC3H10	psi-mi:“MI:0915”(physical association)	0.560
AOC1	NTAQ1	psi-mi:“MI:0915”(physical association)	0.560
POGZ	AOC1	psi-mi:“MI:0915”(physical association)	0.560
TLX3	AOC1	psi-mi:“MI:0915”(physical association)	0.560
CUL1	LGALS8	psi-mi:“MI:0914”(association)	0.350
HADHA	AP3B1	psi-mi:“MI:0914”(association)	0.350
SDC1	TCAF2	psi-mi:“MI:0914”(association)	0.350
ZC3H10	AOC1	psi-mi:“MI:0915”(physical association)	0.000
NTAQ1	AOC1	psi-mi:“MI:0915”(physical association)	0.000
POGZ	AOC1	psi-mi:“MI:0915”(physical association)	0.000
TIAL1	AOC1	psi-mi:“MI:0915”(physical association)	0.000
RBPMS2	AOC1	psi-mi:“MI:0915”(physical association)	0.000
AOC1	KRTAP8-1	psi-mi:“MI:0915”(physical association)	0.000
FOXH1	AOC1	psi-mi:“MI:0915”(physical association)	0.000
DAZAP2	AOC1	psi-mi:“MI:0915”(physical association)	0.000
TLX3	AOC1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (16): AOC1 (Two-hybrid), PFKFB1 (Negative Genetic), CSK (Negative Genetic), UMPS (Negative Genetic), NT5M (Positive Genetic), ZC3H10 (Two-hybrid), POGZ (Two-hybrid), TIAL1 (Two-hybrid), WDYHV1 (Two-hybrid), FOXH1 (Two-hybrid), TLX3 (Two-hybrid), RBPMS2 (Two-hybrid), DAZAP2 (Two-hybrid), KRTAP8-1 (Two-hybrid), AOC1 (Two-hybrid)

ESM2 similar proteins: A5PJN5, A6QQ07, B2RXS4, O08590, O15031, O35632, O95497, O95498, P09172, P14616, P15101, P19801, P26011, P36633, P43251, P83548, Q3SZL5, Q3V5L5, Q4R7M2, Q58CQ9, Q5FVF9, Q5R8R3, Q5XI31, Q64237, Q64716, Q6PD26, Q765H6, Q76HN1, Q8AV84, Q8BG22, Q8CIF4, Q8IRR1, Q8JZQ5, Q8NFI3, Q8SQG7, Q91ZJ9, Q9BDJ5, Q9DA79, Q9DBX3, Q9H3S1

Diamond homologs: H2A0M3, O08590, O46406, O70423, O75106, P19801, P36633, Q16853, Q29437, Q5R9I0, Q812C9, Q8JZQ5, Q9TRC7, Q9TTK6, O23349

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	151
Likely benign	37
Benign	20

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3245694	NC_000007.13:g.(?150324807)(150706375_?)del	Pathogenic

SpliceAI

989 predictions. Top by Δscore:

Variant	Effect	Δscore
7:150858750:T:A	acceptor_gain	1.0000
7:150858753:A:AG	acceptor_gain	1.0000
7:150858754:T:G	acceptor_gain	1.0000
7:150858755:A:AG	acceptor_gain	1.0000
7:150858756:C:G	acceptor_gain	1.0000
7:150858758:TCCA:T	acceptor_loss	1.0000
7:150858760:CA:C	acceptor_loss	1.0000
7:150858761:A:AG	acceptor_gain	1.0000
7:150858761:A:AT	acceptor_loss	1.0000
7:150858762:G:A	acceptor_loss	1.0000
7:150858762:G:GC	acceptor_gain	1.0000
7:150858762:GGCA:G	acceptor_gain	1.0000
7:150858905:G:GT	donor_gain	1.0000
7:150859044:GCAAG:G	donor_gain	1.0000
7:150859046:AAG:A	donor_loss	1.0000
7:150859048:GGT:G	donor_loss	1.0000
7:150859050:T:A	donor_loss	1.0000
7:150860495:T:TA	acceptor_gain	1.0000
7:150860497:GCA:G	acceptor_loss	1.0000
7:150860498:CAGGT:C	acceptor_loss	1.0000
7:150860629:ATGAG:A	donor_loss	1.0000
7:150860631:G:GT	donor_gain	1.0000
7:150860631:GAGGT:G	donor_loss	1.0000
7:150860632:AGGTA:A	donor_loss	1.0000
7:150860633:GGTAC:G	donor_loss	1.0000
7:150860634:GTACT:G	donor_loss	1.0000
7:150860635:T:G	donor_loss	1.0000
7:150856448:A:AG	acceptor_gain	0.9900
7:150856449:TTCCA:T	acceptor_loss	0.9900
7:150856450:TCCA:T	acceptor_loss	0.9900

AlphaMissense

4925 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:150857828:G:C	R453P	0.995
7:150857721:C:G	C417W	0.994
7:150857643:C:G	C391W	0.992
7:150857641:T:C	C391R	0.989
7:150857642:G:A	C391Y	0.989
7:150857719:T:C	C417R	0.989
7:150857850:T:A	N460K	0.989
7:150857850:T:G	N460K	0.989
7:150857720:G:A	C417Y	0.988
7:150858004:C:G	H512D	0.988
7:150860994:G:C	D681H	0.988
7:150857641:T:A	C391S	0.987
7:150857642:G:C	C391S	0.987
7:150857725:T:C	F419L	0.987
7:150857727:T:A	F419L	0.987
7:150857727:T:G	F419L	0.987
7:150857863:T:A	W465R	0.986
7:150857863:T:C	W465R	0.986
7:150859041:T:A	W617R	0.986
7:150859041:T:C	W617R	0.986
7:150860955:T:A	W668R	0.985
7:150860955:T:C	W668R	0.985
7:150857434:T:A	W322R	0.984
7:150857434:T:C	W322R	0.984
7:150860544:A:C	S634R	0.984
7:150860546:C:A	S634R	0.984
7:150860546:C:G	S634R	0.984
7:150857719:T:A	C417S	0.982
7:150857720:G:C	C417S	0.982
7:150857918:G:T	G483V	0.982

dbSNP variants (sampled 300 via entrez): RS1000276464 (7:150855277 A>T), RS1000369600 (7:150852048 A>C,G), RS1000610720 (7:150853920 G>A), RS1000641977 (7:150854218 G>A), RS1001536841 (7:150859706 A>G), RS1001621070 (7:150860164 G>A), RS1002317600 (7:150852829 G>C), RS1003062845 (7:150853712 T>G), RS1003200116 (7:150861622 C>G,T), RS1003622603 (7:150857715 C>A,T), RS1004066381 (7:150852490 A>C), RS1005109712 (7:150851098 A>C,G,T), RS1005134394 (7:150855963 G>A,C), RS1005283528 (7:150861696 T>TA), RS1005415751 (7:150856190 T>C,G)

Disease associations

OMIM: gene MIM:104610 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
amyotrophic lateral sclerosis	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
amyotrophic lateral sclerosis	Refuted	AD

Mondo (2): amyotrophic lateral sclerosis (MONDO:0004976), long QT syndrome (MONDO:0002442)

Orphanet (1): Amyotrophic lateral sclerosis (Orphanet:803)

HPO phenotypes

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

HPO	Term
HP:0007354	Amyotrophic lateral sclerosis

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST003476_9	Eyebrow thickness	7.000000e-06
GCST005648_3	Serum metabolite concentrations in chronic kidney disease	2.000000e-12
GCST006585_78	Blood protein levels	3.000000e-239
GCST006611_18	HDL cholesterol	9.000000e-10
GCST006613_150	Triglycerides	2.000000e-09
GCST006631_14	Nicotine dependence and major depression (severity of comorbidity)	8.000000e-06
GCST007490_16	Anthropometric traits (multi-trait analysis)	5.000000e-17
GCST007581_12	Carpal tunnel syndrome	1.000000e-08
GCST009379_78	Type 2 diabetes	1.000000e-10
GCST009733_137	Urinary metabolite levels in chronic kidney disease	1.000000e-32
GCST009733_60	Urinary metabolite levels in chronic kidney disease	2.000000e-20
GCST009733_61	Urinary metabolite levels in chronic kidney disease	6.000000e-13
GCST010241_242	Apolipoprotein A1 levels	3.000000e-09
GCST010241_72	Apolipoprotein A1 levels	7.000000e-14
GCST010242_22	HDL cholesterol levels	2.000000e-16
GCST010244_361	Triglyceride levels	5.000000e-08
GCST010703_222	Brain morphology (MOSTest)	6.000000e-13
GCST012332_19	Multisite chronic pain	4.000000e-08
GCST90000025_317	Appendicular lean mass	1.000000e-113
GCST90002388_409	Lymphocyte count	1.000000e-11
GCST90002389_165	Lymphocyte percentage of white cells	3.000000e-10
GCST90002395_139	Mean platelet volume	7.000000e-28
GCST90007526_6	Low hand grip strength (60 years and older) (EWGSOP)	2.000000e-08
GCST90011900_194	Serum alkaline phosphatase levels	3.000000e-10

EFO canonical traits (14, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0007006	depressive symptom measurement
EFO:0009262	nicotine dependence symptom count
EFO:0004324	body weights and measures
EFO:0005116	urinary metabolite measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004346	neuroimaging measurement
EFO:0010100	multisite chronic pain
EFO:0004980	appendicular lean mass
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0006941	grip strength measurement
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2118 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 53,492 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL55	PENTAMIDINE	4	27,049
CHEMBL225304	PIMAGEDINE	2	24,450
CHEMBL35241	DIMINAZENE	2	1,993

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

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs55944529	Metabolism/PK	3	methadone	Heroin Dependence
rs55944529	Dosage	3	methadone	Heroin Dependence
rs55944529	Efficacy	3	methadone

PharmGKB variants

6 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs6977381	AOC1		0.00	0
rs12539	AOC1		0.00	0
rs11114083	DAO		0.00	0
rs2070586	DAO		0.00	0
rs2070587	DAO		0.00	0
rs55944529	DAO	3	3.25	3	methadone

ChEMBL bioactivities

19 potent at pChembl≥5 of 26 total, top 19 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.89	Ki	13	nM	DIMINAZENE
7.21	IC50	61	nM	CHEMBL534467
6.92	IC50	120	nM	CHEMBL537845
6.85	Ki	140	nM	PIMAGEDINE
6.80	IC50	160	nM	CHEMBL534914
6.77	Ki	170	nM	CHEMBL330979
6.70	Ki	200	nM	CHEMBL119195
6.54	Ki	290	nM	PENTAMIDINE
6.52	IC50	300	nM	CHEMBL536953
6.30	IC50	500	nM	CHEMBL537624
6.00	IC50	1000	nM	CHEMBL537405
5.77	Ki	1700	nM	CHEMBL116536
5.60	IC50	2500	nM	CHEMBL537623
5.57	Ki	2700	nM	CHEMBL47011
5.30	IC50	5000	nM	CHEMBL537174
5.26	Ki	5500	nM	CHEMBL331009
5.15	Ki	7100	nM	CHEMBL116538
5.10	Ki	8000	nM	CHEMBL120717
5.00	IC50	1e+04	nM	CHEMBL537406

PubChem BioAssay actives

14 with measured affinity, of 39 total; 14 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
4-[2-(4-carbamimidoylphenyl)iminohydrazinyl]benzenecarboximidamide	1124814: Mixed type inhibition of recombinant human DAO expressed in drosophila S2 cells	ki	0.0130	uM
4-(aminomethyl)-3-N,3-N,5-N-trimethylpyridine-3,5-diamine;dihydrochloride	242423: Inhibition of putrescine binding to against Diamine oxidase of porcine kidney	ic50	0.0610	uM
4-(aminomethyl)-3-N,5-N-dimethylpyridine-3,5-diamine;dihydrochloride	242423: Inhibition of putrescine binding to against Diamine oxidase of porcine kidney	ic50	0.1200	uM
4-(aminomethyl)-N-methylpyridin-3-amine;dihydrochloride	242423: Inhibition of putrescine binding to against Diamine oxidase of porcine kidney	ic50	0.1600	uM
Pentamidine	1124814: Mixed type inhibition of recombinant human DAO expressed in drosophila S2 cells	ki	0.2900	uM
4-(aminomethyl)pyridin-3-amine;dihydrochloride	242423: Inhibition of putrescine binding to against Diamine oxidase of porcine kidney	ic50	0.3000	uM
4-(aminomethyl)-N-ethylpyridin-3-amine;dihydrochloride	242423: Inhibition of putrescine binding to against Diamine oxidase of porcine kidney	ic50	0.5000	uM
4-(aminomethyl)-3-N-methyl-3-N,5-N-di(propan-2-yl)pyridine-3,5-diamine;dihydrochloride	242423: Inhibition of putrescine binding to against Diamine oxidase of porcine kidney	ic50	1.0000	uM
4-(aminomethyl)-3-N,5-N-diethyl-3-N-methylpyridine-3,5-diamine;dihydrochloride	242423: Inhibition of putrescine binding to against Diamine oxidase of porcine kidney	ic50	2.5000	uM
2,2-difluorohex-5-yne-1,4-diamine;dihydrochloride	56742: In vitro inhibition against hog kidney diamine oxidase	ki	2.7000	uM
4-(aminomethyl)-N-cyclopropylpyridin-3-amine;hydrate;dihydrochloride	242423: Inhibition of putrescine binding to against Diamine oxidase of porcine kidney	ic50	5.0000	uM
1-[5-(2-hydroxyphenyl)-3-(2-methylphenyl)-3,4-dihydropyrazol-2-yl]ethanone	56744: Inhibitory activity against Swine kidney diamine oxidase (SKDAO)	ki	5.5000	uM
1-[5-(2-hydroxyphenyl)-3-(3-methylphenyl)-3,4-dihydropyrazol-2-yl]ethanone	56744: Inhibitory activity against Swine kidney diamine oxidase (SKDAO)	ki	8.0000	uM
4-(aminomethyl)-3-N-methyl-3-N,5-N-dipropylpyridine-3,5-diamine;dihydrochloride	242423: Inhibition of putrescine binding to against Diamine oxidase of porcine kidney	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, decreases expression, increases expression, increases methylation	4
ethylisopropylamiloride	affects binding, decreases reaction, increases degradation, decreases activity	2
phenylamil	affects binding, decreases reaction, increases degradation, decreases activity	2
Amiloride	affects binding, decreases reaction, increases degradation, decreases activity	2
Benzo(a)pyrene	decreases expression	2
Putrescine	increases degradation, increases metabolic processing, decreases reaction	2
pimagedine	decreases reaction, increases degradation, decreases activity	1
methyleugenol	decreases expression	1
bisphenol A	decreases methylation	1
glycidyl methacrylate	decreases expression	1
sodium arsenate	decreases expression	1
benzamil	affects binding	1
tele-methylhistamine	increases metabolic processing	1
nickel sulfate	increases expression	1
2,4,5-trihydroxyphenylalanine quinone	affects binding, increases activity	1
perfluoro-n-nonanoic acid	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Calcium	affects binding	1
Copper	affects binding, increases activity	1
Estradiol	decreases expression	1
Histamine	increases metabolic processing	1
Hydralazine	affects cotreatment, increases expression	1
Methotrexate	affects response to substance	1
Theophylline	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	increases expression	1
Valproic Acid	affects cotreatment, increases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	affects expression	1

ChEMBL screening assays

12 unique, capped per target: 11 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3242684	Binding	Mixed type inhibition of recombinant human DAO expressed in drosophila S2 cells	Some non-conventional biomolecular targets for diamidines. A short survey. — Bioorg Med Chem
CHEMBL874951	Functional	Inhibition of putrescine binding to Diamine oxidase of porcine kidney	Alkylamino derivatives of 4-aminomethylpyridine as inhibitors of copper-containing amine oxidases. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	PHASE3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	PHASE3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial
NCT03948178	PHASE3	TERMINATED	Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension
NCT04165824	PHASE3	COMPLETED	Safety Study of Oral Edaravone Administered in Subjects With ALS
NCT04248465	PHASE3	TERMINATED	An Efficacy and Safety Study of Ravulizumab in ALS Participants
NCT04569084	PHASE3	TERMINATED	Efficacy and Safety Study of Oral Edaravone Administered in Subjects With ALS