ADSL

Summary

ADSL (adenylosuccinate lyase, HGNC:291) is a protein-coding gene on chromosome 22q13.1, encoding Adenylosuccinate lyase (P30566). Catalyzes two non-sequential steps in de novo AMP synthesis: converts (S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido)succinate (SAICAR) to fumarate plus 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide, and thereby also contributes to de novo IMP synthesis,…. It is a selective cancer dependency (DepMap: 76.4% of cell lines).

The protein encoded by this gene belongs to the lyase 1 family. It is an essential enzyme involved in purine metabolism, and catalyzes two non-sequential reactions in the de novo purine biosynthetic pathway: the conversion of succinylaminoimidazole carboxamide ribotide (SAICAR) to aminoimidazole carboxamide ribotide (AICAR) and the conversion of adenylosuccinate (S-AMP) to adenosine monophosphate (AMP). Mutations in this gene are associated with adenylosuccinase deficiency (ADSLD), a disorder marked with psychomotor retardation, epilepsy or autistic features. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 158 — RefSeq curated summary.

At a glance

• Gene–disease (curated): adenylosuccinate lyase deficiency (Definitive, ClinGen)
• GWAS associations: 3
• Clinical variants (ClinVar): 927 total — 44 pathogenic, 23 likely-pathogenic
• Phenotypes (HPO): 49
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 76.4% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000026

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:291
Approved symbol	ADSL
Name	adenylosuccinate lyase
Location	22q13.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000239900
Ensembl biotype	protein_coding
OMIM	608222
Entrez	158

Gene structure

Transcript identifiers

Ensembl transcripts: 62 — 42 protein_coding, 11 retained_intron, 7 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000216194, ENST00000342312, ENST00000423176, ENST00000466863, ENST00000477111, ENST00000480775, ENST00000498234, ENST00000623063, ENST00000623287, ENST00000623387, ENST00000623632, ENST00000623978, ENST00000624027, ENST00000624474, ENST00000624503, ENST00000625194, ENST00000636124, ENST00000636265, ENST00000636433, ENST00000636714, ENST00000637666, ENST00000637669, ENST00000638161, ENST00000674592, ENST00000675622, ENST00000679609, ENST00000679656, ENST00000679723, ENST00000679845, ENST00000679904, ENST00000680378, ENST00000680444, ENST00000680978, ENST00000681003, ENST00000681159, ENST00000892506, ENST00000892507, ENST00000892508, ENST00000892509, ENST00000892510, ENST00000892511, ENST00000892512, ENST00000892513, ENST00000892514, ENST00000892515, ENST00000892516, ENST00000932035, ENST00000932036, ENST00000932037, ENST00000932038, ENST00000932039, ENST00000932040, ENST00000932041, ENST00000932042, ENST00000932043, ENST00000932044, ENST00000932045, ENST00000932046, ENST00000932047, ENST00000969087, ENST00000969088, ENST00000969089

RefSeq mRNA: 7 — MANE Select: NM_000026 NM_000026, NM_001123378, NM_001317923, NM_001363840, NM_001410812, NM_001410814, NM_001410816

CCDS: CCDS14001, CCDS46714, CCDS87029, CCDS93169, CCDS93170, CCDS93171

Canonical transcript exons

ENST00000623063 — 13 exons

Exon	Start	End
ENSE00000654864	40361488	40361635
ENSE00000654865	40362981	40363071
ENSE00000654866	40364276	40364365
ENSE00000654867	40364880	40365056
ENSE00001695427	40366436	40369367
ENSE00002140508	40349832	40350035
ENSE00002160623	40353073	40353117
ENSE00002187494	40358864	40359035
ENSE00002197530	40361273	40361342
ENSE00003149424	40354248	40354327
ENSE00003459954	40360402	40360492
ENSE00003503675	40359260	40359306
ENSE00003759080	40346500	40346711

Expression profiles

Bgee: expression breadth ubiquitous, 147 present calls, max score 98.38.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.4647 / max 155.1186, expressed in 1814 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
192420	20.2100	1811
192419	5.2547	1712

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	98.38	gold quality
gastrocnemius	UBERON:0001388	98.33	gold quality
skeletal muscle tissue	UBERON:0001134	98.24	gold quality
muscle of leg	UBERON:0001383	98.19	gold quality
muscle organ	UBERON:0001630	98.06	gold quality
skeletal muscle organ	UBERON:0014892	98.06	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	97.67	gold quality
muscle tissue	UBERON:0002385	97.03	gold quality
adrenal tissue	UBERON:0018303	95.25	gold quality
lymph node	UBERON:0000029	95.01	gold quality
islet of Langerhans	UBERON:0000006	94.79	gold quality
body of pancreas	UBERON:0001150	94.75	gold quality
smooth muscle tissue	UBERON:0001135	94.74	gold quality
stromal cell of endometrium	CL:0002255	94.62	gold quality
ventricular zone	UBERON:0003053	94.46	gold quality
embryo	UBERON:0000922	94.44	gold quality
pancreas	UBERON:0001264	94.44	gold quality
ganglionic eminence	UBERON:0004023	94.44	gold quality
granulocyte	CL:0000094	93.88	gold quality
heart left ventricle	UBERON:0002084	93.82	gold quality
rectum	UBERON:0001052	93.64	gold quality
vermiform appendix	UBERON:0001154	93.59	gold quality
leukocyte	CL:0000738	93.58	gold quality
monocyte	CL:0000576	93.47	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.36	gold quality
lower esophagus	UBERON:0013473	93.34	gold quality
heart	UBERON:0000948	93.12	gold quality
placenta	UBERON:0001987	93.04	gold quality
right ovary	UBERON:0002118	92.96	gold quality
apex of heart	UBERON:0002098	92.94	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.93
E-MTAB-7249	no	1182.70
E-MTAB-6524	no	226.46

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

20 targeting ADSL, 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-3910	99.95	71.13	2227
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-548AG	99.77	69.25	1492
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-548AI	99.69	69.24	1494
HSA-MIR-548BA	99.69	69.14	1514
HSA-MIR-570-5P	99.69	69.24	1494
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-802	99.61	67.70	1254
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-4312	99.34	67.30	511
HSA-MIR-4718	98.55	68.61	814
HSA-MIR-335-5P	97.10	68.12	1022
HSA-MIR-873-3P	96.84	66.09	786
HSA-MIR-6857-3P	96.70	65.43	915
HSA-MIR-516A-5P	93.40	64.96	90

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 76.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 19)

• Mutation of a nuclear respiratory factor 2 binding site in the 5’ untranslated region of the ADSL gene in three patients with adenylosuccinate lyase deficiency. (PMID:12016589)
• Mutations at position 276 result in structurally impaired adenylosuccinate lyases which are assembled into the defective tetramers associated with the mild variant of ADSL deficiency in humans. (PMID:12590570)
• Variable expression of ADSL deficiency is reported in three patients belonging to a family which originates from Portugal. (PMID:12833398)
• a mutation in adenylosuccinate lyase may be associated with autism (PMID:15471876)
• case report of adenylosuccinate lyase deficiency shows a mutation in ASDL (PMID:15571235)
• cloning, expression and purification of catalytically active human adenylosuccinate lyase (PMID:16973378)
• ADSL deficiency may present with prenatal growth restriction, fetal and neonatal hypokinesia, and rapidly fatal neonatal encephalopathy. (PMID:17188615)
• Analysis of the ADSL gene showed a R426H mutation in four unrelated patients with metabolic diseases. (PMID:18524658)
• D-ribose administration in Polish patients with adenylosuccinate lyase deficiency was accompanied by neither reduction in seizure frequency nor growth enhancement. (PMID:18649008)
• Biochemical and biophysical analysis of five disease-associated human adenylosuccinate lyase mutants. (PMID:19405474)
• Case Report: Malaysian patient compound heterozygous for two novel ADSL mutations giving rise to adenylosuccinate lyase deficiency. (PMID:20177786)
• the cases of the only three children diagnosed to date in the United Kingdom with adenylosuccinate lyase deficiency (PMID:20933180)
• Results proved in cultured skin fibroblasts from patients with AICA-ribosiduria and ADSL deficiency that various mutations of ADSL destabilize to various degrees purinosome assembly and found that the ability to form purinosomes correlates with clinical phenotypes of individual ADSL patients. (PMID:22180458)
• structural and biochemical characterization data of WT and mutant R303C ADSL by enzyme kinetics, product binding by isothermal titration calorimetry and X-ray crystallography to reveal the effects of the R303C mutation that results in a nonparallel reduction in enzyme activity (PMID:22812634)
• Missense mutations in the adenylosuccinate lyase is associated with Adenylosuccinate lyase deficiency, an inborn error of purine metabolism characterized by neurological and physiological symptoms. (PMID:23714113)
• involved in endometrial cancer aggressiveness by regulating expression of killer cell lectin-like receptor C3 (PMID:29467457)
• ADSL undergoes conformational changes during catalysis which, together with the crystal structure of a hitherto undetermined product bound conformation, explains the molecular origin of disease for several modern human ADSL mutants. (PMID:30573755)
• Adenylosuccinate lyase (ADSL) is an EglN2 hydroxylase substrate in triple negative breast cancer. (PMID:31729379)
• Electroclinical features and phenotypic differences in adenylosuccinate lyase deficiency: Long-term follow-up of seven patients from four families and appraisal of the literature. (PMID:37842880)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	adsl	ENSDARG00000017049
mus_musculus	Adsl	ENSMUSG00000022407
rattus_norvegicus	Adsl	ENSRNOG00000018655
drosophila_melanogaster	Adsl	FBGN0038467
caenorhabditis_elegans	adsl-1	WBGENE00011064

Paralogs (2): FH (ENSG00000091483), ASL (ENSG00000126522)

Protein

Protein identifiers

Adenylosuccinate lyase — P30566 (reviewed: P30566)

Alternative names: Adenylosuccinase

All UniProt accessions (20): P30566, A0A096LNT0, A0A096LNY4, A0A096LNY5, A0A096LNY6, A0A096LP72, A0A096LP76, A0A096LP92, A0A096LPA2, A0A0A6YY92, A0A1B0GTG9, A0A1B0GTJ7, A0A1B0GWF8, A0A1B0GWJ0, A0A7P0T8E4, A0A7P0T9A7, A0A7P0Z472, B4DEP1, V9GY96, X5D8S6

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes two non-sequential steps in de novo AMP synthesis: converts (S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido)succinate (SAICAR) to fumarate plus 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide, and thereby also contributes to de novo IMP synthesis, and converts succinyladenosine monophosphate (SAMP) to AMP and fumarate.

Subunit / interactions. Homotetramer. Residues from neighboring subunits contribute catalytic and substrate-binding residues to each active site.

Tissue specificity. Ubiquitously expressed. Both isoforms are produced by all tissues. Isoform 2 is 10-fold less abundant than isoform 1.

Disease relevance. Adenylosuccinase deficiency (ADSLD) [MIM:103050] An autosomal recessive disorder characterized by the accumulation in the body fluids of succinylaminoimidazole-carboxamide riboside (SAICA-riboside) and succinyladenosine (S-Ado). Most children display marked psychomotor delay, often accompanied by epilepsy or autistic features, or both, although some patients may be less profoundly retarded. Occasionally, growth retardation and muscular wasting are also present. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The enzyme reaction kinetics indicate cooperativity between subunits.

Pathway. Purine metabolism; AMP biosynthesis via de novo pathway; AMP from IMP: step 2/2. Purine metabolism; IMP biosynthesis via de novo pathway; 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide from 5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxylate: step 2/2.

Miscellaneous. Lacks enzymatic activity.

Similarity. Belongs to the lyase 1 family. Adenylosuccinate lyase subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
P30566-1	1	yes
P30566-2	2, Delta-ADSL

RefSeq proteins (7): NP_000017, NP_001116850, NP_001304852, NP_001350769, NP_001397741, NP_001397743, NP_001397745 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000362	Fumarate_lyase_fam	Family
IPR004769	Pur_lyase	Family
IPR008948	L-Aspartase-like	Homologous_superfamily
IPR019468	AdenyloSucc_lyase_C	Domain
IPR020557	Fumarate_lyase_CS	Conserved_site
IPR022761	Fumarate_lyase_N	Domain

Pfam: PF00206, PF10397

Enzyme classification (BRENDA):

• EC 4.3.2.2 — adenylosuccinate lyase (BRENDA: 22 organisms, 63 substrates, 65 inhibitors, 71 Km, 12 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ADENYLOSUCCINATE	0.0015–0.023	13
ADENYLSUCCINATE	0.0013–0.0551	13
N6-(1,2-DICARBOXYETHYL)AMP	0.0012–0.013	9
SUCCINYLADENOSINE MONOPHOSPHATE	0.0014–0.2042	7
AMP	0.004–0.048	4
5-AMINOIMIDAZOLE-4-(N-SUCCINYLCARBOXAMIDE) RIBON	0.0003–0.0029	3
FUMARATE	0.035–0.76	3
PHOSPHORIBOSYLSUCCINYL-AMINOIMIDAZOLE CARBOXAMID	0.0007–0.009	3
2’-DEOXY-SUCCINO-AMP	0.0008–0.003	2
4-(N-SUCCINO)-5-AMINOIMIDAZOLE-4-CARBOXAMIDE RIB	0.001–0.0081	2
ARABINOSYL-SUCCINO-AMP	0.0027–0.0056	2
(S)-2-[5-AMINO-1-(5-PHOSPHO-D-RIBOSYL)IMIDAZOLE-	0.0111	1
2’,3’-DIDEOXYADENYLOSUCCINATE	0.0437	1
8-AZA-SUCCINO-AMP	0.0095	1
MERCAPTOPURINOSUCCINATE	0.02	1

Catalyzed reactions (Rhea), 2 shown:

• N(6)-(1,2-dicarboxyethyl)-AMP = fumarate + AMP (RHEA:16853)
• (2S)-2-[5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamido]succinate = 5-amino-1-(5-phospho-beta-D-ribosyl)imidazole-4-carboxamide + fumarate (RHEA:23920)

UniProt features (84 total): sequence variant 29, helix 27, binding site 8, strand 6, turn 5, modified residue 3, active site 2, initiator methionine 1, chain 1, cross-link 1, splice variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2J91	X-RAY DIFFRACTION	1.8
2VD6	X-RAY DIFFRACTION	2
4FLC	X-RAY DIFFRACTION	2.6
4FFX	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P30566-F1	96.82	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 (2): 159 (proton donor/acceptor); 289 (proton donor/acceptor)

Ligand- & substrate-binding residues (8): 334 (in other chain); 338 (in other chain); 20–21; 85–87 (in other chain); 111–112 (in other chain); 241 (in other chain); 303; 329 (in other chain)

Post-translational modifications (4): 2, 147, 295, 415

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-73817	Purine ribonucleoside monophosphate biosynthesis

MSigDB gene sets: 295 (showing top): MODULE_52, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, MODULE_16, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, PATIL_LIVER_CANCER, PUJANA_CHEK2_PCC_NETWORK, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, GOBP_RESPONSE_TO_OXYGEN_LEVELS, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, GNF2_RFC3

GO Biological Process (13): response to hypoxia (GO:0001666), purine nucleotide biosynthetic process (GO:0006164), AMP biosynthetic process (GO:0006167), GMP biosynthetic process (GO:0006177), ‘de novo’ IMP biosynthetic process (GO:0006189), response to nutrient (GO:0007584), aerobic respiration (GO:0009060), response to muscle activity (GO:0014850), response to starvation (GO:0042594), ‘de novo’ AMP biosynthetic process (GO:0044208), AMP salvage (GO:0044209), ‘de novo’ XMP biosynthetic process (GO:0097294), purine ribonucleotide biosynthetic process (GO:0009152)

GO Molecular Function (5): N6-(1,2-dicarboxyethyl)AMP AMP-lyase (fumarate-forming) activity (GO:0004018), identical protein binding (GO:0042802), (S)-2-(5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamido) succinate lyase (fumarate-forming) activity (GO:0070626), catalytic activity (GO:0003824), lyase activity (GO:0016829)

GO Cellular Component (2): cytosol (GO:0005829), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Nucleotide biosynthesis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to stress	2
purine ribonucleotide biosynthetic process	2
purine ribonucleoside monophosphate biosynthetic process	2
response to nutrient levels	2
AMP biosynthetic process	2
amidine-lyase activity	2
response to decreased oxygen levels	1
purine nucleotide metabolic process	1
nucleotide biosynthetic process	1
purine-containing compound biosynthetic process	1
AMP metabolic process	1
GMP metabolic process	1
IMP biosynthetic process	1
response to chemical	1
cellular respiration	1
response to activity	1
purine ribonucleotide salvage	1
XMP biosynthetic process	1
purine nucleotide biosynthetic process	1
purine ribonucleotide metabolic process	1
ribonucleotide biosynthetic process	1
protein binding	1
molecular_function	1
catalytic activity	1
cytoplasm	1
cellular anatomical structure	1
cellular_component	1

Protein interactions and networks

STRING

3644 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADSL	PPAT	Q06203	910
ADSL	ADSS2	P30520	856
ADSL	MRPL58	Q14197	823
ADSL	ATIC	P31939	811
ADSL	ADSS1	Q8N142	809
ADSL	PFAS	O15067	801
ADSL	GMPS	P49915	792
ADSL	APRT	P07741	775
ADSL	GART	P22102	760
ADSL	MRPL12	P52815	751
ADSL	PAICS	P22234	746
ADSL	AMPD1	P23109	745
ADSL	AMPD3	Q01432	742
ADSL	AMPD2	Q01433	729
ADSL	IMPDH2	P12268	725

IntAct

78 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CEP104	CCDC66	psi-mi:“MI:2364”(proximity)	0.540
SNRNP27	UBA6	psi-mi:“MI:0914”(association)	0.530
COMTD1	IFRD1	psi-mi:“MI:0914”(association)	0.530
TEKT4	CLOCK	psi-mi:“MI:0914”(association)	0.530
USP47	DENR	psi-mi:“MI:0914”(association)	0.530
ALOX5	DDHD2	psi-mi:“MI:0914”(association)	0.530
USP4	PRPF4	psi-mi:“MI:0914”(association)	0.530
TIMMDC1	NDUFS8	psi-mi:“MI:0914”(association)	0.530
KRR1	MPHOSPH10	psi-mi:“MI:0914”(association)	0.530
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
ADSL	EPDR1	psi-mi:“MI:0915”(physical association)	0.400
ADSL	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.370
CCN3	ADSL	psi-mi:“MI:0915”(physical association)	0.370
OTUB1		psi-mi:“MI:0914”(association)	0.350
OTUB1	EPM2A	psi-mi:“MI:0914”(association)	0.350
NFKB1	NFKB1	psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
ORF69	PEPD	psi-mi:“MI:0914”(association)	0.350
GTF2E2	UBA6	psi-mi:“MI:0914”(association)	0.350
KLHL20	KRBA1	psi-mi:“MI:0914”(association)	0.350
FGB	NME2	psi-mi:“MI:0914”(association)	0.350
TEKT2	GFAP	psi-mi:“MI:0914”(association)	0.350
USP15	KRT35	psi-mi:“MI:0914”(association)	0.350
TIFAB	DDX3X	psi-mi:“MI:0914”(association)	0.350

BioGRID (212): ADSL (Affinity Capture-RNA), ADSL (Affinity Capture-MS), ADSL (Affinity Capture-MS), ADSL (Affinity Capture-MS), ADSL (Affinity Capture-MS), ADSL (Co-fractionation), ADSL (Co-fractionation), ADSL (Co-fractionation), ADSL (Co-fractionation), ADSL (Co-fractionation), ADSL (Co-fractionation), ADSL (Co-fractionation), ADSL (Co-fractionation), ADSL (Co-fractionation), ADSL (Co-fractionation)

ESM2 similar proteins: A3KN12, O88958, P21265, P21343, P30566, P36959, P38024, P50554, P50990, P54822, P61922, P78371, P80147, P80314, P80404, P82197, Q04447, Q0II59, Q259G4, Q2KIG0, Q3ZBF0, Q3ZBH0, Q3ZCI9, Q41141, Q4R4U1, Q4R5J0, Q4R5Y2, Q4R6F8, Q5E982, Q5R5F8, Q5RAP1, Q5XIM9, Q5ZMA6, Q64422, Q6EE31, Q6IA69, Q711T7, Q7XPW5, Q7ZV22, Q812E8

Diamond homologs: A0A0K2JL82, A0A0U2UYC4, A3KN12, E0SKP1, K4R6W4, O27580, O31385, O42889, O58582, O66856, P21265, P30566, P32427, P54822, P72478, P74384, Q2FFI7, Q2G2S0, Q2YU66, Q58339, Q59092, Q5HEL4, Q5HN26, Q6G825, Q6GFE9, Q7A0G9, Q7A4Q3, Q8CRT6, Q8HXY5, Q99SX9, Q9I6Q8, Q9RSE6, Q9UZ99, G4VQX9, O60105, P12047, Q05911, Q21774, Q60Q90, O28041

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
ADSL	“up-regulates quantity”	fumarate(2-)	“chemical modification”
ADSL	“up-regulates quantity”	AMP	“chemical modification”
ADSL	“up-regulates quantity”	5-amino-1-(5-phospho-D-ribosyl)imidazole-4-carboxamide(2-)	“chemical modification”
ADSL	“down-regulates quantity”	SAICAR(4-)	“chemical modification”
ADSL	“down-regulates quantity”	N(6)-(1,2-dicarboxylatoethyl)-AMP(4-)	“chemical modification”
EGLN2	“up-regulates activity”	ADSL	hydroxylation
ADSL	“up-regulates quantity by expression”	MYC

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 103 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Anchoring of the basal body to the plasma membrane	7	11.0×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
cilium assembly	8	6.2×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	44
Likely pathogenic	23
Uncertain significance	517
Likely benign	222
Benign	45

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070255	NM_000026.4(ADSL):c.1026del (p.Glu343fs)	Pathogenic
1070511	NM_000026.4(ADSL):c.802G>A (p.Asp268Asn)	Pathogenic
1070913	NM_000026.4(ADSL):c.666del (p.Asp223fs)	Pathogenic
1071793	NM_000026.4(ADSL):c.829G>T (p.Glu277Ter)	Pathogenic
1074151	NM_000026.4(ADSL):c.955del (p.Leu319fs)	Pathogenic
1420897	NM_000026.4(ADSL):c.187del (p.Gln63fs)	Pathogenic
1452821	NM_000026.4(ADSL):c.628C>T (p.Gln210Ter)	Pathogenic
1454363	NC_000022.10:g.(?40749057)(40750351_?)del	Pathogenic
1454913	NM_000026.4(ADSL):c.733C>T (p.Arg245Ter)	Pathogenic
1455911	NM_000026.4(ADSL):c.1222C>T (p.Gln408Ter)	Pathogenic
1458015	NM_000026.4(ADSL):c.151C>T (p.Gln51Ter)	Pathogenic
1711559	GRCh37/hg19 22q13.1(chr22:40552119-40763622)x1	Pathogenic
1808635	GRCh37/hg19 22q13.1-13.2(chr22:40131240-41556564)x1	Pathogenic
1942226	NM_000026.4(ADSL):c.807dup (p.Arg270fs)	Pathogenic
1962288	NM_000026.4(ADSL):c.701+1G>T	Pathogenic
204788	NM_000026.4(ADSL):c.853C>T (p.Gln285Ter)	Pathogenic
204789	NM_000026.4(ADSL):c.1009C>T (p.Arg337Ter)	Pathogenic
204807	NM_000026.4(ADSL):c.340T>C (p.Tyr114His)	Pathogenic
204814	NM_000026.4(ADSL):c.568C>T (p.Arg190Ter)	Pathogenic
2138451	NM_000026.4(ADSL):c.802G>C (p.Asp268His)	Pathogenic
2422149	NC_000022.10:g.(?40741451)(40756516_?)del	Pathogenic
2461	NM_000026.4(ADSL):c.1312T>C (p.Ser438Pro)	Pathogenic
2462	NM_000026.4(ADSL):c.1277G>A (p.Arg426His)	Pathogenic
2463	NM_000026.4(ADSL):c.298C>G (p.Pro100Ala)	Pathogenic
2468	NM_000026.4(ADSL):c.674T>C (p.Met225Thr)	Pathogenic
2752273	NM_000026.4(ADSL):c.1346dup (p.Thr450fs)	Pathogenic
2854848	NM_000026.4(ADSL):c.372del (p.Arg125fs)	Pathogenic
3247227	NC_000022.10:g.(?40749057)(40756516_?)del	Pathogenic
3247238	NC_000022.10:g.(?40754848)(40762526_?)del	Pathogenic
3251370	NC_000022.10:g.(40757640_40758984)_(40761061_40762439)del	Pathogenic

SpliceAI

2926 predictions. Top by Δscore:

Variant	Effect	Δscore
22:40346707:AGCAG:A	donor_loss	1.0000
22:40346708:GCAGG:G	donor_loss	1.0000
22:40346709:CAGGT:C	donor_loss	1.0000
22:40346710:AGGT:A	donor_loss	1.0000
22:40346711:GG:G	donor_loss	1.0000
22:40346712:G:GC	donor_loss	1.0000
22:40346713:T:A	donor_loss	1.0000
22:40347505:A:T	donor_gain	1.0000
22:40347551:G:GG	donor_gain	1.0000
22:40347612:G:GT	donor_gain	1.0000
22:40347613:A:T	donor_gain	1.0000
22:40349911:C:G	donor_gain	1.0000
22:40349916:G:GT	donor_gain	1.0000
22:40350017:C:G	donor_gain	1.0000
22:40350036:G:GG	donor_gain	1.0000
22:40354328:G:GG	donor_gain	1.0000
22:40358854:G:A	acceptor_gain	1.0000
22:40358970:G:GT	donor_gain	1.0000
22:40358970:G:T	donor_gain	1.0000
22:40358976:AAGG:A	donor_gain	1.0000
22:40359021:G:GT	donor_gain	1.0000
22:40359258:A:G	acceptor_gain	1.0000
22:40359307:G:A	donor_loss	1.0000
22:40360394:A:AG	acceptor_gain	1.0000
22:40360398:CTA:C	acceptor_loss	1.0000
22:40360400:A:AG	acceptor_gain	1.0000
22:40360400:A:AT	acceptor_loss	1.0000
22:40360401:G:GA	acceptor_gain	1.0000
22:40360401:G:GC	acceptor_loss	1.0000
22:40360401:GA:G	acceptor_gain	1.0000

AlphaMissense

3184 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:40361510:G:C	K295N	1.000
22:40361510:G:T	K295N	1.000
22:40346685:T:A	W43R	0.999
22:40346685:T:C	W43R	0.999
22:40349934:C:G	H86D	0.999
22:40349936:T:A	H86Q	0.999
22:40349936:T:G	H86Q	0.999
22:40349997:C:G	H107D	0.999
22:40350013:C:A	S112Y	0.999
22:40350013:C:T	S112F	0.999
22:40350032:T:A	N118K	0.999
22:40350032:T:G	N118K	0.999
22:40354320:C:G	H159D	0.999
22:40354322:T:A	H159Q	0.999
22:40354322:T:G	H159Q	0.999
22:40361493:A:C	S290R	0.999
22:40361495:T:A	S290R	0.999
22:40361495:T:G	S290R	0.999
22:40361500:T:C	M292T	0.999
22:40361501:G:A	M292I	0.999
22:40361501:G:C	M292I	0.999
22:40361501:G:T	M292I	0.999
22:40361508:A:G	K295E	0.999
22:40361509:A:T	K295M	0.999
22:40361516:T:A	N297K	0.999
22:40361516:T:G	N297K	0.999
22:40361619:G:C	D332H	0.999
22:40361622:G:C	D333H	0.999
22:40361625:A:C	S334R	0.999
22:40361627:T:A	S334R	0.999

dbSNP variants (sampled 300 via entrez): RS1000023417 (22:40381739 G>A), RS1000070636 (22:40363912 A>G), RS1000079232 (22:40346406 T>C), RS1000132878 (22:40357340 G>A), RS1000157389 (22:40358398 A>G), RS1000183806 (22:40370381 A>C), RS1000226781 (22:40354868 C>A), RS1000313311 (22:40352363 C>T), RS1000399379 (22:40369948 G>A,C), RS1000441849 (22:40358201 A>G,T), RS1000514659 (22:40368637 A>G), RS1000590797 (22:40350762 G>A), RS1000694858 (22:40363770 A>C,G), RS1000722731 (22:40375130 C>G,T), RS1000735128 (22:40368409 C>T)

Disease associations

OMIM: gene MIM:608222 | disease phenotypes: MIM:103050

GenCC curated gene-disease

Disease	Classification	Inheritance
adenylosuccinate lyase deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
adenylosuccinate lyase deficiency	Definitive	AR

Mondo (2): adenylosuccinate lyase deficiency (MONDO:0007068), intellectual disability (MONDO:0001071)

Orphanet (2): Adenylosuccinate lyase deficiency (Orphanet:46), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

49 total (30 of 49 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000154	Wide mouth
HP:0000219	Thin upper lip vermilion
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000319	Smooth philtrum
HP:0000343	Long philtrum
HP:0000369	Low-set ears
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000639	Nystagmus
HP:0000717	Autism
HP:0000718	Aggressive behavior
HP:0000742	Self-mutilation
HP:0000748	Inappropriate laughter
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0000817	Reduced eye contact
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001272	Cerebellar atrophy
HP:0001290	Generalized hypotonia
HP:0001336	Myoclonus
HP:0001344	Absent speech
HP:0001348	Brisk reflexes
HP:0001510	Growth delay
HP:0001999	Abnormal facial shape

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000431_4	Height	2.000000e-07
GCST005951_24	Body mass index	2.000000e-08
GCST006921_10	Regular attendance at a pub or social club	3.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0009592	social interaction measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C538235	Adenylosuccinate lyase deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066328 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression	4
Smoke	decreases expression	2
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
bisphenol A	decreases expression	1
sodium arsenate	decreases expression	1
hydroxyhydroquinone	decreases expression	1
beta-lapachone	increases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	increases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
CGP 52608	affects binding, increases reaction	1
chloropicrin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Sunitinib	increases expression	1
Zoledronic Acid	decreases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benztropine	affects cotreatment, decreases expression	1
Caffeine	decreases phosphorylation	1
Cuprizone	affects cotreatment, decreases expression	1
Diazinon	increases methylation	1
Diethylhexyl Phthalate	increases methylation, increases abundance	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5650853	Binding	Binding affinity to human ADSL incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT03776656	PHASE2	COMPLETED	Evaluation of a Treatment With Allopurinol in Adenylosuccinate Lyase Deficiency
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability