AAAS

Summary

AAAS (aladin WD repeat nucleoporin, HGNC:13666) is a protein-coding gene on chromosome 12q13.13, encoding Aladin (Q9NRG9). Plays a role in the normal development of the peripheral and central nervous system. It is a selective cancer dependency (DepMap: 14.2% of cell lines).

The protein encoded by this gene is a member of the WD-repeat family of regulatory proteins and may be involved in normal development of the peripheral and central nervous system. The encoded protein is part of the nuclear pore complex and is anchored there by NDC1. Defects in this gene are a cause of achalasia-addisonianism-alacrima syndrome (AAAS), also called triple-A syndrome or Allgrove syndrome. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8086 — RefSeq curated summary.

At a glance

• Gene–disease (curated): triple-A syndrome (Definitive, GenCC)
• Clinical variants (ClinVar): 579 total — 67 pathogenic, 32 likely-pathogenic
• Phenotypes (HPO): 51
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 14.2% of screened cell lines
• MANE Select transcript: NM_015665

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13666
Approved symbol	AAAS
Name	aladin WD repeat nucleoporin
Location	12q13.13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000094914
Ensembl biotype	protein_coding
OMIM	605378
Entrez	8086

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 10 retained_intron, 9 protein_coding, 7 protein_coding_CDS_not_defined

ENST00000209873, ENST00000394384, ENST00000546393, ENST00000546562, ENST00000546572, ENST00000547238, ENST00000547520, ENST00000547757, ENST00000547761, ENST00000548258, ENST00000548880, ENST00000548931, ENST00000549450, ENST00000549821, ENST00000549983, ENST00000550033, ENST00000550286, ENST00000551724, ENST00000552161, ENST00000552876, ENST00000672797, ENST00000672900, ENST00000910147, ENST00000910148, ENST00000922444, ENST00000968131

RefSeq mRNA: 2 — MANE Select: NM_015665 NM_001173466, NM_015665

CCDS: CCDS53797, CCDS8856

Canonical transcript exons

ENST00000209873 — 16 exons

Exon	Start	End
ENSE00001555195	53321343	53321610
ENSE00002374010	53307460	53307713
ENSE00003461117	53308052	53308133
ENSE00003486542	53315094	53315140
ENSE00003489674	53314751	53314849
ENSE00003529116	53320565	53320692
ENSE00003530682	53309157	53309281
ENSE00003563269	53308282	53308349
ENSE00003582842	53308435	53308528
ENSE00003595054	53308960	53309020
ENSE00003637853	53314298	53314441
ENSE00003642453	53315335	53315426
ENSE00003655335	53308725	53308815
ENSE00003656148	53315727	53315782
ENSE00003659272	53309601	53309721
ENSE00003663618	53307845	53307929

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 96.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 40.1649 / max 243.7495, expressed in 1814 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
131229	37.1638	1807
131228	3.0011	1228

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland cortex	UBERON:0035827	96.35	gold quality
right adrenal gland	UBERON:0001233	96.31	gold quality
right uterine tube	UBERON:0001302	96.29	gold quality
adenohypophysis	UBERON:0002196	96.08	gold quality
left adrenal gland cortex	UBERON:0035825	95.89	gold quality
left adrenal gland	UBERON:0001234	95.77	gold quality
apex of heart	UBERON:0002098	95.71	gold quality
adrenal cortex	UBERON:0001235	95.36	gold quality
pituitary gland	UBERON:0000007	95.27	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.92	gold quality
lower esophagus	UBERON:0013473	94.90	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.90	gold quality
right testis	UBERON:0004534	94.71	gold quality
ganglionic eminence	UBERON:0004023	94.64	gold quality
left testis	UBERON:0004533	94.38	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.18	gold quality
adrenal gland	UBERON:0002369	94.17	gold quality
ventricular zone	UBERON:0003053	93.87	gold quality
body of uterus	UBERON:0009853	93.76	gold quality
right coronary artery	UBERON:0001625	93.74	gold quality
popliteal artery	UBERON:0002250	93.54	gold quality
tibial artery	UBERON:0007610	93.53	gold quality
right lobe of thyroid gland	UBERON:0001119	93.51	gold quality
right ovary	UBERON:0002118	93.51	gold quality
endocervix	UBERON:0000458	93.43	gold quality
body of stomach	UBERON:0001161	93.40	gold quality
left ovary	UBERON:0002119	93.40	gold quality
metanephros cortex	UBERON:0010533	93.39	gold quality
aorta	UBERON:0000947	93.35	gold quality
ascending aorta	UBERON:0001496	93.27	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.77

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 14.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 35)

• a homozygous G –>A transition in exon 9 of the newly identified AAAS gene, resulting in a stop codon (W295X) and predicting a truncated protein with loss of function (PMID:11815731)
• plays a cell type-specific role in regulating nucleocytoplasmic transport and that this function is essential for the proper maintenance andor development of certain tissues; NPC targeting is essential for the function of ALADIN (PMID:12730363)
• myoclonus and generalized digestive dysmotility in triple a syndrome is connected to AAAS gene mutation (PMID:15022193)
• In addition to known ophthalmic manifestations, triple-A syndrome can present with accommodative dysregulation and ocular signs of autonomic dysfunction. (PMID:15217518)
• Further studies have to investigate the role of ALADIN at NPCs and to identify interacting proteins. Functional analyses of ALADIN may permit further understanding of its role for adrenocortical function and neurodevelopment. (PMID:15666842)
• Widespread but not ubiquitous or uniform expression of AAAS mRNA in the developing rat embryo. (PMID:15680696)
• Data do not support a pathogenetic role for common AAAS gene mutations in patients with idiopathic achalasia as seen in Allgrove syndrome. (PMID:15843079)
• novel splice variant AAAS-v2 encodes a 513-amino acid polypeptide, which contains three WD40 domains; AAAS-v2 and AAAS-v1 were ubiquitously detected in human tissues (PMID:16022285)
• 3 subjects with classic AAAS did not have mutations in AAAS gene on both alleles. This supports the notion of genetic heterogeneity for this disorder, although other genetic mechanisms cannot be excluded. (PMID:16098009)
• The mutation of the AAAS gene is a novel mutation and this case adds to the clinical and molecular spectrum of triple A syndrome and may provide a new insight into the functions of AAAS gene. (PMID:16543750)
• With transfection experiments, we analyzed the cellular localization of the wild-type and 17 natural mutant variants (9 missense, 5 nonsense, 3 frameshift mutations) of ALADIN. (PMID:16609705)
• novel homozygous mutation within intron 5 (IVS5+1G–>A) illustrates the heterogenous nature and the intrafamilial phenotypic variability of Allgrove syndrome (PMID:16938764)
• Report a case of adult onset Allgrove syndrome had no mutation in the ALADIN gene on chromosome 12q13. (PMID:18175081)
• The prognosis of patients with triple A syndrome depends on the identification and treatment of adrenal insufficiency. (PMID:19011813)
• AAAS gene analysis demonstrated a homozygous A to G mutation at nucleotide position 122 in exon 1 in DNA from the patient. (PMID:19172511)
• The study shows that ALADIN is a protein with a molecular weight of 60 kDa, and expressed in the adrenal gland, pituitary gland and pancreas. ALADIN is localized in the nuclear membrane. (PMID:19322026)
• NDC1-mediated localization of ALADIN to nuclear pore complexes is essential for selective nuclear protein import; abrogation of the interaction between ALADIN and NDC1 may be important for the development of triple-A syndrome. (PMID:19703420)
• ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated. (PMID:19782045)
• ALADIN interact with FTH1 and FTH1 nuclear translocation is enhanced when ALADIN is coexpressed. (PMID:19855093)
• Study broadened the allelic and phenotypic spectrum of Allgrove syndrome due to AAAS mutations; the recurrence of the Leu469Pro mutation highlights a possible major role for this alteration in the Italian population. (PMID:20447142)
• In all children with mutation in AAAS gene, regular follow up of adrenal function is necessary to avoid adrenal crisis and start substitution therapy as soon as adrenal insufficiency is noted. (PMID:20499090)
• Sequencing of the AAAS gene detected a compound heterozygous mutation consisting of a novel mutation p.Ser296Tyr (c.887C>A) in exon 9 and a previously described p.Ser263Pro (c.787T>C) missense mutation in exon 8 in both siblings triple A syndrome. (PMID:20931227)
• identification of two novel mutations in the AAAS gene associated with achalasia adrenocortical insufficiency alacrimia syndrome (PMID:21565631)
• The compromising c.43C>A mutation is predicted to cause a p.Gln15Lys amino acid substitution in the ALADIN protein. (PMID:23073554)
• Data suggest ALADIN is involved in resistance to oxidative stress in adrenocortical cells/neurons; ALADIN knockdown down-regulates StAR (steroidogenic acute regulatory protein) and P45011beta (cytochrome P450 family 11 subfamily B polypeptide 1). (PMID:23825130)
• Triple A syndrome with a novel indel mutation in the AAAS gene and delayed puberty. (PMID:25781531)
• down-regulating ALADIN results in decreased oxidative stress response leading to alteration in steroidogenesis, highlighting our knock-down cell model as an important in-vitro tool for studying the adrenal phenotype in triple A syndrome (PMID:25867024)
• This study demonstrated that a single splicing mutation affects the AAAS transcripts and consequently the ALADIN protein structure and function. (PMID:27414811)
• Nine different AAAS mutations were found, including one new mutation: c.755G>C, p.(Trp252Ser) in a French cohort of Triple A syndrome patients. (PMID:29237697)
• Clinical and genetic characteristics of six patients with triple A syndrome and AAAS mutations are described. (PMID:29255950)
• Mutation in AAAS gene is associated with triple A syndrome. (PMID:29874194)
• AAAS mutations were identified in two families with hereditary spastic paraplegia. (PMID:30381913)
• A homozygous deletion of the entire AAAS gene was identified in a patient with triple A syndrome. (PMID:31071487)
• Triple A (Allgrove) syndrome due to AAAS gene mutation with a rare association of amyotrophy. (PMID:32700293)
• Biallelic NDC1 variants that interfere with ALADIN binding are associated with neuropathy and triple A-like syndrome. (PMID:39003500)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	aaas	ENSDARG00000102274
mus_musculus	Aaas	ENSMUSG00000036678
rattus_norvegicus	Aaas	ENSRNOG00000013445
drosophila_melanogaster	Aladin	FBGN0030122
drosophila_melanogaster	CG13137	FBGN0032188

Protein

Protein identifiers

Aladin — Q9NRG9 (reviewed: Q9NRG9)

Alternative names: Adracalin

All UniProt accessions (4): Q9NRG9, F8VUB6, F8VZ44, H3BU82

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in the normal development of the peripheral and central nervous system. Required for the correct localization of aurora kinase AURKA and the microtubule minus end-binding protein NUMA1 as well as a subset of AURKA targets which ensures proper spindle formation and timely chromosome alignment.

Subunit / interactions. Interacts with NDC1, the interaction is required for nuclear pore localization. Interacts with the inactive form aurora kinase AURKA. Interacts with PGRMC2.

Subcellular location. Nucleus. Nuclear pore complex. Cytoplasm. Cytoskeleton. Spindle pole. Nucleus envelope.

Tissue specificity. Widely expressed. Particularly abundant in cerebellum, corpus callosum, adrenal gland, pituitary gland, gastrointestinal structures and fetal lung.

Disease relevance. Achalasia-addisonianism-alacrima syndrome (AAAS) [MIM:231550] An autosomal recessive disorder characterized by adreno-corticotropic hormone (ACTH)-resistant adrenal failure, achalasia of the esophageal cardia and alacrima. The syndrome is associated with variable and progressive neurological impairment involving the central, peripheral, and autonomic nervous system. Other features such as palmoplantar hyperkeratosis, short stature, facial dysmorphy and osteoporosis may also be present. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Ubiquitously expressed.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NRG9-1	1, AAAS-v1	yes
Q9NRG9-2	2, AAAS-v2

RefSeq proteins (2): NP_001166937, NP_056480* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR019775	WD40_repeat_CS	Conserved_site
IPR045139	Aladin	Family
IPR057403	Beta-prop_Aladin	Domain

Pfam: PF25460

UniProt features (30 total): modified residue 7, repeat 7, sequence variant 7, sequence conflict 3, initiator methionine 1, chain 1, short sequence motif 1, compositionally biased region 1, splice variant 1, region of interest 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7R5K	ELECTRON MICROSCOPY	12
7R5J	ELECTRON MICROSCOPY	50

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NRG9-F1	75.45	0.27

Functional residue map

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

Post-translational modifications (7): 2, 33, 495, 511, 522, 525, 541

Function

Pathways and Gene Ontology

Reactome pathways

82 pathways

ID	Pathway
R-HSA-1169408	ISG15 antiviral mechanism
R-HSA-159227	Transport of the SLBP independent Mature mRNA
R-HSA-159230	Transport of the SLBP Dependant Mature mRNA
R-HSA-159231	Transport of Mature mRNA Derived from an Intronless Transcript
R-HSA-159236	Transport of Mature mRNA derived from an Intron-Containing Transcript
R-HSA-165054	Rev-mediated nuclear export of HIV RNA
R-HSA-168271	Transport of Ribonucleoproteins into the Host Nucleus
R-HSA-168276	NS1 Mediated Effects on Host Pathways
R-HSA-168325	Viral Messenger RNA Synthesis
R-HSA-168333	NEP/NS2 Interacts with the Cellular Export Machinery
R-HSA-170822	Regulation of Glucokinase by Glucokinase Regulatory Protein
R-HSA-180746	Nuclear import of Rev protein
R-HSA-180910	Vpr-mediated nuclear import of PICs
R-HSA-1855170	IPs transport between nucleus and cytosol
R-HSA-1855196	IP3 and IP4 transport between cytosol and nucleus
R-HSA-1855229	IP6 and IP7 transport between cytosol and nucleus
R-HSA-191859	snRNP Assembly
R-HSA-3108214	SUMOylation of DNA damage response and repair proteins
R-HSA-3232142	SUMOylation of ubiquitinylation proteins
R-HSA-3301854	Nuclear Pore Complex (NPC) Disassembly
R-HSA-3371453	Regulation of HSF1-mediated heat shock response
R-HSA-4085377	SUMOylation of SUMOylation proteins
R-HSA-4551638	SUMOylation of chromatin organization proteins
R-HSA-4570464	SUMOylation of RNA binding proteins
R-HSA-4615885	SUMOylation of DNA replication proteins
R-HSA-5619107	Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)
R-HSA-6784531	tRNA processing in the nucleus
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9609690	HCMV Early Events
R-HSA-9610379	HCMV Late Events

MSigDB gene sets: 344 (showing top): GOBP_CHROMOSOME_ORGANIZATION, REACTOME_INTERACTIONS_OF_VPR_WITH_HOST_CELLULAR_PROTEINS, GOBP_COGNITION, GOBP_BEHAVIOR, GCM_GSPT1, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, REACTOME_VIRAL_MESSENGER_RNA_SYNTHESIS, GOBP_GROWTH, GCM_BCL2L1, GOBP_NUCLEAR_TRANSPORT, GOBP_MITOTIC_SPINDLE_ASSEMBLY, REACTOME_HIV_INFECTION, GOBP_ORGANELLE_FISSION, GOBP_REGULATION_OF_NUCLEOCYTOPLASMIC_TRANSPORT, GOBP_AMIDE_METABOLIC_PROCESS

GO Biological Process (11): microtubule bundle formation (GO:0001578), glutathione metabolic process (GO:0006749), nucleocytoplasmic transport (GO:0006913), response to oxidative stress (GO:0006979), learning (GO:0007612), fertilization (GO:0009566), protein transport (GO:0015031), multicellular organism growth (GO:0035264), regulation of nucleocytoplasmic transport (GO:0046822), mRNA transport (GO:0051028), mitotic spindle assembly (GO:0090307)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (13): spindle pole (GO:0000922), nucleus (GO:0005634), nuclear envelope (GO:0005635), nuclear pore (GO:0005643), nucleoplasm (GO:0005654), centrosome (GO:0005813), cytosol (GO:0005829), membrane (GO:0016020), nuclear membrane (GO:0031965), mitotic spindle (GO:0072686), sperm end piece (GO:0097229), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Transport of Mature mRNAs Derived from Intronless Transcripts	3
Inositol phosphate metabolism	3
Interactions of Rev with host cellular proteins	2
Influenza Infection	2
SUMO E3 ligases SUMOylate target proteins	2
Antimicrobial mechanism of IFN-stimulated genes	1
Transport of Mature Transcript to Cytoplasm	1
Late Phase of HIV Life Cycle	1
Influenza Viral RNA Transcription and Replication	1
Export of Viral Ribonucleoproteins from Nucleus	1
Glycolysis	1
Interactions of Vpr with host cellular proteins	1
Metabolism of non-coding RNA	1
Nuclear Envelope Breakdown	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
spindle	2
nucleus	2
nuclear envelope	2
microtubule cytoskeleton organization	1
modified amino acid metabolic process	1
sulfur compound metabolic process	1
nuclear transport	1
response to stress	1
learning or memory	1
sexual reproduction	1
reproductive process	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
multicellular organismal process	1
developmental growth	1
nucleocytoplasmic transport	1
regulation of intracellular transport	1
RNA transport	1
mitotic sister chromatid segregation	1
mitotic spindle organization	1
spindle assembly	1
mitotic nuclear division	1
binding	1
intracellular membrane-bounded organelle	1
endomembrane system	1
organelle envelope	1
nuclear protein-containing complex	1
nuclear lumen	1
centriole	1
microtubule organizing center	1
cytoplasm	1
organelle membrane	1
sperm flagellum	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1020 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AAAS	RANBP2	P49792	903
AAAS	NUP88	Q99567	869
AAAS	RGPD1	P0C839	838
AAAS	NUP214	P35658	820
AAAS	POMC	P01189	759
AAAS	PGRMC2	O15173	755
AAAS	SEH1L	Q96EE3	727
AAAS	GLE1	Q53GS7	709
AAAS	TPR	P12270	681
AAAS	NUP42	O15504	657
AAAS	MC2R	Q01718	651
AAAS	NUP155	O75694	643
AAAS	NUP35	Q8NFH5	625
AAAS	NUP98	P52948	610
AAAS	RAE1	P78406	609

IntAct

97 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
IGF1R	PIK3R2	psi-mi:“MI:2364”(proximity)	0.590
INSR	PIK3R2	psi-mi:“MI:2364”(proximity)	0.570
KPNB1	POM121C	psi-mi:“MI:0914”(association)	0.530
TMEM9	ESYT2	psi-mi:“MI:0914”(association)	0.530
ABHD14A	TMEM259	psi-mi:“MI:0914”(association)	0.530
ANKRD22	ESYT2	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
NUDCD3	AAAS	psi-mi:“MI:0915”(physical association)	0.400
NUDC	AAAS	psi-mi:“MI:0915”(physical association)	0.400
NUP133	AAAS	psi-mi:“MI:0915”(physical association)	0.370
REL	AAAS	psi-mi:“MI:0915”(physical association)	0.370
Nup98	POM121C	psi-mi:“MI:0914”(association)	0.350
Nup107	POM121C	psi-mi:“MI:0914”(association)	0.350
Ranbp2	POM121C	psi-mi:“MI:0914”(association)	0.350
Rcc1	WDR46	psi-mi:“MI:0914”(association)	0.350
Ube2i	POM121C	psi-mi:“MI:0914”(association)	0.350
NUP153	POM121C	psi-mi:“MI:0914”(association)	0.350
SEH1L	POM121C	psi-mi:“MI:0914”(association)	0.350
UBE2I	NUP155	psi-mi:“MI:0914”(association)	0.350
NUP107	POM121C	psi-mi:“MI:0914”(association)	0.350
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
MAPK6		psi-mi:“MI:0914”(association)	0.350
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
	TSPO	psi-mi:“MI:0914”(association)	0.350
UNC93B1		psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350

BioGRID (220): AAAS (Affinity Capture-MS), AAAS (Affinity Capture-MS), AAAS (Affinity Capture-MS), AAAS (Affinity Capture-MS), AAAS (Affinity Capture-MS), AAAS (Affinity Capture-MS), AAAS (Affinity Capture-MS), AAAS (Affinity Capture-MS), AAAS (Affinity Capture-MS), AAAS (Affinity Capture-MS), AAAS (Proximity Label-MS), AAAS (Proximity Label-MS), AAAS (Affinity Capture-MS), AAAS (Affinity Capture-MS), AAAS (Affinity Capture-MS)

ESM2 similar proteins: A2AKB9, A2RRH5, A2RRU4, A2SXS5, A6QM06, O60346, O88559, P30291, P97260, Q08BB3, Q0P5I0, Q12770, Q3B7L5, Q3MHH0, Q3UHE1, Q4R3J7, Q5E9I8, Q5FW06, Q5M9G8, Q5MNU5, Q5QP82, Q5R7H5, Q5T6F0, Q5VW00, Q5ZJL7, Q63ZP7, Q69Z89, Q6AX81, Q6GQT6, Q6NS60, Q6NWH1, Q6P809, Q6ZWB6, Q8AVS9, Q8BGW4, Q8BGZ3, Q8CHE4, Q8NHY2, Q8QZS3, Q8TEB1

Diamond homologs: P58742, Q9NRG9, Q9W351, Q8GWR1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
AAAS	“form complex”	NPC	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 131 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
Postmitotic nuclear pore complex (NPC) reformation	9	46.5×	9e-12
Transport of Ribonucleoproteins into the Host Nucleus	10	45.2×	3e-12
IPs transport between nucleus and cytosol	9	43.4×	1e-11
IP3 and IP4 transport between cytosol and nucleus	9	43.4×	1e-11
IP6 and IP7 transport between cytosol and nucleus	9	43.4×	1e-11
Nuclear import of Rev protein	10	42.5×	3e-12
SUMOylation of SUMOylation proteins	10	41.3×	3e-12
Regulation of Glucokinase by Glucokinase Regulatory Protein	9	40.7×	2e-11

GO biological processes:

GO term	Partners	Fold	FDR
RNA export from nucleus	5	42.2×	2e-05
nucleocytoplasmic transport	8	28.2×	1e-07
mRNA transport	9	21.4×	1e-07
protein import into nucleus	7	9.1×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	67
Likely pathogenic	32
Uncertain significance	142
Likely benign	270
Benign	22

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1119991	NM_015665.6(AAAS):c.399+1G>A	Pathogenic
1119992	NM_015665.6(AAAS):c.250del (p.Trp84fs)	Pathogenic
1322889	NM_015665.6(AAAS):c.856C>T (p.Arg286Ter)	Pathogenic
1323528	NM_015665.6(AAAS):c.852G>A (p.Trp284Ter)	Pathogenic
1685479	NM_015665.6(AAAS):c.1357_1358dup (p.Gln454fs)	Pathogenic
1685480	NM_015665.6(AAAS):c.887C>A (p.Ser296Tyr)	Pathogenic
2159758	NM_015665.6(AAAS):c.855_856delinsTT (p.Arg286Ter)	Pathogenic
2426210	NC_000012.11:g.(?53714329)(53715249_?)del	Pathogenic
2575044	NM_015665.6(AAAS):c.211del (p.His71fs)	Pathogenic
2581608	NM_015665.6(AAAS):c.355C>T (p.Arg119Ter)	Pathogenic
2584864	NM_015665.6(AAAS):c.1264_1273del (p.Gln422fs)	Pathogenic
264988	NM_015665.6(AAAS):c.57_58del (p.Tyr19_Glu20delinsTer)	Pathogenic
264990	NM_015665.6(AAAS):c.1159C>T (p.Gln387Ter)	Pathogenic
264992	NM_015665.6(AAAS):c.1066_1067del (p.Leu356fs)	Pathogenic
264994	NM_015665.6(AAAS):c.1331+1G>A	Pathogenic
2696004	NM_015665.6(AAAS):c.70G>T (p.Glu24Ter)	Pathogenic
2696163	NM_015665.6(AAAS):c.409G>T (p.Glu137Ter)	Pathogenic
2701131	NM_015665.6(AAAS):c.489_511dup (p.Leu171fs)	Pathogenic
2735883	NM_015665.6(AAAS):c.1310_1311del (p.Pro437fs)	Pathogenic
2735885	NM_015665.6(AAAS):c.1024C>T (p.Arg342Ter)	Pathogenic
2735886	NM_015665.6(AAAS):c.771del (p.Arg258fs)	Pathogenic
2735888	NM_015665.6(AAAS):c.709C>T (p.Gln237Ter)	Pathogenic
2735889	NM_015665.6(AAAS):c.618del (p.Ser207fs)	Pathogenic
2735890	NM_015665.6(AAAS):c.580C>T (p.Arg194Ter)	Pathogenic
2735891	NM_015665.6(AAAS):c.500C>T (p.Ala167Val)	Pathogenic
2735892	NM_015665.6(AAAS):c.479A>G (p.His160Arg)	Pathogenic
2735894	NM_015665.6(AAAS):c.433C>T (p.Gln145Ter)	Pathogenic
2735896	NM_015665.6(AAAS):c.43C>T (p.Gln15Ter)	Pathogenic
2759532	NM_015665.6(AAAS):c.816G>A (p.Trp272Ter)	Pathogenic
2761422	NM_015665.6(AAAS):c.254del (p.Arg85fs)	Pathogenic

SpliceAI

1974 predictions. Top by Δscore:

Variant	Effect	Δscore
12:53308434:CCT:C	donor_gain	1.0000
12:53308444:CCAT:C	donor_gain	1.0000
12:53308524:CTCAC:C	acceptor_gain	1.0000
12:53308525:TCAC:T	acceptor_gain	1.0000
12:53308526:CAC:C	acceptor_gain	1.0000
12:53308526:CACC:C	acceptor_gain	1.0000
12:53308527:AC:A	acceptor_gain	1.0000
12:53308528:CC:C	acceptor_gain	1.0000
12:53308528:CCTG:C	acceptor_loss	1.0000
12:53308529:C:A	acceptor_loss	1.0000
12:53308531:G:GC	acceptor_gain	1.0000
12:53309153:TCA:T	donor_loss	1.0000
12:53309154:CA:C	donor_loss	1.0000
12:53309155:A:AC	donor_gain	1.0000
12:53309156:C:CC	donor_gain	1.0000
12:53309156:C:CT	donor_loss	1.0000
12:53309282:C:T	acceptor_loss	1.0000
12:53309290:G:GC	acceptor_gain	1.0000
12:53309722:C:CC	acceptor_gain	1.0000
12:53314442:C:CC	acceptor_gain	1.0000
12:53315721:ACTT:A	donor_loss	1.0000
12:53315722:CTTA:C	donor_loss	1.0000
12:53315723:TTA:T	donor_loss	1.0000
12:53315724:TA:T	donor_loss	1.0000
12:53315725:AC:A	donor_gain	1.0000
12:53315726:CC:C	donor_gain	1.0000
12:53315780:CGC:C	acceptor_gain	1.0000
12:53315783:C:CC	acceptor_gain	1.0000
12:53320693:C:CC	acceptor_gain	1.0000
12:53308131:TTCC:T	acceptor_loss	0.9900

AlphaMissense

3495 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:53314386:A:G	W201R	1.000
12:53314386:A:T	W201R	1.000
12:53308296:G:T	A412D	0.999
12:53308299:A:G	L411P	0.999
12:53308302:C:G	R410P	0.999
12:53308303:G:T	R410S	0.999
12:53308321:A:G	W404R	0.999
12:53308321:A:T	W404R	0.999
12:53308806:A:G	W336R	0.999
12:53308806:A:T	W336R	0.999
12:53309278:A:G	W272R	0.999
12:53309278:A:T	W272R	0.999
12:53309657:A:G	W252R	0.999
12:53309657:A:T	W252R	0.999
12:53314327:C:A	W220C	0.999
12:53314327:C:G	W220C	0.999
12:53314329:A:G	W220R	0.999
12:53314329:A:T	W220R	0.999
12:53314361:A:G	L209S	0.999
12:53314384:C:A	W201C	0.999
12:53314384:C:G	W201C	0.999
12:53314796:G:T	A167E	0.999
12:53314821:A:G	W159R	0.999
12:53314821:A:T	W159R	0.999
12:53307672:A:C	F486L	0.998
12:53307672:A:T	F486L	0.998
12:53307674:A:G	F486L	0.998
12:53307848:A:C	S471R	0.998
12:53307848:A:T	S471R	0.998
12:53307850:T:G	S471R	0.998

dbSNP variants (sampled 300 via entrez): RS1000465909 (12:53316204 C>T), RS1000497071 (12:53315842 G>C), RS1000513577 (12:53310386 C>A,T), RS1000692170 (12:53323121 T>C,G), RS1000953495 (12:53318270 GTGT>G), RS1001407309 (12:53309292 G>A), RS1001549095 (12:53312468 G>C), RS1001783168 (12:53311874 G>A), RS1001856538 (12:53311123 T>C), RS1001916381 (12:53312231 C>A), RS1002131710 (12:53318182 T>C), RS1002162731 (12:53317759 C>A,G), RS1002338899 (12:53317401 C>CA), RS1002455039 (12:53317757 ATC>A), RS1002739958 (12:53323011 TCCAAGATAGCA>T)

Disease associations

OMIM: gene MIM:605378 | disease phenotypes: MIM:231550, MIM:145290

GenCC curated gene-disease

Disease	Classification	Inheritance
triple-A syndrome	Definitive	Autosomal recessive

Mondo (6): triple-A syndrome (MONDO:0009279), neurodevelopmental disorder (MONDO:0700092), hyperreflexia (MONDO:0007774), achalasia-alacrima syndrome (MONDO:0800195), microcephaly (MONDO:0001149), congenital nervous system disorder (MONDO:0002320)

Orphanet (1): Triple A syndrome (Orphanet:869)

HPO phenotypes

51 total (30 of 51 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000407	Sensorineural hearing impairment
HP:0000505	Visual impairment
HP:0000522	Alacrima
HP:0000648	Optic atrophy
HP:0000649	Abnormality of visual evoked potentials
HP:0000846	Adrenal insufficiency
HP:0000953	Hyperpigmentation of the skin
HP:0000972	Palmoplantar hyperkeratosis
HP:0000982	Palmoplantar keratoderma
HP:0001097	Keratoconjunctivitis sicca
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001278	Orthostatic hypotension
HP:0001324	Muscle weakness
HP:0001347	Hyperreflexia
HP:0001531	Failure to thrive in infancy
HP:0001611	Hypernasal speech
HP:0001761	Pes cavus
HP:0001824	Weight loss
HP:0001943	Hypoglycemia
HP:0002013	Vomiting
HP:0002093	Respiratory insufficiency
HP:0002173	Hypoglycemic seizures
HP:0002376	Developmental regression
HP:0002571	Achalasia

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D065886	Neurodevelopmental Disorders	F03.625
D012021	Reflex, Abnormal	C10.597.704; C23.888.592.717; E01.370.376.550.650.655; E01.370.600.550.650.655; G11.561.731.587
C536008	Achalasia Addisonianism Alacrimia syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724744 (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
7.27	Kd	53.65	nM	CHEMBL5653589
7.27	ED50	53.65	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 8 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147763: Binding affinity to human AAAS incubated for 45 mins by Kinobead based pull down assay	kd	0.0537	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression, decreases expression, affects cotreatment	3
bisphenol A	affects cotreatment, increases methylation, decreases methylation, increases expression	2
Paraquat	affects response to substance	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pirinixic acid	affects binding, decreases expression, increases activity	1
beta-lapachone	increases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	1
perfluorooctane sulfonic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
14-deoxy-11,12-didehydroandrographolide	decreases expression	1
bisphenol S	increases methylation	1
LDN 193189	affects cotreatment, decreases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	increases oxidation, affects cotreatment, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Coumestrol	increases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ivermectin	decreases expression	1
Manganese	increases abundance, affects cotreatment, decreases expression	1
Ozone	increases abundance, affects cotreatment, increases oxidation	1
Smoke	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
CHEMBL5650805	Binding	Binding affinity to human AAAS 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

Cellosaurus cell lines

1 cell lines: 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_JL93	GM12123	Finite cell line	Male

Clinical trials (associated diseases)

231 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
NCT02179801	Not specified	UNKNOWN	Screening Cardiovascular Patients for Aortic aNeurysms (SCAN)
NCT02393716	Not specified	TERMINATED	Endurant Evo US Clinical Trial
NCT02461524	Not specified	TERMINATED	Endurant Evo International Clinical Trial
NCT02485496	Not specified	TERMINATED	E-tegra Stent Graft System in the Treatment of Infra-renal Abdominal Aortic Aneurysms
NCT02692664	Not specified	COMPLETED	Prospective Multicenter Study for the Endovascular Treatment of Iliac Aneurysm With the Branched E-liac Stent Graft
NCT03407664	Not specified	UNKNOWN	NHS AAA Screening Programme Data Linkage With HES and ONS Datasets
NCT03762525	Not specified	COMPLETED	Iliac Branch Device Movement During Cardiac Cycle (IBD-dynamics)
NCT04080557	Not specified	COMPLETED	Abdominal Aortic Aneurysm Patients Remain at Risk for Delirium on the Surgical Ward After Intensive Care Unit Dismissal
NCT05064540	Not specified	RECRUITING	JAGUAR Trial: ObJective Analysis to GaUge EVAR Outcomes Through Randomization
NCT05133492	Not specified	ACTIVE_NOT_RECRUITING	First In Human Study for Small to Medium-sized Abdominal Aortic Aneurysm (AAA)
NCT05376514	Not specified	COMPLETED	Central Blood Pressure and Variability Evaluation
NCT05409118	Not specified	WITHDRAWN	JAGUAR Trial (Outside United States; OUS): ObJective Analysis to GaUge EVAR Outcomes Through Randomization
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