KPNA1

Chr 3

karyopherin subunit alpha 1

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

NCBI Gene: 3836 ENSG00000114030 UniProt: P52294 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…

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

—

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.24

LOEUF· LoF intol.

—

Mechanism

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

Background carrier burden — how many people carry a rare variant somewhere in KPNA1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 390

426 rare PASS variants

Rare truncating (LoF)

1 in 6,500

39 rare PASS variants

Rare synonymous (reference)

1 in 180

206 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KPNA1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 420	1 in 6,700
South Asian	~43k	1 in 280	≈ 1 in 14,000
Remaining (unassigned)	~30k	1 in 460	≈ 1 in 30,000
European (Finnish)	~27k	1 in 650	1 in 2,400
Admixed American	~22k	1 in 340	1 in 3,800
African / African American	~21k	1 in 220	≈ 1 in 21,000
East Asian	~20k	1 in 270	≈ 1 in 20,000
Ashkenazi Jewish	~13k	1 in 1,600	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 260	≈ 1 in 2,800

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.