MACROD2

Summary

MACROD2 (mono-ADP ribosylhydrolase 2, HGNC:16126) is a protein-coding gene on chromosome 20p12.1, encoding ADP-ribose glycohydrolase MACROD2 (A1Z1Q3). Removes ADP-ribose from aspartate and glutamate residues in proteins bearing a single ADP-ribose moiety.

The protein encoded by this gene is a deacetylase involved in removing ADP-ribose from mono-ADP-ribosylated proteins. The encoded protein has been shown to translocate from the nucleus to the cytoplasm upon DNA damage.

Source: NCBI Gene 140733 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic disease (Limited, GenCC)
• GWAS associations: 50
• Clinical variants (ClinVar): 115 total — 2 likely-pathogenic
• Phenotypes (HPO): 2
• Druggable target: yes
• MANE Select transcript: NM_001351661

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16126
Approved symbol	MACROD2
Name	mono-ADP ribosylhydrolase 2
Location	20p12.1
Locus type	gene with protein product
Status	Approved
Aliases	dJ631M13.5
Ensembl gene	ENSG00000172264
Ensembl biotype	protein_coding
OMIM	611567
Entrez	140733

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 10 protein_coding_CDS_not_defined, 5 protein_coding

ENST00000217246, ENST00000402914, ENST00000407045, ENST00000462552, ENST00000463861, ENST00000464883, ENST00000477147, ENST00000483997, ENST00000486914, ENST00000490428, ENST00000492055, ENST00000494602, ENST00000497992, ENST00000642719, ENST00000684519

RefSeq mRNA: 5 — MANE Select: NM_001351661 NM_001033087, NM_001351661, NM_001351663, NM_001351664, NM_080676

CCDS: CCDS13120, CCDS33443, CCDS93008

Canonical transcript exons

ENST00000684519 — 18 exons

Exon	Start	End
ENSE00001364692	16044571	16044639
ENSE00001476091	16049830	16053197
ENSE00001476144	15933276	15933338
ENSE00001476145	15885764	15885811
ENSE00003458797	16041201	16041278
ENSE00003458914	15937476	15937544
ENSE00003468354	14085621	14085728
ENSE00003471399	15987066	15987158
ENSE00003507720	15229940	15230061
ENSE00003531787	14684843	14684959
ENSE00003546743	15499774	15499847
ENSE00003556256	14493479	14493508
ENSE00003580860	14002288	14002404
ENSE00003630105	15431405	15431435
ENSE00003654075	15967553	15967630
ENSE00003665642	15986727	15986801
ENSE00003673156	15862745	15862826
ENSE00003920673	13995516	13995809

Expression profiles

Bgee: expression breadth ubiquitous, 214 present calls, max score 95.55.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.3817 / max 265.5468, expressed in 1033 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
183611	7.1509	1015
183616	0.1201	27
183621	0.0977	16
209003	0.0092	3
209006	0.0038	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	95.55	silver quality
buccal mucosa cell	CL:0002336	91.93	silver quality
epithelial cell of pancreas	CL:0000083	91.76	silver quality
lower lobe of lung	UBERON:0008949	91.67	gold quality
cortical plate	UBERON:0005343	91.64	gold quality
Brodmann (1909) area 23	UBERON:0013554	91.05	gold quality
germinal epithelium of ovary	UBERON:0001304	90.01	gold quality
middle temporal gyrus	UBERON:0002771	89.40	gold quality
sural nerve	UBERON:0015488	87.55	gold quality
entorhinal cortex	UBERON:0002728	87.44	gold quality
visceral pleura	UBERON:0002401	87.33	gold quality
Brodmann (1909) area 46	UBERON:0006483	86.01	gold quality
nucleus accumbens	UBERON:0001882	84.90	gold quality
superior frontal gyrus	UBERON:0002661	84.86	gold quality
secondary oocyte	CL:0000655	84.58	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.97	gold quality
primary visual cortex	UBERON:0002436	83.50	gold quality
postcentral gyrus	UBERON:0002581	83.41	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.53	gold quality
caudate nucleus	UBERON:0001873	82.07	gold quality
upper leg skin	UBERON:0004262	81.08	gold quality
prefrontal cortex	UBERON:0000451	81.02	gold quality
parietal lobe	UBERON:0001872	80.92	gold quality
putamen	UBERON:0001874	80.85	gold quality
oviduct epithelium	UBERON:0004804	80.73	gold quality
lung	UBERON:0002048	80.42	gold quality
adrenal tissue	UBERON:0018303	80.03	gold quality
frontal cortex	UBERON:0001870	79.89	gold quality
seminal vesicle	UBERON:0000998	79.88	gold quality
neocortex	UBERON:0001950	79.79	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-2	yes	10265.18
E-HCAD-35	yes	68.24
E-ANND-3	yes	27.88
E-GEOD-130148	yes	9.70
E-MTAB-6678	yes	8.15

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

113 targeting MACROD2, 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-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-4302	99.89	67.94	1187
HSA-MIR-605-3P	99.88	69.22	1833
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-LET-7G-3P	99.85	70.43	1929

Literature-anchored findings (GeneRIF, showing 16)

• A 250 kb de novo microdeletion at 20p12.1, deleting exon 5 of C20orf133, was seen in a Kabuki syndrome case. The de novo deletion, the expression data & the fact that C20orf133 has a macro domain make it a likely candidate to cause KS in this patient. (PMID:17586838)
• Authors describe the results of a deletion assay for the exon 5 in C20orf133 and a mutation analysis of C20orf133 and FLRT3 in patients with Kabuki Syndrome. (PMID:18593871)
• An analysis of 1 million single-nucleotide polymorphisms found a possible commonality for autism in the allele at rs4141463 located in MACROD2. (PMID:20663923)
• this study does not provide support for the reported association between rs4141463, within the MACROD2 gene and autism. (PMID:21656903)
• MACROD2 gene is a strong positional candidate risk factor for autistic-like traits in the general population (PMID:25360606)
• MACROD2 is a key mediator of estrogen independent growth and tamoxifen resistance (PMID:25422431)
• In patients with Graves’ disease, a common genetic variant in MACROD2 may increase susceptibility for thyroid-associated orbitopathy. (PMID:27304844)
• ATM induces MacroD2 nuclear export upon DNA damage. (PMID:28069995)
• Study identifies MACROD2 deletion as a cause of chromosome instability (CIN) in human colorectal cancer. MACROD2 loss causes repression of PARP1 activity, impairing DNA repair. MACROD2 haploinsufficiency promotes CIN and intestinal tumor growth. These results reveal MACROD2 as a major caretaker tumor suppressor gene in intestinal neoplasm. (PMID:29880585)
• A deletion of chromosome 20p12.1 involving the macrodomain containing 2/mono-ADP ribosylhydrolase 2 gene (MACROD2) was found in several members of the family with complex phenotypes, including microcephaly, intellectual disability, dysmorphic features, and polydactyly. This deletion may affect correct embryonic development. Associated epigenetic modifications at the MACROD2 locus, can influence the phenotype severity. (PMID:31055587)
• Comparative analysis of MACROD1, MACROD2 and TARG1 expression, localisation and interactome. (PMID:32427867)
• Human papilloma virus (HPV) integration signature in Cervical Cancer: identification of MACROD2 gene as HPV hot spot integration site. (PMID:33191407)
• Association of MACROD2 gene variants with obesity and physical activity in a Korean population. (PMID:33624934)
• Association of the MACROD2 rs6110695 A>G polymorphism with an increasing WBC count in a Korean population. (PMID:35759225)
• Human papillomavirus (HPV) integration signature in cervical lesions: identification of MACROD2 gene as HPV hot spot integration site. (PMID:36008642)
• Genome-Wide Meta-Analysis Identifies Multiple Novel Rare Variants to Predict Common Human Infectious Diseases Risk. (PMID:37108169)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	macrod2	ENSDARG00000032601
mus_musculus	Macrod2	ENSMUSG00000068205
rattus_norvegicus	Macrod2	ENSRNOG00000050784

Paralogs (2): MACROD1 (ENSG00000133315), GDAP2 (ENSG00000196505)

Protein

Protein identifiers

ADP-ribose glycohydrolase MACROD2 — A1Z1Q3 (reviewed: A1Z1Q3)

Alternative names: MACRO domain-containing protein 2, O-acetyl-ADP-ribose deacetylase MACROD2, [Protein ADP-ribosylaspartate] hydrolase MACROD2, [Protein ADP-ribosylglutamate] hydrolase MACROD2

All UniProt accessions (2): A0A2R8YFN3, A1Z1Q3

UniProt curated annotations — full annotation on UniProt →

Function. Removes ADP-ribose from aspartate and glutamate residues in proteins bearing a single ADP-ribose moiety. Inactive towards proteins bearing poly-ADP-ribose. Deacetylates O-acetyl-ADP ribose, a signaling molecule generated by the deacetylation of acetylated lysine residues in histones and other proteins.

Subunit / interactions. Interacts with ADP-ribosylated PARP1.

Subcellular location. Nucleus.

Activity regulation. Subject to product inhibition by ADP-ribose.

Similarity. Belongs to the MacroD-type family. MacroD1/2-like subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
A1Z1Q3-2	2	yes
A1Z1Q3-1	1
A1Z1Q3-4	4
A1Z1Q3-5	5
A1Z1Q3-6	6

RefSeq proteins (5): NP_001028259, NP_001338590, NP_001338592, NP_001338593, NP_542407 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002589	Macro_dom	Domain
IPR043472	Macro_dom-like	Homologous_superfamily

Pfam: PF01661

Enzyme classification (BRENDA):

• EC 3.1.1.106 — O-acetyl-ADP-ribose deacetylase (BRENDA: 7 organisms, 24 substrates, 11 inhibitors, 10 Km, 24 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
2’’-O-ACETYL-ADP-D-RIBOSE	0.37–2.74	5
O-ACETYL-ADP-D-RIBOSE	0.107–2	4
3’’-O-ACETYL-ADP-D-RIBOSE	0.0043	1

Catalyzed reactions (Rhea), 4 shown:

• 4-O-(ADP-D-ribosyl)-L-aspartyl-[protein] + H2O = L-aspartyl-[protein] + ADP-D-ribose + H(+) (RHEA:54428)
• 2’’-O-acetyl-ADP-D-ribose + H2O = ADP-D-ribose + acetate + H(+) (RHEA:57060)
• 5-O-(ADP-D-ribosyl)-L-glutamyl-[protein] + H2O = L-glutamyl-[protein] + ADP-D-ribose + H(+) (RHEA:58248)
• alpha-NAD(+) + H2O = ADP-D-ribose + nicotinamide + H(+) (RHEA:68792)

UniProt features (49 total): helix 13, strand 7, binding site 5, mutagenesis site 5, compositionally biased region 5, splice variant 4, turn 4, sequence variant 2, chain 1, domain 1, cross-link 1, region of interest 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4IQY	X-RAY DIFFRACTION	1.55
6Y73	X-RAY DIFFRACTION	1.7
6Y4Y	X-RAY DIFFRACTION	1.75
6Y4Z	X-RAY DIFFRACTION	1.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A1Z1Q3-F1	71.87	0.50

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 (5): 97–102; 185–191; 224; 77–79; 90–92

Post-translational modifications (1): 170

Mutagenesis-validated functional residues (5):

Position	Phenotype
92	reduced adp-ribosyl hydrolase activity; when associated with a-102.
100	abolished hydrolase activity and ability to bind adp-d-ribose.
102	reduced adp-ribosyl hydrolase activity. reduced adp-ribosyl hydrolase activity; when associated with a-92.
106	reduced hydrolase activity.
188	abolishes interaction with adp-ribosylated proteins. strongly reduced adp-ribosyl hydrolase activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 140 (showing top): TGCACTT_MIR519C_MIR519B_MIR519A, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GCAAGGA_MIR502, ACTGCAG_MIR173P, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, DAWSON_METHYLATED_IN_LYMPHOMA_TCL1, MCAATNNNNNGCG_UNKNOWN, GOBP_DNA_DAMAGE_RESPONSE, LIAO_METASTASIS, ATGCTGG_MIR338, GOBP_HEAD_DEVELOPMENT, PTF1BETA_Q6, GOBP_PURINE_CONTAINING_COMPOUND_METABOLIC_PROCESS

GO Biological Process (6): DNA damage response (GO:0006974), brain development (GO:0007420), response to bacterium (GO:0009617), purine nucleoside metabolic process (GO:0042278), protein de-ADP-ribosylation (GO:0051725), peptidyl-glutamate ADP-deribosylation (GO:0140291)

GO Molecular Function (5): hydrolase activity, acting on glycosyl bonds (GO:0016798), deacetylase activity (GO:0019213), O-acetyl-ADP-ribose deacetylase activity (GO:0061463), ADP-ribosylglutamate-[protein] hydrolase activity (GO:0140293), hydrolase activity (GO:0016787)

GO Cellular Component (3): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
nuclear lumen	2
cellular response to stress	1
central nervous system development	1
animal organ development	1
head development	1
response to other organism	1
nucleoside metabolic process	1
purine-containing compound metabolic process	1
protein modification process	1
protein de-ADP-ribosylation	1
hydrolase activity	1
deacylase activity	1
deacetylase activity	1
carboxylic ester hydrolase activity	1
hydrolase activity, hydrolyzing N-glycosyl compounds	1
catalytic activity, acting on a protein	1
catalytic activity	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

908 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MACROD2	FLRT3	Q9NZU0	959
MACROD2	OARD1	Q9Y530	811
MACROD2	ADPRS	Q9NX46	795
MACROD2	PARG	Q86W56	777
MACROD2	PARP10	Q53GL7	662
MACROD2	NUDT16	Q96DE0	610
MACROD2	FLRT1	Q9NZU1	587
MACROD2	FHIT	P49789	583
MACROD2	FLRT2	O43155	547
MACROD2	ART5	Q96L15	543
MACROD2	ADPRH	P54922	534
MACROD2	RBFOX1	Q9NWB1	527
MACROD2	PARP3	Q9Y6F1	521
MACROD2	TGFBR1	P36897	510
MACROD2	WWOX	Q9NZC7	507
MACROD2	CDH9	Q9ULB4	507

IntAct

10 interactions, top by confidence:

A	B	Type	Score
	MACROD2	psi-mi:“MI:0407”(direct interaction)	0.560
MACROD2	PARP10	psi-mi:“MI:1310”(de-ADP-ribosylation reaction)	0.440
MACROD2	HSPA5	psi-mi:“MI:0915”(physical association)	0.400
MACROD2	HSPA12A	psi-mi:“MI:0915”(physical association)	0.400
EZR	MACROD2	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (8): MACROD2 (Affinity Capture-MS), MACROD2 (Affinity Capture-RNA), HSPA5 (Proximity Label-MS), HSPA12A (Affinity Capture-MS), SUFU (Co-fractionation), MACROD2 (Affinity Capture-RNA), MACROD2 (Affinity Capture-MS), MACROD2 (Affinity Capture-MS)

ESM2 similar proteins: A1Z1Q3, A2VCV0, A6QP06, B6D5P1, B6F1W5, B8QB46, E1BB03, E1C2V1, E7F7X0, F4JQ51, F8VPQ2, O08815, O15013, O54988, O55092, O70551, O88622, Q24JK4, Q3UYG8, Q5FWF4, Q5RD27, Q5TKR9, Q5U3N0, Q6DFV7, Q6GQJ2, Q6IE82, Q6IVY4, Q6JP77, Q6NZP1, Q6PAV8, Q71M44, Q86VD1, Q86W56, Q8BMD7, Q8BZ21, Q8K3E5, Q8NI08, Q8WML3, Q92613, Q92794

Diamond homologs: A0A166ACJ5, A0A559KX76, A1Z1Q3, A4W960, A7MG20, A7T167, A8AI35, B4T2X8, B5F961, B5RBF3, B5XXK9, B7LT90, C9Y0V8, D2TT52, D3RKJ0, D5CE05, E1PL40, E1SDF1, O28751, O59182, P0A8D6, P0A8D7, P0A8D8, P0DC28, P0DC29, P0DN70, P67341, P67342, P67343, P67344, Q0T5Z6, Q292F9, Q2KHU5, Q2KIX2, Q32E73, Q3UYG8, Q44020, Q4J9D2, Q5CZL1, Q5HIW9

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
MACROD2	“down-regulates quantity”	2’’-O-acetyl-ADP-D-ribose(2-)	“chemical modification”
MACROD2	“up-regulates quantity”	ADP-D-ribose(2-)	“chemical modification”
MACROD2	“up-regulates quantity”	acetate	“chemical modification”
ATM	“down-regulates activity”	MACROD2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	63
Likely benign	19
Benign	16

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
545230	NC_000020.11:g.(?14631584)(14707775_?)del	Likely pathogenic
545232	NC_000020.11:g.(?15307783)(15453889_?)del	Likely pathogenic

SpliceAI

4934 predictions. Top by Δscore:

Variant	Effect	Δscore
20:14000596:C:G	acceptor_gain	1.0000
20:14000597:ATCGT:A	acceptor_gain	1.0000
20:14002282:T:TA	acceptor_gain	1.0000
20:14002285:A:AG	acceptor_gain	1.0000
20:14002286:A:G	acceptor_gain	1.0000
20:14002287:GAAC:G	acceptor_gain	1.0000
20:14002401:GATG:G	donor_gain	1.0000
20:14002404:GGTA:G	donor_loss	1.0000
20:14002405:G:GG	donor_gain	1.0000
20:14002406:TAAGT:T	donor_loss	1.0000
20:14085619:A:AG	acceptor_gain	1.0000
20:14085620:G:GA	acceptor_gain	1.0000
20:14085620:GA:G	acceptor_gain	1.0000
20:14085620:GAA:G	acceptor_gain	1.0000
20:14085620:GAAGA:G	acceptor_gain	1.0000
20:14208110:GAAGA:G	donor_gain	1.0000
20:14208113:GA:G	donor_gain	1.0000
20:14327556:ACCC:A	acceptor_loss	1.0000
20:14000595:A:AG	acceptor_gain	0.9900
20:14000597:A:AG	acceptor_gain	0.9900
20:14000598:T:G	acceptor_gain	0.9900
20:14002279:T:G	acceptor_gain	0.9900
20:14002283:GCAA:G	acceptor_loss	0.9900
20:14002284:CAA:C	acceptor_loss	0.9900
20:14002285:AAG:A	acceptor_loss	0.9900
20:14002286:A:AC	acceptor_loss	0.9900
20:14002287:G:GG	acceptor_gain	0.9900
20:14002287:GA:G	acceptor_gain	0.9900
20:14048262:G:T	donor_gain	0.9900
20:14085615:TTACA:T	acceptor_loss	0.9900

AlphaMissense

3001 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:14085689:G:C	D78H	1.000
20:14085702:T:C	L82P	1.000
20:14085713:G:C	A86P	1.000
20:14085714:C:A	A86D	1.000
20:14085717:T:A	I87K	1.000
20:14085717:T:G	I87R	1.000
20:14085720:T:A	V88D	1.000
20:14085722:A:G	N89D	1.000
20:14085724:T:A	N89K	1.000
20:14085724:T:G	N89K	1.000
20:14085726:C:A	A90D	1.000
20:14493479:C:A	A91E	1.000
20:14493491:T:A	L95H	1.000
20:14493491:T:C	L95P	1.000
20:14493494:T:C	L96P	1.000
20:14493496:G:A	G97R	1.000
20:14493496:G:C	G97R	1.000
20:14493497:G:A	G97E	1.000
20:14493500:G:A	G98E	1.000
20:14493503:G:A	G99E	1.000
20:14493505:G:C	G100R	1.000
20:14493506:G:A	G100D	1.000
20:14684845:G:A	D102N	1.000
20:14684845:G:C	D102H	1.000
20:14684845:G:T	D102Y	1.000
20:14684846:A:C	D102A	1.000
20:14684846:A:G	D102G	1.000
20:14684846:A:T	D102V	1.000
20:14684847:T:A	D102E	1.000
20:14684847:T:G	D102E	1.000

dbSNP variants (sampled 300 via entrez): RS1000000114 (20:14766673 A>G), RS1000000589 (20:15966287 C>T), RS1000001109 (20:15966261 A>C,G), RS1000001702 (20:16005501 C>A,T), RS1000002224 (20:15886535 T>C), RS1000004892 (20:14940494 G>A,C), RS1000007193 (20:14131740 T>G), RS1000008036 (20:14032046 C>T), RS1000008751 (20:14057930 T>G), RS1000011614 (20:15578236 A>G), RS1000013544 (20:14263959 A>G), RS1000014779 (20:15631284 C>T), RS1000016106 (20:15131166 C>G), RS1000019319 (20:14366324 A>G,T), RS1000020943 (20:14454398 T>A)

Disease associations

OMIM: gene MIM:611567 | disease phenotypes: MIM:615271, MIM:181500, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
syndromic disease	Limited	Autosomal dominant

Mondo (5): hypogonadotropic hypogonadism 21 with or without anosmia (MONDO:0014107), autism spectrum disorder (MONDO:0005258), schizophrenia (MONDO:0005090), autism (MONDO:0005260), syndromic disease (MONDO:0002254)

Orphanet (3): Kallmann syndrome (Orphanet:478), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0100753	Schizophrenia
HP:0000717	Autism

GWAS associations

50 associations (top):

Study	Trait	p-value
GCST000426_8	Obesity (extreme)	5.000000e-06
GCST000740_1	Autism	4.000000e-08
GCST000765_12	Non-alcoholic fatty liver disease histology (other)	7.000000e-06
GCST001540_6	Male fertility	9.000000e-06
GCST001762_878	Obesity-related traits	8.000000e-06
GCST001872_9	Presence of antiphospholipid antibodies	7.000000e-06
GCST001889_2	Brain connectivity	1.000000e-10
GCST001889_8	Brain connectivity	2.000000e-09
GCST001960_1	Eating disorders	4.000000e-06
GCST002337_168	Amyotrophic lateral sclerosis (sporadic)	8.000000e-06
GCST002783_234	Body mass index	4.000000e-07
GCST002783_415	Body mass index	4.000000e-07
GCST002817_29	Alzheimer’s disease in APOE e4- carriers	3.000000e-06
GCST002942_7	Percentage gas trapping	3.000000e-07
GCST003151_4	White matter lesion progression	4.000000e-06
GCST003457_1	Soluble receptor for advanced glycation end-product levels	8.000000e-06
GCST003560_17	Coronary artery aneurysm in Kawasaki disease	6.000000e-06
GCST003563_3	Presence of antiphospholipid antibodies	2.000000e-09
GCST003563_4	Presence of antiphospholipid antibodies	3.000000e-09
GCST003640_1	Thyroid-associated orbitopathy in graves’ disease	7.000000e-06
GCST004735_13	Epstein-Barr virus copy number in lymphoblastoid cell lines	2.000000e-08
GCST005184_2	Common carotid intima-media thickness in HIV infection	1.000000e-06
GCST005316_238	Intelligence (MTAG)	4.000000e-08
GCST005756_7	Dimensional psychopathology (Negative)	2.000000e-06
GCST005757_6	Dimensional psychopathology (Positive)	2.000000e-06
GCST005795_10	Femoral neck bone mineral density	3.000000e-08
GCST006269_1079	General cognitive ability	3.000000e-11
GCST006269_1097	General cognitive ability	6.000000e-11
GCST007325_31	General risk tolerance (MTAG)	4.000000e-08
GCST007556_19	Autism spectrum disorder	4.000000e-08

EFO canonical traits (24, from GWAS)

EFO ID	Trait name
EFO:0004802	family size
EFO:0004803	male fertility
EFO:0004627	IGF-1 measurement
EFO:0004340	body mass index
EFO:0007628	gas trapping measurement
EFO:0007746	white matter lesion progression measurement
EFO:0007819	advanced glycation end-product measurement
EFO:1001466	Graves ophthalmopathy
EFO:0004337	intelligence
EFO:0009096	negative domain measurement
EFO:0009097	positive domain measurement
EFO:0007785	femoral neck bone mineral density
EFO:0008579	risk-taking behaviour
EFO:0008328	chronotype measurement
EFO:0004338	body weight
EFO:0007789	BMI-adjusted waist circumference
EFO:0005670	smoking initiation
EFO:0006797	neurofibrillary tangles measurement
EFO:0004847	age at onset
EFO:0008361	environmental tobacco smoke exposure measurement
EFO:0010429	triacylglycerol 56:2 measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0009749	age at first sexual intercourse measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D013577	Syndrome	C23.550.288.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295630 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs76026520	MACROD2		0.00	0

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
6.82	Kd	150	nM	CHEMBL4226903

PubChem BioAssay actives

1 with measured affinity, of 6 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
[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-3,4-dihydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2S,3R,4S,5S)-3,4,5-trihydroxyoxolan-2-yl]methyl hydrogen phosphate	1390099: Binding affinity to human MDO2 by ITC	kd	0.1500	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	increases methylation, affects expression, decreases expression, decreases methylation	6
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	5
Valproic Acid	decreases methylation, increases expression, affects cotreatment, decreases expression, affects expression	5
trichostatin A	affects cotreatment, decreases expression	3
methyleugenol	decreases expression	2
entinostat	affects cotreatment, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
N-Nitrosopyrrolidine	decreases expression	2
Nickel	decreases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
methylmercuric chloride	decreases expression	1
lasiocarpine	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
bisphenol A	affects cotreatment, affects methylation	1
butyraldehyde	decreases expression	1
aflatoxin B2	decreases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects cotreatment, increases methylation	1
Sunitinib	increases expression	1
Fulvestrant	affects cotreatment, affects methylation, increases methylation	1
Acetaminophen	affects expression	1
Amiodarone	increases expression	1
Diacetyl	decreases expression	1
Chlordecone	affects response to substance	1
Malathion	decreases expression	1
Phthalic Acids	increases methylation	1
Silicon Dioxide	decreases expression	1

ChEMBL screening assays

4 unique, capped per target: 2 binding, 2 toxicity

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4221662	Binding	Binding affinity to human MDO2 by ITC	Adenosine analogs bearing phosphate isosteres as human MDO1 ligands. — Bioorg Med Chem
CHEMBL5128980	Toxicity	Inhibition of N-terminal His-TEV-V5 tagged human Mdo2 (7 to 243 residues) expressed in Escherichia coli BL21 (DE3) using BIO-6His tagged linker peptide as substrate by Alphascreen assay	Design, synthesis and evaluation of inhibitors of the SARS-CoV-2 nsp3 macrodomain. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder