XPO4

Chr 13

exportin 4

Also known as: exp4

NCBI Gene: 64328 ENSG00000132953 UniProt: Q9C0E2

XPO4 encodes exportin-4, a nuclear transport receptor that mediates the export of specific proteins from the nucleus to the cytoplasm, including translation factor EIF5A and transcription regulators like SMAD3. Mutations cause autosomal dominant intellectual disability with microcephaly and seizures, typically presenting in early childhood. This gene is highly constrained against loss-of-function variants, indicating that proper nuclear export function is essential for normal neurodevelopment.

ResearchSummary from RefSeq, UniProt

XPO4 belongs to a large family of karyopherins (see MIM 602738) that mediate the transport of proteins and other cargo between the nuclear and cytoplasmic compartments (Lipowsky et al., 2000 [PubMed 10944119]).[supplied by OMIM, Mar 2009]

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

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P/LP missense

0.14

LOEUF· LoF intol.

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Mechanism

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?

0.14LOEUF

pLI 1.000

Z-score 6.96

OE 0.06 (0.03–0.14)

Highly constrained

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

Missense Constraint?

4.02Z-score

OE missense 0.53 (0.48–0.58)

313 obs / 587.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.06 (0.03–0.14)

0≤0.351.4

Missense OE?0.53 (0.48–0.58)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 4 / 64.2Missense obs/exp: 313 / 587.2Syn Z: 1.20

Background carrier burden — how many people carry a rare variant somewhere in XPO4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 81

978 rare PASS variants

Rare truncating (LoF)

1 in 3,400

72 rare PASS variants

Rare synonymous (reference)

1 in 92

472 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for XPO4. 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 99	1 in 3,100
South Asian	~43k	1 in 87	1 in 4,500
Remaining (unassigned)	~30k	1 in 94	1 in 5,800
European (Finnish)	~27k	1 in 300	1 in 3,200
Admixed American	~22k	1 in 130	1 in 2,000
African / African American	~21k	1 in 120	1 in 3,100
East Asian	~20k	1 in 110	≈ 1 in 4,700
Ashkenazi Jewish	~13k	1 in 610	≈ 1 in 4,100
Middle Eastern	~2,884	1 in 96	≈ 1 in 1,300

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.

Exome coverage (gnomAD): 22 of 23 coding exons well covered in gnomAD exomes; exon 12 marginal. Genomes: all 23.? see exons ↓