TNPO3

Chr 7AD

transportin 3

NCBI Gene: 23534ENSG00000064419UniProt: Q9Y5L0

Importin, which transports target proteins into the nucleus (PubMed:10366588, PubMed:10713112, PubMed:11517331, PubMed:12628928, PubMed:24449914). Specifically mediates the nuclear import of splicing factor serine/arginine (SR) proteins, such as RBM4, SFRS1 and SFRS2, by recognizing phosphorylated SR domains (PubMed:10366588, PubMed:10713112, PubMed:11517331, PubMed:12628928, PubMed:24449914). Also mediates the nuclear import of serine/arginine (SR) protein CPSF6, independently of CPSF6 phosphorylation (PubMed:30916345, PubMed:31465518). The nuclear import process is regulated by the small GTPase Ran that partitions between cytoplasm and nucleus in the predominantly GDP- and GTP-bound form, respectively (PubMed:23878195, PubMed:24449914). Importin associates with target cargo proteins in the cytoplasm, and the competitive binding of GTP-bound Ran induces the release of cargos in the nucleus (PubMed:23878195, PubMed:24449914)

Primary Disease Associations & Inheritance

Muscular dystrophy, limb-girdle, autosomal dominant 2MIM #608423
AD
828
ClinVar variants
12
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— TNPO3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
12 Pathogenic / Likely Pathogenic· 256 VUS of 828 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
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.
0.52LOEUF
pLI 0.000
Z-score 4.56
OE 0.36 (0.25–0.52)
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.
3.44Z-score
OE missense 0.58 (0.52–0.63)
300 obs / 521.1 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.36 (0.25–0.52)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.58 (0.52–0.63)
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.0.91
0≤1.21.6
LoF obs/exp: 21 / 58.7Missense obs/exp: 300 / 521.1Syn Z: 0.98

ClinVar Variant Classifications

828 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9
Likely Pathogenic3
VUS256
Likely Benign166
Benign32
Conflicting15
9
Pathogenic
3
Likely Pathogenic
256
VUS
166
Likely Benign
32
Benign
15
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
9
0
9
Likely Pathogenic
3
0
0
0
3
VUS
17
208
27
4
256
Likely Benign
0
3
72
91
166
Benign
0
1
31
0
32
Conflicting
—15
Total2021213995481

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

View in ClinVar →

Protein Context — Lollipop Plot

TNPO3 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
TRANSPORTIN 3; TNPO3
MIM #610032 · *

Muscular dystrophy, limb-girdle, autosomal dominant 2

MIM #608423

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
[Analysis of TNPO3 gene variant and clinical phenotype in a neonate with limb-girdle muscular dystrophies form 1F].
Gao M et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2022Case report
Transportin 3 (TNPO3) and related proteins in limb girdle muscular dystrophy D2 muscle biopsies: A morphological study and pathogenetic hypothesis.
Costa R et al.·Neuromuscul Disord
2020
A novel pathogenic variant in TNPO3 in a Hungarian family with limb-girdle muscular dystrophy 1F.
Pál E et al.·Eur J Med Genet
2019Case report
A survey on mutation spectrum in Iranian patients with limb-girdle muscular dystrophies.
Khalilian S et al.·Hum Genomics
2025Cohort
The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share.
Kottyan LC et al.·Hum Mol Genet
2015
Established risk loci for systemic lupus erythematosus at NCF2, STAT4, TNPO3, IRF5 and ITGAM associate with distinct clinical manifestations: A Danish genome-wide association study.
Leffers HCB et al.·Joint Bone Spine
2022
Phenotype-to-genotype approach reveals head-circumference-associated genes in an autism spectrum disorder cohort.
Wu H et al.·Clin Genet
2020Cohort
Variants at IRF5-TNPO3, 17q12-21 and MMEL1 are associated with primary biliary cirrhosis.
Hirschfield GM et al.·Nat Genet
2010
Novel insights into the molecular mechanisms of LGMDD2: role of TNPO3 in experimental cell and zebrafish models.
Rodia MT et al.·Cell Mol Life Sci
2025Functional
Progress in the genetics of primary biliary cirrhosis.
Hirschfield GM et al.·Semin Liver Dis
2011Review
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