TNPO2

Chr 19

transportin 2

Also known as: IDDHISD, IPO3, KPNB2B, TRN2

NCBI Gene: 30000 ENSG00000105576 UniProt: O14787

TNPO2 encodes transportin-2, a nuclear import receptor that transports proteins containing nuclear localization signals from the cytoplasm into the nucleus through nuclear pores. Mutations cause intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.129), indicating that functional copies are critical for normal development.

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.13

Clinical Summary— TNPO2

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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.

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ClinVar Variants

17 unique Pathogenic / Likely Pathogenic· 84 VUS of 171 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.04 (0.02–0.13)

0≤0.351.4

Missense OE?0.28 (0.25–0.33)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 2 / 48.6Missense obs/exp: 152 / 534.3Syn Z: -0.15

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedTNPO2-related intellectual disabilityOTHERAD

This gene — mechanism propensity

0.3395th %ile

GOF

0.3689th %ile

LOF

0.68top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · LOEUF 0.13

Literature Evidence

LOFStudies of another variant (W727C) suggested a loss-of-function effect.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 34314705 ↗

ClinVar Variant Classifications

171 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic13

VUS84

Likely Benign30

Benign8

Conflicting2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	4	0	0	4
Likely Pathogenic	2	11	0	0	13
VUS	6	71	7	0	84
Likely Benign	0	6	7	17	30
Benign	0	1	3	4	8
Conflicting	—				2
Total	8	93	17	21	141

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

View in ClinVar →

19 pathogenic / likely-pathogenic (of 28) ClinVar copy-number / structural variants overlap TNPO2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →