Aminoacylase 1 deficiency

Summary

Aminoacylase 1 deficiency (MONDO:0012368) is a disease caused by ACY1 (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: ACY1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 37
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		15	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001298	Encephalopathy	Frequent (30-79%)
HP:0003324	Generalized muscle weakness	Frequent (30-79%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002104	Apnea	Occasional (5-29%)
HP:0003396	Syringomyelia	Occasional (5-29%)
HP:0006817	Aplasia/Hypoplasia of the cerebellar vermis	Occasional (5-29%)
HP:0007370	Aplasia/Hypoplasia of the corpus callosum	Occasional (5-29%)
HP:0000316	Hypertelorism	Very rare (<1-4%)
HP:0000407	Sensorineural hearing impairment	Very rare (<1-4%)
HP:0000445	Wide nose	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	aminoacylase 1 deficiency
Mondo ID	MONDO:0012368
EFO	EFO:1001981
MeSH	C538246
OMIM	609924
Orphanet	137754
SNOMED CT	709282004
UMLS	C1835922
MedGen	324393
GARD	0009741
Is cancer (heuristic)	no

Also known as: ACY1 deficiency · ACY1D · aminoacylase 1 deficiency · deficiency of the aminoacylase-1 enzyme · N-acyl-L-amino acid amidohydrolase deficiency · neurological conditions associated with aminoacylase 1 deficiency

Data availability: 37 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › aminoacylase 1 deficiency

Related subtypes (32): disorder of methionine catabolism, inborn serine deficiency, cerebral creatine deficiency syndrome, inborn organic aciduria, gamma-amino butyric acid metabolism disorder, homocystinuria, urea cycle disorder, adenylosuccinate lyase deficiency, systemic primary carnitine deficiency disease, cystathioninuria, hyperlysinemia, Brunner syndrome, glycine encephalopathy, adenine phosphoribosyltransferase deficiency, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, inborn disorder of tryptophan metabolism, inborn disorder of proline metabolism, inborn disorder of ornithine metabolism, inborn disorder of amino acid transport, inborn disorder of histidine metabolism, inborn disorder of phenylalanine and tyrosine metabolism, inborn disorder of branched-chain amino acid metabolism, arakawa syndrome 2, 2-methylacetoacetyl CoA thiolase deficiency, albinism, hyperphenylalaninemia due to DNAJC12 deficiency, inborn disorder of the metabolism of sulfur-containing amino acids and hydrogen sulfide, inborn disorder of glycine and serine metabolism, inborn disorder of ornithine, proline and hydroxyproline metabolism, inborn disorder of glutamate/glutamine and aspartate/asparagine metabolism, hyperglycinemia, transient neonatal, tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

37 retrieved; paginated sample, class counts are floors:

16 uncertain significance, 9 conflicting classifications of pathogenicity, 5 likely pathogenic, 5 pathogenic, 1 benign/likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
162019	NM_000666.3(ACY1):c.1001_1001+5del	ABHD14A-ACY1	Pathogenic	no assertion criteria provided
18109	NM_000666.3(ACY1):c.1104_1105dup (p.Pro369fs)	ABHD14A-ACY1	Pathogenic	no assertion criteria provided
18112	NM_000666.3(ACY1):c.360-1G>A	ABHD14A-ACY1	Pathogenic	no assertion criteria provided
18113	NM_000666.3(ACY1):c.589C>T (p.Arg197Trp)	ABHD14A-ACY1	Pathogenic	no assertion criteria provided
3385014	NM_000666.3(ACY1):c.959C>G (p.Ser320Ter)	ABHD14A-ACY1	Pathogenic	criteria provided, single submitter
800812	NM_000666.3(ACY1):c.575dup (p.Ser192fs)	ABHD14A-ACY1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1696695	NM_000666.3(ACY1):c.734_735del (p.Glu245fs)	ABHD14A-ACY1	Likely pathogenic	criteria provided, single submitter
2682251	NM_000666.3(ACY1):c.160-1G>A	ABHD14A-ACY1	Likely pathogenic	criteria provided, single submitter
4845703	NM_000666.3(ACY1):c.759_762del (p.Thr254fs)	ABHD14A-ACY1	Likely pathogenic	criteria provided, single submitter
1177326	NM_001101.5(ACTB):c.587G>T (p.Arg196Leu)	ACTB	Likely pathogenic	criteria provided, multiple submitters, no conflicts
4849441	NM_000666.3(ACY1):c.526+1G>A	ACY1	Likely pathogenic	criteria provided, single submitter
1029931	NM_000666.3(ACY1):c.437-19G>A	ABHD14A-ACY1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1335986	NM_000666.3(ACY1):c.480_493dup (p.His165fs)	ABHD14A-ACY1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
18110	NM_000666.3(ACY1):c.1057C>T (p.Arg353Cys)	ABHD14A-ACY1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
18111	NM_000666.3(ACY1):c.699A>C (p.Glu233Asp)	ABHD14A-ACY1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
493363	NM_000666.3(ACY1):c.1132C>T (p.Arg378Trp)	ABHD14A-ACY1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
709571	NM_000666.3(ACY1):c.1100G>A (p.Arg367His)	ABHD14A-ACY1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
726734	NM_000666.3(ACY1):c.1177C>T (p.Arg393Cys)	ABHD14A-ACY1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
712435	NM_000666.3(ACY1):c.1156C>T (p.Arg386Cys)	ACY1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
998091	NM_022095.4(ZNF335):c.3346G>A (p.Gly1116Arg)	ZNF335	Conflicting classifications of pathogenicity	no assertion criteria provided
1029929	NM_000666.3(ACY1):c.1201G>T (p.Val401Leu)	ABHD14A-ACY1	Uncertain significance	criteria provided, single submitter
1029930	NM_000666.3(ACY1):c.19G>C (p.Glu7Gln)	ABHD14A-ACY1	Uncertain significance	criteria provided, single submitter
1029932	NM_000666.3(ACY1):c.921+21A>T	ABHD14A-ACY1	Uncertain significance	criteria provided, single submitter
1185137	NM_000666.3(ACY1):c.94+11G>A	ABHD14A-ACY1	Uncertain significance	no assertion criteria provided
1691556	NM_000666.3(ACY1):c.1058G>A (p.Arg353His)	ABHD14A-ACY1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2259561	NM_000666.3(ACY1):c.836C>T (p.Pro279Leu)	ABHD14A-ACY1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3236441	NM_000666.3(ACY1):c.19G>A (p.Glu7Lys)	ABHD14A-ACY1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3382086	NM_000666.3(ACY1):c.348C>A (p.Cys116Ter)	ABHD14A-ACY1	Uncertain significance	criteria provided, single submitter
3382087	NM_000666.3(ACY1):c.583+1G>A	ABHD14A-ACY1	Uncertain significance	criteria provided, single submitter
3589457	NM_000666.3(ACY1):c.91T>A (p.Tyr31Asn)	ABHD14A-ACY1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 7 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ACY1	Definitive	Autosomal recessive	aminoacylase 1 deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACY1	Orphanet:137754	Aminoacylase 1 deficiency
ACTB	Orphanet:2995	Baraitser-Winter cerebrofrontofacial syndrome
ACTB	Orphanet:64755	Becker nevus syndrome
ACTB	Orphanet:673556	Pseudomyogenic hemangioendothelioma
ACTB	Orphanet:674653	Actinomyopathy-associated syndromic thrombocytopenia
ACTB	Orphanet:79107	Developmental malformations-deafness-dystonia syndrome
ZNF335	Orphanet:329228	Microcephalic primordial dwarfism due to ZNF335 deficiency

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACY1	HGNC:177	ENSG00000243989	Q03154	Aminoacylase-1	gencc,clinvar
ACTB	HGNC:132	ENSG00000075624	P60709	Actin, cytoplasmic 1	clinvar
ZNF335	HGNC:15807	ENSG00000198026	Q9H4Z2	Zinc finger protein 335	clinvar
ABHD14A-ACY1	HGNC:38856	ENSG00000114786		ABHD14A-ACY1 readthrough	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACY1	Aminoacylase-1	Aminoacylase involved in the hydrolysis of N-acetylated and N-formylated amino acids.
ACTB	Actin, cytoplasmic 1	Actin is a highly conserved protein that polymerizes to produce filaments that form cross-linked networks in the cytoplasm of cells.
ZNF335	Zinc finger protein 335	Component or associated component of some histone methyltransferase complexes may regulate transcription through recruitment of those complexes on gene promoters.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.25

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	9.2×	0.315
Transcription factor	1	2.1×	0.605
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACY1	Protease	yes	3.5.1.14	ArgE/DapE_CS, Peptidase_M20, N-acyl_aa_amidohydrolase
ACTB	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
ZNF335	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Zinc_finger/UBP_domain
ABHD14A-ACY1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

4 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	2
adult mammalian kidney	1
duodenum	1
postcentral gyrus	1
saphenous vein	1
urethra	1
cerebellar hemisphere	1
granulocyte	1
right hemisphere of cerebellum	1
liver	1
male germ line stem cell (sensu Vertebrata) in testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACY1	134	ubiquitous	marker	duodenum, right lobe of liver, adult mammalian kidney
ACTB	295	ubiquitous	marker	urethra, postcentral gyrus, saphenous vein
ZNF335	199	ubiquitous	marker	granulocyte, right hemisphere of cerebellum, cerebellar hemisphere
ABHD14A-ACY1	133	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, right lobe of liver, liver

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACTB	2,212
ACY1	1,998
ZNF335	1,156
ABHD14A-ACY1	0

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACTB	P60709	88
ACY1	Q03154	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ZNF335	Q9H4Z2	52.13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 109. Enrichment computed across 4 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ACY1 causes encephalopathy	1	3806.7×	0.028	ACY1
Folding of actin by CCT/TriC	1	380.7×	0.028	ACTB
Formation of annular gap junctions	1	346.1×	0.028	ACTB
GBP-mediated host defense	1	346.1×	0.028	ACTB
Gap junction degradation	1	317.2×	0.028	ACTB
Regulation of CDH1 Function	1	317.2×	0.028	ACTB
Metabolic disorders of biological oxidation enzymes	1	292.8×	0.028	ACY1
Cell-extracellular matrix interactions	1	223.9×	0.028	ACTB
Formation of the non-canonical BAF (ncBAF) complex	1	223.9×	0.028	ACTB
Aflatoxin activation and detoxification	1	211.5×	0.028	ACY1
Formation of the canonical BAF (cBAF) complex	1	211.5×	0.028	ACTB
Formation of the polybromo-BAF (pBAF) complex	1	211.5×	0.028	ACTB
Formation of the embryonic stem cell BAF (esBAF) complex	1	200.3×	0.028	ACTB
Gap junction trafficking and regulation	1	158.6×	0.028	ACTB
Gap junction trafficking	1	158.6×	0.028	ACTB
Global Genome Nucleotide Excision Repair (GG-NER)	1	152.3×	0.028	ACTB
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	1	152.3×	0.028	ACTB
Signaling by RAS mutants	1	141.0×	0.028	ACTB
Paracetamol ADME	1	141.0×	0.028	ACY1
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	1	135.9×	0.028	ACTB
Prefoldin mediated transfer of substrate to CCT/TriC	1	131.3×	0.028	ACTB
Interaction between L1 and Ankyrins	1	122.8×	0.028	ACTB
Regulation of endogenous retroelements	1	122.8×	0.028	ACTB
Positive epigenetic regulation of rRNA expression	1	115.3×	0.028	ACTB
RHO GTPases activate IQGAPs	1	115.3×	0.028	ACTB
Parasite infection	1	115.3×	0.028	ACTB
Leishmania phagocytosis	1	115.3×	0.028	ACTB
RHO GTPases Activate WASPs and WAVEs	1	105.7×	0.028	ACTB
Signaling by high-kinase activity BRAF mutants	1	105.7×	0.028	ACTB
Sensory processing of sound	1	102.9×	0.028	ACTB

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of norepinephrine uptake	1	5617.3×	0.004	ACTB
cellular response to cytochalasin B	1	5617.3×	0.004	ACTB
regulation of norepinephrine uptake	1	2808.7×	0.005	ACTB
morphogenesis of a polarized epithelium	1	1404.3×	0.007	ACTB
regulation of transepithelial transport	1	1404.3×	0.007	ACTB
protein localization to adherens junction	1	1123.5×	0.007	ACTB
positive regulation of lymphocyte proliferation	1	624.1×	0.011	ZNF335
adherens junction assembly	1	432.1×	0.012	ACTB
cerebral cortex neuron differentiation	1	401.2×	0.012	ZNF335
apical protein localization	1	330.4×	0.012	ACTB
regulation of synaptic vesicle endocytosis	1	295.6×	0.012	ACTB
amino acid metabolic process	1	267.5×	0.012	ACY1
brain morphogenesis	1	244.2×	0.012	ZNF335
regulation of G0 to G1 transition	1	224.7×	0.012	ACTB
regulation of protein localization to plasma membrane	1	216.1×	0.012	ACTB
regulation of nucleotide-excision repair	1	200.6×	0.012	ACTB
positive regulation of neuroblast proliferation	1	193.7×	0.012	ZNF335
positive regulation of neurogenesis	1	193.7×	0.012	ZNF335
regulation of double-strand break repair	1	193.7×	0.012	ACTB
regulation of mitotic metaphase/anaphase transition	1	165.2×	0.013	ACTB
maintenance of blood-brain barrier	1	160.5×	0.013	ACTB
positive regulation of T cell differentiation	1	151.8×	0.013	ACTB
establishment or maintenance of cell polarity	1	133.8×	0.013	ACTB
cell motility	1	133.8×	0.013	ACTB
epigenetic regulation of gene expression	1	127.7×	0.013	ZNF335
positive regulation of double-strand break repair via homologous recombination	1	127.7×	0.013	ACTB
substantia nigra development	1	122.1×	0.013	ACTB
positive regulation of myoblast differentiation	1	122.1×	0.013	ACTB
positive regulation of stem cell population maintenance	1	114.6×	0.013	ACTB
positive regulation of double-strand break repair	1	114.6×	0.013	ACTB

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 3

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACTB	1	2
ACY1	0	0
ZNF335	0	0
ABHD14A-ACY1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	ACTB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ACTB	21	Binding:21

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACY1	3.5.1.14	N-acyl-aliphatic-L-amino acid amidohydrolase

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	ACTB

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	ACTB
C	Druggable family + PDB, no drug	1	ACY1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	ZNF335, ABHD14A-ACY1

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ACY1	0	—
ZNF335	0	—
ABHD14A-ACY1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.