ATG4A

Summary

ATG4A (autophagy related 4A cysteine peptidase, HGNC:16489) is a protein-coding gene on chromosome Xq22.3, encoding Cysteine protease ATG4A (Q8WYN0). Cysteine protease that plays a key role in autophagy by mediating both proteolytic activation and delipidation of ATG8 family proteins.

Autophagy is the process by which endogenous proteins and damaged organelles are destroyed intracellularly. Autophagy is postulated to be essential for cell homeostasis and cell remodeling during differentiation, metamorphosis, non-apoptotic cell death, and aging. Reduced levels of autophagy have been described in some malignant tumors, and a role for autophagy in controlling the unregulated cell growth linked to cancer has been proposed. This gene encodes a member of the autophagin protein family. The encoded protein is also designated as a member of the C-54 family of cysteine proteases.

Source: NCBI Gene 115201 — RefSeq curated summary.

At a glance

• Gene–disease (curated): infectious meningitis (Limited, GenCC)
• Clinical variants (ClinVar): 174 total — 3 pathogenic, 1 likely-pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_052936

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16489
Approved symbol	ATG4A
Name	autophagy related 4A cysteine peptidase
Location	Xq22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000101844
Ensembl biotype	protein_coding
OMIM	300663
Entrez	115201

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000343524, ENST00000345734, ENST00000372232, ENST00000372246, ENST00000394892, ENST00000457035, ENST00000474825, ENST00000489247, ENST00000882247, ENST00000882248, ENST00000882249, ENST00000951604, ENST00000951605, ENST00000951606

RefSeq mRNA: 7 — MANE Select: NM_052936 NM_001321287, NM_001321288, NM_001321289, NM_001321290, NM_052936, NM_178270, NM_178271

CCDS: CCDS14538, CCDS14539

Canonical transcript exons

ENST00000372232 — 13 exons

Exon	Start	End
ENSE00003508316	108134339	108134411
ENSE00003536845	108150152	108150297
ENSE00003541341	108126077	108126187
ENSE00003549010	108153642	108154671
ENSE00003574887	108128781	108128852
ENSE00003575888	108138113	108138191
ENSE00003578913	108131260	108131358
ENSE00003617173	108137804	108137991
ENSE00003626563	108152979	108153087
ENSE00003637244	108134057	108134158
ENSE00003670918	108137091	108137170
ENSE00003785662	108151802	108151858
ENSE00003843837	108091778	108091836

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 89.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.8822 / max 54.2742, expressed in 1662 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197205	5.2875	1640
197206	0.3958	175
197204	0.1989	74

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	89.72	gold quality
gastrocnemius	UBERON:0001388	88.31	gold quality
hindlimb stylopod muscle	UBERON:0004252	88.26	gold quality
muscle of leg	UBERON:0001383	88.01	gold quality
pancreas	UBERON:0001264	87.71	gold quality
rectum	UBERON:0001052	87.07	gold quality
islet of Langerhans	UBERON:0000006	86.49	gold quality
muscle organ	UBERON:0001630	86.18	gold quality
tibialis anterior	UBERON:0001385	86.03	gold quality
adenohypophysis	UBERON:0002196	85.75	gold quality
heart left ventricle	UBERON:0002084	85.50	gold quality
cardiac ventricle	UBERON:0002082	85.34	gold quality
cervix squamous epithelium	UBERON:0006922	85.30	silver quality
deltoid	UBERON:0001476	85.27	gold quality
right lung	UBERON:0002167	85.24	gold quality
body of stomach	UBERON:0001161	84.98	gold quality
duodenum	UBERON:0002114	84.98	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	84.91	gold quality
colonic epithelium	UBERON:0000397	84.86	gold quality
right atrium auricular region	UBERON:0006631	84.79	gold quality
right lobe of liver	UBERON:0001114	84.68	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	84.64	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.63	gold quality
pituitary gland	UBERON:0000007	84.44	gold quality
pancreatic ductal cell	CL:0002079	84.33	silver quality
parotid gland	UBERON:0001831	84.29	gold quality
choroid plexus epithelium	UBERON:0003911	84.15	gold quality
heart	UBERON:0000948	84.09	gold quality
mucosa of transverse colon	UBERON:0004991	84.07	gold quality
bone marrow cell	CL:0002092	83.98	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.62
E-MTAB-6142	no	158.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

50 targeting ATG4A, 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-4795-3P	100.00	74.62	4024
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-9718	99.94	68.91	918
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-2052	99.79	69.37	2031
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-24-3P	99.59	69.97	1934
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-19A-5P	99.36	66.93	1675
HSA-MIR-19B-1-5P	99.36	67.07	1669
HSA-MIR-19B-2-5P	99.36	67.07	1669
HSA-MIR-542-3P	99.34	67.58	1270
HSA-MIR-3692-5P	99.29	67.04	1421
HSA-MIR-4477B	99.23	70.49	1733
HSA-MIR-505-3P	99.19	69.71	896
HSA-MIR-670-3P	99.03	68.88	2404
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-4742-5P	98.89	68.41	1542
HSA-MIR-491-3P	98.88	68.86	1224
HSA-MIR-6760-5P	98.87	66.73	1515

Literature-anchored findings (GeneRIF, showing 23)

• HsApg4A cleaves the COOH terminus of GATE-16 (PMID:12473658)
• The cysteine protease HsAtg4 is identified as a direct target for oxidation by hydrogen peroxide, and a cysteine residue located near the HsAtg4 catalytic site as critical for this regulation. (PMID:17347651)
• no association between SNP rs807185 and the presence of granulomas in Crohn’s disease (PMID:21122541)
• Atg4B possessed the broadest spectrum against all substrates, followed by Atg4A for ATG8 substrates (PMID:21177865)
• statistical analysis of APG4A gene confirmed the characterisation of each protein-coding gene present in human genome Xq22.1 (PMID:21297227)
• The actions of ATG4 family members (particularly ATG4B) are required for the control of autophagosome fusion with late, degradative compartments in differentiating human erythroblasts. (PMID:23508006)
• The autophagy regulator ATG4A was found to be essential for the maintenance of a sub-population with cancer stem cell properties and to regulate breast cancer cell tumourigenicity. (PMID:24229464)
• The demonstration that expression of ATG4A in cells increased stem properties provided an indication of its biological function. Hypomethylation of ATG4A and HIST1H2BN in ovarian tumor-initiating cells predicts poor prognosis for ovarian cancer patients. (PMID:24256813)
• We conclude that miR-24-3p regulates autophagy by targeting ATG4A (PMID:25426560)
• An intron SNP rs807185 in ATG4A might be a protective factor for lung cancer. (PMID:26061994)
• ATG4A promotes the metastasis of gastric cancer cells via the Notch signaling pathway, which is an autophagy-independent mechanism (PMID:27276686)
• The structure and regulatory machinery of Atg4a [review] (PMID:28253956)
• Human HAP1 and HeLa cells lacking ATG4B exhibit a severe but incomplete defect in LC3/GABARAP processing and autophagy. By further genetic depletion of ATG4 isoforms using CRISPR-Cas9 and siRNA we uncover that ATG4A, ATG4C and ATGD all contribute to residual priming activity, which is sufficient to enable lipidation of endogenous GABARAPL1 on autophagic structures. (PMID:30661429)
• Long-noncoding RNA MALAT1 sponges microRNA-92a-3p to inhibit doxorubicin-induced cardiac senescence by targeting ATG4a. (PMID:32384281)
• Overexpression of ATG4a promotes autophagy and proliferation, and inhibits apoptosis in lens epithelial cells via the AMPK and Akt pathways. (PMID:32626969)
• The insufficiency of ATG4A in macroautophagy. (PMID:32732290)
• Defects in LC3B2 and ATG4A underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans. (PMID:33310865)
• ATG4 family proteins drive phagophore growth independently of the LC3/GABARAP lipidation system. (PMID:33773106)
• Knockdown of ATG4A inhibits breast cancer progression and promotes tamoxifen chemosensitivity by suppressing autophagy. (PMID:35088889)
• ATG4A regulates human erythroid maturation and mitochondrial clearance. (PMID:35443024)
• Alterations of ATG4A and LC3B in neurons derived from Alzheimer’s disease patients. (PMID:36719634)
• Association of ATG4A single nucleotide polymorphism rs807185 on risk of microscopic polyangiitis in Chinese population. (PMID:37494842)
• Loss of ATG4B and ATG4A results in two-stage cell cycle defects in pancreatic ductal adenocarcinoma cells. (PMID:37701987)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	atg4a	ENSDARG00000014531
mus_musculus	Atg4a	ENSMUSG00000079418
mus_musculus	Atg4a-ps	ENSMUSG00000087119
rattus_norvegicus	AABR07040864.1	ENSRNOG00000050960
drosophila_melanogaster	Atg4a	FBGN0031298
caenorhabditis_elegans	atg-4.1	WBGENE00013595

Paralogs (3): ATG4C (ENSG00000125703), ATG4D (ENSG00000130734), ATG4B (ENSG00000168397)

Protein

Protein identifiers

Cysteine protease ATG4A — Q8WYN0 (reviewed: Q8WYN0)

Alternative names: AUT-like 2 cysteine endopeptidase, Autophagy-related cysteine endopeptidase 2, Autophagy-related protein 4 homolog A

All UniProt accessions (5): Q8WYN0, A0A0A0MT61, F8W7J2, G5E979, H7BYM2

UniProt curated annotations — full annotation on UniProt →

Function. Cysteine protease that plays a key role in autophagy by mediating both proteolytic activation and delipidation of ATG8 family proteins. The protease activity is required for proteolytic activation of ATG8 family proteins: cleaves the C-terminal amino acid of ATG8 proteins to reveal a C-terminal glycine. Exposure of the glycine at the C-terminus is essential for ATG8 proteins conjugation to phosphatidylethanolamine (PE) and insertion to membranes, which is necessary for autophagy. Preferred substrate is GABARAPL2 followed by MAP1LC3A and GABARAP. Protease activity is also required to counteract formation of high-molecular weight conjugates of ATG8 proteins (ATG8ylation): acts as a deubiquitinating-like enzyme that removes ATG8 conjugated to other proteins, such as ATG3. In addition to the protease activity, also mediates delipidation of ATG8 family proteins. Catalyzes delipidation of PE-conjugated forms of ATG8 proteins during macroautophagy. Compared to ATG4B, the major protein for proteolytic activation of ATG8 proteins, shows weaker ability to cleave the C-terminal amino acid of ATG8 proteins, while it displays stronger delipidation activity. Involved in phagophore growth during mitophagy independently of its protease activity and of ATG8 proteins: acts by regulating ATG9A trafficking to mitochondria and promoting phagophore-endoplasmic reticulum contacts during the lipid transfer phase of mitophagy.

Subunit / interactions. Interacts with ATG9A; the interaction is direct.

Subcellular location. Cytoplasm.

Activity regulation. Inhibited by N-ethylmaleimide. Redox-regulated during autophagy since reducing conditions activate ATG4A whereas an oxidizing environment such as the presence of H(2)O(2) inhibits its activity.

Domain organisation. The LIR motif (LC3-interacting region) is required for the interaction with the ATG8 family proteins. Required for proteolytic activation and delipidation of ATG8 proteins.

Similarity. Belongs to the peptidase C54 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8WYN0-1	1	yes
Q8WYN0-2	2
Q8WYN0-3	3
Q8WYN0-5	4

RefSeq proteins (7): NP_001308216, NP_001308217, NP_001308218, NP_001308219, NP_443168, NP_840054, NP_840055 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005078	Peptidase_C54	Family
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR046792	Peptidase_C54_cat	Domain
IPR046793	ATG4_LIR	Conserved_site

Pfam: PF03416, PF20166

Catalyzed reactions (Rhea), 1 shown:

• [protein]-C-terminal L-amino acid-glycyl-phosphatidylethanolamide + H2O = [protein]-C-terminal L-amino acid-glycine + a 1,2-diacyl-sn-glycero-3-phosphoethanolamine (RHEA:67548)

UniProt features (46 total): strand 16, helix 11, turn 6, mutagenesis site 3, active site 3, splice variant 3, sequence conflict 2, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2P82	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WYN0-F1	85.20	0.75

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): 77 (nucleophile); 279; 281

Mutagenesis-validated functional residues (3):

Position	Phenotype
397	phospho-mimetic mutant; slightly increased delipidation of atg8 proteins.
81	reduces the redox sensitivity and retains activity in presence of h(2)o(2).
390–398	decreased ability to mediate proteolytic activation and delipidation of atg8 proteins.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1632852	Macroautophagy
R-HSA-9612973	Autophagy

MSigDB gene sets: 94 (showing top): GOBP_VACUOLE_ORGANIZATION, AMIT_EGF_RESPONSE_60_HELA, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_MACROAUTOPHAGY, GOBP_PROTEIN_MATURATION, GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY, GOBP_ORGANELLE_ASSEMBLY, GOBP_LIPID_METABOLIC_PROCESS, CUI_TCF21_TARGETS_2_DN, GOBP_AUTOPHAGOSOME_ORGANIZATION, GOBP_PROTEOLYSIS, GEORGES_TARGETS_OF_MIR192_AND_MIR215, GOMF_PEPTIDASE_ACTIVITY, MIKKELSEN_ES_ICP_WITH_H3K4ME3, MIKKELSEN_NPC_ICP_WITH_H3K4ME3

GO Biological Process (10): autophagosome assembly (GO:0000045), mitophagy (GO:0000423), proteolysis (GO:0006508), lipid metabolic process (GO:0006629), autophagy (GO:0006914), protein transport (GO:0015031), protein processing (GO:0016485), piecemeal microautophagy of the nucleus (GO:0034727), aggrephagy (GO:0035973), protein delipidation (GO:0051697)

GO Molecular Function (6): cysteine-type endopeptidase activity (GO:0004197), cysteine-type peptidase activity (GO:0008234), protein-phosphatidylethanolamide deconjugating activity (GO:0019786), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (1): cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Autophagy	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
macroautophagy	2
hydrolase activity	2
catalytic activity, acting on a protein	2
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1
autophagosome organization	1
autophagy of mitochondrion	1
protein metabolic process	1
primary metabolic process	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
proteolysis	1
protein maturation	1
microautophagy	1
nucleophagy	1
nucleus disassembly	1
protein modification process	1
endopeptidase activity	1
cysteine-type peptidase activity	1
peptidase activity	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1092 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATG4A	ATG3	Q9NT62	880
ATG4A	ATG7	O95352	872
ATG4A	ATG10	Q9H0Y0	864
ATG4A	ATG12	O94817	864
ATG4A	F5GZY7	F5GZY7	857
ATG4A	GABARAPL2	P60520	856
ATG4A	ATG5	Q9H1Y0	852
ATG4A	GABARAP	O95166	846
ATG4A	ATG16L1	Q676U5	804
ATG4A	BECN1	Q14457	715
ATG4A	ATG9A	Q7Z3C6	708
ATG4A	ATG14	Q6ZNE5	705
ATG4A	PIK3C3	Q8NEB9	691
ATG4A	ATG13	O75143	688
ATG4A	WIPI1	Q5MNZ9	686

IntAct

26 interactions, top by confidence:

A	B	Type	Score
ATG4A	GABARAPL1	psi-mi:“MI:0915”(physical association)	0.720
GABARAPL1	ATG4A	psi-mi:“MI:0915”(physical association)	0.720
ATG4A	CDKL3	psi-mi:“MI:0915”(physical association)	0.560
CDKL3	ATG4A	psi-mi:“MI:0915”(physical association)	0.560
NUF2	SPC24	psi-mi:“MI:0914”(association)	0.530
LCN15	POTEF	psi-mi:“MI:0914”(association)	0.530
HSPB6	BAG3	psi-mi:“MI:0914”(association)	0.530
C1orf220	HCCS	psi-mi:“MI:0914”(association)	0.530
MAP1LC3B	ATG4A	psi-mi:“MI:0915”(physical association)	0.520
THOC1	TARS3	psi-mi:“MI:0914”(association)	0.350
SYN1	LUC7L3	psi-mi:“MI:0914”(association)	0.350
USP43	DKFZP586J0619	psi-mi:“MI:0914”(association)	0.350
PDK1	VWA8	psi-mi:“MI:0914”(association)	0.350
MAP1LC3A		psi-mi:“MI:0914”(association)	0.350
ATG4A	GABARAP	psi-mi:“MI:0914”(association)	0.350
BCAS4	SNAPIN	psi-mi:“MI:0914”(association)	0.350
BOD1L2	BPGM	psi-mi:“MI:0914”(association)	0.350
ATG4A	RAB13	psi-mi:“MI:0914”(association)	0.350
ATG4A	KDELR1	psi-mi:“MI:2364”(proximity)	0.270
GABARAPL1	ATG4A	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (43): ATG4A (Two-hybrid), ATG4A (Two-hybrid), ATG4A (Affinity Capture-MS), ATG4A (Affinity Capture-MS), ATG4A (Affinity Capture-MS), ATG4A (Affinity Capture-MS), ATG4A (Affinity Capture-MS), ATG4A (Affinity Capture-MS), ATG4A (Affinity Capture-MS), ATG4A (Affinity Capture-MS), ATG4A (Affinity Capture-MS), ATG4A (Affinity Capture-MS), ATG4A (Affinity Capture-MS), ATG4A (Affinity Capture-MS), ATG4A (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2QC33, A0FKG7, A6H7H7, F1N9S8, O95453, P0C0T1, P42694, P50747, P69341, Q0IIH8, Q0VGM9, Q13572, Q28559, Q4R528, Q5BJZ6, Q5F480, Q5R699, Q5RC51, Q5ZIA0, Q5ZIW7, Q640G7, Q6DDJ3, Q6DFV5, Q6DG88, Q6DJB3, Q6GR37, Q6NYU2, Q6PZ02, Q6PZ03, Q6PZ05, Q7T0P6, Q80UY1, Q80YV4, Q811C2, Q8BGE6, Q8BYN3, Q8C9S8, Q8N4J0, Q8VDG3, Q8WYN0

Diamond homologs: A0A098DRK7, A1CJ08, A2QY50, A3LQU0, A5DEF7, A6SDQ3, A6ZRL7, A7F045, A7KAI3, A7KAL5, A7TQN1, P0CQ10, P0CQ11, P53867, Q0U199, Q1E5M9, Q2HH40, Q2U5B0, Q4U3V5, Q523C3, Q59UG3, Q5B7L0, Q5R699, Q5ZIW7, Q6BYP8, Q6CH28, Q6CQ60, Q6FP20, Q6GPU1, Q6PZ05, Q75E61, Q7S3X7, Q86ZL5, Q8C9S8, Q8NJJ3, Q8WYN0, Q9P373, W0TGM7, A0A0G2QC33, A2Q1V6

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 27 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
autophagosome maturation	5	79.8×	3e-07
autophagosome assembly	5	51.1×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	25
Likely benign	4
Benign	6

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
2424529	NC_000023.10:g.(?106046084)(108868249_?)del	Pathogenic
58666	GRCh38/hg38 Xq22.3(chrX:107523862-108265579)x3	Pathogenic
832248	NC_000023.11:g.(?107628619)(108696388_?)del	Pathogenic
599250	NG_012059.2:g.1_302925del	Likely pathogenic

SpliceAI

1849 predictions. Top by Δscore:

Variant	Effect	Δscore
X:108091835:AG:A	donor_loss	1.0000
X:108091836:GGT:G	donor_loss	1.0000
X:108091837:GTAC:G	donor_loss	1.0000
X:108126073:TCAG:T	acceptor_gain	1.0000
X:108126073:TCAGT:T	acceptor_loss	1.0000
X:108126075:A:AG	acceptor_gain	1.0000
X:108126076:G:GT	acceptor_gain	1.0000
X:108126076:GT:G	acceptor_gain	1.0000
X:108126076:GTT:G	acceptor_gain	1.0000
X:108126076:GTTT:G	acceptor_gain	1.0000
X:108126076:GTTTT:G	acceptor_gain	1.0000
X:108126165:G:T	donor_gain	1.0000
X:108126185:CAGGT:C	donor_loss	1.0000
X:108126186:AGGTA:A	donor_loss	1.0000
X:108126187:GGTAA:G	donor_loss	1.0000
X:108126188:G:T	donor_loss	1.0000
X:108126189:T:A	donor_loss	1.0000
X:108131258:AGGT:A	acceptor_gain	1.0000
X:108131259:GGTG:G	acceptor_gain	1.0000
X:108131356:GGG:G	donor_gain	1.0000
X:108131357:GGG:G	donor_gain	1.0000
X:108134055:A:AG	acceptor_gain	1.0000
X:108134056:G:GG	acceptor_gain	1.0000
X:108134328:A:AG	acceptor_gain	1.0000
X:108134329:T:G	acceptor_gain	1.0000
X:108134412:G:GG	donor_gain	1.0000
X:108137171:G:GG	donor_gain	1.0000
X:108137206:GGTGA:G	donor_gain	1.0000
X:108151799:AAG:A	acceptor_gain	1.0000
X:108091832:GTCAG:G	donor_gain	0.9900

AlphaMissense

2621 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:108128832:G:C	R58T	1.000
X:108128832:G:T	R58I	1.000
X:108128833:A:C	R58S	1.000
X:108128833:A:T	R58S	1.000
X:108131280:G:C	D72H	1.000
X:108131280:G:T	D72Y	1.000
X:108131281:A:T	D72V	1.000
X:108131289:T:A	W75R	1.000
X:108131289:T:C	W75R	1.000
X:108131290:G:C	W75S	1.000
X:108131291:G:C	W75C	1.000
X:108131291:G:T	W75C	1.000
X:108131292:G:A	G76R	1.000
X:108131292:G:C	G76R	1.000
X:108131293:G:A	G76E	1.000
X:108131293:G:T	G76V	1.000
X:108131295:T:C	C77R	1.000
X:108131296:G:A	C77Y	1.000
X:108131297:T:G	C77W	1.000
X:108131304:C:A	R80S	1.000
X:108131308:G:A	C81Y	1.000
X:108131309:T:G	C81W	1.000
X:108131311:G:A	G82E	1.000
X:108134144:C:T	S127F	1.000
X:108134149:C:G	H129D	1.000
X:108134347:G:C	G135R	1.000
X:108134348:G:A	G135D	1.000
X:108134377:T:A	W145R	1.000
X:108134377:T:C	W145R	1.000
X:108134378:G:C	W145S	1.000

dbSNP variants (sampled 300 via entrez): RS1000125068 (X:108096156 T>C), RS1000168904 (X:108115773 C>G), RS1000210757 (X:108146605 C>T), RS1000220135 (X:108129513 A>G), RS1000279749 (X:108115359 A>G), RS1000321147 (X:108139707 G>A), RS1000445969 (X:108103106 G>C), RS1000581800 (X:108140791 CAT>C), RS1000644680 (X:108088478 C>A), RS1000675506 (X:108129049 A>C,G), RS1000683816 (X:108128073 C>T), RS1000707322 (X:108139256 G>T), RS1000732345 (X:108103510 T>A), RS1000816218 (X:108149237 T>C), RS1000852869 (X:108098284 A>G)

Disease associations

OMIM: gene MIM:300663 | disease phenotypes: MIM:301050

GenCC curated gene-disease

Disease	Classification	Inheritance
infectious meningitis	Limited	X-linked

Mondo (2): X-linked Alport syndrome (MONDO:0010520), infectious meningitis (MONDO:0004796)

Orphanet (2): Alport syndrome (Orphanet:63), X-linked Alport syndrome (Orphanet:88917)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5169181 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 15,162 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1200438	TIOCONAZOLE	4	15,162

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

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
5.89	IC50	1300	nM	TIOCONAZOLE

PubChem BioAssay actives

1 with measured affinity, of 1 total; 1 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
Tioconazole	1915518: Inhibition of ATG4A (unknown origin)	ic50	1.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
sodium arsenite	affects cotreatment, increases abundance, increases expression	2
Acetaminophen	increases expression, decreases expression	2
aristolochic acid I	increases expression	1
potassium perchlorate	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
cobaltous chloride	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	increases methylation	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
polyhexamethyleneguanidine	increases expression	1
di-n-butylphosphoric acid	affects expression	1
trovafloxacin	affects cotreatment, increases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	decreases expression	1
Sunitinib	decreases expression	1
Troglitazone	increases expression	1
Vorinostat	increases expression	1
Acetylcysteine	decreases reaction, increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cannabidiol	affects expression, affects response to substance	1
Cisplatin	decreases response to substance, increases expression	1
Drugs, Chinese Herbal	increases expression	1
Manganese	increases expression, affects cotreatment, 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
CHEMBL5215040	Binding	Inhibition of ATG4A (unknown origin)	Targeting Atg4B for cancer therapy: Chemical mediators. — Eur J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1KK	Abcam HeLa ATG4A KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04937907	PHASE2	COMPLETED	Study of Hydroxychloroquine in Patients With X-linked Alport Syndrome in China (CHXLAS)
NCT07523581	PHASE2	NOT_YET_RECRUITING	EXACT Study: A Blinded Study in Patients With Alport Syndrome to Evaluate Exaluren Efficacy and Safety
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns