ADPRS

Summary

ADPRS (ADP-ribosylserine hydrolase, HGNC:21304) is a protein-coding gene on chromosome 1p34.3, encoding ADP-ribosylhydrolase ARH3 (Q9NX46). ADP-ribosylhydrolase that preferentially hydrolyzes the scissile alpha-O-linkage attached to the anomeric C1’’ position of ADP-ribose and acts on different substrates, such as proteins ADP-ribosylated on serine and threonine, free poly(ADP-ribose) and O-acetyl-ADP-D-ribose.

This gene encodes a member of the ADP-ribosylglycohydrolase family. The encoded enzyme catalyzes the removal of ADP-ribose from ADP-ribosylated proteins. This enzyme localizes to the mitochondria, in addition to the nucleus and cytoplasm.

Source: NCBI Gene 54936 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures (Strong, GenCC)
• Clinical variants (ClinVar): 115 total — 10 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 29
• Druggable target: yes
• MANE Select transcript: NM_017825

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21304
Approved symbol	ADPRS
Name	ADP-ribosylserine hydrolase
Location	1p34.3
Locus type	gene with protein product
Status	Approved
Aliases	ARH3, FLJ20446
Ensembl gene	ENSG00000116863
Ensembl biotype	protein_coding
OMIM	610624
Entrez	54936

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000373178, ENST00000896939, ENST00000896940, ENST00000896941, ENST00000932449, ENST00000959573, ENST00000959574

RefSeq mRNA: 1 — MANE Select: NM_017825 NM_017825

CCDS: CCDS402

Canonical transcript exons

ENST00000373178 — 6 exons

Exon	Start	End
ENSE00000766217	36091244	36091340
ENSE00000766220	36092422	36092522
ENSE00000861244	36093097	36093932
ENSE00001399758	36088892	36089115
ENSE00003398258	36091910	36092094
ENSE00003398800	36091618	36091825

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 98.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.9898 / max 205.5660, expressed in 1815 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
2147	17.9898	1815

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oviduct epithelium	UBERON:0004804	98.22	gold quality
right uterine tube	UBERON:0001302	97.79	gold quality
endothelial cell	CL:0000115	97.78	silver quality
gingival epithelium	UBERON:0001949	95.26	gold quality
esophagus squamous epithelium	UBERON:0006920	94.64	gold quality
middle temporal gyrus	UBERON:0002771	94.44	gold quality
gingiva	UBERON:0001828	93.59	gold quality
bronchial epithelial cell	CL:0002328	93.58	gold quality
bronchus	UBERON:0002185	93.19	gold quality
sperm	CL:0000019	93.05	gold quality
Brodmann (1909) area 23	UBERON:0013554	92.83	gold quality
nasal cavity epithelium	UBERON:0005384	92.64	gold quality
epithelial cell of pancreas	CL:0000083	92.48	silver quality
pancreatic ductal cell	CL:0002079	92.02	silver quality
fallopian tube	UBERON:0003889	91.88	gold quality
lower esophagus mucosa	UBERON:0035834	91.76	gold quality
right adrenal gland	UBERON:0001233	91.66	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.66	gold quality
right adrenal gland cortex	UBERON:0035827	91.46	gold quality
left adrenal gland	UBERON:0001234	91.38	gold quality
ventricular zone	UBERON:0003053	91.16	gold quality
apex of heart	UBERON:0002098	91.07	gold quality
left adrenal gland cortex	UBERON:0035825	91.05	gold quality
medial globus pallidus	UBERON:0002477	90.96	gold quality
adrenal cortex	UBERON:0001235	90.85	gold quality
esophagus mucosa	UBERON:0002469	90.62	gold quality
amniotic fluid	UBERON:0000173	90.45	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.30	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.29	gold quality
epithelium of nasopharynx	UBERON:0001951	90.16	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.75
E-MTAB-6379	no	97.53

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

17 targeting ADPRS, 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-137-3P	99.87	74.74	2401
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-548G-3P	99.48	68.67	2159
HSA-MIR-548AS-3P	99.12	69.12	2294
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-1207-3P	98.99	66.22	1532
HSA-MIR-6754-5P	98.60	65.54	1627
HSA-MIR-6878-5P	98.49	67.91	2142
HSA-MIR-892B	98.00	67.11	821
HSA-MIR-6810-3P	97.96	64.57	1023
HSA-MIR-6736-3P	96.98	65.22	1342
HSA-MIR-6874-5P	95.73	64.94	545

Literature-anchored findings (GeneRIF, showing 17)

• ARH3 has poly(ADP-ribose) glycohydrolase activity but is structurally unrelated to poly(ADP-ribose) glycohydrolase (PMID:16278211)
• cloning, recombinant production, purification and crystallization of ARH3 consisting of 347 amino-acid residues (PMID:16511307)
• The molecular architecture of human ARH3 constitutes the archetype of an all-alpha-helical protein fold and suggests reversibility mechanisms of protein ADP-ribosylation. (PMID:17015823)
• poly(ADP-ribose) glycohydrolase ARH3 hydrolyzed O-acetyl-ADP-ribose to produce ADP-ribose in a time- and Mg(2+)-dependent reaction and thus could participate in two signaling pathways (PMID:17075046)
• ADP-ribosylhydrolase 3 (ARH3), not poly(ADP-ribose) glycohydrolase (PARG) isoforms, is responsible for degradation of mitochondrial matrix-associated poly(ADP-ribose). (PMID:22433848)
• By screening for the hydrolase that is responsible for the reversal of Ser-ADP ribosilation, the authors identified ARH3/ADPRHL2 as capable of efficiently and specifically removing Ser-ADP ribosilation of histones and other proteins. (PMID:28650317)
• Study results establish ARH3 as a serine mono-ADP-ribosylhydrolase and as an important regulator of the basal and stress-induced ADP-ribosylome. (PMID:29234005)
• Here, the authors show that serine ADP-ribosylation represents the major fraction of ADP-ribosylation synthesized after DNA damage in mammalian cells and that globally serine ADP-ribosylation is dependent on HPF1, PARP1 and ARH3. In the absence of HPF1, glutamate/aspartate becomes the main target residues for ADP-ribosylation. (PMID:29480802)
• study provides structural and functional insights into the molecular mechanism by which ARH3 hydrolyzes the ADP-ribosyl group from serine and contributes to DNA damage repair (PMID:30045870)
• ADPRHL2 was virtually absent in available affected individuals’ fibroblasts. (PMID:30401461)
• Study identified a family with an ARH3 gene mutation that resulted in a truncated, inactive protein. The 8-year-old proband exhibited a progressive neurodegeneration phenotype. Parthanatos was observed in neurons of the patient’s deceased sibling, and an older sibling exhibited a mild behavioral phenotype. Patient’s fibroblasts were more sensitive to H2O2 stress-induced poly(ADP-ribose) accumulation and cell death. (PMID:30830864)
• Pathogenic ARH3 mutations result in ADP-ribose chromatin scars during DNA strand break repair. (PMID:32636369)
• AI26 inhibits the ADP-ribosylhydrolase ARH3 and suppresses DNA damage repair. (PMID:32753484)
• Structural and biochemical analysis of human ADP-ribosyl-acceptor hydrolase 3 reveals the basis of metal selectivity and different roles for the two magnesium ions. (PMID:33894202)
• Unrestrained poly-ADP-ribosylation provides insights into chromatin regulation and human disease. (PMID:34019811)
• The regulatory landscape of the human HPF1- and ARH3-dependent ADP-ribosylome. (PMID:34625544)
• Delineation of ADPRHL2 Variants: Report of Two New Patients with Review of the Literature. (PMID:38365196)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	adprs	ENSDARG00000019338
mus_musculus	Adprs	ENSMUSG00000042558
rattus_norvegicus	Adprs	ENSRNOG00000010849

Protein

Protein identifiers

ADP-ribosylhydrolase ARH3 — Q9NX46 (reviewed: Q9NX46)

Alternative names: ADP-ribose glycohydrolase ARH3, ADP-ribosylhydrolase 3, O-acetyl-ADP-ribose deacetylase ARH3, Poly(ADP-ribose) glycohydrolase ARH3, [Protein ADP-ribosylarginine] hydrolase-like protein 2, [Protein ADP-ribosylserine] hydrolase

All UniProt accessions (1): Q9NX46

UniProt curated annotations — full annotation on UniProt →

Function. ADP-ribosylhydrolase that preferentially hydrolyzes the scissile alpha-O-linkage attached to the anomeric C1’’ position of ADP-ribose and acts on different substrates, such as proteins ADP-ribosylated on serine and threonine, free poly(ADP-ribose) and O-acetyl-ADP-D-ribose. Specifically acts as a serine mono-ADP-ribosylhydrolase by mediating the removal of mono-ADP-ribose attached to serine residues on proteins, thereby playing a key role in DNA damage response. Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage. Does not hydrolyze ADP-ribosyl-arginine, -cysteine, -diphthamide, or -asparagine bonds. Also able to degrade protein free poly(ADP-ribose), which is synthesized in response to DNA damage: free poly(ADP-ribose) acts as a potent cell death signal and its degradation by ADPRHL2 protects cells from poly(ADP-ribose)-dependent cell death, a process named parthanatos. Also hydrolyzes free poly(ADP-ribose) in mitochondria. Specifically digests O-acetyl-ADP-D-ribose, a product of deacetylation reactions catalyzed by sirtuins. Specifically degrades 1’’-O-acetyl-ADP-D-ribose isomer, rather than 2’’-O-acetyl-ADP-D-ribose or 3’’-O-acetyl-ADP-D-ribose isomers.

Subunit / interactions. Monomer.

Subcellular location. Nucleus. Cytoplasm. Chromosome. Mitochondrion matrix.

Tissue specificity. Ubiquitous. Expressed in skin fibroblasts.

Disease relevance. Neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures (CONDSIAS) [MIM:618170] An autosomal recessive neurodegenerative disorder characterized by pediatric onset of progressive brain atrophy, developmental regression, and seizures in association with periods of stress, such as infections. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The protein undergoes a dramatic conformational switch from closed to open states upon substrate-binding, which enables specific substrate recognition for the 1’’-O-linkage. The glutamate flap (Glu-41) blocks substrate entrance to Mg(2+) in the unliganded closed state. In presence of substrate, Glu-41 is ejected from the active site: this closed-to-open transition significantly widens the substrate-binding channel and precisely positions the scissile 1’’-O-linkage for cleavage while securing tightly 2’- and 3’-hydroxyls of ADP-ribose.

Cofactor. Binds 2 magnesium ions per subunit.

Similarity. Belongs to the ADP-ribosylglycohydrolase family.

RefSeq proteins (1): NP_060295* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005502	Ribosyl_crysJ1	Family
IPR036705	Ribosyl_crysJ1_sf	Homologous_superfamily
IPR050792	ADP-ribosylglycohydrolase	Family

Pfam: PF03747

Enzyme classification (BRENDA):

• EC 3.2.1.143 — poly(ADP-ribose) glycohydrolase (BRENDA: 15 organisms, 83 substrates, 316 inhibitors, 21 Km, 4 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
(ADP-RIBOSE)N	0.0006–0.0066	10
POLY(ADP-RIBOSE)	0.0003–0.0111	7
(ADP-D-RIBOSE)15	0.0054–0.0058	2
ALPHA-NAD+	0.0006	1

Catalyzed reactions (Rhea), 4 shown:

• (1’’->2’)-ADP-alpha-D-ribose + H2O = (1’’->2’)-ADP-alpha-D-ribose + ADP-D-ribose (RHEA:52216)
• 1’’-O-acetyl-ADP-alpha-D-ribose + H2O = ADP-D-ribose + acetate + H(+) (RHEA:58112)
• O-(ADP-D-ribosyl)-L-seryl-[protein] + H2O = ADP-D-ribose + L-seryl-[protein] (RHEA:58256)
• alpha-NAD(+) + H2O = ADP-D-ribose + nicotinamide + H(+) (RHEA:68792)

UniProt features (82 total): mutagenesis site 28, helix 22, binding site 14, sequence variant 10, strand 3, chain 1, site 1, modified residue 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
7ARW	X-RAY DIFFRACTION	1.31
5ZQY	X-RAY DIFFRACTION	1.58
2FOZ	X-RAY DIFFRACTION	1.6
6D3A	X-RAY DIFFRACTION	1.6
6D36	X-RAY DIFFRACTION	1.7
7L9F	X-RAY DIFFRACTION	1.75
7L9I	X-RAY DIFFRACTION	1.8
2G4K	X-RAY DIFFRACTION	1.82
7L9H	X-RAY DIFFRACTION	1.85
9RFD	X-RAY DIFFRACTION	1.85
9RFE	X-RAY DIFFRACTION	1.85
7AKS	X-RAY DIFFRACTION	1.86
7AKR	X-RAY DIFFRACTION	1.95
2FP0	X-RAY DIFFRACTION	2.05

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NX46-F1	95.70	0.95

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 41 (glutamate flap)

Ligand- & substrate-binding residues (14): 41; 271; 314; 316; 316; 317; 76; 77; 77; 78; 78; 146–152 …

Post-translational modifications (1): 64

Mutagenesis-validated functional residues (28):

Position	Phenotype
34	reduces hydrolase activity.
41	significant loss of activity. does not affect recruitment to dna lesion regions following dna damage. strongly reduced a
76	abolishes hydrolase activity.
77–78	retains ability to bind proteins adp-ribosylated on serine but is unable to hydrolyze them.
77–78	complete loss of activity.
77	complete loss of activity. abolishes mg(2+) binding. retains ability to bind adp-ribose. does not affect recruitment to
78	abolishes hydrolase activity.
78	complete loss of activity.
115	abolished ability to bind and hydrolyze proteins adp-ribosylated on serine. no effect on hydrolase activity.
143	abolishes hydrolase activity.
148	complete loss of activity. abolished recruitment to dna lesion regions following dna damage. abolished ability to hydrol
149	significant loss of activity. abolished recruitment to dna lesion regions following dna damage. abolished ability to hyd
149	no effect on hydrolase activity.
150	reduces hydrolase activity.
151	partial loss of activity.
182	complete loss of activity. abolished recruitment to dna lesion regions following dna damage. abolished ability to hydrol
185	no effect on hydrolase activity.
186	no effect on hydrolase activity.
238–239	slight reduction in activity toward poly(adp-ribose). does not affect ability to degrade o-acetyl-adp-d-ribose.
261–262	slight reduction in activity toward poly(adp-ribose). does not affect ability to degrade o-acetyl-adp-d-ribose.
269	no effect on hydrolase activity.
270	no effect on hydrolase activity.
271	no effect on hydrolase activity.
314	complete loss of activity. abolishes mg(2+) and adp-ribose binding. does not affect recruitment to dna lesion regions fo
314	significant loss of activity.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-110362	POLB-Dependent Long Patch Base Excision Repair
R-HSA-110373	Resolution of AP sites via the multiple-nucleotide patch replacement pathway
R-HSA-73884	Base Excision Repair
R-HSA-73894	DNA Repair
R-HSA-73933	Resolution of Abasic Sites (AP sites)

MSigDB gene sets: 157 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, chr1p34, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_DNA_DAMAGE_RESPONSE, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, GCM_NF2, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_RADICAL, REACTOME_DNA_REPAIR, GOBP_RESPONSE_TO_OXYGEN_RADICAL, GOBP_CELLULAR_RESPONSE_TO_REACTIVE_OXYGEN_SPECIES, GOBP_RESPONSE_TO_REACTIVE_OXYGEN_SPECIES, GOCC_MITOCHONDRIAL_MATRIX, GOBP_DNA_METABOLIC_PROCESS, GOMF_MAGNESIUM_ION_BINDING

GO Biological Process (6): DNA repair (GO:0006281), base-excision repair, gap-filling (GO:0006287), negative regulation of necroptotic process (GO:0060546), cellular response to superoxide (GO:0071451), peptidyl-serine ADP-deribosylation (GO:0140290), DNA damage response (GO:0006974)

GO Molecular Function (8): magnesium ion binding (GO:0000287), hydrolase activity, hydrolyzing O-glycosyl compounds (GO:0004553), poly(ADP-ribose) glycohydrolase activity (GO:0004649), O-acetyl-ADP-ribose deacetylase activity (GO:0061463), ADP-ribosylserine-[protein] hydrolase activity (GO:0140292), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), nuclear body (GO:0016604), site of DNA damage (GO:0090734), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Resolution of AP sites via the multiple-nucleotide patch replacement pathway	1
Resolution of Abasic Sites (AP sites)	1
DNA Repair	1
Base Excision Repair	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
DNA metabolic process	2
intracellular membrane-bounded organelle	2
intracellular membraneless organelle	2
DNA damage response	1
base-excision repair	1
regulation of necroptotic process	1
negative regulation of programmed necrotic cell death	1
necroptotic process	1
response to superoxide	1
cellular response to oxygen radical	1
protein de-ADP-ribosylation	1
cellular response to stress	1
metal ion binding	1
hydrolase activity, acting on glycosyl bonds	1
hydrolase activity, hydrolyzing O-glycosyl compounds	1
deacetylase activity	1
carboxylic ester hydrolase activity	1
hydrolase activity, hydrolyzing N-glycosyl compounds	1
catalytic activity, acting on a protein	1
binding	1
catalytic activity	1
cation binding	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
mitochondrion	1
intracellular organelle lumen	1
nucleoplasm	1
chromosome	1

Protein interactions and networks

STRING

510 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADPRS	PARG	Q86W56	874
ADPRS	PARP1	P09874	869
ADPRS	MACROD1	Q9BQ69	834
ADPRS	MACROD2	A1Z1Q3	795
ADPRS	OARD1	Q9Y530	773
ADPRS	HPF1	Q9NWY4	720
ADPRS	NUDT16	Q96DE0	695
ADPRS	PARP2	Q9UGN5	669
ADPRS	ADPRH	P54922	668
ADPRS	PARP10	Q53GL7	656
ADPRS	PARP15	Q460N3	622
ADPRS	TRPT1	Q86TN4	619
ADPRS	PARP3	Q9Y6F1	593
ADPRS	PARP14	Q460N5	574
ADPRS	NUDT5	Q9UKK9	570

IntAct

33 interactions, top by confidence:

A	B	Type	Score
LARP4B	RACK1	psi-mi:“MI:0914”(association)	0.880
LIN37	MYBL2	psi-mi:“MI:0914”(association)	0.730
TNKS	ADPRS	psi-mi:“MI:0915”(physical association)	0.560
PRDM5	ADPRS	psi-mi:“MI:0915”(physical association)	0.560
CRP	QSOX1	psi-mi:“MI:0914”(association)	0.530
ISG15	ADPRS	psi-mi:“MI:0915”(physical association)	0.400
HSPB1	ADPRS	psi-mi:“MI:0915”(physical association)	0.370
PRNP	CARNS1	psi-mi:“MI:0914”(association)	0.350
FRMD6		psi-mi:“MI:0914”(association)	0.350
RIN3		psi-mi:“MI:0914”(association)	0.350
rep	TMEM120B	psi-mi:“MI:0914”(association)	0.350
NEUROD4	POTEF	psi-mi:“MI:0914”(association)	0.350
RAD54L2	DYRK1A	psi-mi:“MI:0914”(association)	0.350
BCAS2	ISY1-RAB43	psi-mi:“MI:0914”(association)	0.350
C10orf53	NIF3L1	psi-mi:“MI:0914”(association)	0.350
CIB2	RIPK2	psi-mi:“MI:0914”(association)	0.350
GAB2	UBA6	psi-mi:“MI:0914”(association)	0.350
GMFB	RIPK2	psi-mi:“MI:0914”(association)	0.350
HBB	HNRNPH2	psi-mi:“MI:0914”(association)	0.350
SMPD2	A2ML1	psi-mi:“MI:0914”(association)	0.350
USP46	UBA6	psi-mi:“MI:0914”(association)	0.350
VENTX	UBA6	psi-mi:“MI:0914”(association)	0.350
RBM15	ILVBL	psi-mi:“MI:2364”(proximity)	0.270
UTP3	NACA	psi-mi:“MI:2364”(proximity)	0.270
YWHAG	RPSA2	psi-mi:“MI:2364”(proximity)	0.270
ZC3H11A	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
ADPRS	TNKS	psi-mi:“MI:0915”(physical association)	0.000
ADPRS	PRDM5	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (37): ADPRHL2 (Affinity Capture-MS), ADPRHL2 (Affinity Capture-MS), ADPRHL2 (Two-hybrid), ADPRHL2 (Co-fractionation), ADPRHL2 (Co-fractionation), ADPRHL2 (Co-fractionation), IMPDH2 (Co-fractionation), PCID2 (Co-fractionation), ADPRHL2 (Affinity Capture-RNA), ADPRHL2 (Affinity Capture-MS), ADPRHL2 (Co-fractionation), ADPRHL2 (Co-fractionation), ADPRHL2 (Co-fractionation), ADPRHL2 (Co-fractionation), ADPRHL2 (Co-fractionation)

ESM2 similar proteins: A0A168WVR6, A0A1D6NER6, A0FKE6, A8GG79, B0KTG8, C8YTM5, H3BCW1, O50046, O82399, P14300, P14671, P16638, P25269, P32232, P35520, P40821, P49915, P53396, P53602, P54923, P76418, Q02589, Q03442, Q03443, Q28FQ6, Q32PF2, Q3SYV9, Q3THK7, Q42972, Q43743, Q4V7C6, Q54H71, Q5R5P3, Q5RA96, Q5U403, Q5ZI51, Q66HT8, Q6JQN1, Q8BH55, Q8CG72

Diamond homologs: H3BCW1, Q28FQ6, Q3SYV9, Q5ZI51, Q66HT8, Q8CG72, Q9NX46, A0A168WVR6, A8GG79, B0KTG8, P14300

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	9
Uncertain significance	74
Likely benign	11
Benign	1

Top pathogenic / likely-pathogenic (19)

Variant ID	HGVS	Classification
1339799	NM_017825.3(ADPRS):c.340_341del (p.Arg114fs)	Pathogenic
1808707	GRCh37/hg19 1p34.3(chr1:35104233-37357913)x1	Pathogenic
2572385	NM_017825.3(ADPRS):c.146del (p.Thr49fs)	Pathogenic
395434	GRCh37/hg19 1p34.3(chr1:34830287-36945093)x1	Pathogenic
4819230	NM_017825.3(ADPRS):c.640C>T (p.Gln214Ter)	Pathogenic
4819231	NM_017825.3(ADPRS):c.726C>A (p.Tyr242Ter)	Pathogenic
590298	NM_017825.3(ADPRS):c.1000C>T (p.Gln334Ter)	Pathogenic
590301	NM_017825.3(ADPRS):c.414_418del (p.Ala139fs)	Pathogenic
590303	NM_017825.3(ADPRS):c.100G>A (p.Asp34Asn)	Pathogenic
852549	NM_017825.3(ADPRS):c.416_426del (p.Ala139fs)	Pathogenic
149964	GRCh38/hg38 1p34.3(chr1:35934217-36821999)x4	Likely pathogenic
1679337	NM_017825.3(ADPRS):c.564C>A (p.Tyr188Ter)	Likely pathogenic
2583170	NM_017825.3(ADPRS):c.166C>T (p.Gln56Ter)	Likely pathogenic
2687771	NM_017825.3(ADPRS):c.545A>G (p.His182Arg)	Likely pathogenic
590299	NM_017825.3(ADPRS):c.316C>T (p.Gln106Ter)	Likely pathogenic
590302	NM_017825.3(ADPRS):c.530C>T (p.Ser177Leu)	Likely pathogenic
599344	NM_017825.3(ADPRS):c.292del (p.Val98fs)	Likely pathogenic
801466	NM_017825.3(ADPRS):c.485T>C (p.Leu162Pro)	Likely pathogenic
804377	NM_017825.3(ADPRS):c.169_170del (p.Leu58fs)	Likely pathogenic

SpliceAI

1116 predictions. Top by Δscore:

Variant	Effect	Δscore
1:36089068:TCCA:T	donor_gain	1.0000
1:36089104:G:GG	donor_gain	1.0000
1:36091238:CCACA:C	acceptor_loss	1.0000
1:36091239:CACA:C	acceptor_loss	1.0000
1:36091240:ACAGA:A	acceptor_loss	1.0000
1:36091242:A:AG	acceptor_gain	1.0000
1:36091242:AGA:A	acceptor_loss	1.0000
1:36091243:G:GA	acceptor_gain	1.0000
1:36091243:GA:G	acceptor_gain	1.0000
1:36091243:GAA:G	acceptor_gain	1.0000
1:36091243:GAAGC:G	acceptor_gain	1.0000
1:36091608:T:TA	acceptor_gain	1.0000
1:36091616:A:AG	acceptor_gain	1.0000
1:36091617:G:GT	acceptor_gain	1.0000
1:36091617:GA:G	acceptor_gain	1.0000
1:36091617:GAT:G	acceptor_gain	1.0000
1:36091617:GATT:G	acceptor_gain	1.0000
1:36091617:GATTT:G	acceptor_gain	1.0000
1:36091745:A:T	donor_gain	1.0000
1:36091749:GCTCC:G	donor_gain	1.0000
1:36091764:G:GT	donor_gain	1.0000
1:36091814:G:GT	donor_gain	1.0000
1:36091821:AGAAG:A	donor_loss	1.0000
1:36091822:GAAG:G	donor_gain	1.0000
1:36091823:A:T	donor_gain	1.0000
1:36091823:AAGGT:A	donor_loss	1.0000
1:36091824:AGGTA:A	donor_loss	1.0000
1:36091825:GGTAT:G	donor_loss	1.0000
1:36091826:GT:G	donor_loss	1.0000
1:36091827:T:G	donor_loss	1.0000

AlphaMissense

2355 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:36091262:A:T	D77V	0.999
1:36091265:A:T	D78V	0.999
1:36091736:T:C	F143L	0.999
1:36091738:T:A	F143L	0.999
1:36091738:T:G	F143L	0.999
1:36091762:T:A	N151K	0.999
1:36091762:T:G	N151K	0.999
1:36093234:G:C	D314H	0.999
1:36093235:A:C	D314A	0.999
1:36093235:A:G	D314G	0.999
1:36093235:A:T	D314V	0.999
1:36093236:C:A	D314E	0.999
1:36093236:C:G	D314E	0.999
1:36093241:A:C	D316A	0.999
1:36093241:A:T	D316V	0.999
1:36093242:C:A	D316E	0.999
1:36093242:C:G	D316E	0.999
1:36093244:C:T	T317I	0.999
1:36089004:G:C	D34H	0.998
1:36091259:C:T	T76I	0.998
1:36091261:G:C	D77H	0.998
1:36091262:A:C	D77A	0.998
1:36091263:T:A	D77E	0.998
1:36091263:T:G	D77E	0.998
1:36091264:G:C	D78H	0.998
1:36091265:A:C	D78A	0.998
1:36091266:C:A	D78E	0.998
1:36091266:C:G	D78E	0.998
1:36091939:C:A	H182Q	0.998
1:36091939:C:G	H182Q	0.998

dbSNP variants (sampled 300 via entrez): RS1000591876 (1:36093609 T>A,C), RS1000815191 (1:36088819 G>A), RS1000887309 (1:36089016 T>C), RS1000983800 (1:36089301 G>A), RS1001086312 (1:36094362 A>G), RS1001099965 (1:36089560 C>T), RS1001505904 (1:36091400 C>A,G,T), RS1002438530 (1:36089723 C>G,T), RS1003181405 (1:36092540 G>A), RS1003238165 (1:36087126 C>T), RS1003415100 (1:36092818 C>G,T), RS1003520343 (1:36092301 G>A,T), RS1003917661 (1:36089360 G>A,C,T), RS1003948792 (1:36089640 C>A,T), RS1004533026 (1:36092743 TA>T)

Disease associations

OMIM: gene MIM:610624 | disease phenotypes: MIM:618170, MIM:608323

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures	Strong	Autosomal recessive

Mondo (2): neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures (MONDO:0100095), Charcot-Marie-Tooth disease dominant intermediate C (MONDO:0012012)

Orphanet (2): Childhood-onset stress-induced neurodegenerative ataxia-seizure syndrome (Orphanet:694922), Autosomal dominant intermediate Charcot-Marie-Tooth disease type C (Orphanet:100045)

HPO phenotypes

29 total (29 of 29 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000602	Ophthalmoplegia
HP:0000639	Nystagmus
HP:0000651	Diplopia
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001308	Tongue fasciculations
HP:0001310	Dysmetria
HP:0001324	Muscle weakness
HP:0001761	Pes cavus
HP:0002059	Cerebral atrophy
HP:0002069	Bilateral tonic-clonic seizure
HP:0002080	Intention tremor
HP:0002093	Respiratory insufficiency
HP:0002121	Generalized non-motor (absence) seizure
HP:0002376	Developmental regression
HP:0002465	Poor speech
HP:0003447	Axonal loss
HP:0003487	Babinski sign
HP:0006855	Cerebellar vermis atrophy
HP:0011463	Childhood onset
HP:0031165	Multifocal seizures

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C564257	Charcot-Marie-Tooth Disease, Dominant Intermediate C (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295963 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Leflunomide	decreases expression	2
Cyclosporine	decreases expression, increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
bisphenol A	decreases expression	1
sodium arsenite	increases expression	1
cylindrospermopsin	increases expression	1
2-palmitoylglycerol	increases expression	1
abrine	increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	decreases expression	1
jinfukang	increases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Sunitinib	increases expression	1
Adenosine Diphosphate Ribose	decreases reaction, increases hydrolysis	1
Air Pollutants	decreases expression, increases abundance	1
Benzene	increases expression	1
Benzo(a)pyrene	increases methylation	1
Estradiol	affects expression	1
Lead	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Asbestos, Crocidolite	increases expression	1
Copper Sulfate	decreases expression	1
O-Acetyl-ADP-Ribose	decreases reaction, increases hydrolysis	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4265327	Binding	Inhibition of human full length C-terminus His-tagged ARH3 expressed in Escherichia coli using Bt-NAD ribosylated PARP1 substrate after 30 mins by TR-FRET assay	Cell-Active Small Molecule Inhibitors of the DNA-Damage Repair Enzyme Poly(ADP-ribose) Glycohydrolase (PARG): Discovery and Optimization of Orally Bioavailable Quinazolinedione Sulfonamides. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D7JP	Ubigene A-549 ADPRS KO	Cancer cell line	Male
CVCL_D8GW	Ubigene HCC1806 ADPRS KO	Cancer cell line	Female
CVCL_E1PL	HAP1 ADPRHL2 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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