NUP188

Summary

NUP188 (nucleoporin 188, HGNC:17859) is a protein-coding gene on chromosome 9q34.11, encoding Nucleoporin NUP188 (Q5SRE5). Component of the nuclear pore complex (NPC), a complex required for the trafficking across the nuclear envelope. It is a selective cancer dependency (DepMap: 10.3% of cell lines).

The nuclear pore complex (NPC) is found on the nuclear envelope and forms a gateway that regulates the flow of proteins and RNAs between the cytoplasm and nucleoplasm. The NPC is comprised of approximately 30 distinct proteins collectively known as nucleoporins. Nucleoporins are pore-complex-specific glycoproteins which often have cytoplasmically oriented O-linked N-acetylglucosamine residues and numerous repeats of the pentapeptide sequence XFXFG. However, the nucleoporin protein encoded by this gene does not contain the typical FG repeat sequences found in most vertebrate nucleoporins. This nucleoporin is thought to form part of the scaffold for the central channel of the nuclear pore.

Source: NCBI Gene 23511 — RefSeq curated summary.

At a glance

• Gene–disease (curated): sandestig-stefanova syndrome (Definitive, ClinGen)
• Clinical variants (ClinVar): 440 total — 9 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 35
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 10.3% of screened cell lines
• MANE Select transcript: NM_015354

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17859
Approved symbol	NUP188
Name	nucleoporin 188
Location	9q34.11
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000095319
Ensembl biotype	protein_coding
OMIM	615587
Entrez	23511

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 16 protein_coding, 5 retained_intron, 5 protein_coding_CDS_not_defined

ENST00000372577, ENST00000464729, ENST00000465344, ENST00000467044, ENST00000477069, ENST00000485158, ENST00000487952, ENST00000491502, ENST00000491990, ENST00000495726, ENST00000550219, ENST00000870698, ENST00000870699, ENST00000870700, ENST00000935256, ENST00000935257, ENST00000935258, ENST00000935259, ENST00000935260, ENST00000935261, ENST00000935262, ENST00000935263, ENST00000935264, ENST00000935265, ENST00000935266, ENST00000935267

RefSeq mRNA: 1 — MANE Select: NM_015354 NM_015354

CCDS: CCDS35156

Canonical transcript exons

ENST00000372577 — 44 exons

Exon	Start	End
ENSE00000984558	129003317	129003454
ENSE00000984559	129005147	129005221
ENSE00000984560	129005303	129005530
ENSE00000984561	129005645	129005776
ENSE00000984562	129006050	129006123
ENSE00000984563	129006239	129006368
ENSE00001592068	128958802	128958894
ENSE00001603849	128983474	128983550
ENSE00001618438	128982902	128983028
ENSE00001622388	128973160	128973249
ENSE00001705018	128980606	128980725
ENSE00001714918	128979262	128979327
ENSE00001721626	128984900	128985014
ENSE00001732095	128982549	128982701
ENSE00001739038	128968506	128968717
ENSE00001743090	128983293	128983380
ENSE00001749697	128981264	128981390
ENSE00001750947	128970758	128970958
ENSE00001775593	128969400	128969514
ENSE00001798884	128959015	128959134
ENSE00001861347	129006502	129007096
ENSE00001904216	128947699	128947751
ENSE00003426919	128958010	128958054
ENSE00003461082	128987589	128987717
ENSE00003464059	128995319	128995514
ENSE00003476825	128998151	128998228
ENSE00003481029	128994856	128994923
ENSE00003485268	128999624	128999805
ENSE00003485940	128993525	128993694
ENSE00003491491	128986809	128986875
ENSE00003496091	128993197	128993403
ENSE00003497858	128999172	128999317
ENSE00003499096	128994373	128994442
ENSE00003524798	128949189	128949243
ENSE00003544583	128998538	128998623
ENSE00003552996	129001884	129001976
ENSE00003557176	128956350	128956434
ENSE00003558041	128990120	128990226
ENSE00003614043	128988047	128988186
ENSE00003631390	128952773	128952846
ENSE00003637202	128956952	128957032
ENSE00003653524	128986558	128986678
ENSE00003658038	129002817	129002975
ENSE00003692432	129001529	129001729

Expression profiles

Bgee: expression breadth ubiquitous, 219 present calls, max score 96.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.4509 / max 310.2371, expressed in 1807 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
98863	23.0395	1807
205629	0.1419	58
98867	0.1006	41
98865	0.0738	15
98868	0.0658	41
98864	0.0294	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	96.16	gold quality
left testis	UBERON:0004533	96.10	gold quality
testis	UBERON:0000473	94.20	gold quality
cerebellar hemisphere	UBERON:0002245	93.18	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.13	gold quality
cerebellar cortex	UBERON:0002129	92.93	gold quality
adenohypophysis	UBERON:0002196	92.36	gold quality
lower esophagus mucosa	UBERON:0035834	92.19	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.86	gold quality
stromal cell of endometrium	CL:0002255	91.76	gold quality
endometrium epithelium	UBERON:0004811	91.59	gold quality
skin of leg	UBERON:0001511	91.39	gold quality
mucosa of stomach	UBERON:0001199	91.35	gold quality
ectocervix	UBERON:0012249	91.11	gold quality
right uterine tube	UBERON:0001302	91.09	gold quality
ventricular zone	UBERON:0003053	91.06	gold quality
skin of abdomen	UBERON:0001416	90.97	gold quality
pituitary gland	UBERON:0000007	90.87	gold quality
esophagus mucosa	UBERON:0002469	90.69	gold quality
left lobe of thyroid gland	UBERON:0001120	90.67	gold quality
ganglionic eminence	UBERON:0004023	90.66	gold quality
left uterine tube	UBERON:0001303	90.53	gold quality
right lobe of thyroid gland	UBERON:0001119	90.40	gold quality
upper lobe of left lung	UBERON:0008952	90.32	gold quality
esophagus	UBERON:0001043	90.26	gold quality
cerebellum	UBERON:0002037	90.21	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	90.18	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.15	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.09	gold quality
lower esophagus	UBERON:0013473	90.04	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.99

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): USF1

miRNA regulators (miRDB)

29 targeting NUP188, 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-3163	100.00	77.23	8605
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-548AV-3P	99.43	68.50	1721
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-3911	99.38	66.95	1087
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-877-3P	99.09	68.10	1637
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-4290	98.51	65.17	907
HSA-MIR-6880-5P	98.08	65.59	1282
HSA-MIR-6502-3P	97.86	65.43	569
HSA-MIR-3652	97.71	65.43	1890
HSA-MIR-3190-3P	97.61	66.95	1406
HSA-MIR-4430	97.47	65.61	1813
HSA-MIR-3194-5P	96.80	64.90	1027
HSA-MIR-6821-3P	95.21	66.79	578

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 10.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 4)

• we show that knockdown of Nup188 or its binding partner Nup93 leads to a loss of cilia during embryonic development while leaving NPC function largely intact. Many data, including the localization of endogenous Nup188/93 at cilia bases, support their direct role at cilia. Super-resolution imaging of Nup188 shows two barrel-like structures (PMID:27593162)
• Results identified Nup188 as a novel TDP-43 target which controls the mRNA splicing of Nup188. (PMID:31527135)
• Differential turnover of Nup188 controls its levels at centrosomes and role in centriole duplication. (PMID:32211895)
• results implicate bi-allelic loss-of-function NUP188 variants in a recessive syndrome characterized by a distinct neurologic, ophthalmologic, and facial phenotype (PMID:32275884)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nup188	ENSDARG00000030022
mus_musculus	Nup188	ENSMUSG00000052533
rattus_norvegicus	Nup188	ENSRNOG00000025185
drosophila_melanogaster	Nup188	FBGN0033766

Protein

Protein identifiers

Nucleoporin NUP188 — Q5SRE5 (reviewed: Q5SRE5)

All UniProt accessions (1): Q5SRE5

UniProt curated annotations — full annotation on UniProt →

Function. Component of the nuclear pore complex (NPC), a complex required for the trafficking across the nuclear envelope. Required for proper protein transport into the nucleus.

Subunit / interactions. Part of the nuclear pore complex (NPC).

Subcellular location. Nucleus. Nuclear pore complex.

Disease relevance. Copy number variations of NUP188 gene may be a cause of heterotaxy, a congenital heart disease resulting from abnormalities in left-right (LR) body patterning. Sandestig-Stefanova syndrome (SANDSTEF) [MIM:618804] An autosomal recessive syndrome characterized by pre- and postnatal microcephaly, trigonocephaly, congenital bilateral cataract, microphthalmia, cleft lip and palate or high-arched palate, camptodactyly, rocker-bottom feet, heart anomalies, specific brain changes such as loss of periventricular white matter, thin corpus callosum, and delayed myelinization. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the Nup188 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5SRE5-1	1	yes
Q5SRE5-2	2

RefSeq proteins (1): NP_056169* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR016024	ARM-type_fold	Homologous_superfamily
IPR018864	Nucleoporin_Nup188_N	Domain
IPR044840	Nup188	Family
IPR048883	Nup188_N-subdom_III	Domain

Pfam: PF10487, PF21093, PF21094

UniProt features (22 total): sequence variant 7, modified residue 5, sequence conflict 3, region of interest 2, compositionally biased region 2, initiator methionine 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
7R5K	ELECTRON MICROSCOPY	12
5IJO	ELECTRON MICROSCOPY	21.4
7R5J	ELECTRON MICROSCOPY	50

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5SRE5-F1	81.99	0.34

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 (5): 1717, 2, 1523, 1709, 1712

Function

Pathways and Gene Ontology

Reactome pathways

32 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-9609690	HCMV Early Events
R-HSA-9610379	HCMV Late Events
R-HSA-9615933	Postmitotic nuclear pore complex (NPC) reformation

MSigDB gene sets: 325 (showing top): MORF_MTA1, MORF_DNMT1, REACTOME_INTERACTIONS_OF_VPR_WITH_HOST_CELLULAR_PROTEINS, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, REACTOME_VIRAL_MESSENGER_RNA_SYNTHESIS, MORF_UBE2I, MORF_CDK2, MITSIADES_RESPONSE_TO_APLIDIN_DN, MORF_HDAC2, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_NUCLEAR_TRANSPORT, MORF_RAF1, GCM_RING1, REACTOME_HIV_INFECTION

GO Biological Process (5): RNA export from nucleus (GO:0006405), protein import into nucleus (GO:0006606), nucleocytoplasmic transport (GO:0006913), mRNA transport (GO:0051028), protein transport (GO:0015031)

GO Molecular Function (1): structural constituent of nuclear pore (GO:0017056)

GO Cellular Component (6): nuclear envelope (GO:0005635), nuclear pore (GO:0005643), cytosol (GO:0005829), membrane (GO:0016020), nuclear pore inner ring (GO:0044611), nucleus (GO:0005634)

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
RNA transport	2
nuclear pore	2
nuclear protein-containing complex	2
cellular anatomical structure	2
nuclear export	1
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
nuclear transport	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
structural molecule activity	1
nucleocytoplasmic transport	1
nucleus	1
endomembrane system	1
organelle envelope	1
nuclear envelope	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1096 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NUP188	NUP35	Q8NFH5	997
NUP188	NUP205	Q92621	995
NUP188	NUP155	O75694	990
NUP188	NUP93	Q8N1F7	986
NUP188	NUP160	Q12769	865
NUP188	NUP37	Q8NFH4	845
NUP188	NUP62	P37198	821
NUP188	NUP210	Q8TEM1	819
NUP188	NUP88	Q99567	809
NUP188	NUP85	Q9BW27	788
NUP188	NUP107	P57740	773
NUP188	NUP58	Q9BVL2	768
NUP188	NUP98	P52948	750
NUP188	NUP43	Q8NFH3	749
NUP188	NUP133	Q8WUM0	743

IntAct

119 interactions, top by confidence:

A	B	Type	Score
SPC24	NDC80	psi-mi:“MI:0914”(association)	0.920
RAD51D	RAD51B	psi-mi:“MI:0914”(association)	0.850
NS	PIK3R2	psi-mi:“MI:0914”(association)	0.750
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SLX4	ERCC1	psi-mi:“MI:0914”(association)	0.640
KPNB1	POM121C	psi-mi:“MI:0914”(association)	0.530
EGFR	NDUFA4	psi-mi:“MI:0914”(association)	0.530
VCAM1	PSMD11	psi-mi:“MI:0914”(association)	0.530
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
Nup214	OGT	psi-mi:“MI:0915”(physical association)	0.400
Nup188		psi-mi:“MI:0915”(physical association)	0.400
GPC1	GANAB	psi-mi:“MI:0915”(physical association)	0.400
AHCTF1	NUP155	psi-mi:“MI:0915”(physical association)	0.400
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
Ypel5	KIF1B	psi-mi:“MI:0914”(association)	0.350
Nup214	NUP155	psi-mi:“MI:0914”(association)	0.350
Psmd6	MIF4GD	psi-mi:“MI:0914”(association)	0.350
Rcc1	WDR46	psi-mi:“MI:0914”(association)	0.350

BioGRID (189): NUP188 (Affinity Capture-MS), NUP188 (Affinity Capture-MS), NUP188 (Affinity Capture-MS), NUP188 (Affinity Capture-MS), NUP188 (Affinity Capture-MS), NUP188 (Affinity Capture-MS), NUP188 (Affinity Capture-MS), NUP188 (Affinity Capture-MS), NUP188 (Co-fractionation), NUP188 (Co-fractionation), NUP188 (Co-fractionation), NUP93 (Co-fractionation), NUP188 (Affinity Capture-MS), NUP188 (Affinity Capture-MS), NUP188 (Proximity Label-MS)

ESM2 similar proteins: A0A0B4K859, A1Z7L1, A1ZBE8, A8WTE8, F4JC97, F4KBW6, F6S215, F6WXT2, O13665, O60287, O75691, P34343, P40090, P42173, P48322, P49815, P49816, P78527, P78847, Q03280, Q09716, Q21106, Q571H0, Q5SRE5, Q5WNI9, Q61037, Q6ZQH8, Q750S2, Q8BH53, Q8IQV9, Q8MYL1, Q8QGX4, Q8WN22, Q93903, Q95YE9, Q9C8Z4, Q9DEI1, Q9FIN7, Q9HDV6, Q9P7M6

Diamond homologs: F6WXT2, Q5SRE5, Q6ZQH8

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
NUP188	“form complex”	NPC	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 153 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
NEP/NS2 Interacts with the Cellular Export Machinery	10	35.3×	6e-11
Nuclear import of Rev protein	10	34.3×	6e-11
Postmitotic nuclear pore complex (NPC) reformation	8	33.3×	6e-09
Transport of Ribonucleoproteins into the Host Nucleus	9	32.8×	6e-10
Rev-mediated nuclear export of HIV RNA	10	32.4×	7e-11
IPs transport between nucleus and cytosol	8	31.1×	8e-09
IP3 and IP4 transport between cytosol and nucleus	8	31.1×	8e-09
IP6 and IP7 transport between cytosol and nucleus	8	31.1×	8e-09

GO biological processes:

GO term	Partners	Fold	FDR
RNA export from nucleus	5	38.4×	4e-05
nucleocytoplasmic transport	9	28.9×	2e-08
positive regulation of telomere maintenance	6	25.1×	4e-05
protein import into nucleus	12	14.2×	3e-08
mRNA transport	6	12.9×	1e-03
mRNA export from nucleus	5	12.1×	6e-03
mitotic spindle organization	5	11.1×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	9
Uncertain significance	285
Likely benign	56
Benign	22

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
1527545	GRCh37/hg19 9q32-34.11(chr9:116422275-131713233)	Pathogenic
2148927	NM_015354.3(NUP188):c.2020C>T (p.Gln674Ter)	Pathogenic
2659550	NM_015354.3(NUP188):c.124C>T (p.Arg42Ter)	Pathogenic
3383398	NM_015354.3(NUP188):c.873_879del (p.Arg291fs)	Pathogenic
918007	NM_015354.3(NUP188):c.904_907del (p.Ile302fs)	Pathogenic
918008	NM_015354.3(NUP188):c.3144C>G (p.Tyr1048Ter)	Pathogenic
918009	NM_015354.3(NUP188):c.5032dup (p.Arg1678fs)	Pathogenic
918010	NM_015354.3(NUP188):c.1890G>A (p.Trp630Ter)	Pathogenic
918011	NM_015354.3(NUP188):c.4078C>T (p.Gln1360Ter)	Pathogenic
1172616	NM_015354.3(NUP188):c.3515+1G>A	Likely pathogenic
1172617	NM_015354.3(NUP188):c.1851_1852delinsG (p.Cys617fs)	Likely pathogenic
1806790	NM_015354.3(NUP188):c.1516+1G>T	Likely pathogenic
3349458	NM_015354.3(NUP188):c.2573dup (p.Tyr858Ter)	Likely pathogenic
3382125	NM_015354.3(NUP188):c.4102_4103del (p.Ser1368fs)	Likely pathogenic
3891866	NM_015354.3(NUP188):c.2533+23_2533+51del	Likely pathogenic
4081565	NM_015354.3(NUP188):c.4509+1G>T	Likely pathogenic
4087685	NM_015354.3(NUP188):c.4024del (p.Thr1342fs)	Likely pathogenic
810438	NM_015354.3(NUP188):c.337C>T (p.Gln113Ter)	Likely pathogenic

SpliceAI

6017 predictions. Top by Δscore:

Variant	Effect	Δscore
9:128949240:GCTG:G	donor_gain	1.0000
9:128949243:GGT:G	donor_loss	1.0000
9:128949244:G:GG	donor_gain	1.0000
9:128949244:GT:G	donor_loss	1.0000
9:128949245:TAAGT:T	donor_loss	1.0000
9:128956348:A:AG	acceptor_gain	1.0000
9:128956349:G:GA	acceptor_gain	1.0000
9:128956349:GTC:G	acceptor_gain	1.0000
9:128956349:GTCCA:G	acceptor_gain	1.0000
9:128956433:TGG:T	donor_loss	1.0000
9:128956433:TGGT:T	donor_loss	1.0000
9:128956435:G:GC	donor_loss	1.0000
9:128956435:G:GG	donor_gain	1.0000
9:128956436:TGA:T	donor_loss	1.0000
9:128956437:GAGT:G	donor_loss	1.0000
9:128956437:GAGTA:G	donor_loss	1.0000
9:128956438:AGTAA:A	donor_loss	1.0000
9:128956944:T:TA	acceptor_gain	1.0000
9:128956948:TCA:T	acceptor_loss	1.0000
9:128956950:A:AG	acceptor_gain	1.0000
9:128956950:A:C	acceptor_loss	1.0000
9:128956950:AG:A	acceptor_gain	1.0000
9:128956950:AGG:A	acceptor_gain	1.0000
9:128956951:G:A	acceptor_gain	1.0000
9:128956951:G:GG	acceptor_gain	1.0000
9:128956951:GGG:G	acceptor_gain	1.0000
9:128956951:GGGT:G	acceptor_gain	1.0000
9:128956951:GGGTC:G	acceptor_gain	1.0000
9:128957026:A:AG	donor_gain	1.0000
9:128957027:G:GG	donor_gain	1.0000

AlphaMissense

11404 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:128982626:T:A	W532R	1.000
9:128982626:T:C	W532R	1.000
9:128982647:T:A	W539R	1.000
9:128982647:T:C	W539R	1.000
9:128993651:T:A	W992R	1.000
9:128993651:T:C	W992R	1.000
9:128958857:T:C	L143P	0.999
9:128982944:T:C	L571P	0.999
9:128983487:T:C	L633P	0.999
9:128983508:C:A	P640Q	0.999
9:128986642:T:A	W721R	0.999
9:128986642:T:C	W721R	0.999
9:128988108:T:C	S819P	0.999
9:128990198:C:A	A871D	0.999
9:128990207:T:C	L874P	0.999
9:128990210:T:C	L875P	0.999
9:128993312:T:C	L919P	0.999
9:128993321:T:C	L922P	0.999
9:128993329:G:C	A925P	0.999
9:128993351:T:C	L932P	0.999
9:128993366:T:C	L937P	0.999
9:128993649:T:C	L991P	0.999
9:128993673:C:A	A999D	0.999
9:128993685:T:C	L1003P	0.999
9:128993688:G:C	R1004P	0.999
9:128994383:T:A	W1010R	0.999
9:128994383:T:C	W1010R	0.999
9:128994905:A:T	E1046V	0.999
9:128995482:T:A	W1107R	0.999
9:128995482:T:C	W1107R	0.999

dbSNP variants (sampled 300 via entrez): RS1000103444 (9:128954116 C>G,T), RS1000134766 (9:128953889 G>A), RS1000153756 (9:128966752 C>G,T), RS1000280468 (9:128948315 A>G), RS1000361309 (9:128948564 G>A), RS1000380320 (9:128973229 C>T), RS1000459529 (9:128965775 G>A), RS1000463436 (9:128984020 C>A), RS1000490403 (9:128965335 A>T), RS1000533099 (9:128997781 T>C), RS1000559564 (9:129007405 G>T), RS1000617080 (9:128959263 C>A,G), RS1000680163 (9:128960519 T>C), RS1000687353 (9:128971983 G>A), RS1000711449 (9:129003109 C>A,G)

Disease associations

OMIM: gene MIM:615587 | disease phenotypes: MIM:618804, MIM:610768

GenCC curated gene-disease

Disease	Classification	Inheritance
sandestig-stefanova syndrome	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
sandestig-stefanova syndrome	Definitive	AR

Mondo (3): microcephaly (MONDO:0001149), sandestig-stefanova syndrome (MONDO:0032926), DK1-congenital disorder of glycosylation (MONDO:0012556)

Orphanet (1): DK1-CDG (Orphanet:91131)

HPO phenotypes

35 total (30 of 35 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000202	Orofacial cleft
HP:0000218	High palate
HP:0000243	Trigonocephaly
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000341	Narrow forehead
HP:0000369	Low-set ears
HP:0000431	Wide nasal bridge
HP:0000444	Convex nasal ridge
HP:0000470	Short neck
HP:0000519	Developmental cataract
HP:0000568	Microphthalmia
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0001558	Decreased fetal movement
HP:0001838	Rocker bottom foot
HP:0002079	Hypoplasia of the corpus callosum
HP:0002119	Ventriculomegaly
HP:0002188	Delayed CNS myelination
HP:0002353	EEG abnormality
HP:0002553	Highly arched eyebrow
HP:0002878	Respiratory failure
HP:0005487	Prominent metopic ridge
HP:0006610	Wide intermamillary distance
HP:0007598	Bilateral single transverse palmar creases
HP:0011230	Laterally extended eyebrow
HP:0011236	Angulated antihelix
HP:0011272	Underdeveloped tragus
HP:0011451	Primary microcephaly

GWAS associations

0 associations (top):

MeSH disease descriptors (2)

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
C563666	Congenital Disorder Of Glycosylation, Type Im (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066449 (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
6.66	Kd	218.8	nM	CHEMBL5653589
6.66	ED50	218.8	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 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	2148903: Binding affinity to human NUP188 incubated for 45 mins by Kinobead based pull down assay	kd	0.2188	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Benzo(a)pyrene	increases expression, increases methylation	2
Estradiol	increases expression	2
Aflatoxin B1	increases methylation, increases expression	2
Cadmium Chloride	decreases expression	2
FR900359	decreases phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
nobiletin	decreases reaction, increases expression	1
sodium arsenate	decreases reaction, increases expression	1
arsenite	affects binding, decreases reaction	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
coumarin	decreases phosphorylation	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
ICG 001	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	decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Diazinon	decreases methylation	1
Dimethyl Sulfoxide	increases expression	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Ozone	affects expression, increases abundance	1
Quercetin	increases phosphorylation	1
Ribonucleotides	affects binding	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
CHEMBL5651945	Binding	Binding affinity to human NUP188 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 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_F1QB	HyCyte Hep-G2 KO-hNUP188	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.