ATAD3A

Summary

ATAD3A (ATPase family AAA domain containing 3A, HGNC:25567) is a protein-coding gene on chromosome 1p36.33, encoding ATPase family AAA domain-containing protein 3A (Q9NVI7). Essential for mitochondrial network organization, mitochondrial metabolism and cell growth at organism and cellular level.

This gene encodes a ubiquitously expressed mitochondrial membrane protein that contributes to mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. This gene is a member of the ATPase family AAA-domain containing 3 gene family which, in humans, includes two other paralogs. Naturally occurring mutations in this gene are associated with distinct neurological syndromes including Harel-Yoon syndrome. High-level expression of this gene is associated with poor survival in breast cancer patients. A homozygous knockout of the orthologous gene in mice results in embryonic lethality at day 7.5 due to growth retardation and defective development of the trophoblast lineage. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 55210 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Harel-Yoon syndrome (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 467 total — 15 pathogenic, 19 likely-pathogenic
• Phenotypes (HPO): 66
• Druggable target: yes
• MANE Select transcript: NM_001170535

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25567
Approved symbol	ATAD3A
Name	ATPase family AAA domain containing 3A
Location	1p36.33
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10709
Ensembl gene	ENSG00000197785
Ensembl biotype	protein_coding
OMIM	612316
Entrez	55210

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000339113, ENST00000378755, ENST00000378756, ENST00000400830, ENST00000429957, ENST00000439513, ENST00000536055, ENST00000672388, ENST00000904938, ENST00000936381, ENST00000936382, ENST00000936383, ENST00000936384, ENST00000936385

RefSeq mRNA: 3 — MANE Select: NM_001170535 NM_001170535, NM_001170536, NM_018188

CCDS: CCDS31, CCDS53259, CCDS53260

Canonical transcript exons

ENST00000378756 — 16 exons

Exon	Start	End
ENSE00000875540	1525240	1525291
ENSE00001304286	1527695	1527862
ENSE00001386419	1533926	1534685
ENSE00001615816	1522744	1522899
ENSE00001664426	1526461	1526531
ENSE00001745869	1523511	1523567
ENSE00001769953	1517311	1517412
ENSE00001784657	1523839	1523964
ENSE00001792016	1524273	1524397
ENSE00001948795	1512162	1512473
ENSE00003505667	1520548	1520617
ENSE00003592232	1516012	1516088
ENSE00003607995	1520141	1520306
ENSE00003620804	1518921	1518990
ENSE00003689904	1517716	1517775
ENSE00003791544	1529223	1529331

Expression profiles

Bgee: expression breadth ubiquitous, 247 present calls, max score 91.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.6806 / max 203.1193, expressed in 1803 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
119	28.6806	1803

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	91.32	gold quality
gastrocnemius	UBERON:0001388	89.94	gold quality
mucosa of transverse colon	UBERON:0004991	89.63	gold quality
apex of heart	UBERON:0002098	89.34	gold quality
stromal cell of endometrium	CL:0002255	89.28	gold quality
muscle of leg	UBERON:0001383	88.97	gold quality
adenohypophysis	UBERON:0002196	88.73	gold quality
lower esophagus mucosa	UBERON:0035834	88.32	gold quality
pituitary gland	UBERON:0000007	87.53	gold quality
right lobe of liver	UBERON:0001114	87.47	gold quality
hindlimb stylopod muscle	UBERON:0004252	87.46	gold quality
esophagus mucosa	UBERON:0002469	87.20	gold quality
body of pancreas	UBERON:0001150	86.75	gold quality
left adrenal gland cortex	UBERON:0035825	86.72	gold quality
right adrenal gland	UBERON:0001233	86.68	gold quality
left adrenal gland	UBERON:0001234	86.56	gold quality
heart left ventricle	UBERON:0002084	86.55	gold quality
skin of leg	UBERON:0001511	86.37	gold quality
cardiac ventricle	UBERON:0002082	86.33	gold quality
metanephros cortex	UBERON:0010533	86.28	gold quality
muscle organ	UBERON:0001630	86.19	gold quality
right adrenal gland cortex	UBERON:0035827	86.14	gold quality
adrenal cortex	UBERON:0001235	86.06	gold quality
right atrium auricular region	UBERON:0006631	85.93	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	85.80	gold quality
body of stomach	UBERON:0001161	85.79	gold quality
granulocyte	CL:0000094	85.77	gold quality
esophagus	UBERON:0001043	85.75	gold quality
skin of abdomen	UBERON:0001416	85.44	gold quality
right lobe of thyroid gland	UBERON:0001119	85.37	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.46

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting ATAD3A, 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-6867-5P	100.00	82.21	3464
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-5009-3P	99.45	69.43	1341
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-1233-5P	98.19	66.71	1201
HSA-MIR-6778-5P	98.19	66.59	1239
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-6765-3P	97.83	64.59	1165
HSA-MIR-342-5P	97.25	64.10	817
HSA-MIR-365A-5P	94.91	63.72	471
HSA-MIR-365B-5P	94.91	63.79	470

Literature-anchored findings (GeneRIF, showing 37)

• Results suggest that mitochondrial DNA displacement loops serve to recruit ATAD3 protein for the purpose of forming or segregating mitochondrial nucleoids. (PMID:17210950)
• We also have shown that the loss of ATAD 3A/3B may be involved in the transformation pathway and the chemosensitivity of oligodendrogliomas. (PMID:18639545)
• Data show that the mitochondrial AAA(+) ATPase protein ATAD3A is involved in dynamic interactions between components of the outer and inner mitochondrial membranes which control a number of critical mitochondrial functions. (PMID:20154147)
• gene expression in lung adenocarcinoma correlates with drug resistance and poor prognosis (PMID:20332122)
• The N-terminal part of ATAD3A is outside the inner mitochondrial membrane and that the C-terminal part is inside the matrix. (PMID:20349121)
• Data show that ATAD3A is a calcium-dependent S100B target protein in oligodendrocyte progenitor cells and suggest that S100B could assist the newly synthesized ATAD3A protein in proper folding and subcellular localization. (PMID:20351179)
• silencing of ATAD3A expression reduced PSA secretion and cisplatin resistance, suggesting that ATAD3A was associated with PSA secretion and drug resistance in PCa. (PMID:21584487)
• Results show that HPV infection correlates with increased ATAD3A expression and drug resistance in uterine cervical cancer. (PMID:21743956)
• ATAD3 may therefore be implicated in an unknown but essential and growth-linked mitochondrial function existing since pluri-cellular -organization and involved in tumorigenesis. (PMID:22192748)
• ATAD3 may be implicated in an unknown but essential and growth-linked mitochondrial function existing since pluri-cellular organization and involved in tumorigenesis. (PMID:22318359)
• Engineered a high copy strain expressing human ATAD3A-Myc-HIS at a relative high level (2.5mg/l of yeast culture)without significantly affecting yeast growth.Urea-denaturated ATAD3A-Myc-HIS bound to agarose-nickel beads and could be renatured and eluted. (PMID:22542587)
• ATAD3B is a negative regulator of ATAD3A and may function as an adaptor of mitochondrial homeostasis and metabolism in human pluripotent embryonic stem cells and cancer cells. (PMID:22664726)
• High ATAD3A expression correlates with radioresistance in glioblastoma. (PMID:24057885)
• exploring ATAD3 mRNA expression, we confirmed the existence of an alternative splicing in rodent and of several mRNA isoforms in human (PMID:24239551)
• These results demonstrate that ATAD3-mediated mitochondrial membrane formation participates in the optimal transfer of cholesterol from the endoplasmic reticulum into mitochondria. (PMID:25375035)
• stabilization of WASF3 function occurs through its interaction with ATAD3A and GRP78, which may provide a bridge between the ER and mitochondria, allowing communication between the two organelles (PMID:25823022)
• identification of a recurrent de novo ATAD3A c.1582C>T (p.Arg528Trp) variant by whole-exome sequencing in five unrelated individuals with a core phenotype of global developmental delay, hypotonia, optic atrophy, axonal neuropathy, and hypertrophic cardiomyopathy (PMID:27640307)
• Mutations in ATAD3A can thus be dominantly inherited and underlie variable neurological phenotypes, including hereditary spastic paraplegia with intrafamiliar variability. This finding extends the group of mitochondrial inner membrane AAA proteins associated with spasticity. (PMID:28158749)
• ATAD3A region deletions cause cerebellar dysfunction associated with altered mitochondrial DNA and cholesterol metabolism. (PMID:28549128)
• ATAD3A plays a key role in neurodegeneration by linking Drp1-induced mitochondrial fragmentation to defective mtDNA maintenance. (PMID:30914652)
• Our findings exclude the causative role of ATAD3B on this severe phenotype, expand the phenotypical spectrum of ATAD3A pathogenic variants and emphasize the vital role of ATAD3A in mitochondrial biogenesis. (PMID:31727539)
• Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism. (PMID:32004445)
• Using Genome-Editing Tools to Develop a Novel In Situ Coincidence Reporter Assay for Screening ATAD3A Transcriptional Inhibitors. (PMID:32219745)
• Mitochondrial dysfunction caused by novel ATAD3A mutations. (PMID:32933822)
• Emerging Links between Control of Mitochondrial Protein ATAD3A and Cancer. (PMID:33113782)
• Mitophagy promotes sorafenib resistance through hypoxia-inducible ATAD3A dependent Axis. (PMID:33280610)
• ATAD3A stabilizes GRP78 to suppress ER stress for acquired chemoresistance in colorectal cancer. (PMID:33580514)
• Functional interpretation of ATAD3A variants in neuro-mitochondrial phenotypes. (PMID:33845882)
• Enhanced cGAS-STING-dependent interferon signaling associated with mutations in ATAD3A. (PMID:34387651)
• ATAD3A has a scaffolding role regulating mitochondria inner membrane structure and protein assembly. (PMID:34936866)
• The oncoprotein MUC1 facilitates breast cancer progression by promoting Pink1-dependent mitophagy via ATAD3A destabilization. (PMID:36289190)
• Targeting ATAD3A-PINK1-mitophagy axis overcomes chemoimmunotherapy resistance by redirecting PD-L1 to mitochondria. (PMID:36627348)
• ATAD3A-related pontocerebellar hypoplasia: new patients and insights into phenotypic variability. (PMID:37095554)
• The value of ATAD3A as a potential biomarker for bladder cancer. (PMID:38018291)
• Identification of ATAD3A as a key regulator in non-small cell lung cancer by promoting STAT3-induced cell proliferation and tumor angiogenesis. (PMID:38050826)
• “ATAD3C regulates ATAD3A assembly and function in the mitochondrial membrane”. (PMID:38092275)
• PERK-ATAD3A interaction provides a subcellular safe haven for protein synthesis during ER stress. (PMID:39116259)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Atad3a	ENSMUSG00000029036
rattus_norvegicus	Atad3a	ENSRNOG00000018118
drosophila_melanogaster	bor	FBGN0287225

Paralogs (2): ATAD3B (ENSG00000160072), ATAD3C (ENSG00000215915)

Protein

Protein identifiers

ATPase family AAA domain-containing protein 3A — Q9NVI7 (reviewed: Q9NVI7)

All UniProt accessions (3): H0Y2W2, Q5SV16, Q9NVI7

UniProt curated annotations — full annotation on UniProt →

Function. Essential for mitochondrial network organization, mitochondrial metabolism and cell growth at organism and cellular level. May play an important role in mitochondrial protein synthesis. May also participate in mitochondrial DNA replication. May bind to mitochondrial DNA D-loops and contribute to nucleoid stability. Required for enhanced channeling of cholesterol for hormone-dependent steroidogenesis. Involved in mitochondrial-mediated antiviral innate immunity. Required to protect mitochondria from the PERK-mediated unfolded protein response: specifically inhibits the activity of EIF2AK3/PERK at mitochondria-endoplasmic reticulum contact sites, thereby providing a safe haven for mitochondrial protein translation during endoplasmic reticulum stress. Ability to inhibit EIF2AK3/PERK is independent of its ATPase activity. Also involved in the mitochondrial DNA damage response by promoting signaling between damaged genomes and the mitochondrial membrane, leading to activation of the integrated stress response (ISR).

Subunit / interactions. Can form homooligomers. Homodimer formation at the N-terminus may be regulated by ATP and is required for the interaction with the inner surface of the mitochondrial outer membrane and correct mitochondrial homeostasis. Interacts with components of the mitochondrial ribosome and with other proteins involved in mitochondrial RNA metabolism. May also interact with protein involved in lipid metabolism, including STARD9. May interact with FAM210A. Interacts with GADD45GIP1. Interacts with S100B in a Ca(+2)- and Zn(+2)-dependent manner; this interaction probably occurs in the cytosol prior to mitochondrial targeting. S100B could assist ATAD3A cytoplasmic processing, preventing aggregation and favoring mitochondrial localization. Interacts with HSP60/HSPD1. Forms heterooligomers with ATAD3B; this interaction may affect ATAD3A activity. Interacts with CLPB. Interacts with EIF2AK3/PERK; ATAD3A and EIF2S1/eIF-2-alpha occupy a common binding site within the cytoplasmic loop of EIF2AK3/PERK, leading to prevent EIF2AK3/PERK association with its substrate EIF2S1/eIF-2-alpha.

Subcellular location. Mitochondrion inner membrane. Mitochondrion matrix. Mitochondrion nucleoid.

Tissue specificity. Overexpressed in lung adenocarcinomas (at protein level).

Disease relevance. Harel-Yoon syndrome (HAYOS) [MIM:617183] A syndrome characterized by global developmental delay, hypotonia, intellectual disability, and axonal neuropathy. Some patients have optic atrophy and hypertrophic cardiomyopathy. HAYOS inheritance can be autosomal dominant or autosomal recessive. The disease is caused by variants affecting the gene represented in this entry. Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal (PHRINL) [MIM:618810] An autosomal recessive multisystem disorder with onset in utero and death in the neonatal period. Affected infants show respiratory insufficiency and almost no spontaneous movement at birth. Additional features include corneal clouding, seizures, dysmorphic facies, contractures, and progressive pontocerebellar hypoplasia with simplified gyral pattern and white matter abnormalities. Some patients may have cardiac anomalies or cardiac hypertrophy. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The transmembrane domain and a C-terminal adjacent region contain all information necessary for mitochondrial targeting.

Induction. Up-regulated by Angiotensin/AGT.

Similarity. Belongs to the AAA ATPase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9NVI7-2	2	yes
Q9NVI7-1	1
Q9NVI7-3	3

RefSeq proteins (3): NP_001164006, NP_001164007, NP_060658 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003593	AAA+_ATPase	Domain
IPR003959	ATPase_AAA_core	Domain
IPR021911	ATAD3_N	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00004, PF12037

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (33 total): sequence variant 6, mutagenesis site 6, region of interest 4, compositionally biased region 3, modified residue 3, splice variant 2, topological domain 2, sequence conflict 2, initiator methionine 1, chain 1, binding site 1, transmembrane region 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NVI7-F1	82.35	0.40

Functional residue map

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

Ligand- & substrate-binding residues (1): 352–359

Post-translational modifications (3): 2, 321, 491

Mutagenesis-validated functional residues (6):

Position	Phenotype
293	loss of s100b-binding; when associated with s-297.
297	loss of s100b-binding; when associated with s-293.
301–302	decrease in s100b-binding.
358	no effect on homooligomerization. immediate fragmentation of the mitochondrial network.
411	no effect on homooligomerization. immediate fragmentation of the mitochondrial network.
412	abolished atpase activity without affecting its ability to interact with and inhibit eif2ak3/perk.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 300 (showing top): GOBP_NEGATIVE_REGULATION_OF_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, TGCGCANK_UNKNOWN, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_GROWTH, GOBP_CELLULAR_RESPONSE_TO_TOPOLOGICALLY_INCORRECT_PROTEIN, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_ER_NUCLEUS_SIGNALING_PATHWAY, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, MYCMAX_01, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_DNA_DAMAGE_RESPONSE, GOCC_MITOCHONDRIAL_ENVELOPE, GOBP_NEGATIVE_REGULATION_OF_ENDOPLASMIC_RETICULUM_UNFOLDED_PROTEIN_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_VIRUS

GO Biological Process (9): regulation of cell growth (GO:0001558), DNA damage response (GO:0006974), mitochondrion organization (GO:0007005), negative regulation of apoptotic process (GO:0043066), antiviral innate immune response (GO:0140374), HRI-mediated signaling (GO:0140468), negative regulation of PERK-mediated unfolded protein response (GO:1903898), translational initiation (GO:0006413), PERK-mediated unfolded protein response (GO:0036499)

GO Molecular Function (7): ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), protein serine/threonine kinase inhibitor activity (GO:0030291), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (6): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), mitochondrial nucleoid (GO:0042645), mitochondria-associated endoplasmic reticulum membrane contact site (GO:0044233), membrane (GO:0016020), mitochondrial membrane (GO:0031966)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
integrated stress response signaling	2
mitochondrion	2
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
cellular response to stress	1
organelle organization	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
innate immune response	1
defense response to virus	1
PERK-mediated unfolded protein response	1
negative regulation of endoplasmic reticulum unfolded protein response	1
regulation of PERK-mediated unfolded protein response	1
formation of translation initiation ternary complex	1
translation	1
metabolic process	1
ER-nucleus signaling pathway	1
endoplasmic reticulum unfolded protein response	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
ATP-dependent activity	1
protein serine/threonine kinase activity	1
protein kinase inhibitor activity	1
protein binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
organelle inner membrane	1
mitochondrial membrane	1
mitochondrial matrix	1
nucleoid	1
intracellular membraneless organelle	1
organelle membrane contact site	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1852 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATAD3A	TSPO	P30536	739
ATAD3A	HSPA9	P30036	702
ATAD3A	VDAC1	P21796	636
ATAD3A	DENR	O43583	627
ATAD3A	STAR	P49675	623
ATAD3A	ATP5MG	O75964	617
ATAD3A	RMDN3	Q96TC7	604
ATAD3A	ISCU	Q9H1K1	596
ATAD3A	LYRM4	Q9HD34	581
ATAD3A	SIGMAR1	Q99720	559
ATAD3A	TST	Q16762	547
ATAD3A	HSPD1	P10809	537
ATAD3A	ERLIN2	O94905	518
ATAD3A	FTMT	Q8N4E7	515
ATAD3A	SDHA	P31040	505

IntAct

225 interactions, top by confidence:

A	B	Type	Score
PPP1CC	CCDC85C	psi-mi:“MI:0914”(association)	0.740
PPP1CC	CCDC85C	psi-mi:“MI:2364”(proximity)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
BRAF	KRAS	psi-mi:“MI:0914”(association)	0.680
PPP1CA	CCDC85C	psi-mi:“MI:0914”(association)	0.670
PPP1CA	CCDC85C	psi-mi:“MI:2364”(proximity)	0.670
INAVA	CYTH3	psi-mi:“MI:0914”(association)	0.640
MAPK7	PFDN6	psi-mi:“MI:0914”(association)	0.640
RAF1	CALU	psi-mi:“MI:0914”(association)	0.640
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
ATAD3A	HSPD1	psi-mi:“MI:0914”(association)	0.580
HSPD1	ATAD3A	psi-mi:“MI:0915”(physical association)	0.580
PPP2R2D	ENSA	psi-mi:“MI:0914”(association)	0.570
MAP3K5	MAP3K6	psi-mi:“MI:0914”(association)	0.550
	XPO1	psi-mi:“MI:0914”(association)	0.530
PSME1	POLR3A	psi-mi:“MI:0914”(association)	0.530
DNM1L	ATAD3A	psi-mi:“MI:0915”(physical association)	0.500
ATAD3B	HSPD1	psi-mi:“MI:0914”(association)	0.480
COA3	ATAD3A	psi-mi:“MI:0915”(physical association)	0.460
COA3	ATAD3A	psi-mi:“MI:0403”(colocalization)	0.460
ESR1		psi-mi:“MI:0914”(association)	0.460

BioGRID (442): ATAD3A (Affinity Capture-MS), ATAD3A (Affinity Capture-MS), ATAD3A (Affinity Capture-MS), ATAD3A (Affinity Capture-MS), ATAD3A (Affinity Capture-MS), ATAD3A (Affinity Capture-MS), ATAD3A (Affinity Capture-MS), ATAD3A (Affinity Capture-MS), ATAD3A (Affinity Capture-MS), ATAD3A (Affinity Capture-MS), ATAD3A (Co-fractionation), ATAD3A (Co-fractionation), ATAD3A (Co-fractionation), ATAD3A (Co-fractionation), COPB1 (Co-fractionation)

ESM2 similar proteins: A2S1Q0, A3MCG8, A3NLD5, A3P6Z7, A7YWC4, B0KTG9, O84947, P02978, P04480, P0ADS9, P0ADT0, P0ADT1, P18011, P22901, P37131, P37132, P54911, P55400, Q03945, Q04628, Q05129, Q06114, Q06131, Q2T708, Q2T711, Q2YJ75, Q3JL23, Q3KRE0, Q47108, Q47125, Q47500, Q52328, Q56019, Q56134, Q56136, Q57239, Q57A18, Q5PEC2, Q62B07, Q63K34

Diamond homologs: A7YWC4, C8W731, D1C4U5, D5H7Z5, O27092, P42811, Q20748, Q3KRE0, Q58889, Q58E76, Q5T2N8, Q5T9A4, Q6NVR9, Q6PAX2, Q925I1, Q9NVI7, Q9VEX6, A7I8B8, B3DV46, C7N914, D7Y2H4, O26824, O64982, P03974, P0DKJ9, P0DKK0, P23787, P25694, P32795, P46462, P54811, P54812, P55072, P73437, Q01853, Q01939, Q05AS3, Q2NIN5, Q3ULF4, Q3UMC0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 204 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
RAF activation	5	12.4×	5e-03
SPOP-mediated proteasomal degradation of PD-L1(CD274)	6	10.2×	4e-03
Defective CFTR causes cystic fibrosis	6	9.8×	4e-03
Cross-presentation of soluble exogenous antigens (endosomes)	5	9.4×	7e-03
SCF(Skp2)-mediated degradation of p27/p21	6	9.2×	5e-03
FBXL7 down-regulates AURKA during mitotic entry and in early mitosis	5	9.2×	7e-03
GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	5	9.2×	7e-03
SCF-beta-TrCP mediated degradation of Emi1	5	8.8×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
stress granule assembly	5	17.0×	5e-03
cellular response to transforming growth factor beta stimulus	7	10.9×	2e-03
MAPK cascade	8	6.9×	5e-03
cellular response to hypoxia	9	6.2×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	19
Uncertain significance	291
Likely benign	55
Benign	29

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1077177	NM_001170535.3(ATAD3A):c.282+484_444+231del	Pathogenic
1180503	GRCh37/hg19 1p36.33(chr1:1418289-1454405)x1	Pathogenic
225698	Single allele	Pathogenic
2446185	NM_001170535.3(ATAD3A):c.562C>T (p.Arg188Ter)	Pathogenic
2682365	NC_000001.10:g.(?1447541)(1447854_1451391)del	Pathogenic
3068946	NC_000001.10:g.(?1447541)(1454371_1455520)del	Pathogenic
3374905	NM_001170535.3(ATAD3A):c.1365_1366del (p.Gln455fs)	Pathogenic
592109	NM_001170535.3(ATAD3A):c.283-60del	Pathogenic
637018	NM_001170535.3(ATAD3A):c.1217T>G (p.Leu406Arg)	Pathogenic
828050	NM_001170535.3(ATAD3A):c.490C>T (p.Gln164Ter)	Pathogenic
828051	NM_001170535.3(ATAD3A):c.230T>G (p.Leu77Arg)	Pathogenic
992492	Single allele	Pathogenic
992493	Single allele	Pathogenic
992494	Single allele	Pathogenic
992495	Single allele	Pathogenic
1196697	NM_001170535.3(ATAD3A):c.281_282+1del	Likely pathogenic
1213715	NC_000001.11:g.(1475764_1482998)_(1517413_1518921)del	Likely pathogenic
1679823	NM_001170535.3(ATAD3A):c.1583G>A (p.Arg528Gln)	Likely pathogenic
1710696	NM_001170535.3(ATAD3A):c.2T>A (p.Met1Lys)	Likely pathogenic
1810561	NM_001170535.3(ATAD3A):c.1689del (p.Gln563fs)	Likely pathogenic
2136073	NM_001170535.3(ATAD3A):c.1266+1G>A	Likely pathogenic
2499615	NM_001170535.3(ATAD3A):c.385-2A>C	Likely pathogenic
2506007	NM_001170535.3(ATAD3A):c.1611G>A (p.Trp537Ter)	Likely pathogenic
3235907	GRCh38/hg38 1p36.33(chr1:1482000-1519400)	Likely pathogenic
3235910	NM_001170535.3(ATAD3A):c.207_213delinsCCATGTCA (p.Tyr70fs)	Likely pathogenic
3572945	NM_001170535.3(ATAD3A):c.278T>C (p.Leu93Pro)	Likely pathogenic
3893290	NM_001170535.3(ATAD3A):c.288T>G (p.Tyr96Ter)	Likely pathogenic
4294448	NM_001170535.3(ATAD3A):c.1071del (p.Lys358fs)	Likely pathogenic
452211	NM_001170535.3(ATAD3A):c.658C>T (p.Gln220Ter)	Likely pathogenic
806418	GRCh37/hg19 1p36.33(chr1:1451392-1452792)x1	Likely pathogenic

SpliceAI

3118 predictions. Top by Δscore:

Variant	Effect	Δscore
1:1512469:CTCGC:C	donor_gain	1.0000
1:1512470:TCGC:T	donor_gain	1.0000
1:1512471:CGCG:C	donor_loss	1.0000
1:1512472:GC:G	donor_gain	1.0000
1:1512473:CGTG:C	donor_loss	1.0000
1:1512474:G:GG	donor_gain	1.0000
1:1512474:GTGA:G	donor_loss	1.0000
1:1516001:T:TA	acceptor_gain	1.0000
1:1516003:C:CA	acceptor_gain	1.0000
1:1516010:A:AG	acceptor_gain	1.0000
1:1516010:AG:A	acceptor_gain	1.0000
1:1516010:AGGT:A	acceptor_loss	1.0000
1:1516011:G:A	acceptor_loss	1.0000
1:1516011:G:GG	acceptor_gain	1.0000
1:1516011:GG:G	acceptor_gain	1.0000
1:1516011:GGT:G	acceptor_gain	1.0000
1:1516011:GGTT:G	acceptor_gain	1.0000
1:1516011:GGTTA:G	acceptor_gain	1.0000
1:1516084:TCAAA:T	donor_gain	1.0000
1:1516085:CAAA:C	donor_gain	1.0000
1:1516086:AAA:A	donor_gain	1.0000
1:1516086:AAAGT:A	donor_loss	1.0000
1:1516087:AA:A	donor_gain	1.0000
1:1516087:AAG:A	donor_loss	1.0000
1:1516088:AG:A	donor_loss	1.0000
1:1516089:GTGA:G	donor_gain	1.0000
1:1517410:GCC:G	donor_gain	1.0000
1:1517715:GA:G	acceptor_gain	1.0000
1:1517772:GCAG:G	donor_gain	1.0000
1:1517773:CAGG:C	donor_loss	1.0000

AlphaMissense

3810 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:1518960:T:C	S210P	0.999
1:1518985:G:C	R218P	0.998
1:1520269:G:C	A263P	0.998
1:1522766:C:A	A306D	0.998
1:1522784:C:A	A312D	0.998
1:1518952:A:C	Q207P	0.997
1:1518973:A:C	Q214P	0.997
1:1520197:G:C	A239P	0.997
1:1527714:A:C	S501R	0.997
1:1527716:C:A	S501R	0.997
1:1527716:C:G	S501R	0.997
1:1512416:T:C	F50L	0.996
1:1512418:C:A	F50L	0.996
1:1512418:C:G	F50L	0.996
1:1512441:C:A	A58D	0.996
1:1520165:T:C	L228P	0.996
1:1522772:G:A	G308E	0.996
1:1522783:G:C	A312P	0.996
1:1524280:C:A	A414D	0.996
1:1512440:G:C	A58P	0.995
1:1512443:G:C	A59P	0.995
1:1512449:G:C	A61P	0.995
1:1517744:G:C	R186P	0.995
1:1518990:G:C	A220P	0.995
1:1520168:G:C	R229P	0.995
1:1520552:G:C	A277P	0.995
1:1522757:C:A	T303K	0.995
1:1524304:C:A	A422D	0.995
1:1529326:T:A	W585R	0.995
1:1529326:T:C	W585R	0.995

dbSNP variants (sampled 300 via entrez): RS1000123352 (1:1528348 G>GAT), RS1000203911 (1:1518816 G>A), RS1000289399 (1:1510419 A>G), RS1000423491 (1:1532630 A>T), RS1000447192 (1:1514807 C>T), RS1000482129 (1:1510167 C>A,T), RS1000613827 (1:1517903 G>A), RS1000681967 (1:1519098 T>C), RS1000711857 (1:1513465 G>A,C), RS1000743063 (1:1513761 C>G,T), RS1001007647 (1:1525437 A>C,G,T), RS1001054094 (1:1522171 A>C), RS1001312870 (1:1524840 C>A,G,T), RS1001354949 (1:1521179 G>C), RS1001385922 (1:1521298 CAAAAAAAAAAAAAAAAAAAAAAA>C,CA,CAAAA,CAAAAA,CAAAAAA,CAAAAAAA,CAAAAAAAA,CAAAAAAAAA,CAAAAAAAAAA,CAAAAAAAAAAA,CAAAAAAAAAAAA,CAAAAAAAAAAAAA,CAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAAAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA,CAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA)

Disease associations

OMIM: gene MIM:612316 | disease phenotypes: MIM:617183, MIM:618810, MIM:213000

GenCC curated gene-disease

Disease	Classification	Inheritance
Harel-Yoon syndrome	Definitive	Autosomal dominant
pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal	Strong	Autosomal recessive

Mondo (7): Harel-Yoon syndrome (MONDO:0014958), pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal (MONDO:0032931), hearing loss disorder (MONDO:0005365), intellectual disability (MONDO:0001071), disorder of development or morphogenesis (MONDO:0021147), epilepsy (MONDO:0005027), isolated cerebellar hypoplasia/agenesis (MONDO:0008939)

Orphanet (5): Ocular anomalies-axonal neuropathy-developmental delay syndrome (Orphanet:496790), Lethal pontocerebellar hypoplasia-hypotonia-respiratory insufficiency syndrome (Orphanet:615954), Isolated cerebellar agenesis (Orphanet:1398), Cerebellar hypoplasia-tapetoretinal degeneration syndrome (Orphanet:2246), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

66 total (30 of 66 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000034	Hydrocele testis
HP:0000054	Micropenis
HP:0000160	Narrow mouth
HP:0000276	Long face
HP:0000303	Mandibular prognathia
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000490	Deeply set eye
HP:0000518	Cataract
HP:0000519	Developmental cataract
HP:0000545	Myopia
HP:0000565	Esotropia
HP:0000582	Upslanted palpebral fissure
HP:0000609	Optic nerve hypoplasia
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000750	Delayed speech and language development
HP:0000768	Pectus carinatum
HP:0000823	Delayed puberty
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001263	Global developmental delay

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005951_34	Body mass index	3.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C562568	Cerebellar Hypoplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067382 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.05	Kd	8.901	nM	CHEMBL3752910
8.05	ED50	8.901	nM	CHEMBL3752910
5.10	Kd	7993	nM	CHEMBL5653589
5.10	ED50	7993	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 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-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147900: Binding affinity to human ATAD3A incubated for 45 mins by Kinobead based pull down assay	kd	0.0089	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147900: Binding affinity to human ATAD3A incubated for 45 mins by Kinobead based pull down assay	kd	7.9934	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	3
Valproic Acid	affects expression, increases expression, increases methylation	3
bisphenol A	decreases expression	2
afuresertib	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
alpha-pinene	increases abundance, affects cotreatment, decreases expression	1
glycidyl methacrylate	decreases expression	1
tetrahydropalmatine	increases expression	1
zinc chromate	decreases expression, increases abundance	1
cupric chloride	increases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
NSC 689534	decreases expression, affects binding	1
bisphenol AF	increases expression	1
Arsenic Trioxide	decreases expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Caffeine	decreases phosphorylation	1
Cisplatin	decreases expression	1
Clozapine	decreases expression	1
Copper	affects binding, decreases expression	1
Diethylstilbestrol	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Estradiol	increases expression	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
CHEMBL5650942	Binding	Binding affinity to human ATAD3A incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	PHASE1/PHASE2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound
NCT01109576	EARLY_PHASE1	COMPLETED	Workshops for Veterans With Vision and Hearing Loss