TNPO2

Chr 19AD

transportin 2

Also known as: IDDHISD, IPO3, KPNB2B, TRN2

NCBI Gene: 30000ENSG00000105576UniProt: O14787

Predicted to enable nuclear import signal receptor activity and nuclear localization sequence binding activity. Predicted to be involved in protein import into nucleus. Predicted to act upstream of or within negative regulation of muscle cell differentiation. Predicted to be active in cytoplasm and nucleus. Implicated in intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies. [provided by Alliance of Genome Resources, Jul 2025]

Primary Disease Associations & Inheritance

Intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic faciesMIM #619556
AD
156
ClinVar variants
35
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— TNPO2
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
35 Pathogenic / Likely Pathogenic· 89 VUS of 156 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.13LOEUF
pLI 1.000
Z-score 6.20
OE 0.04 (0.02–0.13)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

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.
5.88Z-score
OE missense 0.28 (0.25–0.33)
152 obs / 534.3 exp
Constrained

Extremely missense-constrained (top ~0.01%)

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.0.04 (0.02–0.13)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.28 (0.25–0.33)
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.1.01
0≤1.21.6
LoF obs/exp: 2 / 48.6Missense obs/exp: 152 / 534.3Syn Z: -0.15

ClinVar Variant Classifications

156 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21
Likely Pathogenic14
VUS89
Likely Benign23
Benign7
Conflicting2
21
Pathogenic
14
Likely Pathogenic
89
VUS
23
Likely Benign
7
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
4
17
0
21
Likely Pathogenic
2
10
2
0
14
VUS
6
71
12
0
89
Likely Benign
0
6
6
11
23
Benign
0
1
3
3
7
Conflicting
—2
Total8924014156

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

View in ClinVar →

Protein Context — Lollipop Plot

TNPO2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

TNPO2-related intellectual disability

limited
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
TRANSPORTIN 2; TNPO2
MIM #603002 · *

Intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies

MIM #619556

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Identification of HSPA8 as an interacting partner of MAB21L2 and an important factor in eye development.
Seese SE et al.·Dev Dyn
2023
Integration of the cancer cell secretome and transcriptome reveals potential noninvasive diagnostic markers for bladder cancer.
Chen YT et al.·Proteomics Clin Appl
2024
A Rare Missense Variant in TNPO2 in an Individual With a Neurodevelopmental Disability.
Cohen R et al.·Am J Med Genet A
2026Case report
Enlightening the path to NSCLC biomarkers: Utilizing the power of XAI-guided deep learning.
Dwivedi K et al.·Comput Methods Programs Biomed
2024
High-throughput behavioural phenotyping of 25 C. elegans disease models including patient-specific mutations.
O'Brien TJ et al.·BMC Biol
2025Functional
Development of a novel gene signature in patients without Helicobacter pylori infection gastric cancer.
Lv X et al.·J Cell Biochem
2020Cohort
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