ASPA

Summary

ASPA (aspartoacylase, HGNC:756) is a protein-coding gene on chromosome 17p13.2, encoding Aspartoacylase (P45381). Catalyzes the deacetylation of N-acetylaspartic acid (NAA) to produce acetate and L-aspartate.

This gene encodes an enzyme that catalyzes the conversion of N-acetyl_L-aspartic acid (NAA) to aspartate and acetate. NAA is abundant in the brain where hydrolysis by aspartoacylase is thought to help maintain white matter. This protein is an NAA scavenger in other tissues. Mutations in this gene cause Canavan disease. Alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 443 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Canavan disease (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 510 total — 60 pathogenic, 90 likely-pathogenic
• Phenotypes (HPO): 61
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000049

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:756
Approved symbol	ASPA
Name	aspartoacylase
Location	17p13.2
Locus type	gene with protein product
Status	Approved
Aliases	ASP, ACY2
Ensembl gene	ENSG00000108381
Ensembl biotype	protein_coding
OMIM	608034
Entrez	443

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 4 protein_coding, 1 nonsense_mediated_decay

ENST00000263080, ENST00000456349, ENST00000571278, ENST00000577034, ENST00000858436

RefSeq mRNA: 2 — MANE Select: NM_000049 NM_000049, NM_001128085

CCDS: CCDS11028

Canonical transcript exons

ENST00000263080 — 6 exons

Exon	Start	End
ENSE00000669166	3489235	3489342
ENSE00000669168	3494350	3494459
ENSE00001116147	3475997	3476395
ENSE00001923034	3498891	3503405
ENSE00003474668	3483499	3483592
ENSE00003477626	3481603	3481798

Expression profiles

Bgee: expression breadth ubiquitous, 238 present calls, max score 97.25.

FANTOM5 (CAGE): breadth broad, TPM avg 3.5357 / max 271.3708, expressed in 322 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158870	3.1923	306
158869	0.1427	68
158871	0.0949	45
158874	0.0569	35
158873	0.0259	14
158872	0.0230	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	97.25	gold quality
nephron tubule	UBERON:0001231	95.27	gold quality
medial globus pallidus	UBERON:0002477	92.90	gold quality
globus pallidus	UBERON:0001875	92.56	gold quality
kidney epithelium	UBERON:0004819	92.20	gold quality
jejunal mucosa	UBERON:0000399	92.14	gold quality
trigeminal ganglion	UBERON:0001675	92.12	gold quality
inferior vagus X ganglion	UBERON:0005363	90.97	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.61	gold quality
endothelial cell	CL:0000115	90.47	gold quality
spinal cord	UBERON:0002240	89.85	gold quality
inferior olivary complex	UBERON:0002127	89.81	gold quality
renal glomerulus	UBERON:0000074	89.66	gold quality
substantia nigra	UBERON:0002038	89.36	gold quality
postcentral gyrus	UBERON:0002581	89.12	gold quality
metanephric glomerulus	UBERON:0004736	88.94	gold quality
midbrain	UBERON:0001891	88.77	gold quality
lateral globus pallidus	UBERON:0002476	88.67	gold quality
dorsal root ganglion	UBERON:0000044	88.64	gold quality
subthalamic nucleus	UBERON:0001906	88.45	gold quality
Brodmann (1909) area 46	UBERON:0006483	87.94	gold quality
Ammon’s horn	UBERON:0001954	87.80	gold quality
parietal lobe	UBERON:0001872	87.44	gold quality
adult organism	UBERON:0007023	87.29	gold quality
substantia nigra pars reticulata	UBERON:0001966	86.65	gold quality
tibial nerve	UBERON:0001323	86.33	gold quality
kidney	UBERON:0002113	86.03	gold quality
adult mammalian kidney	UBERON:0000082	85.92	gold quality
cranial nerve II	UBERON:0000941	85.48	gold quality
medulla oblongata	UBERON:0001896	85.38	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.23
E-MTAB-6379	no	76.50
E-MTAB-9543	no	1.22

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

23 targeting ASPA, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-6516-3P	99.65	68.57	1238
HSA-MIR-4687-3P	99.48	66.41	968
HSA-MIR-4427	99.34	70.33	1854
HSA-MIR-138-2-3P	98.91	68.33	1643
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-96-3P	97.47	68.03	839
HSA-MIR-3139	96.68	66.77	652
HSA-MIR-28-5P	96.16	66.12	579
HSA-MIR-708-5P	96.16	66.12	576
HSA-MIR-675-3P	95.77	69.27	675

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 20)

• the ASPA gene was analysed in 22 unrelated non-Jewish patients with Canavan disease, and 24 different mutations were found (PMID:12638939)
• Mild-onset presentation of Canavan’s disease associated with novel G212A point mutation in aspartoacylase gene (PMID:16437572)
• molecular weight of the purified enzyme is higher than predicted, suggesting the presence of post-translational modifications. Deglycosylation of aspartoacylase or mutation at glycosylation site causes decreased enzyme stability and catalytic activity (PMID:16669630)
• a green fluorescent protein-human ASPA fusion protein larger than the permissible size for the nuclear pore complex was enzymatically active and showed mixed nuclear-cytoplasmic distribution. (PMID:16935940)
• The finding that wild-type and Glu178Asp have the same K(m) but different k(cat) values confirms the idea that the carboxylate group contributes importantly to the enzymatic activity of aspartoacylase. (PMID:17027983)
• the N-terminal domain of aspartoacylase adopts a protein fold similar to that of zinc-dependent hydrolases related to carboxypeptidases A (PMID:17194761)
• These results show that aspartoacylase is a member of the caboxypeptidase A family and offer novel explanations for most loss-of-function aspartoacylase mutations associated with Canavan Disease. (PMID:17391648)
• New structure of human aspartoacylase complexed with a catalytic intermediate analogue, N-phosphonomethyl- l-aspartate, supports a carboxypeptidase-type mechanism for hydrolysis of the amide bond of the substrate, N-acetyl- l-aspartate. (PMID:18293939)
• We report on an Italian female patient with Canavan disease due to a missense mutation of the aspartoacylase gene and a 17p13.3 chromosomal microdeletion (PMID:22019069)
• Gene ASPA (NM_000049) was undertaken to sequence for mutation analysis. (PMID:22219087)
• a novel mutation Y88X within the aspartoacylase gene in a consanguineous family with an affected child diagnosed as Canavan disease. (PMID:22468686)
• Human aspartoacylase gene expression was high not only in brain and kidney, but also in lung and liver. (PMID:22750302)
• This is the first case report of ASPA mutation studies in Canavan disease from Indian subcontinent. (PMID:22878930)
• report of 2 Egyptian sibling patients suspected of Canavan disease (CD); study revealed homozygosity for substitution T530C (Ile177Thr) in exon 4 of the ASPA gene in both sibs; substitution T530C (Ile177Thr) results in a novel missense mutation causing a CD phenotype with severe clinical characteristics (PMID:24036223)
• Definitive evidence is presented to show that the recombinantly-expressed human aspartoacylase is not a glycoprotein. (PMID:24632142)
• Four ASPA missense mutations associated with Canavan disease are structurally characterized. (PMID:25003821)
• Allosteric Control of N-Acetyl-Aspartate Hydrolysis by the Y231C and F295S Mutants of Human Aspartoacylase (PMID:30431265)
• In one case, the homozygous pathogenic variant NM_000049.2:c.914C>A;p.Ala305Glu, which is previously reported in ClinVar, in the gene ASPA was identified causing Canavan disease. In the second case, the homozygous novel variant NM_000487.5:c.256C>G;p.Arg86Gly in the gene ARSA was identified causing metachromatic leukodystrophy. (PMID:30834272)
• Mapping the degradation pathway of a disease-linked aspartoacylase variant. (PMID:33914734)
• Aspartoacylase promotes the process of tumour development and is associated with immune infiltrates in gastric cancer. (PMID:37391709)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	aspa	ENSDARG00000005154
mus_musculus	Aspa	ENSMUSG00000020774
rattus_norvegicus	Aspa	ENSRNOG00000019659

Paralogs (1): ACY3 (ENSG00000132744)

Protein

Protein identifiers

Aspartoacylase — P45381 (reviewed: P45381)

Alternative names: Aminoacylase-2

All UniProt accessions (4): P45381, I3L0T3, I3L4M0, Q6FH48

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the deacetylation of N-acetylaspartic acid (NAA) to produce acetate and L-aspartate. NAA occurs in high concentration in brain and its hydrolysis NAA plays a significant part in the maintenance of intact white matter. In other tissues it acts as a scavenger of NAA from body fluids.

Subunit / interactions. Homodimer.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Brain white matter, skeletal muscle, kidney, adrenal glands, lung and liver.

Disease relevance. Canavan disease (CAND) [MIM:271900] A rare neurodegenerative condition of infancy or childhood characterized by white matter vacuolization and demyelination that gives rise to a spongy appearance. The clinical features are onset in early infancy, atonia of neck muscles, hypotonia, hyperextension of legs and flexion of arms, blindness, severe mental defect, megalocephaly, and death by 18 months on the average. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 zinc ion per subunit.

Similarity. Belongs to the AspA/AstE family. Aspartoacylase subfamily.

RefSeq proteins (2): NP_000040, NP_001121557 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007036	Aste_AspA_hybrid_dom	Domain
IPR016708	Aspartoacylase	Family
IPR050178	AspA/AstE_fam	Family
IPR055438	AstE_AspA_cat	Domain

Pfam: PF04952, PF24827

Enzyme classification (BRENDA):

• EC 3.5.1.15 — aspartoacylase (BRENDA: 16 organisms, 65 substrates, 14 inhibitors, 22 Km, 13 kcat entries)

Substrate kinetics (BRENDA)

11 substrates with measured Km, best-characterized 11. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
N-ACETYLASPARTIC ACID	0.12–0.36	4
N-ACETYLASPARTATE	0.163–1.69	2
N-ACYL L-ASPARTIC ACID	0.2	2
N-ACYL-L-ASPARTIC ACID	0.85–5.1	2
N-TRIFLUOROACETYLASPARTIC ACID	0.15–0.21	2
N-ACETYL-L-ASPARTATE	0.36	1
N-ACETYL-L-ASPARTIC ACID	0.1	1
N-CHLOROACETYL-L-ASPARTATE	0.59	1
N-DICHLOROACETYL-L-ASPARTATE	0.23	1
N-FORMYL-L-ASPARTATE	0.95	1
N-TRIFLUOROACETYL-L-ASPARTATE	0.21	1

Catalyzed reactions (Rhea), 2 shown:

• an N-acyl-L-aspartate + H2O = a carboxylate + L-aspartate (RHEA:10872)
• N-acetyl-L-aspartate + H2O = L-aspartate + acetate (RHEA:59408)

UniProt features (95 total): sequence variant 44, strand 19, helix 10, binding site 9, mutagenesis site 8, turn 2, chain 1, active site 1, site 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
4MXU	X-RAY DIFFRACTION	2.6
2O4H	X-RAY DIFFRACTION	2.7
2O53	X-RAY DIFFRACTION	2.7
2I3C	X-RAY DIFFRACTION	2.8
2Q51	X-RAY DIFFRACTION	2.8
4MRI	X-RAY DIFFRACTION	2.8
4TNU	X-RAY DIFFRACTION	2.9
4NFR	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P45381-F1	96.14	0.94

Functional residue map

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

Catalytic / active sites (2): 178 (proton donor/acceptor); 63 (transition state stabilizer)

Ligand- & substrate-binding residues (9): 288; 21; 24; 63; 70; 71; 116; 164; 168

Mutagenesis-validated functional residues (8):

Position	Phenotype
71	reduces activity by 99%.
164	reduces activity by 99%.
168	reduces activity by 99%.
178	reduces activity by 99%.
178	abolishes enzymatic activity.
285	5-fold decrease in activity.
288	reduces activity by 99%.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-8963693	Aspartate and asparagine metabolism
R-HSA-1430728	Metabolism
R-HSA-71291	Metabolism of amino acids and derivatives

MSigDB gene sets: 257 (showing top): JAEGER_METASTASIS_DN, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, HNF1_Q6, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, CAGCTG_AP4_Q5, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, SRF_Q5_01, CAIRO_HEPATOBLASTOMA_CLASSES_DN, SRF_C, KEGG_HISTIDINE_METABOLISM, TGCTGAY_UNKNOWN, IRF1_Q6, HFH8_01, WTGAAAT_UNKNOWN

GO Biological Process (2): acetate metabolic process (GO:0006083), aspartate metabolic process (GO:0006531)

GO Molecular Function (7): hydrolase activity, acting on ester bonds (GO:0016788), hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides (GO:0016811), aspartoacylase activity (GO:0019807), identical protein binding (GO:0042802), metal ion binding (GO:0046872), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (3): nucleus (GO:0005634), cytosol (GO:0005829), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
monocarboxylic acid metabolic process	1
amino acid metabolic process	1
dicarboxylic acid metabolic process	1
hydrolase activity	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides	1
protein binding	1
cation binding	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
cytoplasm	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

626 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ASPA	ACY1	Q03154	981
ASPA	ASPNAT	Q8N9F0	780
ASPA	APEH	P13798	664
ASPA	CNP	P09543	515
ASPA	SHPK	Q9UHJ6	487
ASPA	MBP	P02686	474
ASPA	GLB1	P16278	449
ASPA	VCAN	P13611	433
ASPA	ACSS2	Q9NR19	427
ASPA	MAL	P21145	421
ASPA	ACY3	Q96HD9	417
ASPA	TRPV1	Q8NER1	410
ASPA	SUMF1	Q8NBK3	405
ASPA	OLIG2	Q13516	400
ASPA	SPHK1	Q9NYA1	384

IntAct

44 interactions, top by confidence:

A	B	Type	Score
ASPA	ACY3	psi-mi:“MI:0915”(physical association)	0.810
ACY3	ASPA	psi-mi:“MI:0915”(physical association)	0.810
WASL	WIPF3	psi-mi:“MI:0914”(association)	0.740
ASPA	KEAP1	psi-mi:“MI:0915”(physical association)	0.600
ASPA	ASPA	psi-mi:“MI:0407”(direct interaction)	0.590
ASPA	ASPA	psi-mi:“MI:0915”(physical association)	0.590
ASPA	DUSP29	psi-mi:“MI:0915”(physical association)	0.560
COPS3	ASPA	psi-mi:“MI:0915”(physical association)	0.560
PIAS1	ASPA	psi-mi:“MI:0915”(physical association)	0.560
UBQLN2	ASPA	psi-mi:“MI:0915”(physical association)	0.560
UBQLN3	ASPA	psi-mi:“MI:0915”(physical association)	0.560
UBQLNL	ASPA	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (10): ACY3 (Two-hybrid), ASPA (Two-hybrid), ACY3 (Two-hybrid), RUFY1 (Affinity Capture-MS), ASPA (Affinity Capture-MS), PGK2 (Affinity Capture-MS), ACY3 (Two-hybrid), DUPD1 (Two-hybrid), ASPA (Affinity Capture-MS), ASPA (Two-hybrid)

ESM2 similar proteins: A0JMS7, A2X0Q3, A7YW45, A8BQB4, A8KB34, A9RBS1, B1PK17, D3Z6H8, F1RQM2, O14744, O95394, P0DMN7, P17707, P17708, P28918, P35573, P35574, P45381, P46446, P50243, P51398, P79888, P82185, Q28C61, Q2PQH8, Q4R5M3, Q5BJ91, Q5M876, Q5R698, Q5R9E0, Q60HE5, Q60HH2, Q641Y5, Q6DHI0, Q6DHQ3, Q6ESI7, Q6NUA1, Q6YXZ7, Q8AVL0, Q8BMF3

Diamond homologs: A0JMS7, A2BP19, A2BUK0, A3PAU1, A8G2N0, A8KB34, B0C2K7, B1PK17, P45381, P46446, P59829, P59830, P72208, P73211, Q10VR3, Q28C61, Q31CV9, Q3AM91, Q3AV13, Q3MC79, Q46HE9, Q5BJ91, Q5M876, Q5R9E0, Q60HH2, Q6DHI0, Q6DHQ3, Q7V5L6, Q8R3P0, Q8YQC1, Q91XE4, Q96HD9, Q9R1T5, A2C055, A4TJU3, A5W0D8, A6VA73, A7FIL2, A9QZ59, B0KR44

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
ASPA	“down-regulates quantity”	N-acetyl-L-aspartate(2-)	“chemical modification”
ASPA	“up-regulates quantity”	“acetic acid”	“chemical modification”
ASPA	“up-regulates quantity”	L-aspartate(1-)	“chemical modification”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 14 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.

GO biological processes:

GO term	Partners	Fold	FDR
ubiquitin-dependent protein catabolic process	5	28.6×	6e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	60
Likely pathogenic	90
Uncertain significance	134
Likely benign	153
Benign	12

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069303	NM_000049.4(ASPA):c.230dup (p.Asn77fs)	Pathogenic
1071154	NC_000017.10:g.(?3397634)(3397763_?)del	Pathogenic
1071503	NC_000017.10:g.(?3379444)(3402392_?)del	Pathogenic
1071504	NC_000017.10:g.(?3384887)(3386896_?)del	Pathogenic
1071506	NC_000017.10:g.(?3392519)(3397763_?)del	Pathogenic
1180511	GRCh37/hg19 17p13.3-13.2(chr17:2313096-3735525)x1	Pathogenic
1323943	NM_000049.4(ASPA):c.342C>A (p.Asp114Glu)	Pathogenic
1342193	NM_000049.4(ASPA):c.124C>T (p.Gln42Ter)	Pathogenic
1411157	NM_000049.4(ASPA):c.426C>A (p.Tyr142Ter)	Pathogenic
1449340	NC_000017.10:g.(?3392509)(3571820_?)del	Pathogenic
1454394	NC_000017.10:g.(?3402175)(3402392_?)del	Pathogenic
1454528	NM_000049.4(ASPA):c.27dup (p.His10fs)	Pathogenic
150948	GRCh38/hg38 17p13.3-13.2(chr17:2062429-4141883)x3	Pathogenic
1698457	NC_000017.10:g.(?3379295)(3402701_?)del	Pathogenic
1705145	NM_000049.4(ASPA):c.697dup (p.Arg233fs)	Pathogenic
1786218	NM_000049.4(ASPA):c.211C>A (p.Arg71Ser)	Pathogenic
1807785	GRCh37/hg19 17p13.3-13.2(chr17:1095592-3484368)x3	Pathogenic
189005	NM_000049.4(ASPA):c.244_245del (p.Met82fs)	Pathogenic
1998122	NM_000049.4(ASPA):c.80del (p.Gly27fs)	Pathogenic
2000932	NM_000049.4(ASPA):c.291del (p.His98fs)	Pathogenic
2033374	NM_000049.4(ASPA):c.577del (p.Asp193fs)	Pathogenic
2089364	NM_000049.4(ASPA):c.325_328dup (p.Asp110delinsValTer)	Pathogenic
2119193	NM_000049.4(ASPA):c.25G>T (p.Glu9Ter)	Pathogenic
2137874	NM_000049.4(ASPA):c.557T>A (p.Val186Asp)	Pathogenic
2167806	NM_000049.4(ASPA):c.434del (p.Thr145fs)	Pathogenic
2418719	NM_000049.4(ASPA):c.20_205del (p.Ala7_Leu69delinsVal)	Pathogenic
2422201	NC_000017.10:g.(?3379444)(3379699_?)del	Pathogenic
2422203	NC_000017.10:g.(?3379454)(3385112_?)del	Pathogenic
2607	NM_000049.4(ASPA):c.914C>A (p.Ala305Glu)	Pathogenic
2608	NM_000049.4(ASPA):c.654C>A (p.Cys218Ter)	Pathogenic

SpliceAI

1191 predictions. Top by Δscore:

Variant	Effect	Δscore
17:3474172:AAGG:A	donor_loss	1.0000
17:3474174:GGTA:G	donor_loss	1.0000
17:3474175:GTA:G	donor_loss	1.0000
17:3475834:ATT:A	donor_gain	1.0000
17:3481762:G:GT	donor_gain	1.0000
17:3489341:AGG:A	donor_loss	1.0000
17:3489343:G:A	donor_loss	1.0000
17:3489344:TAA:T	donor_loss	1.0000
17:3474170:ACAAG:A	donor_gain	0.9900
17:3474171:CAAG:C	donor_gain	0.9900
17:3474172:AAG:A	donor_gain	0.9900
17:3474173:AG:A	donor_gain	0.9900
17:3474174:GG:G	donor_gain	0.9900
17:3474175:G:GG	donor_gain	0.9900
17:3475548:T:A	acceptor_gain	0.9900
17:3481345:T:G	acceptor_gain	0.9900
17:3481356:T:G	acceptor_gain	0.9900
17:3481591:T:A	acceptor_gain	0.9900
17:3481601:A:AG	acceptor_gain	0.9900
17:3481602:G:GA	acceptor_gain	0.9900
17:3481602:GC:G	acceptor_gain	0.9900
17:3481602:GCA:G	acceptor_gain	0.9900
17:3481602:GCAA:G	acceptor_gain	0.9900
17:3481602:GCAAA:G	acceptor_gain	0.9900
17:3483589:GTGG:G	donor_gain	0.9900
17:3483591:GGGT:G	donor_loss	0.9900
17:3483592:GGT:G	donor_loss	0.9900
17:3483593:G:GA	donor_loss	0.9900
17:3483593:G:GG	donor_gain	0.9900
17:3483594:T:TG	donor_loss	0.9900

AlphaMissense

2087 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:3476371:G:C	R71P	0.997
17:3476223:G:T	G22W	0.996
17:3476230:A:T	E24V	0.996
17:3498990:T:C	F282L	0.996
17:3498992:T:A	F282L	0.996
17:3498992:T:G	F282L	0.996
17:3499000:A:T	E285V	0.996
17:3476347:G:C	R63T	0.995
17:3499001:G:C	E285D	0.995
17:3499001:G:T	E285D	0.995
17:3476224:G:A	G22E	0.994
17:3476224:G:T	G22V	0.994
17:3481712:C:G	H116D	0.994
17:3481717:C:A	N117K	0.993
17:3481717:C:G	N117K	0.993
17:3498900:T:A	W252R	0.993
17:3498900:T:C	W252R	0.993
17:3476321:C:A	N54K	0.992
17:3476321:C:G	N54K	0.992
17:3476347:G:T	R63I	0.992
17:3476348:A:C	R63S	0.992
17:3476348:A:T	R63S	0.992
17:3489242:A:C	E178D	0.992
17:3489242:A:T	E178D	0.992
17:3476228:T:A	N23K	0.991
17:3476228:T:G	N23K	0.991
17:3476370:C:A	R71S	0.991
17:3476376:T:C	F73L	0.991
17:3476378:T:A	F73L	0.991
17:3476378:T:G	F73L	0.991

dbSNP variants (sampled 300 via entrez): RS1000039541 (17:3475277 A>G), RS1000254278 (17:3493803 A>T), RS1000364486 (17:3501767 A>G), RS1000412151 (17:3474852 T>C), RS1000478747 (17:3499296 G>A), RS1000538279 (17:3491056 G>A), RS1000568154 (17:3480018 T>C), RS1000969862 (17:3503187 A>G,T), RS1001010949 (17:3473318 T>G), RS1001099494 (17:3486460 C>T), RS1001107305 (17:3496803 A>G), RS1001207966 (17:3492059 T>C), RS1001258570 (17:3492299 T>A,C), RS1001307865 (17:3481211 GA>G), RS1001338969 (17:3481461 T>A,C)

Disease associations

OMIM: gene MIM:608034 | disease phenotypes: MIM:271900, MIM:219750, MIM:219900, MIM:209850, MIM:115200, MIM:617667

GenCC curated gene-disease

Disease	Classification	Inheritance
Canavan disease	Definitive	Autosomal recessive
severe Canavan disease	Supportive	Autosomal recessive
mild Canavan disease	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Canavan disease	Definitive	AR

Mondo (9): Canavan disease (MONDO:0010079), ocular cystinosis (MONDO:0009064), juvenile nephropathic cystinosis (MONDO:0009066), mild Canavan disease (MONDO:0017831), intellectual disability (MONDO:0001071), autism (MONDO:0005260), familial dilated cardiomyopathy (MONDO:0016333), Fraser syndrome 3 (MONDO:0054739), severe Canavan disease (MONDO:0017830)

Orphanet (7): Canavan disease (Orphanet:141), Cystinosis (Orphanet:213), Juvenile nephropathic cystinosis (Orphanet:411634), Ocular cystinosis (Orphanet:411641), Mild Canavan disease (Orphanet:314918), Familial dilated cardiomyopathy (Orphanet:217607), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

61 total (30 of 61 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000365	Hearing impairment
HP:0000505	Visual impairment
HP:0000510	Rod-cone dystrophy
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000737	Irritability
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001328	Specific learning disability
HP:0001344	Absent speech
HP:0001347	Hyperreflexia
HP:0001355	Megalencephaly
HP:0001387	Joint stiffness
HP:0001476	Delayed closure of the anterior fontanelle
HP:0001612	Weak cry
HP:0002013	Vomiting
HP:0002020	Gastroesophageal reflux
HP:0002033	Poor suck
HP:0002069	Bilateral tonic-clonic seizure
HP:0002179	Opisthotonus
HP:0002200	Pseudobulbar signs

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001712_57	Myopia (pathological)	4.000000e-16

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004207	pathological myopia

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D017825	Canavan Disease	C10.228.140.163.100.362.375; C10.228.140.695.625.375; C10.314.400.375; C10.574.500.300; C16.320.400.150; C16.320.565.189.362.375; C18.452.132.100.362.375; C18.452.648.189.362.375
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C562683	Cystinosis, Late-Onset Juvenile or Adolescent Nephropathic Type (supp.)
C535765	Cystinosis, ocular nonnephropathic (supp.)
C536231	familial dilated cardiomyopathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	decreases methylation, increases expression, increases methylation, affects expression	4
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Dexamethasone	increases expression, affects cotreatment	2
Nickel	decreases expression	2
Zinc	affects binding	2
Cyclosporine	decreases expression	2
bisphenol F	increases expression	1
alpha phellandrene	increases expression	1
pirinixic acid	increases activity, increases expression, affects binding	1
bisphenol A	affects cotreatment, increases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
sodium arsenite	affects methylation	1
1,10-phenanthroline	decreases activity	1
CGP 52608	affects binding, increases reaction	1
O,O-diethylphosphorylcholine iodide	decreases activity	1
quinocetone	increases expression	1
bisphenol S	increases expression	1
incobotulinumtoxinA	increases expression	1
Troglitazone	increases expression	1
Acetaminophen	decreases expression	1
Edetic Acid	decreases activity	1
Ethyl Methanesulfonate	increases expression	1
Folic Acid	decreases expression	1
Formaldehyde	increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Methyl Methanesulfonate	increases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases expression, increases methylation	1

Cellosaurus cell lines

20 cell lines: 10 induced pluripotent stem cell, 7 finite cell line, 3 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0P14	GM00059	Finite cell line	Female
CVCL_0P15	GM00060	Finite cell line	Male
CVCL_0P45	GM04268	Finite cell line	Male
CVCL_0P73	GM17821	Transformed cell line	Female
CVCL_0P74	GM18929	Transformed cell line	Male
CVCL_7415	GM04663	Finite cell line	Female
CVCL_A5RK	CD#59 ipsC	Induced pluripotent stem cell	Female
CVCL_A5RL	CD#60 ipsC	Induced pluripotent stem cell	Male
CVCL_A5RM	CD#68 iPSC	Induced pluripotent stem cell	Male
CVCL_A5RN	FF08711992	Finite cell line	Female

Clinical trials (associated diseases)

290 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
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With 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
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
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
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
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder