HNMT

Summary

HNMT (histamine N-methyltransferase, HGNC:5028) is a protein-coding gene on chromosome 2q22.1, encoding Histamine N-methyltransferase (P50135). Inactivates histamine by N-methylation.

In mammals, histamine is metabolized by two major pathways: N(tau)-methylation via histamine N-methyltransferase and oxidative deamination via diamine oxidase. This gene encodes the first enzyme which is found in the cytosol and uses S-adenosyl-L-methionine as the methyl donor. In the mammalian brain, the neurotransmitter activity of histamine is controlled by N(tau)-methylation as diamine oxidase is not found in the central nervous system. A common genetic polymorphism affects the activity levels of this gene product in red blood cells. Multiple alternatively spliced transcript variants that encode different proteins have been found for this gene.

Source: NCBI Gene 3176 — RefSeq curated summary.

At a glance

• Gene–disease (curated): intellectual disability, autosomal recessive 51 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 73 total — 2 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 13
• Druggable target: yes
• MANE Select transcript: NM_006895

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5028
Approved symbol	HNMT
Name	histamine N-methyltransferase
Location	2q22.1
Locus type	gene with protein product
Status	Approved
Aliases	HMT
Ensembl gene	ENSG00000150540
Ensembl biotype	protein_coding
OMIM	605238
Entrez	3176

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 7 protein_coding, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000280096, ENST00000280097, ENST00000329366, ENST00000410115, ENST00000467390, ENST00000475675, ENST00000480534, ENST00000485653, ENST00000894492, ENST00000894493, ENST00000894494

RefSeq mRNA: 3 — MANE Select: NM_006895 NM_001024074, NM_001024075, NM_006895

CCDS: CCDS2181, CCDS33296, CCDS33297

Canonical transcript exons

ENST00000280097 — 6 exons

Exon	Start	End
ENSE00001071685	138013775	138016364
ENSE00001848424	137964473	137964628
ENSE00003469934	138005132	138005225
ENSE00003670905	138002064	138002194
ENSE00003684326	138000918	138001025
ENSE00003686287	137970165	137970217

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 97.70.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.3305 / max 281.5342, expressed in 1406 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
22721	11.2983	1352
22723	1.1381	452
22720	0.9932	600
22719	0.5544	251
22722	0.2319	114
22724	0.1038	41
22725	0.0107	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gall bladder	UBERON:0002110	97.70	gold quality
monocyte	CL:0000576	97.36	gold quality
mononuclear cell	CL:0000842	97.04	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.92	gold quality
rectum	UBERON:0001052	96.84	gold quality
nephron tubule	UBERON:0001231	96.82	gold quality
leukocyte	CL:0000738	96.80	gold quality
colonic mucosa	UBERON:0000317	96.73	gold quality
liver	UBERON:0002107	96.60	gold quality
calcaneal tendon	UBERON:0003701	96.44	gold quality
skin of hip	UBERON:0001554	96.39	gold quality
left ovary	UBERON:0002119	96.21	gold quality
bronchial epithelial cell	CL:0002328	96.08	gold quality
right lobe of liver	UBERON:0001114	96.07	gold quality
endometrium	UBERON:0001295	96.07	gold quality
adipose tissue	UBERON:0001013	96.06	gold quality
subcutaneous adipose tissue	UBERON:0002190	95.98	gold quality
synovial joint	UBERON:0002217	95.75	gold quality
connective tissue	UBERON:0002384	95.75	gold quality
right coronary artery	UBERON:0001625	95.65	gold quality
superficial temporal artery	UBERON:0001614	95.49	gold quality
seminal vesicle	UBERON:0000998	95.41	gold quality
right ovary	UBERON:0002118	95.33	gold quality
renal medulla	UBERON:0000362	95.01	gold quality
mammary duct	UBERON:0001765	94.84	gold quality
lower lobe of lung	UBERON:0008949	94.75	gold quality
thoracic mammary gland	UBERON:0005200	94.74	gold quality
adipose tissue of abdominal region	UBERON:0007808	94.69	gold quality
mammary gland	UBERON:0001911	94.63	gold quality
germinal epithelium of ovary	UBERON:0001304	94.62	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	46.47
E-HCAD-4	yes	18.02
E-CURD-112	yes	15.57
E-HCAD-9	yes	15.12
E-ANND-3	yes	14.92
E-MTAB-6678	yes	10.84
E-MTAB-10042	yes	4.20
E-GEOD-124858	no	222.11

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ASCL1, ESR2, EZH2

miRNA regulators (miRDB)

11 targeting HNMT, 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-6809-3P	99.91	71.45	3814
HSA-MIR-6832-5P	99.58	64.82	1132
HSA-MIR-3190-5P	98.87	64.89	1345
HSA-MIR-1304-3P	98.29	66.44	1207
HSA-MIR-1285-5P	98.01	68.71	779
HSA-MIR-3159	97.94	66.79	1098
HSA-MIR-6869-5P	97.17	67.06	634
HSA-MIR-215-3P	97.02	68.01	1209
HSA-MIR-4435	95.90	65.47	1201
HSA-MIR-3615	95.04	65.37	109
HSA-MIR-3917	88.03	62.50	44

Literature-anchored findings (GeneRIF, showing 35)

• identification of several novel HNMT polymorphisms, identification of the HNMT core promoter (PMID:12167489)
• for the histamine N-methyltransferase gene no differences in allele distribution were found in patients with food allergy and sprue compared to controls except for the 314t allele (PMID:12755416)
• Single nucleotide polymorphisms were identified in HNMT in Chinese and their relationship assessed with its activity. (PMID:12835614)
• the C314T polymorphism was functionally important and contributes in part to phenotypic variance of histamine N-methyltransferase activity in Chinese Han population (PMID:12867290)
• Studies showed a new brain HNMT mRNA species, named HNMT-Short (HNMT-S), which encodes a 126-amino-acid protein. (PMID:14667820)
• no evidence for the involvement of HNMT polymorphisms in the susceptibility to gastric ulcer (PMID:15551002)
• Polymorphisms and haplotypes in the the HNMT gene are not associated with asthma in the Indian population. (PMID:16205835)
• 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)
• No association can be found in the involvement of HNMT C314T polymorphism in the susceptibility to duodenal ulcer (PMID:18086566)
• Molecular dynamics simulations indicate that the histamine N-methyltransferase T105I polymorphism affects both active site structure and dynamics. (PMID:18154359)
• histamine N-methyltransferase is not related with the risk for migraine. (PMID:18266724)
• These results, combined with previous findings indicating alterations in the frequency for the HNMT Thr105Ile polymorphism in patients with PD, suggest that alterations of histamine homeostasis in the SNC are associated with risk of movement disorders. (PMID:18543121)
• Increased histamine levels in patients with atopic dermatitis may result, at least in part, from reduced enzymatic inactivation via HNMT. (PMID:19025430)
• The HNMT 939A>G polymorphism lowers HNMT enzymatic activity by decreasing HNMT mRNA stability, which leads to an increase in the histamine level and contributes to the development of aspirin intolerant chronic urticaria. (PMID:19178400)
• our results suggest that, despite the possible role of histamine in the inflammatory processes related with the pathogenesis of MS, HNMT polymorphism is not related with the risk for MS in Caucasian Spanish people (PMID:19538200)
• This study do not support the HNMT Thr105Ile variant as a factor in disease development or a genetic link between the disorders. (PMID:19773194)
• Lack of the association of HNMT Thr105Ile functional polymorphism with Alzheimer’s disease is found. (PMID:21138759)
• The results of this study indicated that Histamine N-methyltransferase Thr105Ile polymorphism is associated Parkinson’s disease. (PMID:21794955)
• The A939G HNMT polymorphism is associated with autoimmune MG, while no association with C314T SNP was found. (PMID:23932992)
• The polymorphisms of HNMT and HRH3 were irrelevant with breast cancer in the present study. (PMID:24835231)
• results suggest that the heterozygous Thr/Ile genotype at the HNMT-Thr105Ile locus and the minor Ile105 allele protect against Parkinson’s disease and schizophrenia in Han Chinese. (PMID:25768024)
• 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)
• HNMT is identified as a novel gene responsible for intellectual disability. The consequences of the identified missense mutations on the protein function are discussed. (PMID:26206890)
• 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)
• The C allele for the HNMT polymorphism was associated with a lower degree of disability due to migraine (OR, 10.0; 95% CI, 2.65-37.6). In contrast, presence of the T allele (in heterozygous individuals) was associated with higher degree of disability (OR, 37.1; 95% CI, 4.37-315.2) (PMID:27130307)
• this study shows that single nucleotide polymorphism is associated with the severity of allergic rhinitis in a group of Mexican children (PMID:27255477)
• The present meta-analysis confirms published evidence suggesting that the HNMT rs11558538 minor allele is related to a reduced risk of developing Parkinson disease (PMID:27399132)
• Histamine N-methyltransferase plays a central role in the degradation of the neurotransmitter histamine. Leucine 208 is a critical amino acid residue to maintain the structural integrity of the protein. Replacements by other amino acid residues have profound effects on stability and catalytic activity. (PMID:27769936)
• Genotype and allelic variant frequencies of HNMT rs11558538 SNP 205 restless legs syndrome (RLS) patients and 410 controls using a TaqMan assay: HNMT rs11558538 genotypes allelic variants frequencies were similar between RLS patients and controls and not influenced by gender, family history of RLS, or RLS severity. Some evidence that RLS patients carrying the genotype rs11558538TT had an earlier age at onset. (PMID:27837280)
• This study shown that eight linked SNPs (r(2) = 1) in the HNMT gene were associated with sedation according to the generalized linear model, adjusted for age, gender and BMI (false-discovery-rate-adjusted p = 0.013). (PMID:28400155)
• miR-223 participates in the pathogenesis of atopic dermatitis through upregulating HNMT indirectly to degrade the excessive histamine. (PMID:29506638)
• NHMT polymorphisms are not associated with Parkinson’s disease, ALS and multiple system atrophy in Chinese population. (PMID:29564728)
• Inhibition of Astrocytic Histamine N-Methyltransferase as a Possible Target for the Treatment of Alzheimer’s Disease. (PMID:34680041)
• HNMT Upregulation Induces Cancer Stem Cell Formation and Confers Protection against Oxidative Stress through Interaction with HER2 in Non-Small-Cell Lung Cancer. (PMID:35163585)
• The Thr105Ile Variant (rs11558538) of the Histamine N-methyltransferase Gene may be associated with Reduced Risk of Parkinson Disease: A Meta-analysis. (PMID:36378841)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hnmt	ENSDARG00000012796
mus_musculus	Hnmt	ENSMUSG00000026986
rattus_norvegicus	Hnmt	ENSRNOG00000005223

Protein

Protein identifiers

Histamine N-methyltransferase — P50135 (reviewed: P50135)

All UniProt accessions (1): P50135

UniProt curated annotations — full annotation on UniProt →

Function. Inactivates histamine by N-methylation. Plays an important role in degrading histamine and in regulating the airway response to histamine.

Subunit / interactions. Monomer.

Subcellular location. Cytoplasm.

Disease relevance. Intellectual developmental disorder, autosomal recessive 51 (MRT51) [MIM:616739] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry.

Polymorphism. Variant Ile-105 has a reduced activity and seems to be linked with a predisposition to asthma.

Miscellaneous. Has no histamine-methylating activity.

Similarity. Belongs to the class I-like SAM-binding methyltransferase superfamily. HNMT family.

Isoforms (3)

UniProt ID	Names	Canonical?
P50135-1	1	yes
P50135-2	2, HNMT-S
P50135-3	3

RefSeq proteins (3): NP_001019245, NP_001019246, NP_008826* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR016673	HHMT-like	Family
IPR029063	SAM-dependent_MTases_sf	Homologous_superfamily

Pfam: PF13489

Enzyme classification (BRENDA):

• EC 2.1.1.8 — histamine N-methyltransferase (BRENDA: 9 organisms, 12 substrates, 93 inhibitors, 21 Km, 4 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
HISTAMINE	0.0011–0.043	10
S-ADENOSYL-L-METHIONINE	0.0017–0.38	10

Catalyzed reactions (Rhea), 1 shown:

• histamine + S-adenosyl-L-methionine = N(tau)-methylhistamine + S-adenosyl-L-homocysteine + H(+) (RHEA:19301)

UniProt features (48 total): helix 16, strand 13, binding site 7, splice variant 3, sequence variant 3, turn 3, sequence conflict 2, chain 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
2AOT	X-RAY DIFFRACTION	1.9
1JQE	X-RAY DIFFRACTION	1.91
1JQD	X-RAY DIFFRACTION	2.28
2AOU	X-RAY DIFFRACTION	2.3
2AOV	X-RAY DIFFRACTION	2.48
2AOW	X-RAY DIFFRACTION	2.97
2AOX	X-RAY DIFFRACTION	3.12

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P50135-F1	95.92	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.

Ligand- & substrate-binding residues (7): 28; 60; 89; 94; 120; 142; 283

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2408508	Metabolism of ingested SeMet, Sec, MeSec into H2Se
R-HSA-70921	Histidine catabolism

MSigDB gene sets: 236 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, MODULE_93, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, BEIER_GLIOMA_STEM_CELL_DN, PICCALUGA_ANGIOIMMUNOBLASTIC_LYMPHOMA_UP, KEGG_HISTIDINE_METABOLISM, JIANG_TIP30_TARGETS_UP, chr2q22, GOBP_AROMATIC_AMINO_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, RIGGI_EWING_SARCOMA_PROGENITOR_DN, HSIAO_LIVER_SPECIFIC_GENES, ATTCTTT_MIR186

GO Biological Process (6): histamine metabolic process (GO:0001692), histamine catabolic process (GO:0001695), L-histidine catabolic process (GO:0006548), chemical synaptic transmission (GO:0007268), respiratory gaseous exchange by respiratory system (GO:0007585), methylation (GO:0032259)

GO Molecular Function (4): histamine N-methyltransferase activity (GO:0046539), methyltransferase activity (GO:0008168), N-methyltransferase activity (GO:0008170), transferase activity (GO:0016740)

GO Cellular Component (6): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), centrosome (GO:0005813), cytosol (GO:0005829), synapse (GO:0045202), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Selenoamino acid metabolism	1
Metabolism of amino acids and derivatives	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
imidazole-containing compound catabolic process	2
biogenic amine metabolic process	1
imidazole-containing compound metabolic process	1
histamine metabolic process	1
biogenic amine catabolic process	1
aromatic amino acid catabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
anterograde trans-synaptic signaling	1
multicellular organismal process	1
metabolic process	1
N-methyltransferase activity	1
S-adenosylmethionine-dependent methyltransferase activity	1
transferase activity, transferring one-carbon groups	1
methyltransferase activity	1
catalytic activity	1
nuclear lumen	1
intracellular anatomical structure	1
centriole	1
microtubule organizing center	1
cytoplasm	1
cell junction	1
extracellular vesicle	1

Protein interactions and networks

STRING

1144 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HNMT	AOC1	P19801	891
HNMT	ASH2L	Q9UBL3	820
HNMT	WDR5	P61964	818
HNMT	HCFC1	P51610	814
HNMT	SETD1A	O15047	800
HNMT	DNMT1	P26358	746
HNMT	RBBP5	Q15291	742
HNMT	WDR82	Q6UXN9	728
HNMT	SETD1B	Q9UPS6	722
HNMT	HRH3	Q9Y5N1	720
HNMT	HDAC1	Q13547	693
HNMT	H3C1	P02295	690
HNMT	HDC	P19113	675
HNMT	MLLT10	P55197	672
HNMT	H3-7	Q5TEC6	670
HNMT	H3-5	Q6NXT2	670

IntAct

7 interactions, top by confidence:

A	B	Type	Score
TERF1	HNMT	psi-mi:“MI:0915”(physical association)	0.370
TINF2	HNMT	psi-mi:“MI:0915”(physical association)	0.370
HNMT	POT1	psi-mi:“MI:0915”(physical association)	0.370
HNMT	CAMK2D	psi-mi:“MI:0915”(physical association)	0.370
CFTR	HNMT	psi-mi:“MI:0915”(physical association)	0.370
Tpm1	PLEKHG3	psi-mi:“MI:0914”(association)	0.350

BioGRID (15): HNMT (Biochemical Activity), HNMT (Affinity Capture-MS), PARVA (Co-fractionation), TRMT6 (Co-fractionation), HNMT (Affinity Capture-MS), HNMT (Affinity Capture-RNA), HNMT (PCA), HNMT (Affinity Capture-RNA), RAD51D (Cross-Linking-MS (XL-MS)), HNMT (Affinity Capture-MS), HNMT (Two-hybrid), HNMT (Two-hybrid), HNMT (Two-hybrid), HNMT (Co-fractionation), HNMT (Two-hybrid)

ESM2 similar proteins: A0A075D5I4, A0A075D654, A0A075D657, A0A075D6M1, A0A1D6NER6, A0A482NB13, A0A8X8M4T9, A0A8X8M4W6, A0A8X8M501, A0A8X8M505, A4GNA8, A6ZRD1, C8YTM5, O74529, O94634, P32643, P34254, P49915, P50135, P52788, P97355, Q09580, Q10170, Q16KN5, Q22993, Q29LW1, Q3SZA5, Q3THK7, Q4V7C6, Q55DH6, Q5PP70, Q5R7C3, Q5RA96, Q6C3P4, Q6DC37, Q6DW73, Q83WC3, Q8IDQ9, Q8VYX1, Q93V78

Diamond homologs: P50135, Q01984, Q0V9P1, Q4SBY6, Q58DV7, Q5R7C3, Q5U4V2, Q6DC37, Q7SYS9, Q91VF2, Q9EST2, U3NEE3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	2
Uncertain significance	40
Likely benign	17
Benign	1

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
219125	NM_006895.3(HNMT):c.179G>A (p.Gly60Asp)	Pathogenic
3251876	NC_000002.11:g.(?138722042)(138722199_138727734)del	Pathogenic
219126	NM_006895.3(HNMT):c.623T>C (p.Leu208Pro)	Likely pathogenic
2664508	GRCh37/hg19 2q22.1(chr2:138458639-141918297)x1	Likely pathogenic

SpliceAI

1315 predictions. Top by Δscore:

Variant	Effect	Δscore
2:137964155:G:GT	donor_gain	1.0000
2:137964625:G:GT	donor_gain	1.0000
2:137964626:A:T	donor_gain	1.0000
2:138001021:CAAAG:C	donor_loss	1.0000
2:138001022:AAAGG:A	donor_loss	1.0000
2:138001023:AAGGT:A	donor_loss	1.0000
2:138001024:AGGTA:A	donor_loss	1.0000
2:138001025:GGTA:G	donor_loss	1.0000
2:138001026:GT:G	donor_loss	1.0000
2:138001027:T:A	donor_loss	1.0000
2:138002059:TTTA:T	acceptor_loss	1.0000
2:138002060:TTA:T	acceptor_loss	1.0000
2:138002061:TA:T	acceptor_loss	1.0000
2:138002062:A:AG	acceptor_gain	1.0000
2:138002062:A:T	acceptor_loss	1.0000
2:138002063:G:GG	acceptor_gain	1.0000
2:138002063:GA:G	acceptor_gain	1.0000
2:138002063:GAGC:G	acceptor_gain	1.0000
2:138002170:G:GG	donor_gain	1.0000
2:138002193:AAGT:A	donor_loss	1.0000
2:138002194:AGTA:A	donor_loss	1.0000
2:138002195:G:C	donor_loss	1.0000
2:138002195:G:GG	donor_gain	1.0000
2:138002196:T:TC	donor_loss	1.0000
2:138005126:TTCTA:T	acceptor_loss	1.0000
2:138005127:TCTA:T	acceptor_loss	1.0000
2:138005128:CTAG:C	acceptor_loss	1.0000
2:138005129:TAGAT:T	acceptor_loss	1.0000
2:138005130:A:AG	acceptor_gain	1.0000
2:138005130:A:G	acceptor_loss	1.0000

AlphaMissense

1963 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:137964555:T:C	F22L	0.990
2:137964557:T:A	F22L	0.990
2:137964557:T:G	F22L	0.990
2:137964546:T:C	F19L	0.987
2:137964548:C:A	F19L	0.987
2:137964548:C:G	F19L	0.987
2:137970199:A:C	S58R	0.986
2:137970201:C:A	S58R	0.986
2:137970201:C:G	S58R	0.986
2:138002108:T:A	W115R	0.984
2:138002108:T:C	W115R	0.984
2:138013978:T:C	F243L	0.984
2:138013980:T:A	F243L	0.984
2:138013980:T:G	F243L	0.984
2:138000990:T:A	V88D	0.982
2:138013786:T:A	W179R	0.981
2:138013786:T:C	W179R	0.981
2:137964567:T:C	S26P	0.980
2:137964568:C:T	S26F	0.980
2:137964594:T:C	F35L	0.977
2:137964596:C:A	F35L	0.977
2:137964596:C:G	F35L	0.977
2:138000918:G:T	G64V	0.977
2:138000918:G:A	G64D	0.976
2:137964556:T:C	F22S	0.971
2:137964534:T:C	Y15H	0.969
2:137970197:T:C	L57P	0.969
2:138005138:T:C	Y146H	0.969
2:138014000:T:C	F250S	0.969
2:137970206:G:A	G60D	0.968

dbSNP variants (sampled 300 via entrez): RS1000046703 (2:137976053 G>T), RS1000099050 (2:138004735 A>G), RS1000186304 (2:137991822 G>A), RS1000221863 (2:137980386 T>C), RS1000291630 (2:137974671 A>G), RS1000320719 (2:137974289 T>C), RS1000322674 (2:137986706 A>C), RS1000362791 (2:138006544 C>T), RS1000428869 (2:137988669 G>A), RS1000586626 (2:137999920 A>T), RS1000613043 (2:137981779 C>T), RS1000681313 (2:137986367 G>C), RS1000793201 (2:137993263 A>C), RS1000852971 (2:138012437 C>A), RS1000885395 (2:137980585 A>G)

Disease associations

OMIM: gene MIM:605238 | disease phenotypes: MIM:616739, MIM:600807

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, autosomal recessive 51	Strong	Autosomal recessive
autosomal recessive non-syndromic intellectual disability	Supportive	Autosomal recessive

Mondo (5): intellectual disability, autosomal recessive 51 (MONDO:0014759), inherited susceptibility to asthma (MONDO:0010940), syndromic craniosynostosis (MONDO:0015338), pulmonary arterial hypertension (MONDO:0015924), autosomal recessive non-syndromic intellectual disability (MONDO:0019502)

Orphanet (4): Autosomal recessive non-syndromic intellectual disability (Orphanet:88616), Syndromic craniosynostosis (Orphanet:139393), Pulmonary arterial hypertension (Orphanet:182090), Idiopathic/heritable pulmonary arterial hypertension (Orphanet:422)

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000750	Delayed speech and language development
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001426	Non-Mendelian inheritance
HP:0002099	Asthma
HP:0003593	Infantile onset
HP:0010864	Severe intellectual disability
HP:0032933	Airway hyperresponsiveness
HP:4000007	Bronchoconstriction

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003518_80	Daytime sleep phenotypes	8.000000e-06
GCST009391_1628	Metabolite levels	7.000000e-06
GCST009391_508	Metabolite levels	2.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement
EFO:0010465	beta-hydroxybutyric acid measurement
EFO:0010527	pyridoxate measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D000081029	Pulmonary Arterial Hypertension	C08.381.423.847

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2190 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs1050891	Toxicity	3	aspirin
rs17583889	Toxicity	4	anthracyclines and related substances	Neoplasms

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1050891	HNMT	3	2.25	1	aspirin
rs11558538	HNMT		0.00	0
rs17583889	HNMT	4	-1.50	1	anthracyclines and related substances
rs2737385	HNMT		0.00	0

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.72	Ki	19	nM	CHEMBL1630

PubChem BioAssay actives

1 with measured affinity, of 6100 total; 1 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-[(7-chloroquinolin-4-yl)amino]-2-(diethylaminomethyl)phenol;hydrochloride	672049: Inhibition of histamine N-methyltransferase by radiochemical assay	ki	0.0190	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, affects cotreatment, increases expression	6
trichostatin A	increases expression, decreases expression, affects cotreatment	4
Acetaminophen	affects cotreatment, decreases expression	3
Estradiol	affects cotreatment, decreases expression, increases expression	3
Cyclosporine	decreases expression	3
mercuric bromide	increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	decreases expression, increases expression, decreases reaction	2
Nickel	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Smoke	decreases expression, increases abundance	2
Tobacco Smoke Pollution	decreases expression	2
dicrotophos	decreases expression	1
methylmercuric chloride	increases expression	1
methyleugenol	decreases expression	1
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	affects cotreatment, affects response to substance	1
Allura Red AC Dye	affects cotreatment, affects response to substance	1
azo rubin S	affects cotreatment, affects response to substance	1
bisphenol A	affects cotreatment, increases expression	1
senecionine	decreases expression	1
senkirkine	decreases expression	1
heliotrine	decreases expression	1
arsenite	increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	affects expression	1
butyraldehyde	decreases expression	1
quinoline yellow	affects cotreatment, affects response to substance	1
perfluorooctanoic acid	increases expression	1
SK&F 91488	decreases reaction, increases methylation	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1

ChEMBL screening assays

9 unique, capped per target: 7 binding, 2 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2059994	Binding	Inhibition of histamine N-methyltransferase by radiochemical assay	Crystal structure of phosphoethanolamine methyltransferase from Plasmodium falciparum in complex with amodiaquine. — Bioorg Med Chem Lett
CHEMBL4416340	ADMET	Inhibition of human HNMT expressed in Escherichia coli at 10 uM assessed as reduction in SAH level using histamine as substrate in presence of SAM incubated for 15 mins by LC-MS/MS analysis relative to control	High-Affinity Alkynyl Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT). — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00058929	PHASE4	COMPLETED	A Transition Study From Flolan® to Remodulin® in Patients With Pulmonary Arterial Hypertension
NCT00303459	PHASE4	COMPLETED	Effects of the Combination of Bosentan and Sildenafil Versus Sildenafil Monotherapy on Pulmonary Arterial Hypertension (PAH)
NCT00323297	PHASE4	COMPLETED	Assess the Efficacy and Safety of Sildenafil When Added to Bosentan in the Treatment of Pulmonary Arterial Hypertension
NCT00367770	PHASE4	COMPLETED	BREATHE 5-OL: Tracleer (Bosentan) in Patients With Pulmonary Arterial Hypertension Related to Eisenmenger Physiology
NCT00403650	PHASE4	COMPLETED	Inhaled Iloprost for Sarcoidosis-associated Pulmonary Hypertension
NCT00430716	PHASE4	TERMINATED	To Assess The Efficacy and Safety Of Oral Sildenafil in the Treatment of Pulmonary Arterial Hypertension.
NCT00433329	PHASE4	COMPLETED	Combination Therapy in Pulmonary Arterial Hypertension
NCT00439946	PHASE4	TERMINATED	Safety, Efficacy, and Treatment Satisfaction Switching From Flolan to Remodulin Using the Crono Five Ambulatory Pump in Patients With PAH
NCT00483626	PHASE4	UNKNOWN	Hemodynamic Response After Six Months of Sildenafil
NCT00494533	PHASE4	TERMINATED	Study of Intravenous Remodulin in Patients in India With Pulmonary Arterial Hypertension
NCT00617305	PHASE4	COMPLETED	Study of Add-on Ambrisentan Therapy to Background Phosphodiesterase Type-5 Inhibitor (PDE5i) Therapy in Pulmonary Arterial Hypertension (ATHENA-1)
NCT00625079	PHASE4	WITHDRAWN	Pulmonary Hypertension Secondary to Idiopathic Pulmonary Fibrosis And Treatment With Sildenafil
NCT00625469	PHASE4	WITHDRAWN	Pulmonary Arterial Hypertension Secondary to Idiopathic Pulmonary Fibrosis and Treatment With Bosentan
NCT00705588	PHASE4	UNKNOWN	Long Acting Phosphodiesterase 5 Inhibitors as Add-on Therapy for Patients With Pulmonary Hypertension Treated With Prostanoids.
NCT00741819	PHASE4	COMPLETED	Safety Evaluation of Inhaled Treprostinil Administration Following Transition From Inhaled Ventavis in Pulmonary Arterial Hypertension (PAH) Subjects
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT01105091	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension
NCT01105117	PHASE4	COMPLETED	Epoprostenol for Injection in Pulmonary Arterial Hypertension - Extension of AC-066A401
NCT01268553	PHASE4	COMPLETED	Transition From Injectable Prostacyclin Medication to Inhaled Prostacyclin Medication
NCT01302444	PHASE4	TERMINATED	Treprostinil Combined With Tadalafil for Pulmonary Hypertension
NCT01330108	PHASE4	COMPLETED	Safely Change From Bosentan to Ambrisentan in Pulmonary Hypertension
NCT01433328	PHASE4	TERMINATED	Lidocaine Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01508780	PHASE4	WITHDRAWN	Combined Use of Angiography, Optical Coherence Tomography and Intravascular Ultrasound in Evaluation of Pulmonary Vascular Structure and Function in Patients With Pulmonary Arterial Hypertension Treated With Oral Bosentan
NCT01615627	PHASE4	WITHDRAWN	Hypotonic Treprostinil Subcutaneous Infusion for Control of Treprostinil Related Site Pain
NCT01642407	PHASE4	COMPLETED	Safety And Efficacy Of Sildenafil In Children With Pulmonary Arterial Hypertension
NCT01649739	PHASE4	UNKNOWN	Vardenafil as add-on Therapy for Patients With Pulmonary Hypertension Treated With Inhaled Iloprost
NCT02060487	PHASE4	TERMINATED	Effects of Oral Sildenafil on Mortality in Adults With PAH
NCT02253394	PHASE4	TERMINATED	The Combination Ambrisentan Plus Spironolactone in Pulmonary Arterial Hypertension Study
NCT02284737	PHASE4	TERMINATED	A Study to Investigate the Efficacy of PADN to Improved Functional Capacity and Hemodynamics in Patients With PAH
NCT02310672	PHASE4	COMPLETED	REPAIR: Right vEntricular Remodeling in Pulmonary ArterIal hypeRtension
NCT02847260	PHASE4	COMPLETED	Safety and Tolerability of Rapid Dose Titration of Subcutaneous Remodulin® Therapy in PAH Subjects (RAPID)
NCT02882126	PHASE4	WITHDRAWN	An Open Label Extension Study to Evaluate the Safety of Continued Therapy of Subcutanous Remodulin® in Pulmonary Arterial Hypertension
NCT02885012	PHASE4	TERMINATED	Crossover Study From Macitentan or Bosentan Over to Ambrisentan
NCT02891850	PHASE4	COMPLETED	Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy
NCT02893995	PHASE4	WITHDRAWN	Safety, Tolerability, Pharmacokinetics and Efficacy of Two Different Rates of Subcutanous Remodulin® Dose Titration in Pulmonary Arterial Hypertension
NCT02968901	PHASE4	TERMINATED	Clinical Study Evaluating the Effects of First-line Oral cOmbination theraPy of maciTentan and tadalafIl in Patients With Newly Diagnosed pulMonary Arterial Hypertension (OPTIMA)
NCT03055221	PHASE4	COMPLETED	TRUST-2: Safety and Efficacy of Intravenous Remodulin® in Patients in India With Pulmonary Arterial Hypertension (PAH)
NCT03078907	PHASE4	COMPLETED	Effect of Selexipag on Daily Life Physical Activity of Patients With Pulmonary Arterial Hypertension.
NCT03236818	PHASE4	UNKNOWN	Goal Oriented Strategy to Preserve Ejection Fraction Trial
NCT03344159	PHASE4	COMPLETED	Spironolactone Therapy in Chronic Stable Right HF Trial