ATP6AP1

Summary

ATP6AP1 (ATPase H+ transporting accessory protein 1, HGNC:868) is a protein-coding gene on chromosome Xq28, encoding V-type proton ATPase subunit S1 (Q15904). Accessory subunit of the proton-transporting vacuolar (V)-ATPase protein pump, which is required for luminal acidification of secretory vesicles. It is a common-essential gene (DepMap: required in 93.5% of cancer cell lines).

This gene encodes a component of a multisubunit enzyme that mediates acidification of eukaryotic intracellular organelles. Vacuolar ATPase (V-ATPase) is comprised of a cytosolic V1 (site of the ATP catalytic site) and a transmembrane V0 domain. V-ATPase dependent organelle acidification is necessary for such intracellular processes as protein sorting, zymogen activation, and receptor-mediated endocytosis. The encoded protein of this gene may assist in the V-ATPase-mediated acidification of neuroendocrine secretory granules. This protein may also play a role in early development.

Source: NCBI Gene 537 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital disorder of glycosylation type II (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 425 total — 20 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 47
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 93.5% of screened cell lines (common-essential)
• MANE Select transcript: NM_001183

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:868
Approved symbol	ATP6AP1
Name	ATPase H+ transporting accessory protein 1
Location	Xq28
Locus type	gene with protein product
Status	Approved
Aliases	ORF, XAP-3, VATPS1, 16A, Ac45, XAP3, CF2
Ensembl gene	ENSG00000071553
Ensembl biotype	protein_coding
OMIM	300197
Entrez	537

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 14 protein_coding, 7 nonsense_mediated_decay, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000369762, ENST00000422890, ENST00000429585, ENST00000439372, ENST00000446552, ENST00000449556, ENST00000455205, ENST00000484908, ENST00000491569, ENST00000619046, ENST00000677332, ENST00000677342, ENST00000678317, ENST00000679241, ENST00000862435, ENST00000862436, ENST00000862437, ENST00000862438, ENST00000862439, ENST00000862440, ENST00000945275, ENST00000945276, ENST00000945277, ENST00000945278

RefSeq mRNA: 1 — MANE Select: NM_001183 NM_001183

CCDS: CCDS35451

Canonical transcript exons

ENST00000369762 — 10 exons

Exon	Start	End
ENSE00001281536	154429048	154429174
ENSE00001450826	154435682	154436516
ENSE00001450844	154428677	154428853
ENSE00003467686	154432931	154432971
ENSE00003511050	154433635	154433720
ENSE00003532741	154432266	154432459
ENSE00003536990	154435274	154435505
ENSE00003597766	154434208	154434446
ENSE00003598997	154435139	154435186
ENSE00003670554	154431830	154431904

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 98.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 133.6133 / max 793.9385, expressed in 1828 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198156	108.7995	1827
198155	24.0891	1817
198157	0.3672	165
198159	0.3574	171

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endometrium epithelium	UBERON:0004811	98.65	gold quality
Brodmann (1909) area 10	UBERON:0013541	98.63	gold quality
paraflocculus	UBERON:0005351	98.46	gold quality
prefrontal cortex	UBERON:0000451	98.44	gold quality
islet of Langerhans	UBERON:0000006	98.39	gold quality
stromal cell of endometrium	CL:0002255	98.37	gold quality
cerebellar cortex	UBERON:0002129	98.37	gold quality
cerebellar hemisphere	UBERON:0002245	98.37	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.35	gold quality
right frontal lobe	UBERON:0002810	98.27	gold quality
cerebellum	UBERON:0002037	98.18	gold quality
adenohypophysis	UBERON:0002196	98.12	gold quality
frontal pole	UBERON:0002795	98.10	gold quality
pituitary gland	UBERON:0000007	98.08	gold quality
middle frontal gyrus	UBERON:0002702	98.04	gold quality
cingulate cortex	UBERON:0003027	97.95	gold quality
anterior cingulate cortex	UBERON:0009835	97.93	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.92	gold quality
frontal cortex	UBERON:0001870	97.88	gold quality
type B pancreatic cell	CL:0000169	97.74	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.74	gold quality
neocortex	UBERON:0001950	97.66	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.64	gold quality
right lung	UBERON:0002167	97.62	gold quality
right adrenal gland cortex	UBERON:0035827	97.56	gold quality
metanephros cortex	UBERON:0010533	97.54	gold quality
right adrenal gland	UBERON:0001233	97.53	gold quality
cerebellar vermis	UBERON:0004720	97.53	gold quality
hypothalamus	UBERON:0001898	97.46	gold quality
upper lobe of left lung	UBERON:0008952	97.46	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10042	yes	9.63
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): JUN

miRNA regulators (miRDB)

34 targeting ATP6AP1, 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-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-1324	99.46	66.57	1302
HSA-MIR-6507-5P	99.36	70.46	2524
HSA-MIR-1206	99.30	69.32	1016
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-449B-3P	99.20	67.24	1047
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-887-5P	98.82	65.90	1347
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-30C-1-3P	97.80	66.36	1499
HSA-MIR-30C-2-3P	97.80	66.45	1499

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 93.5% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 12)

• Experimental investigation of five specific genes, AP3B1, ATP6AP1, BLOC1S1, LAMP2, and RAB11A, has confirmed novel roles for these proteins in the proper initiation of macroautophagy in amino acid-starved fibroblasts. (PMID:19246570)
• ATP6AP1 is somatically mutated in 12% of follicular lymphoma tumors. Mutations clustered around the transmembrane domain. (PMID:25713363)
• Data indicate V-ATPase Ac45 subunit assembly with immunoglobulin production and cognitive function. (PMID:27231034)
• Here we report on the previously unreported finding of CL due to a hemizygous mutation in the gene ATP6AP1 (MIM 300972), a component of the V-ATPase complex that was recently described to cause an X-linked N-glycosylation disorder with liver disease (PMID:29192153)
• inactivating mutations of ATP6AP1 are likely oncogenic drivers of Granular cell tumors;a genetic link between endosomal pH regulation and tumorigenesis (PMID:30166553)
• Prenatal and postnatal phenotype of a pathologic variant in the ATP6AP1 gene. (PMID:32058063)
• Severe phenotype of ATP6AP1-CDG in two siblings with a novel mutation leading to a differential tissue-specific ATP6AP1 protein pattern, cellular oxidative stress and hepatic copper accumulation. (PMID:32216104)
• Prognostic and immunological value of ATP6AP1 in breast cancer: implications for SARS-CoV-2. (PMID:34228637)
• SARS-CoV-2 non-structural protein 6 triggers NLRP3-dependent pyroptosis by targeting ATP6AP1. (PMID:34997207)
• Expanding the phenotype of ATP6AP1 deficiency. (PMID:35732497)
• ATP6AP1 as a potential prognostic biomarker in CRC by comprehensive analysis and verification. (PMID:38369634)
• Genome and RNA sequencing were essential to reveal cryptic intronic variants associated to defective ATP6AP1 mRNA processing. (PMID:38878498)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	atp6ap1b	ENSDARG00000037153
danio_rerio	atp6ap1a	ENSDARG00000041417
mus_musculus	Atp6ap1	ENSMUSG00000019087
rattus_norvegicus	Atp6ap1	ENSRNOG00000054352
drosophila_melanogaster	VhaAC45	FBGN0262515
caenorhabditis_elegans		WBGENE00021952

Protein

Protein identifiers

V-type proton ATPase subunit S1 — Q15904 (reviewed: Q15904)

Alternative names: Protein XAP-3, V-ATPase Ac45 subunit, V-ATPase S1 accessory protein, Vacuolar proton pump subunit S1

All UniProt accessions (11): Q15904, A0A0C4DGX8, A0A384MQW4, A0A7I2V2G3, A0A7I2V3T8, A0A7I2YQA5, A6NLC6, A6QRJ1, F2Z3L8, H7C0T7, H7C2Y8

UniProt curated annotations — full annotation on UniProt →

Function. Accessory subunit of the proton-transporting vacuolar (V)-ATPase protein pump, which is required for luminal acidification of secretory vesicles. Guides the V-type ATPase into specialized subcellular compartments, such as neuroendocrine regulated secretory vesicles or the ruffled border of the osteoclast, thereby regulating its activity. Involved in membrane trafficking and Ca(2+)-dependent membrane fusion. May play a role in the assembly of the V-type ATPase complex. In aerobic conditions, involved in intracellular iron homeostasis, thus triggering the activity of Fe(2+) prolyl hydroxylase (PHD) enzymes, and leading to HIF1A hydroxylation and subsequent proteasomal degradation. In islets of Langerhans cells, may regulate the acidification of dense-core secretory granules.

Subunit / interactions. Accessory component of the multisubunit proton-transporting vacuolar (V)-ATPase protein pump. Interacts (via N-terminus) with ATP6AP2 (via N-terminus). Interacts with RNASEK. Interacts with TMEM106B (via C-terminus).

Subcellular location. Endoplasmic reticulum membrane. Endoplasmic reticulum-Golgi intermediate compartment membrane. Cytoplasmic vesicle. Secretory vesicle. Synaptic vesicle membrane. Clathrin-coated vesicle membrane.

Tissue specificity. widely expressed, with highest levels in brain and lowest in liver and duodenum.

Post-translational modifications. N-glycosylated.

Disease relevance. Immunodeficiency 47 (IMD47) [MIM:300972] A complex immunodeficiency syndrome characterized by hypogammaglobulinemia, recurrent bacterial infections, defective glycosylation of serum proteins, and liver disease with neonatal jaundice and hepatosplenomegaly. Some patients may also have neurologic features, including seizures, mild intellectual disability, and behavioral abnormalities. Inheritance is X-linked recessive. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the vacuolar ATPase subunit S1 family.

RefSeq proteins (1): NP_001174* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008388	Ac45_acc_su	Family
IPR046755	VAS1_LD	Domain
IPR046756	VAS1/VOA1_TM	Domain

Pfam: PF05827, PF20520

UniProt features (42 total): strand 12, glycosylation site 7, sequence conflict 5, sequence variant 4, helix 2, topological domain 2, turn 2, signal peptide 1, chain 1, disulfide bond 1, propeptide 1, mutagenesis site 1, transmembrane region 1, site 1, modified residue 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
6WLW	ELECTRON MICROSCOPY	3
9DET	ELECTRON MICROSCOPY	3
6WM2	ELECTRON MICROSCOPY	3.1
6WM3	ELECTRON MICROSCOPY	3.4
9CF8	ELECTRON MICROSCOPY	3.46
9CFC	ELECTRON MICROSCOPY	3.47
6WM4	ELECTRON MICROSCOPY	3.6
7U4T	ELECTRON MICROSCOPY	3.6
7UNF	ELECTRON MICROSCOPY	4.08

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15904-F1	79.60	0.32

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 (1): 231–232 (cleavage; by furin)

Post-translational modifications (1): 465

Disulfide bonds (1): 371–418

Glycosylation sites (7): 273, 296, 303, 350, 357, 170, 261

Mutagenesis-validated functional residues (1):

Position	Phenotype
470	retained in the endoplasmic reticulum when transfected into yeast cells. restores v-atpase-dependent growth in voa1 muta

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-77387	Insulin receptor recycling
R-HSA-8980692	RHOA GTPase cycle
R-HSA-917977	Transferrin endocytosis and recycling
R-HSA-983712	Ion channel transport

MSigDB gene sets: 367 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, REACTOME_SIGNALING_BY_INSULIN_RECEPTOR, MODY_HIPPOCAMPUS_POSTNATAL, GOBP_ENDOSOME_ORGANIZATION, GOBP_VACUOLE_ORGANIZATION, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_MYELOID_CELL_DEVELOPMENT, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOCC_VACUOLAR_MEMBRANE, GOBP_VESICLE_ORGANIZATION, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_INTRACELLULAR_IRON_ION_HOMEOSTASIS, MORF_HDAC1, GOBP_BONE_CELL_DEVELOPMENT, KEGG_LYSOSOME

GO Biological Process (13): intracellular iron ion homeostasis (GO:0006879), vacuolar acidification (GO:0007035), lysosomal lumen acidification (GO:0007042), obsolete regulation of cellular pH (GO:0030641), osteoclast development (GO:0036035), cellular response to increased oxygen levels (GO:0036295), endosomal lumen acidification (GO:0048388), intracellular pH reduction (GO:0051452), Golgi lumen acidification (GO:0061795), synaptic vesicle lumen acidification (GO:0097401), endosome to plasma membrane protein transport (GO:0099638), proton transmembrane transport (GO:1902600), monoatomic ion transport (GO:0006811)

GO Molecular Function (4): ATPase activator activity (GO:0001671), small GTPase binding (GO:0031267), transporter activator activity (GO:0141109), protein binding (GO:0005515)

GO Cellular Component (19): Golgi membrane (GO:0000139), lysosomal membrane (GO:0005765), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), endosome membrane (GO:0010008), membrane (GO:0016020), proton-transporting two-sector ATPase complex (GO:0016469), clathrin-coated vesicle membrane (GO:0030665), synaptic vesicle membrane (GO:0030672), endoplasmic reticulum-Golgi intermediate compartment membrane (GO:0033116), proton-transporting V-type ATPase complex (GO:0033176), extracellular exosome (GO:0070062), endoplasmic reticulum (GO:0005783), endomembrane system (GO:0012505), cytoplasmic vesicle membrane (GO:0030659), cytoplasmic vesicle (GO:0031410), synapse (GO:0045202), bounding membrane of organelle (GO:0098588), presynapse (GO:0098793)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Signaling by Insulin receptor	1
RHO GTPase cycle	1
Iron uptake and transport	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular pH reduction	3
bounding membrane of organelle	3
cellular anatomical structure	3
molecular function activator activity	2
organelle membrane	2
cytoplasm	2
intracellular monoatomic cation homeostasis	1
inorganic ion homeostasis	1
vacuolar acidification	1
osteoclast differentiation	1
myeloid cell development	1
bone cell development	1
response to increased oxygen levels	1
cellular response to oxygen levels	1
endosome organization	1
regulation of intracellular pH	1
intercellular transport	1
synaptic vesicle maturation	1
establishment of localization in cell	1
neuron cellular homeostasis	1
synaptic vesicle cycle	1
proton transmembrane transport	1
intracellular protein transport	1
endocytic recycling	1
establishment of protein localization to plasma membrane	1
protein localization to plasma membrane	1
monoatomic cation transmembrane transport	1
transport	1
ATP-dependent activity	1
GTPase binding	1
transporter activity	1
transporter regulator activity	1
binding	1
Golgi apparatus	1
lysosome	1
lytic vacuole membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1374 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ATP6AP1	ATP6AP2	O75787	879
ATP6AP1	ATP6V0B	Q99437	847
ATP6AP1	GDI1	P31150	834
ATP6AP1	RNASEK	Q6P5S7	816
ATP6AP1	ATP6V1A	P38606	800
ATP6AP1	ATP6V0C	P27449	791
ATP6AP1	VMA22	Q96NT0	765
ATP6AP1	ATP6V1G1	O75348	723
ATP6AP1	ATP6V0E2	Q8NHE4	709
ATP6AP1	CXXC5	Q7LFL8	700
ATP6AP1	ATP6V1C1	P21283	695
ATP6AP1	ATP6V0D1	P12953	655
ATP6AP1	ATP6V0E1	O15342	647
ATP6AP1	ATP6V1H	Q9UI12	643
ATP6AP1	AOC3	Q16853	639

IntAct

150 interactions, top by confidence:

A	B	Type	Score
ATP6AP1	rep	psi-mi:“MI:0915”(physical association)	0.830
ATP6AP2	ATP6V0C	psi-mi:“MI:0914”(association)	0.730
ATP6V0A2	ATP6AP2	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
TCIRG1	ATP6AP2	psi-mi:“MI:0914”(association)	0.640
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
CANX	PGRMC1	psi-mi:“MI:0914”(association)	0.570
HTT	ATP6AP1	psi-mi:“MI:0915”(physical association)	0.560
PICK1	ILVBL	psi-mi:“MI:0914”(association)	0.530
ATP6V0A2	B4GALT3	psi-mi:“MI:0914”(association)	0.530
ATP6AP2	ATP6V1C1	psi-mi:“MI:0914”(association)	0.530
rep	ATP5MG	psi-mi:“MI:0914”(association)	0.530
atp6v0d_human	ATP6AP2	psi-mi:“MI:0914”(association)	0.530
TCIRG1	AP3D1	psi-mi:“MI:0914”(association)	0.530
ATP6AP2	CLGN	psi-mi:“MI:0914”(association)	0.530
CLGN	NPC1	psi-mi:“MI:0914”(association)	0.530

BioGRID (235): ATP6AP1 (Affinity Capture-RNA), ATP6AP1 (Affinity Capture-RNA), ATP6AP1 (Affinity Capture-MS), ATP6AP1 (Affinity Capture-MS), ATP6AP1 (Two-hybrid), ATP6AP1 (Proximity Label-MS), ATP6AP1 (Proximity Label-MS), ATP6AP1 (Proximity Label-MS), ATP6AP1 (Proximity Label-MS), ATP6AP1 (Proximity Label-MS), ATP6AP1 (Proximity Label-MS), ATP6AP1 (Affinity Capture-MS), ATP6AP1 (Affinity Capture-MS), ATP6AP1 (Affinity Capture-MS), ATP6AP1 (Affinity Capture-MS)

ESM2 similar proteins: A1L2K1, A4FV27, A4IGL3, A7E2Z9, A8WFR0, B0S5G3, L7VG99, O14525, O43556, O54715, O70258, O70367, O75829, O77049, O77770, O88823, P05300, P13473, P17046, P17047, P17404, P40682, P49130, Q15904, Q29S03, Q4R5B1, Q5PPI4, Q5R5V2, Q5RAP2, Q5VW38, Q61137, Q6AXF6, Q6Q3F5, Q6YAT4, Q6ZQE4, Q8BXN9, Q8NBN3, Q8VDA1, Q90617, Q9D387

Diamond homologs: O54715, P40682, Q15904, Q52LC2, Q7JR49, Q9R1Q9, Q9TYW1

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
ATP6AP1	“down-regulates quantity by destabilization”	HIF1A
ATP6AP1	“form complex”	V-ATPase	binding
ATP6AP1	“up-regulates activity”	RAB7A	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 160 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
Regulation of MITF-M-dependent genes involved in lysosome biogenesis and autophagy	8	50.7×	1e-10
Insulin receptor recycling	12	43.1×	6e-15
Transferrin endocytosis and recycling	12	41.7×	6e-15
ROS and RNS production in phagocytes	12	38.0×	2e-14
Amino acids regulate mTORC1	9	17.0×	2e-07
Ion channel transport	12	10.9×	9e-08
Macroautophagy	7	7.6×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
synaptic vesicle lumen acidification	10	66.4×	5e-14
vacuolar acidification	10	52.0×	6e-13
proton transmembrane transport	11	24.4×	2e-10
lysosomal lumen acidification	5	23.9×	2e-04
mitophagy	9	20.3×	9e-08
regulation of macroautophagy	9	18.9×	2e-07
autophagosome maturation	6	14.9×	2e-04
autophagosome assembly	9	14.3×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	20
Likely pathogenic	7
Uncertain significance	147
Likely benign	115
Benign	38

Top pathogenic / likely-pathogenic (27)

Variant ID	HGVS	Classification
1013587	GRCh37/hg19 Xq28(chrX:153263517-155260560)x2	Pathogenic
151807	GRCh38/hg38 Xq28(chrX:154348522-154770053)x2	Pathogenic
1684654	Single allele	Pathogenic
1807675	GRCh37/hg19 Xq28(chrX:153613883-155233731)x2	Pathogenic
1808427	GRCh37/hg19 Xq28(chrX:153282944-153681801)x3	Pathogenic
236239	NM_001183.6(ATP6AP1):c.1284G>A (p.Met428Ile)	Pathogenic
236240	NM_001183.6(ATP6AP1):c.431T>C (p.Leu144Pro)	Pathogenic
236242	NM_001183.6(ATP6AP1):c.938A>G (p.Tyr313Cys)	Pathogenic
253514	GRCh37/hg19 Xq28(chrX:153627408-154089925)x2	Pathogenic
2685778	GRCh37/hg19 Xq28(chrX:153549167-153858492)x2	Pathogenic
2685779	GRCh37/hg19 Xq28(chrX:153606456-153828848)x2	Pathogenic
2687781	NM_001183.6(ATP6AP1):c.289-289G>A	Pathogenic
3370389	GRCh38/hg38 Xq28(chrX:154348522-154594454)x3	Pathogenic
3391868	GRCh37/hg19 Xq28(chrX:153614665-153858492)x2	Pathogenic
4683036	GRCh37/hg19 Xq28(chrX:153622204-153783167)x3	Pathogenic
58018	GRCh38/hg38 Xq28(chrX:154394598-154554969)x1	Pathogenic
58743	GRCh38/hg38 Xq28(chrX:153932045-155611794)x3	Pathogenic
685262	GRCh37/hg19 Xq28(chrX:153556428-153868487)x2	Pathogenic
915879	NM_001183.6(ATP6AP1):c.221T>C (p.Leu74Pro)	Pathogenic
973847	NM_001183.6(ATP6AP1):c.649T>A (p.Tyr217Asn)	Pathogenic
1254051	NM_001183.6(ATP6AP1):c.953_963delinsACATTCAAGTGACAGGACTC (p.Gly318_Val321delinsAspIleGlnValThrGlyLeu)	Likely pathogenic
1305964	NM_001183.6(ATP6AP1):c.288+5G>A	Likely pathogenic
1686802	NM_001183.6(ATP6AP1):c.230_232del (p.Tyr77del)	Likely pathogenic
2442381	NM_001183.6(ATP6AP1):c.530T>C (p.Leu177Pro)	Likely pathogenic
2661896	NM_001493.3(GDI1):c.671A>G (p.Tyr224Cys)	Likely pathogenic
2687780	NM_001183.6(ATP6AP1):c.289-233C>T	Likely pathogenic
4819731	NM_001183.6(ATP6AP1):c.401C>T (p.Pro134Leu)	Likely pathogenic

SpliceAI

1788 predictions. Top by Δscore:

Variant	Effect	Δscore
X:154431825:A:AG	acceptor_gain	1.0000
X:154431828:A:AG	acceptor_gain	1.0000
X:154431829:G:GA	acceptor_gain	1.0000
X:154431829:GC:G	acceptor_gain	1.0000
X:154431829:GCT:G	acceptor_gain	1.0000
X:154431829:GCTGA:G	acceptor_gain	1.0000
X:154431903:AGG:A	donor_loss	1.0000
X:154431904:GGT:G	donor_loss	1.0000
X:154431905:GTGA:G	donor_loss	1.0000
X:154431906:T:G	donor_loss	1.0000
X:154432257:T:TA	acceptor_gain	1.0000
X:154432260:CCCCA:C	acceptor_loss	1.0000
X:154432261:CCCA:C	acceptor_loss	1.0000
X:154432262:CCAG:C	acceptor_loss	1.0000
X:154432263:CAGAA:C	acceptor_loss	1.0000
X:154432264:A:AG	acceptor_gain	1.0000
X:154432264:A:T	acceptor_loss	1.0000
X:154432264:AGAAT:A	acceptor_gain	1.0000
X:154432265:G:GC	acceptor_gain	1.0000
X:154432265:GA:G	acceptor_gain	1.0000
X:154432265:GAA:G	acceptor_gain	1.0000
X:154432265:GAAT:G	acceptor_gain	1.0000
X:154432265:GAATG:G	acceptor_gain	1.0000
X:154432455:GCCAG:G	donor_gain	1.0000
X:154432456:CCAGG:C	donor_loss	1.0000
X:154432457:CAG:C	donor_loss	1.0000
X:154432458:AGGTA:A	donor_loss	1.0000
X:154432461:T:A	donor_loss	1.0000
X:154432928:T:G	acceptor_gain	1.0000
X:154432929:A:AG	acceptor_gain	1.0000

AlphaMissense

3060 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:154428840:T:A	W50R	0.996
X:154428840:T:C	W50R	0.996
X:154431831:T:C	L97P	0.995
X:154433704:C:A	A223E	0.995
X:154429161:T:C	F92S	0.994
X:154432309:T:A	V136D	0.994
X:154435691:T:C	F405L	0.994
X:154435693:C:A	F405L	0.994
X:154435693:C:G	F405L	0.994
X:154435712:T:C	F412L	0.994
X:154435713:T:G	F412C	0.994
X:154435714:C:A	F412L	0.994
X:154435714:C:G	F412L	0.994
X:154435844:T:C	F456L	0.993
X:154435846:T:A	F456L	0.993
X:154435846:T:G	F456L	0.993
X:154431842:G:C	D101H	0.991
X:154431846:T:C	F102S	0.991
X:154432345:T:C	L148P	0.991
X:154433691:G:C	A219P	0.991
X:154428842:G:C	W50C	0.990
X:154428842:G:T	W50C	0.990
X:154431833:A:C	S98R	0.989
X:154431835:C:A	S98R	0.989
X:154431835:C:G	S98R	0.989
X:154433692:C:A	A219E	0.989
X:154435713:T:C	F412S	0.989
X:154431891:T:C	F117S	0.988
X:154435806:G:A	G443D	0.988
X:154431843:A:C	D101A	0.987

dbSNP variants (sampled 300 via entrez): RS1000689552 (X:154430753 T>C), RS1000720453 (X:154431028 G>A), RS1001440437 (X:154426943 T>C), RS1001589429 (X:154435851 A>G), RS1001620566 (X:154436280 G>A), RS1002359264 (X:154428660 G>A,T), RS1002852664 (X:154428994 A>C), RS1003273303 (X:154433192 G>A), RS1003302630 (X:154433907 G>A), RS1003941708 (X:154434504 G>A), RS1004756364 (X:154427368 C>T), RS1004946806 (X:154436615 C>A), RS1005382729 (X:154426969 G>T), RS1005586818 (X:154431819 T>A), RS1006031978 (X:154432126 G>A)

Disease associations

OMIM: gene MIM:300197 | disease phenotypes: MIM:300972, MIM:300584, MIM:300636, MIM:308300, MIM:300291, MIM:309530, MIM:300849, MIM:607906

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 47	Strong	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
congenital disorder of glycosylation type II	Definitive	XL

Mondo (10): intellectual disability (MONDO:0001071), immunodeficiency 47 (MONDO:0010504), immunodeficiency 33 (MONDO:0010386), incontinentia pigmenti (MONDO:0010631), ectodermal dysplasia and immunodeficiency 1 (MONDO:0020740), non-syndromic X-linked intellectual disability (MONDO:0019181), intellectual disability, X-linked 41 (MONDO:0010451), ALG2-congenital disorder of glycosylation (MONDO:0011933), neutropenia (MONDO:0001475), lymphopenia (MONDO:0003783)

Orphanet (9): ATP6AP1-CDG (Orphanet:692790), Hypohidrotic ectodermal dysplasia (Orphanet:238468), X-linked mendelian susceptibility to mycobacterial diseases (Orphanet:319605), OBSOLETE: X-linked mendelian susceptibility to mycobacterial diseases due to IKBKG deficiency (Orphanet:319612), Incontinentia pigmenti (Orphanet:464), Hypohidrotic ectodermal dysplasia with immunodeficiency (Orphanet:98813), X-linked non-syndromic intellectual disability (Orphanet:777), ALG2-CDG (Orphanet:79326), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

47 total (30 of 47 shown, HPO-id order):

HPO	Term
HP:0000348	High forehead
HP:0000407	Sensorineural hearing impairment
HP:0000540	Hypermetropia
HP:0000601	Hypotelorism
HP:0000973	Cutis laxa
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001382	Joint hypermobility
HP:0001394	Cirrhosis
HP:0001395	Hepatic fibrosis
HP:0001396	Cholestasis
HP:0001397	Hepatic steatosis
HP:0001419	X-linked recessive inheritance
HP:0001508	Failure to thrive
HP:0001522	Death in infancy
HP:0001738	Exocrine pancreatic insufficiency
HP:0001744	Splenomegaly
HP:0001747	Accessory spleen
HP:0001873	Thrombocytopenia
HP:0001882	Decreased total leukocyte count
HP:0001897	Normocytic anemia
HP:0002028	Chronic diarrhea
HP:0002240	Hepatomegaly
HP:0002718	Recurrent bacterial infections
HP:0002719	Recurrent infections
HP:0002850	Decreased circulating total IgM
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003124	Hypercholesterolemia

GWAS associations

0 associations (top):

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D007184	Incontinentia Pigmenti	C16.131.077.445; C16.131.831.580; C16.320.850.420; C17.800.621.497; C17.800.804.580; C17.800.827.420
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008231	Lymphopenia	C15.378.243.750.605; C15.378.553.546.605; C20.673.627
D009503	Neutropenia	C15.378.243.750.184.564; C15.378.553.546.184.564
C536289	Immunodeficiency without anhidrotic ectodermal dysplasia (supp.)
C564490	Mental Retardation, X-Linked Nonsyndromic (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4790 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.00	IC50	100	nM	BAFILOMYCIN A1
5.72	IC50	1900	nM	CHEMBL39097

PubChem BioAssay actives

2 with measured affinity, of 39 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
(3Z,5E,7R,8S,9S,11E,13E,15S,16R)-16-[(2S,3R,4S)-4-[(2R,4R,5S,6R)-2,4-dihydroxy-5-methyl-6-propan-2-yloxan-2-yl]-3-hydroxypentan-2-yl]-8-hydroxy-3,15-dimethoxy-5,7,9,11-tetramethyl-1-oxacyclohexadeca-3,5,11,13-tetraen-2-one	213625: Compound was tested for inhibition of V-ATPase from Chicken osteoclasts (cOc)	ic50	0.1000	uM
methyl (2E,4E)-5-(5,6-dichloro-1H-indol-2-yl)-2-methoxypenta-2,4-dienoate	213624: Compound was tested for inhibition of V-ATPase from Chicken osteoclasts (cOc)	ic50	1.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation, increases methylation	2
Smoke	increases abundance, increases expression, decreases expression	2
Tretinoin	increases expression	2
Valproic Acid	affects cotreatment, increases expression, increases methylation	2
aristolochic acid I	increases expression	1
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
sodium arsenite	increases expression	1
cobaltous chloride	increases expression	1
potassium chromate(VI)	decreases expression	1
yessotoxin	increases expression	1
MT19c compound	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	increases expression	1
Hydralazine	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Isoniazid	increases expression	1
Niclosamide	decreases expression	1
Rotenone	increases expression	1
Selenium	increases expression	1
Testosterone	increases expression	1
Vanadium	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	decreases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL812903	Binding	Compound was tested for inhibition of V-ATPase from Chicken osteoclasts (cOc)	5-(5,6-Dichloro-2-indolyl)-2-methoxy-2,4-pentadienamides: novel and selective inhibitors of the vacuolar H+-ATPase of osteoclasts with bone antiresorptive activity. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders