ATG4D

Summary

ATG4D (autophagy related 4D cysteine peptidase, HGNC:20789) is a protein-coding gene on chromosome 19p13.2, encoding Cysteine protease ATG4D (Q86TL0). 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 belongs to the autophagy-related protein 4 (Atg4) family of C54 endopeptidases. Members of this family encode proteins that play a role in the biogenesis of autophagosomes, which sequester the cytosol and organelles for degradation by lysosomes. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 84971 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 110 total — 7 pathogenic
• Phenotypes (HPO): 10
• MANE Select transcript: NM_032885

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20789
Approved symbol	ATG4D
Name	autophagy related 4D cysteine peptidase
Location	19p13.2
Locus type	gene with protein product
Status	Approved
Aliases	APG4-D
Ensembl gene	ENSG00000130734
Ensembl biotype	protein_coding
OMIM	611340
Entrez	84971

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 18 protein_coding, 5 nonsense_mediated_decay, 1 retained_intron

ENST00000309469, ENST00000585437, ENST00000585752, ENST00000586417, ENST00000586477, ENST00000586863, ENST00000587256, ENST00000588667, ENST00000588857, ENST00000588972, ENST00000589753, ENST00000590096, ENST00000908547, ENST00000908548, ENST00000908549, ENST00000908550, ENST00000908551, ENST00000908552, ENST00000908553, ENST00000923589, ENST00000923590, ENST00000923591, ENST00000947911, ENST00000947912

RefSeq mRNA: 2 — MANE Select: NM_032885 NM_001281504, NM_032885

CCDS: CCDS12241

Canonical transcript exons

ENST00000309469 — 10 exons

Exon	Start	End
ENSE00000954233	10544783	10544866
ENSE00003520681	10548904	10549034
ENSE00003527137	10547189	10547253
ENSE00003570434	10544957	10545130
ENSE00003617855	10546839	10547115
ENSE00003626837	10552885	10553418
ENSE00003627409	10552205	10552324
ENSE00003693459	10551897	10551975
ENSE00003787823	10552045	10552121
ENSE00003842731	10543904	10544325

Expression profiles

Bgee: expression breadth ubiquitous, 138 present calls, max score 96.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.2458 / max 240.0940, expressed in 1812 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
173811	23.2038	1812
173813	0.0382	4
173812	0.0038	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	96.87	gold quality
left testis	UBERON:0004533	96.45	gold quality
apex of heart	UBERON:0002098	96.11	gold quality
right testis	UBERON:0004534	96.09	gold quality
lower esophagus mucosa	UBERON:0035834	96.08	gold quality
testis	UBERON:0000473	95.77	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.07	gold quality
duodenum	UBERON:0002114	94.54	gold quality
gastrocnemius	UBERON:0001388	94.36	gold quality
heart left ventricle	UBERON:0002084	93.99	gold quality
granulocyte	CL:0000094	93.98	gold quality
skeletal muscle tissue	UBERON:0001134	93.67	gold quality
skin of leg	UBERON:0001511	93.50	gold quality
muscle of leg	UBERON:0001383	93.45	gold quality
skin of abdomen	UBERON:0001416	93.40	gold quality
zone of skin	UBERON:0000014	93.37	gold quality
metanephros cortex	UBERON:0010533	93.29	gold quality
esophagus mucosa	UBERON:0002469	93.14	gold quality
transverse colon	UBERON:0001157	93.00	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.75	gold quality
cortex of kidney	UBERON:0001225	92.68	gold quality
cerebellum	UBERON:0002037	92.68	gold quality
cerebellar hemisphere	UBERON:0002245	92.60	gold quality
cerebellar cortex	UBERON:0002129	92.59	gold quality
primary visual cortex	UBERON:0002436	92.18	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.15	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.06	gold quality
blood	UBERON:0000178	92.04	gold quality
adenohypophysis	UBERON:0002196	91.95	gold quality
small intestine	UBERON:0002108	91.89	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.24

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

15 targeting ATG4D, 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-5692A	100.00	74.40	6850
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-3122	99.50	66.33	821
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-423-5P	98.69	67.48	1522
HSA-MIR-3184-5P	98.56	67.13	1491
HSA-MIR-6890-3P	97.50	65.71	997
HSA-MIR-5194	96.77	63.91	1021
HSA-MIR-1291	96.28	65.89	1224
HSA-MIR-6775-3P	95.76	65.91	982

Literature-anchored findings (GeneRIF, showing 10)

• Caspase cleavage of Atg4D stimulates GABARAP-L1 processing and triggers mitochondrial targeting and apoptosis. (PMID:19549685)
• the import of Atg4D during cellular stress and differentiation may play important roles in the regulation of mitochondrial physiology, reactive oxygen species, mitophagy and cell viability. (PMID:22441018)
• 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)
• This study highlights the transcriptional inactivation mechanisms of ATG2B, ATG4D, ATG9A and ATG9B promoter methylation status and the possible origin of autophagy signal pathway repression in invasive ductal carcinomas. (PMID:27265029)
• study elucidated a novel Malat1-miR-101-STMN1/RAB5A/ATG4D regulatory network that Malat1 activates autophagy and promotes cell proliferation by sponging miR-101 and upregulating STMN1, RAB5A and ATG4D expression in glioma cells (PMID:28834690)
• High ATG4D expression is associated with Colorectal Cancer. (PMID:30374741)
• 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)
• ATG4 family proteins drive phagophore growth independently of the LC3/GABARAP lipidation system. (PMID:33773106)
• Pathogenic variants of ATG4D in infertile men with non-obstructive azoospermia identified using whole-exome sequencing. (PMID:33988247)
• Silencing of ATG4D suppressed proliferation and enhanced cisplatin-induced apoptosis in hepatocellular carcinoma through Akt/Caspase-3 pathway. (PMID:34313895)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	atg4da	ENSDARG00000043548
danio_rerio	atg4db	ENSDARG00000088145
mus_musculus	Atg4d	ENSMUSG00000002820
rattus_norvegicus	Atg4d	ENSRNOG00000047625
drosophila_melanogaster	Atg4b	FBGN0038325

Paralogs (3): ATG4A (ENSG00000101844), ATG4C (ENSG00000125703), ATG4B (ENSG00000168397)

Protein

Protein identifiers

Cysteine protease ATG4D — Q86TL0 (reviewed: Q86TL0)

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

All UniProt accessions (11): Q86TL0, K7EJA5, K7EKP6, K7EMB9, K7EN30, K7EP43, K7EPJ0, K7EQ67, K7EQN3, K7ERK1, K7ESM7

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 MAP1LC3 and GABARAPL2, 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. In addition to the protease activity, also mediates delipidation of ATG8 family proteins. Catalyzes delipidation of PE-conjugated forms of ATG8 proteins during macroautophagy. Also involved in non-canonical autophagy, a parallel pathway involving conjugation of ATG8 proteins to single membranes at endolysosomal compartments, by catalyzing delipidation of ATG8 proteins conjugated to phosphatidylserine (PS). ATG4D plays a role in the autophagy-mediated neuronal homeostasis in the central nervous system. Compared to other members of the family (ATG4A, ATG4B or ATG4C), constitutes the major protein for the delipidation activity, while it promotes weak proteolytic activation of ATG8 proteins. 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. Plays a role as an autophagy regulator that links mitochondrial dysfunction with apoptosis. The mitochondrial import of ATG4D during cellular stress and differentiation may play important roles in the regulation of mitochondrial physiology, ROS, mitophagy and cell viability.

Subcellular location. Cytoplasm Cytoplasm. Mitochondrion matrix.

Tissue specificity. Widely expressed in testis.

Post-translational modifications. Cleaved by CASP3 during apoptosis which leads to increased activity. The cleavage by CASP3 reveals a cryptic mitochondrial targeting sequence immediately downstream of their canonical caspase cleavage sites which leads to mitochondrial import of the protein.

Activity regulation. Inhibited by N-ethylmaleimide.

Domain organisation. The cryptic mitochondrial transit peptide is revealed after cleavage by caspase upon oxidative stress and cell death. It acts then as a functional transit peptide, and allows the import of the cleaved protein into the mitochondria.

Similarity. Belongs to the peptidase C54 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q86TL0-1	1	yes
Q86TL0-2	2

RefSeq proteins (2): NP_001268433, NP_116274* (*=MANE)

Domains & families (InterPro)

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

Pfam: PF03416

Catalyzed reactions (Rhea), 2 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)
• [protein]-C-terminal L-amino acid-glycyl-phosphatidylserine + H2O = [protein]-C-terminal L-amino acid-glycine + a 1,2-diacyl-sn-glycero-3-phospho-L-serine (RHEA:67576)

UniProt features (17 total): sequence variant 4, active site 3, chain 2, region of interest 2, compositionally biased region 2, modified residue 1, splice variant 1, mutagenesis site 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86TL0-F1	78.22	0.61

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 (4): 144 (nucleophile); 356; 358; 63–64 (cleavage; by casp3)

Post-translational modifications (1): 467

Mutagenesis-validated functional residues (1):

Position	Phenotype
63	abolishes cleavage by casp3.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

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

MSigDB gene sets: 105 (showing top): GOBP_VACUOLE_ORGANIZATION, MODULE_255, MODULE_317, GOBP_MACROAUTOPHAGY, RICKMAN_METASTASIS_DN, GOBP_PROTEIN_MATURATION, MODULE_205, WANG_LMO4_TARGETS_DN, GOMF_CYSTEINE_TYPE_PEPTIDASE_ACTIVITY, GOBP_ORGANELLE_ASSEMBLY, COATES_MACROPHAGE_M1_VS_M2_DN, MODULE_207, CHANDRAN_METASTASIS_UP, GOBP_AUTOPHAGOSOME_ORGANIZATION, GOCC_MITOCHONDRIAL_MATRIX

GO Biological Process (11): autophagosome assembly (GO:0000045), mitophagy (GO:0000423), proteolysis (GO:0006508), autophagy (GO:0006914), apoptotic process (GO:0006915), protein transport (GO:0015031), protein processing (GO:0016485), protein localization to phagophore assembly site (GO:0034497), 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), cysteine-type exopeptidase activity (GO:0070004), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (4): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759)

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
intracellular protein localization	2
cysteine-type peptidase activity	2
hydrolase activity	2
catalytic activity, acting on a protein	2
cellular anatomical structure	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
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
transport	1
establishment of protein localization	1
proteolysis	1
protein maturation	1
autophagosome assembly	1
microautophagy	1
nucleophagy	1
nucleus disassembly	1
protein modification process	1
endopeptidase activity	1
peptidase activity	1
exopeptidase activity	1
catalytic activity	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1

Protein interactions and networks

STRING

938 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATG4D	ATG7	O95352	900
ATG4D	ATG3	Q9NT62	898
ATG4D	ATG5	Q9H1Y0	888
ATG4D	ATG12	O94817	874
ATG4D	ATG10	Q9H0Y0	848
ATG4D	F5GZY7	F5GZY7	846
ATG4D	GABARAPL2	P60520	842
ATG4D	GABARAP	O95166	811
ATG4D	ATG16L1	Q676U5	793
ATG4D	BECN1	Q14457	713
ATG4D	ATG14	Q6ZNE5	706
ATG4D	ATG13	O75143	703
ATG4D	PIK3C3	Q8NEB9	690
ATG4D	BCL2	P10415	690
ATG4D	ATG9A	Q7Z3C6	668

IntAct

9 interactions, top by confidence:

A	B	Type	Score
IMPDH1	BCAT2	psi-mi:“MI:0914”(association)	0.530
ATG4D	PRPF40A	psi-mi:“MI:0915”(physical association)	0.400
P4HA2	CCDC85C	psi-mi:“MI:0914”(association)	0.350
IMPDH1	LCMT2	psi-mi:“MI:0914”(association)	0.350
GOPC	ZBTB5	psi-mi:“MI:0914”(association)	0.350
ATG4C	SPAG9	psi-mi:“MI:0914”(association)	0.350
ATG4D	ARFIP2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (19): ATG4D (Biochemical Activity), ATG4D (Biochemical Activity), GABARAPL2 (Biochemical Activity), GABARAPL1 (Biochemical Activity), GABARAPL1 (Biochemical Activity), ATG4D (Affinity Capture-MS), ATG4D (Affinity Capture-MS), ATG4D (Affinity Capture-MS), ATG4D (Reconstituted Complex), ATG4D (Reconstituted Complex), ATG4D (Two-hybrid), ATG4D (Affinity Capture-RNA), ATG4D (Affinity Capture-MS), ATG4D (Affinity Capture-MS), ATG4D (Affinity Capture-MS)

ESM2 similar proteins: A0JMH0, A2ARP1, A5PK74, A7Z050, A9JTG5, B5DE73, B5DFG1, D3YY23, D3ZU57, O00562, O35954, O43304, P0C644, P0CB42, P16386, Q01433, Q02356, Q09200, Q10468, Q32P28, Q3SZL5, Q3U308, Q3V1T4, Q4KLM6, Q5HZW3, Q5RDF1, Q5RF50, Q5U2N3, Q5ZMM1, Q68J42, Q6ICH7, Q6JHU7, Q6PD26, Q6PFW1, Q6YRM6, Q80VP9, Q86TL0, Q8BGV9, Q8BGW1, Q8CG71

Diamond homologs: A0A0G2QC33, A1CJ08, A2Q1V6, A2QY50, A2XHJ5, A6SDQ3, A7F045, A7KAL5, E2RDP2, K8ESC5, P0CQ10, P0CQ11, Q1E5M9, Q2HH40, Q2U5B0, Q2XPP4, Q4U3V5, Q523C3, Q5B7L0, Q5R699, Q5ZIW7, Q640G7, Q684M2, Q68FJ9, Q6CH28, Q6DG88, Q6GPU1, Q6PZ02, Q6PZ03, Q6PZ05, Q75KP8, Q7S3X7, Q7XPW8, Q86TL0, Q86ZL5, Q8BGE6, Q8BGV9, Q8C9S8, Q8S929, Q8WYN0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	0
Uncertain significance	79
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1322026	NM_032885.6(ATG4D):c.1066G>A (p.Asp356Asn)	Pathogenic
1801476	NM_032885.6(ATG4D):c.1310_1328del (p.Asp437fs)	Pathogenic
4057226	NM_032885.6(ATG4D):c.374G>T (p.Arg125Leu)	Pathogenic
4057227	NM_032885.6(ATG4D):c.817G>A (p.Val273Ile)	Pathogenic
4057228	NM_032885.6(ATG4D):c.1183G>A (p.Val395Met)	Pathogenic
4057229	NM_032885.6(ATG4D):c.9_23del (p.Val4_Ala8del)	Pathogenic
4057230	NM_032885.6(ATG4D):c.884C>A (p.Ala295Asp)	Pathogenic

SpliceAI

1062 predictions. Top by Δscore:

Variant	Effect	Δscore
19:10544317:TC:T	donor_gain	1.0000
19:10544321:G:GG	donor_gain	1.0000
19:10544865:GG:G	donor_gain	1.0000
19:10544866:GG:G	donor_gain	1.0000
19:10548900:CCA:C	acceptor_loss	1.0000
19:10548902:A:AG	acceptor_gain	1.0000
19:10548902:A:AT	acceptor_loss	1.0000
19:10548902:AGT:A	acceptor_gain	1.0000
19:10548903:G:A	acceptor_loss	1.0000
19:10548903:G:GA	acceptor_gain	1.0000
19:10548903:GT:G	acceptor_gain	1.0000
19:10548903:GTG:G	acceptor_gain	1.0000
19:10548903:GTGT:G	acceptor_gain	1.0000
19:10548903:GTGTA:G	acceptor_gain	1.0000
19:10549036:T:G	donor_loss	1.0000
19:10551891:CTGCA:C	acceptor_loss	1.0000
19:10551892:TGCA:T	acceptor_loss	1.0000
19:10551893:GCA:G	acceptor_loss	1.0000
19:10551894:CAGGA:C	acceptor_loss	1.0000
19:10551895:A:AG	acceptor_gain	1.0000
19:10551895:A:T	acceptor_loss	1.0000
19:10551895:AG:A	acceptor_gain	1.0000
19:10551896:G:GT	acceptor_gain	1.0000
19:10551896:GG:G	acceptor_gain	1.0000
19:10551896:GGA:G	acceptor_gain	1.0000
19:10551896:GGAA:G	acceptor_gain	1.0000
19:10552118:GGAG:G	donor_gain	1.0000
19:10552119:GAG:G	donor_gain	1.0000
19:10552119:GAGG:G	donor_gain	1.0000
19:10552120:AGGT:A	donor_loss	1.0000

AlphaMissense

3054 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:10547081:T:A	W246R	1.000
19:10547081:T:C	W246R	1.000
19:10545010:C:A	R125S	0.999
19:10545061:T:A	W142R	0.999
19:10545061:T:C	W142R	0.999
19:10545063:G:C	W142C	0.999
19:10545063:G:T	W142C	0.999
19:10545064:G:T	G143W	0.999
19:10547083:G:C	W246C	0.999
19:10547083:G:T	W246C	0.999
19:10552071:C:G	H358D	0.999
19:10552256:A:C	S392R	0.999
19:10552258:C:A	S392R	0.999
19:10552258:C:G	S392R	0.999
19:10544998:T:A	W121R	0.998
19:10544998:T:C	W121R	0.998
19:10545011:G:C	R125P	0.998
19:10545052:G:C	D139H	0.998
19:10545053:A:T	D139V	0.998
19:10545064:G:A	G143R	0.998
19:10545064:G:C	G143R	0.998
19:10545065:G:A	G143E	0.998
19:10545074:T:C	L146S	0.998
19:10545079:A:C	S148R	0.998
19:10545081:C:A	S148R	0.998
19:10545081:C:G	S148R	0.998
19:10545083:G:A	G149D	0.998
19:10547084:T:G	Y247D	0.998
19:10547088:G:A	G248E	0.998
19:10547091:C:A	P249Q	0.998

dbSNP variants (sampled 300 via entrez): RS1000024901 (19:10548634 G>A), RS1000179148 (19:10542729 C>T), RS1000543180 (19:10544124 C>A,T), RS1000613152 (19:10543077 G>A,T), RS1000916464 (19:10544006 C>A,T), RS1001239575 (19:10550618 T>G), RS1001487489 (19:10551174 A>G), RS1001587434 (19:10550378 G>A), RS1001961637 (19:10550985 T>A,C), RS1002185508 (19:10545012 C>A,T), RS1002546876 (19:10546651 G>A), RS1002803464 (19:10548062 A>G), RS1002924446 (19:10546489 G>A,T), RS1003648439 (19:10543650 A>C), RS1003700029 (19:10552481 G>A)

Disease associations

OMIM: gene MIM:611340 | disease phenotypes: MIM:621269

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal recessive
complex neurodevelopmental disorder	Limited	Autosomal recessive

Mondo (3): neurodevelopmental disorder (MONDO:0700092), spermatogenic failure 101 (MONDO:0979572), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (0):

HPO phenotypes

10 total (10 of 10 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0003251	Male infertility
HP:0011462	Young adult onset
HP:0011961	Non-obstructive azoospermia
HP:0025133	Abnormal serum estradiol
HP:0030087	Abnormal circulating testosterone concentration
HP:0030345	Abnormal circulating luteinizing hormone concentration
HP:0030346	Abnormal circulating follicle-stimulating hormone concentration
HP:0040171	Decreased serum testosterone concentration
HP:6000135	Low semen volume

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression	2
Tobacco Smoke Pollution	increases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
arsenite	increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
polyhexamethyleneguanidine	increases expression	1
abrine	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation	1
Ethyl Methanesulfonate	increases expression	1
Methotrexate	increases expression	1
Methyl Methanesulfonate	increases expression	1
Testosterone	increases expression	1
Tretinoin	affects reaction, increases expression	1
Aflatoxin B1	increases methylation	1
Particulate Matter	increases abundance, decreases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1KM	Abcam HeLa ATG4D KO	Cancer cell line	Female
CVCL_E1RG	HAP1 ATG4D (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism