TNPO3

Chr 7AD

transportin 3

Also known as: IPO12, LGMD1F, LGMDD2, MTR10A, TRN-SR, TRN-SR2, TRNSR

NCBI Gene: 23534ENSG00000064419UniProt: Q9Y5L0OMIM: 610032

The protein functions as a nuclear importin that transports serine/arginine-rich splicing factors and other target proteins from the cytoplasm into the nucleus. Mutations cause autosomal dominant limb-girdle muscular dystrophy type 2, affecting the skeletal muscle system. The gene shows low constraint against loss-of-function variants (pLI near 0, LOEUF 0.515), which is consistent with the autosomal dominant inheritance pattern observed clinically.

OMIMResearchSummary from RefSeq, OMIM, UniProt
GOFmechanismADLOEUF 0.521 OMIM phenotype
Clinical Summary— TNPO3
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Gene-Disease Validity (ClinGen)
muscular dystrophy, limb-girdle, autosomal dominant · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
34 unique Pathogenic / Likely Pathogenic· 397 VUS of 833 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
LoF Constraint
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
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
LoF OE0.36 (0.25–0.52)
0≤0.351.4
Missense OE0.58 (0.52–0.63)
0≤0.61.4
Synonymous OE0.91
0≤1.21.6
LoF obs/exp: 21 / 58.7Missense obs/exp: 300 / 521.1Syn Z: 0.98
DN
0.6065th %ile
GOF
0.6444th %ile
LOF
0.2969th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

833 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic28
Likely Pathogenic6
VUS397
Likely Benign291
Benign50
Conflicting42
28
Pathogenic
6
Likely Pathogenic
397
VUS
291
Likely Benign
50
Benign
42
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
1
25
0
28
Likely Pathogenic
6
0
0
0
6
VUS
43
325
21
8
397
Likely Benign
0
6
135
150
291
Benign
0
1
42
7
50
Conflicting
—42
Total51333223165814

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.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
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
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
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
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
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients