KPNA1

Chr 3

karyopherin subunit alpha 1

Also known as: IPOA5, NPI-1, RCH2, SRP1

NCBI Gene: 3836 ENSG00000114030 OMIM: 600686

The KPNA1 protein functions as an adapter for nuclear protein import, binding to nuclear localization signals on cargo proteins and facilitating their transport into the nucleus through nuclear pores. Mutations in KPNA1 cause an autosomal recessive intellectual developmental disorder with seizures, hypotonia, and developmental delay, with onset in infancy or early childhood. This gene is highly constrained against loss-of-function variants, indicating that disruption of nuclear import machinery has severe developmental consequences.

OMIM ResearchSummary from RefSeq, UniProt

The transport of molecules between the nucleus and the cytoplasm in eukaryotic cells is mediated by the nuclear pore complex (NPC), which consists of 60-100 proteins. Small molecules (up to 70 kD) can pass through the nuclear pore by nonselective diffusion while larger molecules are transported by an active process. The protein encoded by this gene belongs to the importin alpha family, and is involved in nuclear protein import. This protein interacts with the recombination activating gene 1 (RAG1) protein and is a putative substrate of the RAG1 ubiquitin ligase. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2012]

OMIM ResearchGenerating clinical summary…

LOEUF 0.24

Clinical Summary— KPNA1

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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

31 VUS of 58 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.24LOEUF

pLI 0.998

Z-score 4.72

OE 0.09 (0.04–0.24)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.20Z-score

OE missense 0.46 (0.40–0.54)

131 obs / 282.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.09 (0.04–0.24)

0≤0.351.4

Missense OE?0.46 (0.40–0.54)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 3 / 31.6Missense obs/exp: 131 / 282.4Syn Z: 1.13

ClinVar Variant Classifications

58 submitted variants in ClinVar

ClinVar

Classification Summary

VUS31

Likely Benign1

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	31	0	31
Likely Benign	0	1	1
Benign	0	1	1
Total	31	2	33

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

View in ClinVar →

18 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap KPNA1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →