ACR

Summary

ACR (acrosin, HGNC:126) is a protein-coding gene on chromosome 22q13.33, encoding Acrosin (P10323). Acrosin is the major protease of mammalian spermatozoa.

Acrosin is the major proteinase present in the acrosome of mature spermatozoa. It is a typical serine proteinase with trypsin-like specificity. It is stored in the acrosome in its precursor form, proacrosin. The active enzyme functions in the lysis of the zona pellucida, thus facilitating penetration of the sperm through the innermost glycoprotein layers of the ovum. The mRNA for proacrosin is synthesized only in the postmeiotic stages of spermatogenesis. In humans proacrosin first appears in the haploid spermatids.

Source: NCBI Gene 49 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 197 total — 102 pathogenic
• Phenotypes (HPO): 4
• Druggable target: yes
• MANE Select transcript: NM_001097

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:126
Approved symbol	ACR
Name	acrosin
Location	22q13.33
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000100312
Ensembl biotype	protein_coding
OMIM	102480
Entrez	49

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000216139, ENST00000527761, ENST00000529621, ENST00000533930

RefSeq mRNA: 1 — MANE Select: NM_001097 NM_001097

CCDS: CCDS14101

Canonical transcript exons

ENST00000216139 — 5 exons

Exon	Start	End
ENSE00000657865	50744061	50744206
ENSE00000935813	50739694	50739977
ENSE00001294892	50744653	50745339
ENSE00003676371	50738204	50738312
ENSE00003680460	50739271	50739474

Expression profiles

Bgee: expression breadth ubiquitous, 121 present calls, max score 95.94.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3868 / max 396.0526, expressed in 4 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193055	0.3868	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	95.94	gold quality
testis	UBERON:0000473	95.75	gold quality
right testis	UBERON:0004534	95.64	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.52	gold quality
subcutaneous adipose tissue	UBERON:0002190	75.89	gold quality
mucosa of stomach	UBERON:0001199	73.87	gold quality
spleen	UBERON:0002106	72.55	gold quality
upper lobe of left lung	UBERON:0008952	72.28	gold quality
right lung	UBERON:0002167	72.05	gold quality
adipose tissue	UBERON:0001013	72.00	gold quality
thoracic mammary gland	UBERON:0005200	70.91	gold quality
gastrocnemius	UBERON:0001388	68.58	gold quality
apex of heart	UBERON:0002098	68.55	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	68.24	gold quality
left uterine tube	UBERON:0001303	67.79	gold quality
omental fat pad	UBERON:0010414	67.59	gold quality
muscle of leg	UBERON:0001383	66.90	gold quality
ectocervix	UBERON:0012249	66.28	gold quality
right uterine tube	UBERON:0001302	66.03	gold quality
skin of leg	UBERON:0001511	65.71	gold quality
tibial nerve	UBERON:0001323	64.85	gold quality
body of uterus	UBERON:0009853	64.70	gold quality
zone of skin	UBERON:0000014	64.49	gold quality
myometrium	UBERON:0001296	64.28	gold quality
skin of abdomen	UBERON:0001416	63.27	gold quality
lower esophagus muscularis layer	UBERON:0035833	63.26	gold quality
lower esophagus	UBERON:0013473	63.23	gold quality
lung	UBERON:0002048	63.21	gold quality
cortex of kidney	UBERON:0001225	63.07	gold quality
fallopian tube	UBERON:0003889	62.52	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.20

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREM, SREBF2, YY1

Literature-anchored findings (GeneRIF, showing 19)

• a constitutively active arrestin mutant can both induce agonist-independent internalization and stabilize the agonist-high affinity state of an arrestin-insensitive G protein coupled receptor. (PMID:12695524)
• news: beta-arrestin is now identified as a regulator of ubiquination and degradation of the Notch receptor (PMID:16319967)
• data suggest a novel model of arrestin-2 regulation mediated by inositol hexakisphosphate (PMID:16439357)
• Data show that the endocytic adapter protein AP-2 is essential for rhodopsin endocytosis through an arrestin2-AP-2beta interaction. (PMID:16835270)
• CaMKII is involved in the negative regulation of the visual response affecting light adaptation, possibly by catalyzing phosphorylation of Arr2 (PMID:19254957)
• We developed a steady-state stochastic model to interpret the dependence of the PDA on effective light intensity and arrestin content and to help deduce the arrestin to rhodopsin ratio from the sensitivity and PDA data. (PMID:19924417)
• Findings demonstrate that light-induced translocation of Arr2 occurs through a noncanonical rhodopsin/Rac2 pathway, which is distinct from the classical phototransduction cascade. (PMID:20176938)
• This study indicated that Arr2 translocation in Drosophila photoreceptors is driven by diffusion, but profoundly accelerated by phototransduction and Ca2+ influx. (PMID:20869596)
• Rapid calcium/calmodulin-dependent release of arrestin (Arr)2 from NINAC upon Ca2+ influx accounts for the acceleration of translocation by phototransduction. (PMID:22764229)
• identify a previously uncharacterized enzyme of ecdysone biosynthesis, GstE14, and find that ecdysone triggers pri expression to define the onset of epidermal trichome development (PMID:25344753)
• The pleiotropic functions of Pri smORF peptides synchronize leg development regulators. (PMID:37903161)
• crystal structure of an inactive T4 endo VII(N62D) complexed with an immobile four-way junction with alternating arm lengths of 10 and 14 base pairs (PMID:17873859)
• endo VII is the enzyme that recognizes mismatches in recombinational heteroduplexes and performs their incision (PMID:21237725)
• Binding sites for recombinant human zona pellucida (ZP) glycoproteins located at the N- and C-termini of proacrosin reveal a key role of the proenzyme in the interaction. (PMID:15950651)
• DNA immunization against proacrosin impairs fertility in male mice. (PMID:22452365)
• Sperm DNA damage is closely related with sperm-nucleoprotein transition, acrosin activity and seminal parameters. (PMID:23297503)
• Data indicate that the positive expression of studied genes fertilization rate for GAPDHS positive subset was 66%, ACR - 71%, SPATA22 - 68%, MND1 - 70%, pregnancy rates were 8%, 6%, 18% and 36% respectively. (PMID:23675907)
• Study revealed significantly higher acrosin activity and a lower DNA fragmentation index in subjects with moderate or high mitochondrial membrane potential (MMP) compared to those with low MMP. (PMID:30428044)
• Low acrosin activity is associated with decreased Spam1/acrosin expression and GSH deficiency-caused premature acrosome release of human sperm cells. (PMID:37833433)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Acr	ENSMUSG00000022622
rattus_norvegicus	Acr	ENSRNOG00000029762

Protein

Protein identifiers

Acrosin — P10323 (reviewed: P10323)

All UniProt accessions (2): P10323, E9PLV5

UniProt curated annotations — full annotation on UniProt →

Function. Acrosin is the major protease of mammalian spermatozoa. It is a serine protease of trypsin-like cleavage specificity, it is synthesized in a zymogen form, proacrosin and stored in the acrosome.

Subunit / interactions. Heavy chain (catalytic) and a light chain linked by two disulfide bonds. Forms a heterodimer with SERPINA5.

Disease relevance. Spermatogenic failure 87 (SPGF87) [MIM:620500] An autosomal recessive male infertility disorder characterized by inability of mutant sperm to penetrate the zona pellucida, resulting in fertilization failure. The disease may be caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by SERPINA5.

Similarity. Belongs to the peptidase S1 family.

RefSeq proteins (1): NP_001088* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR012267	Pept_S1A_acrosin	Family
IPR018114	TRYPSIN_HIS	Active_site
IPR033116	TRYPSIN_SER	Active_site
IPR043504

Pfam: PF00089

Enzyme classification (BRENDA):

• EC 3.4.21.10 — acrosin (BRENDA: 49 organisms, 36 substrates, 243 inhibitors, 9 Km, 4 kcat entries)

Substrate kinetics (BRENDA)

9 substrates with measured Km, best-characterized 9. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
AMINOBENZOYL-SER-LYS-GLY-ARG-SER-LEU-ILE-GLY-LYS	0.022	1
NALPHA-BENZOYL-DL-LYSINE P-NITROANILIDE	0.65	1
NALPHA-BENZOYL-L-ARGININE 2-NAPHTHYLAMIDE	2.7	1
NALPHA-BENZOYL-L-ARGININE ETHYL ESTER	0.44	1
NALPHA-BENZOYL-L-ARGININE ETHYL ESTER HYDROCHLOR	0.28	1
NALPHA-BENZOYL-L-ARGININE P-NITROANILIDE	1.1	1
NALPHA-TOSYL-L-ARGININE METHYL ESTER	0.77	1
TOLUENE-P-SULFONYL-L-ARGININE METHYL ESTER	0.021	1
METHYL N2-[(4-METHYLPHENYL)SULFONYL]-L-ARGININAT	—	0

UniProt features (32 total): disulfide bond 6, sequence conflict 5, compositionally biased region 4, chain 3, active site 3, sequence variant 3, region of interest 3, glycosylation site 2, signal peptide 1, propeptide 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10323-F1	80.10	0.53

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 (3): 88 (charge relay system); 142 (charge relay system); 240 (charge relay system)

Disulfide bonds (6): 25–154, 29–162, 73–89, 177–246, 209–225, 236–266

Glycosylation sites (2): 22, 210

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1300645	Acrosome Reaction and Sperm:Oocyte Membrane Binding
R-HSA-1187000	Fertilization
R-HSA-1474165	Reproduction

MSigDB gene sets: 129 (showing top): GOBP_SINGLE_FERTILIZATION, MODULE_52, GOCC_SECRETORY_GRANULE, MODULE_45, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_LYASE_ACTIVITY, TGACCTY_ERR1_Q2, MODULE_16, GGGTGGRR_PAX4_03, MODULE_118, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_REGULATION_OF_ADENYLATE_CYCLASE_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, TGCTGAY_UNKNOWN, GOBP_SPERM_EGG_RECOGNITION

GO Biological Process (9): acrosome matrix dispersal (GO:0002077), activation of adenylate cyclase activity (GO:0007190), single fertilization (GO:0007338), binding of sperm to zona pellucida (GO:0007339), acrosome reaction (GO:0007340), penetration of zona pellucida (GO:0007341), response to steroid hormone (GO:0048545), proteolysis (GO:0006508), protein catabolic process (GO:0030163)

GO Molecular Function (12): protease binding (GO:0002020), DNA binding (GO:0003677), amidase activity (GO:0004040), serine-type endopeptidase activity (GO:0004252), copper ion binding (GO:0005507), D-mannose binding (GO:0005537), serine-type peptidase activity (GO:0008236), zinc ion binding (GO:0008270), fucose binding (GO:0042806), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (6): extracellular region (GO:0005576), nucleus (GO:0005634), Golgi-associated vesicle (GO:0005798), protein-containing complex (GO:0032991), acrosomal matrix (GO:0043159), acrosomal vesicle (GO:0001669)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Fertilization	1
Reproduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
single fertilization	2
protein metabolic process	2
transition metal ion binding	2
monosaccharide binding	2
cellular anatomical structure	2
acrosome reaction	1
protein catabolic process	1
positive regulation of adenylate cyclase activity	1
fertilization	1
sperm-egg recognition	1
membrane fusion involved in acrosome reaction	1
reproductive process	1
acrosomal vesicle exocytosis	1
multi-multicellular organism process	1
multicellular organismal reproductive process	1
response to hormone	1
response to lipid	1
macromolecule catabolic process	1
enzyme binding	1
nucleic acid binding	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amides	1
endopeptidase activity	1
serine-type peptidase activity	1
peptidase activity	1
serine hydrolase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
intracellular membrane-bounded organelle	1
cytoplasmic vesicle	1
cellular_component	1
acrosomal vesicle	1
vacuole	1
secretory granule	1

Protein interactions and networks

STRING

1332 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACR	ZP2	Q05996	796
ACR	SPATA16	Q9BXB7	729
ACR	TNP1	P09430	712
ACR	D6RI10	D6RI10	694
ACR	ACRBP	Q8NEB7	654
ACR	BOLL	Q8N9W6	652
ACR	CREM	Q03060	590
ACR	SYCP3	Q8IZU3	573
ACR	IZUMO1	Q8IYV9	564
ACR	SPA17	Q15506	560
ACR	ZAN	Q9Y493	557
ACR	DAZL	Q92904	551
ACR	STRA8	Q7Z7C7	549
ACR	ZP3	P21754	547
ACR	ADGRA3	Q8IWK6	546

IntAct

11 interactions, top by confidence:

A	B	Type	Score
ZP4	ACR	psi-mi:“MI:0407”(direct interaction)	0.440
ZP3	ACR	psi-mi:“MI:0407”(direct interaction)	0.440
ZP2	ACR	psi-mi:“MI:0407”(direct interaction)	0.440
GSK3A	PRSS37	psi-mi:“MI:0914”(association)	0.350
GSK3B	PRSS37	psi-mi:“MI:0914”(association)	0.350

BioGRID (7): ACR (Reconstituted Complex), ACR (Affinity Capture-MS), ACR (Positive Genetic), ACR (Affinity Capture-MS), ACR (Affinity Capture-MS), ACR (Two-hybrid), ACR (Affinity Capture-Western)

ESM2 similar proteins: A0A126GUP6, A0A1S4GMJ4, A0A1S4H5M5, A0A1S4H5S2, A0A1S4HE51, A0A6I8TBG6, A8JUP7, B3A0R6, F5HKX0, G5ECX0, O15393, O16977, P05049, P08001, P08471, P0CV23, P10323, P21997, P23578, P28175, P29293, P31178, P35443, P48038, P49744, P55114, Q05319, Q17800, Q19040, Q21059, Q26422, Q27081, Q3UQ41, Q4QXT9, Q7JLI1, Q7K5M0, Q804X6, Q8I6K0, Q8MZM7, Q93118

Diamond homologs: A0A126GUP6, A0A182C2Z2, A0A1S4H5M5, A8JUP7, B5U2W0, B7YZU2, F5HKX0, O15393, O35453, O60235, O60259, O97366, P00774, P03951, P03952, P05049, P05981, P08419, P09871, P10323, P13582, P14272, P21902, P23578, P25155, P26262, P28175, P29293, P31394, P33587, P35035, P35036, P35037, P35039, P35041, P35045, P35046, P35047, P40313, P48038

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	102
Likely pathogenic	0
Uncertain significance	78
Likely benign	6
Benign	6

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1047893	GRCh37/hg19 22q13.33(chr22:51123491-51219009)	Pathogenic
1180542	GRCh37/hg19 22q13.33(chr22:50099570-51187115)x1	Pathogenic
1328103	GRCh37/hg19 22q13.33(chr22:50984491-51179298)x1	Pathogenic
1340060	GRCh37/hg19 22q13.31-13.33(chr22:47567951-51183840)x1	Pathogenic
144377	GRCh38/hg38 22q13.33(chr22:49378128-50739836)x1	Pathogenic
146310	GRCh38/hg38 22q13.31-13.33(chr22:46919818-50739836)x1	Pathogenic
146391	GRCh38/hg38 22q13.33(chr22:49504768-50780581)x1	Pathogenic
147377	GRCh38/hg38 22q13.31-13.33(chr22:44797239-50739836)x3	Pathogenic
147807	GRCh38/hg38 22q13.32-13.33(chr22:48614336-50739836)x1	Pathogenic
148302	GRCh38/hg38 22q13.32-13.33(chr22:48500344-50780581)x1	Pathogenic
149104	GRCh38/hg38 22q13.33(chr22:50694375-50780581)x1	Pathogenic
150859	GRCh38/hg38 22q13.33(chr22:49535113-50780581)x1	Pathogenic
151373	GRCh38/hg38 22q13.33(chr22:50149563-50780522)x1	Pathogenic
151977	GRCh38/hg38 22q13.33(chr22:50685063-50780581)x1	Pathogenic
152137	GRCh38/hg38 22q13.31-13.33(chr22:46732445-50780522)x1	Pathogenic
152340	GRCh38/hg38 22q13.2-13.33(chr22:43187980-50745444)x1	Pathogenic
1526745	GRCh37/hg19 22q13.33(chr22:49729747-51197838)	Pathogenic
1526747	GRCh37/hg19 22q13.33(chr22:51121452-51183872)	Pathogenic
1526748	GRCh37/hg19 22q13.33(chr22:51127903-51197838)	Pathogenic
1526749	GRCh37/hg19 22q13.33(chr22:51147983-51183871)	Pathogenic
153560	GRCh38/hg38 22q13.33(chr22:50689468-50759410)x1	Pathogenic
155057	GRCh38/hg38 22q13.33(chr22:50682932-50745412)x1	Pathogenic
155420	GRCh38/hg38 22q13.31-13.33(chr22:46361165-50759299)x1	Pathogenic
155641	GRCh38/hg38 22q13.33(chr22:49529760-50759410)x1	Pathogenic
160852	GRCh38/hg38 22q13.33(chr22:50685063-50739836)x1	Pathogenic
161055	GRCh38/hg38 22q13.33(chr22:50658268-50739836)x1	Pathogenic
1703238	Single allele	Pathogenic
1703550	GRCh37/hg19 22q13.33(chr22:51121452-51197838)	Pathogenic
1703551	GRCh37/hg19 22q13.33(chr22:49602454-51183869)	Pathogenic
1803808	GRCh37/hg19 22q13.2-13.33(chr22:43436847-51188164)x3	Pathogenic

SpliceAI

607 predictions. Top by Δscore:

Variant	Effect	Δscore
22:50739692:A:AG	acceptor_gain	1.0000
22:50739693:G:GG	acceptor_gain	1.0000
22:50739693:GTAAT:G	acceptor_gain	1.0000
22:50739831:G:T	donor_gain	1.0000
22:50738307:GT:G	donor_gain	0.9900
22:50738311:GA:G	donor_gain	0.9900
22:50738313:G:GG	donor_gain	0.9900
22:50739693:GTA:G	acceptor_gain	0.9900
22:50744059:A:AG	acceptor_gain	0.9900
22:50744060:G:GG	acceptor_gain	0.9900
22:50744203:CCAGG:C	donor_loss	0.9900
22:50744204:CAGGT:C	donor_loss	0.9900
22:50744205:AGGTA:A	donor_loss	0.9900
22:50744206:GGT:G	donor_loss	0.9900
22:50744207:G:C	donor_loss	0.9900
22:50744208:T:A	donor_loss	0.9900
22:50738309:GTGA:G	donor_gain	0.9800
22:50739269:A:AG	acceptor_gain	0.9800
22:50739270:G:GG	acceptor_gain	0.9800
22:50744059:AGC:A	acceptor_loss	0.9800
22:50744060:G:C	acceptor_loss	0.9800
22:50744060:GCCCC:G	acceptor_gain	0.9800
22:50739269:AGT:A	acceptor_gain	0.9700
22:50739270:GT:G	acceptor_gain	0.9700
22:50739270:GTG:G	acceptor_gain	0.9700
22:50739693:GT:G	acceptor_gain	0.9700
22:50740531:C:G	donor_gain	0.9700
22:50739915:C:T	donor_gain	0.9600
22:50740500:GC:G	donor_gain	0.9600
22:50743021:AGAG:A	donor_gain	0.9600

AlphaMissense

2697 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:50739958:G:C	W182C	0.999
22:50739958:G:T	W182C	0.999
22:50744120:T:A	C209S	0.999
22:50744121:G:A	C209Y	0.999
22:50744121:G:C	C209S	0.999
22:50744201:T:A	C236S	0.999
22:50744202:G:C	C236S	0.999
22:50744737:T:A	C266S	0.999
22:50744738:G:C	C266S	0.999
22:50744793:G:C	W284C	0.999
22:50744793:G:T	W284C	0.999
22:50744122:T:G	C209W	0.998
22:50744168:T:A	C225S	0.998
22:50744169:G:C	C225S	0.998
22:50744202:G:A	C236Y	0.998
22:50739842:G:C	A144P	0.997
22:50739956:T:A	W182R	0.997
22:50739956:T:C	W182R	0.997
22:50744120:T:C	C209R	0.997
22:50744121:G:T	C209F	0.997
22:50744169:G:A	C225Y	0.997
22:50744203:C:G	C236W	0.997
22:50744738:G:A	C266Y	0.997
22:50739459:G:A	C89Y	0.996
22:50739460:C:G	C89W	0.996
22:50744137:G:C	W214C	0.996
22:50744137:G:T	W214C	0.996
22:50744168:T:C	C225R	0.996
22:50744170:C:G	C225W	0.996
22:50744186:G:T	G231C	0.996

dbSNP variants (sampled 300 via entrez): RS1000049898 (22:50743702 C>T), RS1000082147 (22:50743462 C>T), RS1002439534 (22:50738762 G>C), RS1002463827 (22:50737410 G>A,T), RS1002648495 (22:50742462 T>C,G), RS1002937072 (22:50736259 A>C), RS1003271074 (22:50737656 C>T), RS1003878132 (22:50743761 A>G), RS1004107506 (22:50744321 C>A), RS1004569051 (22:50744478 C>A), RS1004621379 (22:50740683 C>A), RS1004947597 (22:50739023 C>T), RS1005012977 (22:50739190 C>A,G), RS1005348788 (22:50740174 G>A,C,T), RS1005527134 (22:50743147 T>C,G)

Disease associations

OMIM: gene MIM:102480 | disease phenotypes: MIM:209850, MIM:615538, MIM:606232, MIM:620500

GenCC curated gene-disease

Mondo (7): autism (MONDO:0005260), chromosome 22q13 duplication syndrome (MONDO:0014235), Phelan-McDermid syndrome (MONDO:0011652), epilepsy (MONDO:0005027), autism spectrum disorder (MONDO:0005258), spermatogenic failure 87 (MONDO:0957594), intellectual disability (MONDO:0001071)

Orphanet (3): Phelan-McDermid syndrome (Orphanet:48652), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

4 total (5 of 4 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0003251	Male infertility
HP:0011462	Young adult onset
HP:6000501	Ruffled acrosome
HP:0000717	Autism

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D004827	Epilepsy	C10.228.140.490
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C536801	Telomeric 22q13 Monosomy Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2738 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — S1: Chymotrypsin

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 9 [PMID: 3514912]	Inhibition	8.48	pIC50

ChEMBL bioactivities

47 potent at pChembl≥5 of 82 total, top 47 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.17	IC50	0.67	nM	CHEMBL554140
8.92	IC50	1.2	nM	CHEMBL151747
8.52	IC50	3	nM	CHEMBL357455
8.48	IC50	3.3	nM	CHEMBL151454
8.46	IC50	3.5	nM	CHEMBL358868
8.27	IC50	5.4	nM	CHEMBL542258
8.25	IC50	5.6	nM	CHEMBL149324
8.18	IC50	6.6	nM	CHEMBL149135
8.14	IC50	7.2	nM	CHEMBL542261
8.10	IC50	8	nM	CHEMBL539058
8.03	IC50	9.3	nM	CHEMBL540096
7.94	IC50	11.4	nM	CHEMBL147344
7.89	IC50	12.9	nM	CHEMBL148957
7.86	IC50	13.7	nM	CHEMBL149157
7.79	IC50	16.3	nM	CHEMBL148731
7.75	IC50	17.6	nM	CHEMBL357708
7.70	IC50	19.8	nM	CHEMBL543454
7.56	IC50	27.3	nM	CHEMBL148833
7.54	IC50	28.5	nM	CHEMBL146905
7.48	IC50	33	nM	CHEMBL356950
7.42	IC50	38.5	nM	CHEMBL150009
7.00	IC50	99.7	nM	CHEMBL440176
6.52	IC50	300	nM	CHEMBL545564
6.52	IC50	300	nM	CHEMBL149156
5.90	IC50	1260	nM	CHEMBL3596546
5.85	IC50	1400	nM	CHEMBL3287446
5.64	IC50	2300	nM	CHEMBL3287445
5.62	IC50	2380	nM	CHEMBL3596545
5.62	IC50	2420	nM	CHEMBL3596567
5.62	IC50	2410	nM	CHEMBL1195245
5.46	IC50	3440	nM	CHEMBL3596564
5.37	IC50	4320	nM	CHEMBL3596563
5.24	IC50	5700	nM	CHEMBL3287450
5.24	IC50	5730	nM	CHEMBL3596551
5.23	IC50	5870	nM	CHEMBL3596562
5.19	IC50	6400	nM	CHEMBL3287455
5.18	IC50	6600	nM	CHEMBL3287459
5.13	IC50	7470	nM	CHEMBL3596558
5.11	IC50	7800	nM	CHEMBL3287448
5.08	IC50	8400	nM	CHEMBL3287458
5.07	IC50	8450	nM	CHEMBL3596556
5.03	IC50	9300	nM	CHEMBL3287447
5.03	IC50	9400	nM	CHEMBL3287462
5.03	IC50	9430	nM	CHEMBL3596547
5.02	IC50	9460	nM	CHEMBL3596554
5.00	IC50	1e+04	nM	CHEMBL2397955
5.00	IC50	1.01e+04	nM	CHEMBL3287449

PubChem BioAssay actives

34 with measured affinity, of 243 total; 34 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(4-methoxycarbonylphenyl) 4-(diaminomethylideneamino)benzoate;hydrochloride	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.0007	uM
(4-cyanophenyl) 4-(diaminomethylideneamino)benzoate;4-methylbenzenesulfonic acid	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.0012	uM
(4-chlorophenyl) 4-(diaminomethylideneamino)benzoate;4-methylbenzenesulfonic acid	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.0030	uM
(4-methylphenyl) 4-(diaminomethylideneamino)benzoate	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.0033	uM
(4-bromophenyl) 4-(diaminomethylideneamino)benzoate;4-methylbenzenesulfonic acid	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.0035	uM
methyl 3-[4-(diaminomethylideneamino)benzoyl]oxybenzoate;hydrochloride	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.0054	uM
phenyl 4-(diaminomethylideneamino)benzoate	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.0056	uM
(4-propan-2-ylphenyl) 4-(diaminomethylideneamino)benzoate	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.0066	uM
(3-cyanophenyl) 4-(diaminomethylideneamino)benzoate;hydrochloride	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.0072	uM
(4-acetamidophenyl) 4-(diaminomethylideneamino)benzoate;hydrochloride	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.0080	uM
(4-ethoxycarbonylphenyl) 4-(diaminomethylideneamino)benzoate;hydrochloride	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.0093	uM
(4-butoxyphenyl) 4-(diaminomethylideneamino)benzoate	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.0114	uM
methyl 2-[4-(diaminomethylideneamino)benzoyl]oxybenzoate	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.0129	uM
(2-methoxy-4-prop-2-enylphenyl) 4-(diaminomethylideneamino)benzoate	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.0137	uM
(4-methoxyphenyl) 4-(diaminomethylideneamino)benzoate	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.0163	uM
(3-methoxyphenyl) 4-(diaminomethylideneamino)benzoate	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.0176	uM
quinolin-8-yl 4-(diaminomethylideneamino)benzoate;hydrochloride	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.0198	uM
(2-methoxyphenyl) 4-(diaminomethylideneamino)benzoate	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.0273	uM
(4-tert-butylphenyl) 4-(diaminomethylideneamino)benzoate	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.0285	uM
[4-(trifluoromethyl)phenyl] 4-(diaminomethylideneamino)benzoate	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.0330	uM
[3-(trifluoromethyl)phenyl] 4-(diaminomethylideneamino)benzoate	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.0385	uM
(4-hexyl-3-hydroxyphenyl) 4-(diaminomethylideneamino)benzoate	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.0997	uM
(2-carbamoylphenyl) 4-(diaminomethylideneamino)benzoate;hydrochloride	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.3000	uM
4-methylbenzenesulfonic acid;(5-methyl-2-propan-2-ylphenyl) 4-(diaminomethylideneamino)benzoate	30425: Inhibition of human acrosin and control activity being 11.3 umol/min/mg	ic50	0.3000	uM
5-[4-(diaminomethylideneamino)phenyl]-N-(2,4-dimethoxyphenyl)-1,2-oxazole-3-carboxamide;hydrochloride	1153329: Inhibition of human acrosin using N-alpha-benzoyl-L-arginine p-nitroanilide as substrate after 3 hrs by spectrophotometry	ic50	1.4000	uM
5-[4-(diaminomethylideneamino)phenyl]-N-(2,5-dimethoxyphenyl)-1,2-oxazole-3-carboxamide;hydrochloride	1153329: Inhibition of human acrosin using N-alpha-benzoyl-L-arginine p-nitroanilide as substrate after 3 hrs by spectrophotometry	ic50	2.3000	uM
5-[4-(diaminomethylideneamino)phenyl]-N-(2,6-dimethylphenyl)-1,2-oxazole-3-carboxamide;hydrochloride	1153329: Inhibition of human acrosin using N-alpha-benzoyl-L-arginine p-nitroanilide as substrate after 3 hrs by spectrophotometry	ic50	5.7000	uM
5-[4-(diaminomethylideneamino)phenyl]-N-(4-ethoxyphenyl)-1,2-oxazole-3-carboxamide;hydrochloride	1153329: Inhibition of human acrosin using N-alpha-benzoyl-L-arginine p-nitroanilide as substrate after 3 hrs by spectrophotometry	ic50	6.4000	uM
5-[4-(diaminomethylideneamino)phenyl]-N-(3-methoxyphenyl)-1,2-oxazole-3-carboxamide;hydrochloride	1153329: Inhibition of human acrosin using N-alpha-benzoyl-L-arginine p-nitroanilide as substrate after 3 hrs by spectrophotometry	ic50	6.6000	uM
N-(4-tert-butylphenyl)-5-[4-(diaminomethylideneamino)phenyl]-1,2-oxazole-3-carboxamide;hydrochloride	1153329: Inhibition of human acrosin using N-alpha-benzoyl-L-arginine p-nitroanilide as substrate after 3 hrs by spectrophotometry	ic50	7.8000	uM
5-[4-(diaminomethylideneamino)phenyl]-N-(2-methoxyphenyl)-1,2-oxazole-3-carboxamide;hydrochloride	1153329: Inhibition of human acrosin using N-alpha-benzoyl-L-arginine p-nitroanilide as substrate after 3 hrs by spectrophotometry	ic50	8.4000	uM
ethyl 4-[[5-[4-(diaminomethylideneamino)phenyl]-1,2-oxazole-3-carbonyl]amino]benzoate;hydrochloride	1153329: Inhibition of human acrosin using N-alpha-benzoyl-L-arginine p-nitroanilide as substrate after 3 hrs by spectrophotometry	ic50	9.3000	uM
5-[4-(diaminomethylideneamino)phenyl]-N-(3-methylphenyl)-1,2-oxazole-3-carboxamide;hydrochloride	1153329: Inhibition of human acrosin using N-alpha-benzoyl-L-arginine p-nitroanilide as substrate after 3 hrs by spectrophotometry	ic50	9.4000	uM
N,N-bis(2-hydroxypropyl)-3-phenyl-1H-pyrazole-5-carboxamide	756546: Inhibition of human sperm acrosin using BAPNA as substrate after 3 hrs by spectrophotometric analysis	ic50	10.0000	uM

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
butyraldehyde	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Testosterone	decreases expression	1
Triclosan	increases expression	1
Valproic Acid	increases methylation	1

ChEMBL screening assays

20 unique, capped per target: 18 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1839245	Binding	Inhibition of human acrosin using N-alpha-benzoyl-DL-arginine para-nitroanilide-HCl as substrate after 3 hrs by spectrophotometry	Synthesis and acrosin inhibitory activities of substituted ethyl 5-(4-aminophenyl)-1H-pyrazole-3-carboxylate derivatives. — Bioorg Med Chem Lett
CHEMBL639048	Functional	Compound was evaluated for the reactivity in the inactivation of trypsin like boar acrosin	Inactivation of trypsin-like proteases by depsipeptides of p-guanidinobenzoic acid. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
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
NCT00352248	PHASE3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder
NCT00352352	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00355329	PHASE3	COMPLETED	Randomized Control Trial of Using Tongue Acupuncture in Autistic Spectrum Disorder Using PET Scan for Clinical Correlation
NCT00498173	PHASE3	COMPLETED	Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism
NCT00541346	PHASE3	COMPLETED	A Pilot Study of Daytrana TM in Children With Autism Co-Morbid for Attention Deficit Hyperactivity Disorder (ADHD) Symptoms