NUP188

protein-coding

nucleoporin 188, the group of Armadillo like helical domain containing|Nucleoporins

Gene summary

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. [provided by RefSeq, Jan 2013]

Previous symbols:

KIAA0169

MANE transcript

NM_015354.3

Inheritance

ClinVar variants

P:22U:322B:78

Top phenotype

Sandestig-Stefanova syndrome

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chr9:128,947,699-129,007,096

External References & Databases

Ensembl (ENSG00000095319)

Transcript & Mutation Effects

hg38 • Region Span ~59.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

sandestig-stefanova syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032926

Submitter: Labcorp Genetics (formerly Invitae)

sandestig-stefanova syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032926

Submitter: G2P

sandestig-stefanova syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032926

Submitter: Ambry Genetics

sandestig-stefanova syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032926

Submitter: PanelApp Australia

sandestig-stefanova syndromeLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0032926

Submitter: Labcorp Genetics (formerly Invitae)

sandestig-stefanova syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0032926

Submitter: ClinGen

*NUP188* (Nucleoporin 188-KD) is located on chromosome 9 at 9q34.11. The protein is key in controlling movement of macromolecules into and out of the nucleus and is predicted to interact with other proteins to form the scaffold of the nuclear pore. *NUP188* was first reported in relation to autosomal recessive Sandestig-Stefanova Syndrome in 2019 (Sandestig et al., PMID: 32021605). Sandestig-Stefanova Syndrome is a condition impacting development and characterized by pre- and postnatal microcephaly, trigonocephaly, cataracts at birth, microphthalmia, facial anomalies, digit anomalies (such as camptodactyly), brain malformations (including reduced periventricular white matter volume), and delayed myelination. 9 variants (frameshift, nonsense) that have been reported in at least 9 probands in 4 publications (PMIDs: 32021605; Muir et al., 2020, PMID: 32275884; Korulmaz et al., 2022, PMID: 36158057; Bulut et al., 2025, PMID: 39911172) are included in this curation. The mechanism of pathogenicity appears to be loss-of-function. This gene-disease relationship is also supported by experimental evidence including Drosophila model, expression-level evidence, interaction evidence (Vishnoi et al., 2020, PMID: 32211895; PMID: 32275884). A knockout model in Drosophila showed that *NUP188* deficiency is associated with neonatal death, inhibited sensory dendrite tiling, reduced negative geotaxis, and seizures. Expression-level evidence in HeLa cells demonstrated that *NUP188* concentrations at centrosomes rise during mitosis. Interaction evidence indicated localization of *NUP188* and CEP152 to the pericentriolar membrane. CEP152 was curated as definitive for autosomal recessive microcephaly with/without short stature. A morpholino knockdown in Xenopus was also evaluated, but not scored due to not being fully replicative of the phenotype (Farhro et al., 2011, PMID: 21282601). In summary, there is definitive evidence supporting the relationship between *NUP188* and autosomal recessive Sandestig-Stefanova Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date 5/7/2025 (SOP Version 11).

Clinical Genomic Database (CGD)

Sandestig-Stefanova syndromeAR

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Cardiovascular

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 32021605; 32275884

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NUP188 variants in ClinVar

8 Conditions Cataloged

Inborn genetic diseasesTotal: 277

not providedTotal: 88

NUP188-related disorderTotal: 59

not specifiedTotal: 23

Sandestig-stefanova syndromeTotal: 22

MicrocephalyTotal: 2

DK1-congenital disorder of glycosylationTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015354.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	47 clinvar	8 clinvar	61
missense			302 clinvar	22 clinvar	1 clinvar	325
nonsense	5 clinvar	4 clinvar	2 clinvar			11
start loss						0
frameshift	3 clinvar	6 clinvar	2 clinvar			11
splice donor/acceptor (+/-2bp)		4 clinvar	10 clinvar			14
Total	8	14	322	69	9	422

Highest pathogenic variant AF is 0.00004274971

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015354.3	RefSeq	NP_056169.1	44	MANE Select
ENST00000372577.2	Ensembl	ENSP00000361658.2	44	MANE Select
ENST00000870698.1	Ensembl	ENSP00000540757.1	44	Standard
ENST00000870698.2	Ensembl	ENSP00000540757.1	44	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

RNA transport - Homo sapiens (human)
tRNA processing
Disease
Gene expression (Transcription)
Regulation of HSF1-mediated heat shock response

Biological Process

mRNA export from nucleus
protein import into nucleus
viral process
glomerular visceral epithelial cell migration

Molecular Function

structural constituent of nuclear pore

Cellular Component

nuclear envelope
membrane
nuclear pore inner ring

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000372577
Coding exons: 44
Length: 59398
Individuals with no LoFs: 125624
Homozygous LoFs: 1
Heterozygous LoFs: 123
Defined: 125748
p: 0.000493

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.12	881	980	0.899	0.0000559	11343
Missense (PolyPhen)		313	397.13	0.78816		4695
Synonymous	-0.731	398	380	1.05	0.0000207	3503
Loss of Function	7.29	20	97.9	0.204	0.00000483	1133

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00092	0.00092	rare
Latino/Admixed American	0.00053	0.00052	rare
Ashkenazi Jewish	0.00040	0.00040	rare
East Asian	0.00022	0.00022	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00047	0.00047	rare
South Asian	0.00086	0.00082	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May function as a component of the nuclear pore complex (NPC).;
Disease: DISEASE: Note=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. {ECO:0000269|PubMed:21282601}.;

Recessive Scores

pRec: 0.126

Intolerance Scores

LoFtool: 0.710
RVIS EVS: -1.25
RVIS percentile EVS: 5.37

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.842

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium