NMNAT2

Summary

NMNAT2 (nicotinamide nucleotide adenylyltransferase 2, HGNC:16789) is a protein-coding gene on chromosome 1q25.3, encoding Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2 (Q9BZQ4). Nicotinamide/nicotinate-nucleotide adenylyltransferase that acts as an axon maintenance factor.

This gene product belongs to the nicotinamide mononucleotide adenylyltransferase (NMNAT) enzyme family, members of which catalyze an essential step in NAD (NADP) biosynthetic pathway. Unlike the other human family member, which is localized to the nucleus, and is ubiquitously expressed; this enzyme is cytoplasmic, and is predominantly expressed in the brain. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 23057 — RefSeq curated summary.

At a glance

• Gene–disease (curated): peripheral vascular disease (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 11
• Clinical variants (ClinVar): 34 total — 2 likely-pathogenic
• MANE Select transcript: NM_015039

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16789
Approved symbol	NMNAT2
Name	nicotinamide nucleotide adenylyltransferase 2
Location	1q25.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0479, PNAT2
Ensembl gene	ENSG00000157064
Ensembl biotype	protein_coding
OMIM	608701
Entrez	23057

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000287713, ENST00000294868, ENST00000464047, ENST00000473046, ENST00000918147

RefSeq mRNA: 2 — MANE Select: NM_015039 NM_015039, NM_170706

CCDS: CCDS1353, CCDS1354

Canonical transcript exons

ENST00000287713 — 11 exons

Exon	Start	End
ENSE00001030079	183293705	183293793
ENSE00001176213	183278553	183278629
ENSE00001176220	183283995	183284039
ENSE00001176260	183292790	183292857
ENSE00001270454	183418183	183418380
ENSE00001837996	183248237	183252743
ENSE00003460036	183284710	183284790
ENSE00003490277	183286662	183286788
ENSE00003538279	183290128	183290206
ENSE00003569636	183261202	183261303
ENSE00003631004	183261002	183261069

Expression profiles

Bgee: expression breadth ubiquitous, 208 present calls, max score 97.56.

FANTOM5 (CAGE): breadth broad, TPM avg 14.3815 / max 878.5959, expressed in 698 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
16203	7.1153	401
16204	6.2935	387
16197	0.2878	151
16201	0.2111	78
201841	0.1082	46
16196	0.1031	41
16190	0.1014	23
16205	0.0902	27
16202	0.0709	28

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	97.56	gold quality
cortical plate	UBERON:0005343	97.49	gold quality
frontal pole	UBERON:0002795	97.42	gold quality
paraflocculus	UBERON:0005351	97.20	gold quality
Brodmann (1909) area 10	UBERON:0013541	96.89	gold quality
orbitofrontal cortex	UBERON:0004167	96.37	gold quality
cerebellum	UBERON:0002037	96.13	gold quality
cerebellar cortex	UBERON:0002129	96.13	gold quality
cerebellar hemisphere	UBERON:0002245	96.11	gold quality
cerebellar vermis	UBERON:0004720	95.66	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.58	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.58	gold quality
Brodmann (1909) area 46	UBERON:0006483	95.22	gold quality
superior frontal gyrus	UBERON:0002661	95.14	gold quality
prefrontal cortex	UBERON:0000451	94.29	gold quality
middle frontal gyrus	UBERON:0002702	94.02	gold quality
frontal lobe	UBERON:0016525	93.90	gold quality
frontal cortex	UBERON:0001870	93.89	gold quality
postcentral gyrus	UBERON:0002581	93.85	gold quality
parietal lobe	UBERON:0001872	93.56	gold quality
primary visual cortex	UBERON:0002436	93.49	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.31	gold quality
endothelial cell	CL:0000115	93.24	gold quality
neocortex	UBERON:0001950	92.98	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.95	gold quality
occipital lobe	UBERON:0002021	92.61	gold quality
entorhinal cortex	UBERON:0002728	92.54	gold quality
right frontal lobe	UBERON:0002810	92.44	gold quality
cerebral cortex	UBERON:0000956	92.19	gold quality
cardiac muscle of right atrium	UBERON:0003379	91.04	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	65.85
E-HCAD-25	yes	40.27
E-GEOD-93593	yes	15.46
E-ANND-3	yes	5.03

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1

miRNA regulators (miRDB)

201 targeting NMNAT2, 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-6867-5P	100.00	82.21	3464
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-302C-5P	99.97	72.56	3642

Literature-anchored findings (GeneRIF, showing 21)

• cloning, isolation and kinetics (PMID:12359228)
• Nicotinamide 5’-mononucleotide adenylyltransferase-2 is markedly expressed in the islets of Langerhans. (PMID:14516279)
• NMNAT1 is a nuclear protein, whereas NMNAT2 and -3 are localized to the Golgi complex and the mitochondria (PMID:16118205)
• ATP binds before NMN with Golgi apparatus NMNAT2. NMNH conversion to NADH by NMNAT1 and NMNAT3 occurs at similar rates, conversion by NMNAT2 is much slower. (PMID:17402747)
• analysis of isoform-specific targeting and interaction domains in human nicotinamide mononucleotide adenylyltransferases (PMID:20388704)
• that overexpression of Nmnat2 in M-cells significantly delayed axon degeneration in vivo (PMID:20857515)
• Nmnat2 is a neuronal protein peripherally attached to membranes via palmitoylation and suggest that Nmnat2 is transported to synaptic terminals via an endosomal pathway. (PMID:20943658)
• Decreased endogenous NMNAT2 function caused by reduced CREB signaling during pathological insults may be one of underlying mechanisms for neuronal death in tauopathies (PMID:22027994)
• affects tau phosphorylation by regulating PP2A activity (PMID:23579329)
• Overexpression of NMNAT2 in colorectal cancer cells renders them sensitive to Tiazofurin antineoplastic action. (PMID:23764899)
• Knockdown of NMNAT-2 significantly reduces cellular NAD(+) levels and protects cells from p53-dependent cell death upon DNA damage, suggesting an important functional role of NMNAT-2 in p53-mediated signaling. (PMID:24552824)
• Nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) is essential for axon growth and survival. (PMID:24840802)
• We confirmed association at NMNAT2 and identified independent SMG7 association with systemic lupus erythematosus in European American and Amerindian/Hispanic ancestries. (PMID:26783109)
• NMNAT2 might participate in tumorigenesis of CRC. (PMID:27218101)
• Data indicate a chaperone function of nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2), independent from its enzymatic activity, and NMNAT2 complexes with heat shock protein 90 (HSP90) to refold aggregated protein substrates. (PMID:27254664)
• analyses found that rs10494561, located in the intron region within NMNAT2, was associated with the severity of the prodromal symptoms of psychosis implicitly, mediated through the volume of the left hemisphere of the superior frontal region (PMID:28544218)
• Six single-nucleotide polymorphisms (SNPs) in three loci were associated significantly with Kawasaki disease (KD) susceptibility, including the previously reported BLK locus. The other two loci were newly identified: NMNAT2 on chromosome 1q25.3 and the human leukocyte antigen (HLA) region on chromosome 6p21.3 (HLA-C, HLA-B, MICA and HCP5). (PMID:28855716)
• PAM polyubiquitinates NMNAT2 and regulates NMNAT2 protein stability and degradation by the proteasome (PMID:29997255)
• We identified a homozygous missense mutation in the gene encoding NAD synthesizing enzyme NMNAT2 in two siblings with childhood onset polyneuropathy with erythromelalgia (PMID:31132363)
• we present the first human variants in NMNAT2 identified in two fetuses with severe skeletal muscle hypoplasia and fetal akinesia. Functional studies in vitro showed that the mutations impair both NMNAT2 NAD(+) synthase and chaperone functions. This work identifies the critical role of NMNAT2 in human development. (PMID:31136762)
• Downregulation of SIRT6 and NMNAT2 is associated with proliferative diabetic retinopathy. (PMID:38222451)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	nmnat2	ENSDARG00000004580
mus_musculus	Nmnat2	ENSMUSG00000042751
rattus_norvegicus	Nmnat2	ENSRNOG00000027697
drosophila_melanogaster	Nmnat	FBGN0039254
caenorhabditis_elegans	nmat-2	WBGENE00009176
caenorhabditis_elegans		WBGENE00012295

Paralogs (2): NMNAT3 (ENSG00000163864), NMNAT1 (ENSG00000173614)

Protein

Protein identifiers

Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 2 — Q9BZQ4 (reviewed: Q9BZQ4)

Alternative names: Nicotinamide mononucleotide adenylyltransferase 2, Nicotinate-nucleotide adenylyltransferase 2

All UniProt accessions (1): Q9BZQ4

UniProt curated annotations — full annotation on UniProt →

Function. Nicotinamide/nicotinate-nucleotide adenylyltransferase that acts as an axon maintenance factor. Axon survival factor required for the maintenance of healthy axons: acts by delaying Wallerian axon degeneration, an evolutionarily conserved process that drives the loss of damaged axons. Catalyzes the formation of NAD(+) from nicotinamide mononucleotide (NMN) and ATP. Can also use the deamidated form; nicotinic acid mononucleotide (NaMN) as substrate but with a lower efficiency. Cannot use triazofurin monophosphate (TrMP) as substrate. Also catalyzes the reverse reaction, i.e. the pyrophosphorolytic cleavage of NAD(+). For the pyrophosphorolytic activity prefers NAD(+), NADH and NaAD as substrates and degrades nicotinic acid adenine dinucleotide phosphate (NHD) less effectively. Fails to cleave phosphorylated dinucleotides NADP(+), NADPH and NaADP(+). Also acts as an activator of ADP-ribosylation by supporting the catalytic activity of PARP16 and promoting mono-ADP-ribosylation of ribosomes by PARP16. May be involved in the maintenance of axonal integrity.

Subunit / interactions. Monomer.

Subcellular location. Golgi apparatus membrane. Cytoplasmic vesicle membrane. Cytoplasm. Cell projection. Axon.

Tissue specificity. Highly expressed in brain, in particular in cerebrum, cerebellum, occipital lobe, frontal lobe, temporal lobe and putamen. Also found in the heart, skeletal muscle, pancreas and islets of Langerhans.

Post-translational modifications. Degraded in response to injured neurite. Degradation is caused by polyubiquitination by MYCBP2 after recognition by FBXO45. Palmitoylated; palmitoylation is required for membrane association.

Activity regulation. Inhibited by P1-(adenosine-5’)-P3-(nicotinamide-riboside-5’)-triphosphate (Np3AD) and P1-(adenosine-5’)-P4-(nicotinamide-riboside-5’)-tetraphosphate (Np4AD).

Cofactor. Divalent metal cations. Mg(2+) confers the highest activity.

Pathway. Cofactor biosynthesis; NAD(+) biosynthesis; NAD(+) from nicotinamide D-ribonucleotide: step 1/1. Cofactor biosynthesis; NAD(+) biosynthesis; deamido-NAD(+) from nicotinate D-ribonucleotide: step 1/1.

Similarity. Belongs to the eukaryotic NMN adenylyltransferase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BZQ4-1	1	yes
Q9BZQ4-2	2

RefSeq proteins (2): NP_055854, NP_733820 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004821	Cyt_trans-like	Domain
IPR014729	Rossmann-like_a/b/a_fold	Homologous_superfamily
IPR045094	NMNAT_euk	Family
IPR051182	Euk_NMN_adenylyltrnsfrase	Family

Pfam: PF01467

Enzyme classification (BRENDA):

• EC 2.7.7.1 — nicotinamide-nucleotide adenylyltransferase (BRENDA: 35 organisms, 118 substrates, 59 inhibitors, 203 Km, 57 kcat entries)
• EC 2.7.7.18 — nicotinate-nucleotide adenylyltransferase (BRENDA: 18 organisms, 31 substrates, 52 inhibitors, 74 Km, 22 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ATP	0.0008–3.5	53
NMN	—	37
NICOTINAMIDE RIBONUCLEOTIDE	0.0029–178.5	32
ATP	0.0017–4	22
DIPHOSPHATE	0.083–166.6	13
NICOTINATE BETA-D-RIBONUCLEOTIDE	0.0358–2.8	12
NAD+	0.023–412.2	11
NICOTINIC ACID MONONUCLEOTIDE	0.0145–0.15	11
NMNH	0.13–0.304	6
DIPHOSPHATE	0.083–4.2	5
NAD+	0.069–1.7	5
NICOTINATE RIBONUCLEOTIDE	0.025–1.3	5
NICOTINATE RIBONUCLEOTIDE	0.08–5	4
NICOTINIC ACID RIBONUCLEOTIDE	0.011–0.323	4
NICOTINAMIDE MONONUCLEOTIDE	0.021–0.7	3

Catalyzed reactions (Rhea), 2 shown:

• beta-nicotinamide D-ribonucleotide + ATP + H(+) = diphosphate + NAD(+) (RHEA:21360)
• nicotinate beta-D-ribonucleotide + ATP + H(+) = deamido-NAD(+) + diphosphate (RHEA:22860)

UniProt features (18 total): binding site 11, mutagenesis site 3, lipid moiety-binding region 2, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BZQ4-F1	80.34	0.64

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 (11): 16; 232; 271–274 (in other chain); 17; 24 (in other chain); 92; 95; 200; 202; 212; 213

Post-translational modifications (2): 164, 165

Mutagenesis-validated functional residues (3):

Position	Phenotype
24	reduces activity by 95%.
24	abolished nicotinamide-nucleotide adenylyltransferase activity; abolished ability to promote mono-adp-ribosylation of ri
92	abolished nicotinamide-nucleotide adenylyltransferase activity; abolished ability to promote mono-adp-ribosylation of ri

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-196807	Nicotinate metabolism

MSigDB gene sets: 231 (showing top): GOBP_CYTOPLASMIC_TRANSLATION, GNF2_RTN1, HNF3ALPHA_Q6, GOBP_NADPPLUS_METABOLIC_PROCESS, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_NEUROGENESIS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, FOXO4_01, FOXO1_01, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_PURINE_CONTAINING_COMPOUND_SALVAGE, GOBP_NEGATIVE_REGULATION_OF_TRANSLATION, GOBP_NADPLUS_METABOLIC_PROCESS

GO Biological Process (13): NADP+ biosynthetic process (GO:0006741), nicotinamide metabolic process (GO:0006769), nucleotide biosynthetic process (GO:0009165), NAD+ biosynthetic process (GO:0009435), ‘de novo’ NAD+ biosynthetic process from L-tryptophan (GO:0034354), NAD+ biosynthetic process via the salvage pathway (GO:0034355), nicotinamide riboside metabolic process (GO:0046495), axon development (GO:0061564), negative regulation of cytoplasmic translation (GO:2000766), cytoplasmic translation (GO:0002181), biosynthetic process (GO:0009058), pyridine nucleotide biosynthetic process (GO:0019363), organophosphate biosynthetic process (GO:0090407)

GO Molecular Function (8): nicotinamide-nucleotide adenylyltransferase activity (GO:0000309), nicotinate-nucleotide adenylyltransferase activity (GO:0004515), ATP binding (GO:0005524), protein ADP-ribosyltransferase-substrate adaptor activity (GO:0140768), nucleotide binding (GO:0000166), catalytic activity (GO:0003824), transferase activity (GO:0016740), nucleotidyltransferase activity (GO:0016779)

GO Cellular Component (14): Golgi membrane (GO:0000139), late endosome (GO:0005770), Golgi apparatus (GO:0005794), trans-Golgi network (GO:0005802), cytosol (GO:0005829), extrinsic component of membrane (GO:0019898), transport vesicle (GO:0030133), axon (GO:0030424), cytoplasmic vesicle membrane (GO:0030659), synapse (GO:0045202), cytoplasm (GO:0005737), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoplasm	3
purine nucleotide biosynthetic process	2
nicotinamide nucleotide biosynthetic process	2
NAD+ biosynthetic process	2
adenylyltransferase activity	2
endomembrane system	2
cytoplasmic vesicle	2
NADP+ metabolic process	1
alkaloid metabolic process	1
pyridine-containing compound metabolic process	1
nucleotide metabolic process	1
nucleoside phosphate biosynthetic process	1
NAD+ metabolic process	1
aromatic amino acid metabolic process	1
indole-containing compound metabolic process	1
L-amino acid metabolic process	1
proteinogenic amino acid metabolic process	1
pyridine nucleotide salvage	1
purine nucleotide salvage	1
pyridine nucleoside metabolic process	1
neuron projection development	1
cytoplasmic translation	1
negative regulation of translation	1
regulation of cytoplasmic translation	1
translation	1
metabolic process	1
nucleotide biosynthetic process	1
pyridine-containing compound biosynthetic process	1
biosynthetic process	1
organophosphate metabolic process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
enzyme-substrate adaptor activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
molecular_function	1
catalytic activity	1
transferase activity, transferring phosphorus-containing groups	1
Golgi apparatus	1

Protein interactions and networks

STRING

1844 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NMNAT2	SMG7	Q92540	861
NMNAT2	SARM1	Q6SZW1	848
NMNAT2	SIRT3	Q9NTG7	841
NMNAT2	NAPRT	Q6XQN6	767
NMNAT2	LAMC2	Q13753	762
NMNAT2	NAMPT	P43490	740
NMNAT2	UBE4B	O95155	739
NMNAT2	NMRK1	Q9NWW6	705
NMNAT2	HSP90AB1	P08238	698
NMNAT2	HSP90AA1	P07900	696
NMNAT2	NCF2	P19878	687
NMNAT2	QPRT	Q15274	672
NMNAT2	NADK	O95544	604
NMNAT2	SIRT1	Q96EB6	567
NMNAT2	STMN2	Q93045	542

IntAct

4 interactions, top by confidence:

A	B	Type	Score
NMNAT2	MYCBP2	psi-mi:“MI:0914”(association)	0.350
NMNAT2	TOMM40	psi-mi:“MI:0914”(association)	0.350

BioGRID (27): NMNAT2 (Affinity Capture-RNA), NMNAT2 (Biochemical Activity), MYCBP2 (Affinity Capture-Western), FBXO45 (Affinity Capture-Western), SKP1 (Affinity Capture-Western), HSP90AA1 (Affinity Capture-Western), NMNAT2 (Affinity Capture-Western), MUM1 (Affinity Capture-MS), ZNF318 (Affinity Capture-MS), SALL2 (Affinity Capture-MS), LRIF1 (Affinity Capture-MS), YEATS2 (Affinity Capture-MS), RBM14-RBM4 (Affinity Capture-MS), FBXO7 (Affinity Capture-MS), PTBP3 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2K344, A0JMU5, A1A4L5, A2PYH4, A2RUV5, A4IH61, A8Y5H7, B3M1E1, B3P4N5, B4GZ20, B4HJC0, B4JXV2, B4KA23, B4LVS8, B4NKI9, B4PVH6, B4QVW6, O18475, O94830, P32871, P42336, P42337, P42338, Q0HA29, Q0VC59, Q0VD50, Q13057, Q29B63, Q2TBM9, Q3U213, Q5RBL5, Q5SNQ7, Q6PC93, Q80VJ4, Q80Y20, Q80Y98, Q8BNJ3, Q8BTI9, Q8C0L9, Q922E4

Diamond homologs: A4IH61, A8ZXR7, B0TGU9, F4K687, Q0HA29, Q0VC59, Q0VD50, Q5RBL5, Q6PC93, Q7UFN6, Q8BNJ3, Q96T66, Q99JR6, Q9BZQ4, Q9EPA7, Q9HAN9, Q9UT53, Q9VC03, P53204, P91851, Q06178, Q0DWH7, A3DEU4, A6V0A4, B0K413, B0KAB6, B0KJY4, B1J134, B1YKR5, B4U7J9, B5EEI3, B9M0D7, C1A4H9, Q1AVU4, Q2JNW7, Q2JWZ1, Q2LU86, Q2S0V3, Q3A1E1, Q3MAP9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	24
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
520700	NM_015039.4(NMNAT2):c.403dup (p.Gln135fs)	Likely pathogenic
520701	NM_015039.4(NMNAT2):c.695G>A (p.Arg232Gln)	Likely pathogenic

SpliceAI

2524 predictions. Top by Δscore:

Variant	Effect	Δscore
1:183260997:CATA:C	donor_loss	1.0000
1:183260998:ATAC:A	donor_loss	1.0000
1:183260999:TA:T	donor_loss	1.0000
1:183261000:AC:A	donor_loss	1.0000
1:183261195:GACTC:G	donor_loss	1.0000
1:183261196:ACTC:A	donor_loss	1.0000
1:183261198:TCA:T	donor_loss	1.0000
1:183261199:CACTT:C	donor_loss	1.0000
1:183261200:A:AC	donor_gain	1.0000
1:183261200:A:C	donor_loss	1.0000
1:183261201:C:CT	donor_gain	1.0000
1:183261201:CT:C	donor_gain	1.0000
1:183261201:CTT:C	donor_gain	1.0000
1:183261201:CTTT:C	donor_gain	1.0000
1:183261300:CCAT:C	acceptor_gain	1.0000
1:183261301:CAT:C	acceptor_gain	1.0000
1:183261301:CATC:C	acceptor_gain	1.0000
1:183261303:TCTA:T	acceptor_loss	1.0000
1:183261304:C:CC	acceptor_gain	1.0000
1:183261304:CT:C	acceptor_loss	1.0000
1:183261305:T:C	acceptor_loss	1.0000
1:183286656:CCCTA:C	donor_loss	1.0000
1:183286657:CCTAC:C	donor_loss	1.0000
1:183286658:CTACC:C	donor_loss	1.0000
1:183286659:TACCT:T	donor_loss	1.0000
1:183286660:A:AC	donor_gain	1.0000
1:183286660:A:T	donor_loss	1.0000
1:183286661:C:CA	donor_loss	1.0000
1:183286661:C:CC	donor_gain	1.0000
1:183286784:ACCCT:A	acceptor_gain	1.0000

AlphaMissense

2037 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:183252690:A:T	V292D	1.000
1:183252702:A:G	L288P	1.000
1:183252735:A:G	L277P	1.000
1:183252743:C:A	R274S	1.000
1:183252743:C:G	R274S	1.000
1:183261002:C:A	R274M	1.000
1:183261002:C:G	R274T	1.000
1:183261016:G:C	S269R	1.000
1:183261016:G:T	S269R	1.000
1:183261018:T:G	S269R	1.000
1:183261272:A:T	V228E	1.000
1:183261278:C:A	G226V	1.000
1:183261278:C:T	G226E	1.000
1:183261279:C:A	G226W	1.000
1:183261279:C:G	G226R	1.000
1:183261279:C:T	G226R	1.000
1:183261280:A:C	F225L	1.000
1:183261280:A:T	F225L	1.000
1:183261282:A:G	F225L	1.000
1:183261290:A:T	V222D	1.000
1:183261293:A:T	I221N	1.000
1:183278565:C:A	W213C	1.000
1:183278565:C:G	W213C	1.000
1:183278566:C:G	W213S	1.000
1:183278567:A:G	W213R	1.000
1:183278567:A:T	W213R	1.000
1:183278569:A:G	L212P	1.000
1:183278584:A:G	F207S	1.000
1:183278587:G:A	S206F	1.000
1:183278588:A:G	S206P	1.000

dbSNP variants (sampled 300 via entrez): RS1000005326 (1:183340349 T>C,G), RS1000036265 (1:183296207 T>C), RS1000065548 (1:183352879 G>A), RS1000087266 (1:183392183 G>C), RS1000106590 (1:183388704 T>A), RS1000112171 (1:183268331 C>A,T), RS1000126783 (1:183376564 A>G), RS1000139221 (1:183272675 G>T), RS1000156767 (1:183419197 G>A), RS1000180787 (1:183256199 C>A,T), RS1000202422 (1:183253502 A>T), RS1000206331 (1:183346381 C>T), RS1000213651 (1:183387128 T>C), RS1000232092 (1:183268115 A>G), RS1000240899 (1:183262571 T>C)

Disease associations

OMIM: gene MIM:608701 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
peripheral vascular disease	Moderate	Autosomal recessive
developmental defect during embryogenesis	Moderate	Autosomal recessive

Mondo (3): vascular dementia (MONDO:0004648), peripheral vascular disease (MONDO:0005294), developmental defect during embryogenesis (MONDO:0019755)

Orphanet (0):

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST001762_466	Obesity-related traits	1.000000e-06
GCST001762_691	Obesity-related traits	5.000000e-06
GCST002069_9	Systemic lupus erythematosus and Systemic sclerosis	5.000000e-06
GCST002595_11	Clozapine-induced agranulocytosis	1.000000e-06
GCST005752_111	Systemic lupus erythematosus	1.000000e-37
GCST006268_231	Reaction time	2.000000e-09
GCST006268_491	Reaction time	2.000000e-09
GCST006269_1200	General cognitive ability	4.000000e-08
GCST006269_720	General cognitive ability	2.000000e-09
GCST007565_106	Morning person	2.000000e-14
GCST008179_3	Moderate-to-late spontaneous preterm birth	3.000000e-06

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004736	aspartate aminotransferase measurement
EFO:0004810	interleukin-6 measurement
EFO:0008393	reaction time measurement
EFO:0004337	intelligence
EFO:0008328	chronotype measurement
EFO:0006917	spontaneous preterm birth

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D015140	Dementia, Vascular	C10.228.140.300.400; C10.228.140.300.510.800.500; C10.228.140.380.230; C10.228.140.695.500; C14.907.137.126.372.500; C14.907.253.560.350.500; F03.615.400.350
D016491	Peripheral Vascular Diseases	C14.907.617

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	9
trichostatin A	affects cotreatment, increases expression	3
Panobinostat	affects cotreatment, affects expression, increases expression	3
arsenite	affects binding, decreases reaction, increases methylation	2
sodium arsenite	decreases expression, increases abundance, increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
Arsenic	increases abundance, increases methylation, affects cotreatment, decreases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Aflatoxin B1	decreases expression, increases methylation	2
aristolochic acid I	increases expression	1
sotorasib	affects cotreatment, increases expression	1
propionaldehyde	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
beta-methylcholine	affects expression	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
NSC 689534	affects binding, increases expression	1
trametinib	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Air Pollutants	increases expression	1
Ethanol	increases expression	1
Cadmium	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00180505	PHASE4	COMPLETED	ASSESS Study: Evaluation of ABSOLUTE™ Stent System for Occluded Arteries
NCT00228384	PHASE4	COMPLETED	GORE VIABAHN ENDOPROSTHESIS Peripheral Vascular Disease Study
NCT00355537	PHASE4	COMPLETED	Testosterone Replacement in Diabetes With Vascular Disease (Version 2)
NCT00431249	PHASE4	COMPLETED	Effects of Cilostazol on VEGF and Oxidative Stress Biomarkers in Hemodialysis Patients With Peripheral Vascular Disease
NCT00437905	PHASE4	TERMINATED	Balloon Angioplasty vs. Cutting Balloon Angioplasty of Femoropopliteal Arteries- a Randomized Controlled Trial
NCT00442325	PHASE4	COMPLETED	Benefits Of Using Various Starting Doses Of Atorvastatin On Achievement Of Cholesterol Targets
NCT00442845	PHASE4	COMPLETED	Establish The Benefits Of Using Various Starting Doses Of Atorvastatin On Achievement Of Cholesterol Targets (ACTFAST)
NCT00481741	PHASE4	COMPLETED	Study of the SafeSeal(TM) Hemostasis Patch Following Percutaneous Coronary Artery and Peripheral Vascular Interventions
NCT00504088	PHASE4	TERMINATED	Plaque Removal Versus Open Bypass Surgery For Critical Limb Ischemia
NCT00504712	PHASE4	COMPLETED	Testosterone for Peripheral Vascular Disease
NCT00637741	PHASE4	COMPLETED	DURABILITY-200: EverFlex 200mm Long Nitinol Stents in TASC C&D Femoropopliteal Lesions
NCT00715416	PHASE4	COMPLETED	PTA vs. Primary Stenting of SFA Using Self-Expandable Nitinol Stents
NCT00764777	PHASE4	COMPLETED	Efficacy Study of Iliac Stents to Treat TASC A-B-C-D Iliac Artery Lesions
NCT00822172	PHASE4	COMPLETED	Evaluation of Cilostazol in Combination With L-Carnitine
NCT00837954	PHASE4	COMPLETED	Trial to Evaluate the Hemostatic Effect of Lyostypt® Versus Surgicel® in Arterial Bypass Anastomosis
NCT00911417	PHASE4	COMPLETED	A Study to Collect Intravascular Ultrasound Images Before and After Treatment With the Jetstream System
NCT00986752	PHASE4	UNKNOWN	Efficacy Study of Stenting, Paclitaxel Eluting Balloon or Atherectomy to Treat Peripheral Artery Disease
NCT01083394	PHASE4	UNKNOWN	Paclitaxel Eluting Balloon and Conventional Balloon for In-Stent Restenosis of the Superficial Femoral Artery
NCT01108861	PHASE4	COMPLETED	GORE VIABAHN® Versus Plain Old Balloon Angioplasty (POBA) for Superficial Femoral Artery (SFA) In-Stent Restenosis
NCT01150617	PHASE4	TERMINATED	Normalization of Fasting Glucose and the Incidence of Restenosis After Peripheral Angioplasty
NCT01305070	PHASE4	COMPLETED	Standard Balloon Angioplasty Versus Angioplasty With a Paclitaxel-eluting Balloon for Femoral Artery In-stent Restenosis
NCT01413139	PHASE4	COMPLETED	4-EVER : a Trial Investigating the Safety of 4F Endovascular Treatment of Infra-Inguinal Arterial Stenotic Disease
NCT01952457	PHASE4	UNKNOWN	The Cook Zilver PTX Drug-eluting Stent Versus Bypass Surgery for the Treatment The Cook Zilver PTX Drug-eluting Stent Versus Bypass Surgery of Femoropopliteal TASC C&D Lesions
NCT02211664	PHASE4	COMPLETED	Physician-Initiated Trial Investigating the Efficacy of Endovascular Treatment of Femoropopliteal Arterial Stenotic Disease With the Biotronik Passeo-18 Lux Drug Releasing Balloon and the Biotronik Pulsar-18 Stent (Comparing With 4EVER Trial Results)
NCT02211716	PHASE4	COMPLETED	Physician-Initiated Trial Investigating the BeGraft Peripheral Stent Graft System
NCT02212470	PHASE4	COMPLETED	Drug Eluting Balloon Angioplasty Versus Nitinol Stent Implantation in the Superficial Femoral Artery
NCT02212626	PHASE4	COMPLETED	Prospective, Non-randomized Multi-center, Controlled Physician-initiated Trial: Rotarex Belgium In-stent Occlusion
NCT03207451	PHASE4	COMPLETED	Vorapaxar on Thrombin Generation and Coagulability
NCT03404180	PHASE4	COMPLETED	Peripheral Nerve Blocks for Above-the-knee Amputations
NCT05804097	PHASE4	ACTIVE_NOT_RECRUITING	Does Increasing Oxygen Nurture Your Symptomatic Ischemic Ulcer Sufficiently?
NCT06613191	PHASE4	NOT_YET_RECRUITING	Colonoscopy and Antiplatelet Therapy Trial
NCT00165763	PHASE4	COMPLETED	Efficacy and Safety of Donepezil Hydrochloride (Aricept) in Vascular Dementia
NCT00847860	PHASE4	COMPLETED	Cilostazol Verse Asprin for Vascular Dementia in Poststroke Patients With White Matter Lesions
NCT00947531	PHASE4	COMPLETED	A Clinical Trial to Evaluate the Safety and Efficacy of 20 ml Cerebrolysin in Patients With Vascular Dementia
NCT00950430	PHASE4	ENROLLING_BY_INVITATION	Imaging of Brain Amyloid Plaques in the Aging Population
NCT00000614	PHASE3	COMPLETED	Prevention of Recurrent Venous Thromboembolism (PREVENT)
NCT00032357	PHASE3	COMPLETED	Does the Reduction of Total Body Iron Storage (TBIS) Alter Mortality in a Population of Patients With Advanced PVD?
NCT00059644	PHASE3	TERMINATED	Efficacy/Safety of Ecraprost in Lipid Emulsion for Treatment of Critical Leg Ischemia Due to Peripheral Arterial Disease
NCT00059657	PHASE3	COMPLETED	Efficacy/Safety of Ecraprost in Lipid Emulsion for Treatment of Critical Leg Ischemia Due to Peripheral Arterial Disease
NCT00060996	PHASE3	TERMINATED	Study of Remodulin in Patients With Critical Limb Ischemia With No Planned Revascularization Procedures