IPO8

Chr 12

importin 8

Also known as: RANBP8, VISS

NCBI Gene: 10526ENSG00000133704UniProt: O15397

The importin-alpha/beta complex and the GTPase Ran mediate nuclear import of proteins with a classical nuclear localization signal. The protein encoded by this gene is a member of a class of approximately 20 potential Ran targets that share a sequence motif related to the Ran-binding site of importin-beta. This protein binds to the nuclear pore complex and, along with RanGTP and RANBP1, inhibits the GAP stimulation of the Ran GTPase. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

Primary Disease Associations & Inheritance

UniProtVISS syndrome
194
ClinVar variants
59
Pathogenic / LP
0.23
pLI score
0
Active trials
Clinical Summary— IPO8
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.23) despite low pLI — interpret in context.
📋
ClinVar Variants
59 Pathogenic / Likely Pathogenic· 111 VUS of 194 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.36LOEUF
pLI 0.234
Z-score 5.71
OE 0.23 (0.15–0.36)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.12Z-score
OE missense 0.75 (0.69–0.81)
408 obs / 547.4 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.23 (0.15–0.36)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.75 (0.69–0.81)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.03
0≤1.21.6
LoF obs/exp: 15 / 64.5Missense obs/exp: 408 / 547.4Syn Z: -0.32

ClinVar Variant Classifications

194 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic45
Likely Pathogenic14
VUS111
Likely Benign19
Benign3
Conflicting2
45
Pathogenic
14
Likely Pathogenic
111
VUS
19
Likely Benign
3
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
9
0
36
0
45
Likely Pathogenic
4
3
7
0
14
VUS
1
107
3
0
111
Likely Benign
0
1
4
14
19
Benign
0
1
2
0
3
Conflicting
—2
Total141125214194

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

IPO8 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

IPO8-related syndromic thoracic aortic aneurysm

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

📖
GeneReview available — IPO8
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Combining exome/genome sequencing with data repository analysis reveals novel gene-disease associations for a wide range of genetic disorders.
Bertoli-Avella AM et al.·Genet Med
2021
Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation.
Ziegler A et al.·Am J Hum Genet
2021Case report
A human importin-β-related disorder: Syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8.
Van Gucht I et al.·Am J Hum Genet
2021Case report
Transcriptomic and proteomic analyses of SH-SY5Y neuroblastoma cells treated with amisulpride.
Hu TM et al.·Acta Neuropsychiatr
2025
Identification of importin 8 (IPO8) as the most accurate reference gene for the clinicopathological analysis of lung specimens.
Nguewa PA et al.·BMC Mol Biol
2008
Identification of potential biomarkers related to glioma survival by gene expression profile analysis.
Hsu JB et al.·BMC Med Genomics
2019
Identification and Validation of Reference Genes for RT-qPCR Studies of Hypoxia in Squamous Cervical Cancer Patients.
Fjeldbo CS et al.·PLoS One
2016Cohort
Genome-wide association study meta-analysis of dizygotic twinning illuminates genetic regulation of female fecundity.
Mbarek H et al.·Hum Reprod
2024Meta-analysis
Expression stability of common housekeeping genes is differently affected by bowel inflammation and cancer: implications for finding suitable normalizers for inflammatory bowel disease studies.
Krzystek-Korpacka M et al.·Inflamm Bowel Dis
2014
A 1.37-Mb 12p11.22-p11.21 deletion coincident with a 367-kb 22q11.2 duplication detected by array comparative genomic hybridization in an adolescent girl with autism and difficulty in self-care of menstruation.
Chen CP et al.·Taiwan J Obstet Gynecol
2014Case report
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools