GLE1

Chr 9AR

GLE1 RNA export mediator

Also known as: CAAHC, CAAHD, GLE1L, LCCS, LCCS1, hGLE1

NCBI Gene: 2733 ENSG00000119392 UniProt: Q53GS7

This gene encodes a predicted 75-kDa polypeptide with high sequence and structure homology to yeast Gle1p, which is nuclear protein with a leucine-rich nuclear export sequence essential for poly(A)+RNA export. Inhibition of human GLE1L by microinjection of antibodies against GLE1L in HeLa cells resulted in inhibition of poly(A)+RNA export. Immunoflourescence studies show that GLE1L is localized at the nuclear pore complexes. This localization suggests that GLE1L may act at a terminal step in the export of mature RNA messages to the cytoplasm. Two alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Congenital arthrogryposis with anterior horn cell diseaseMIM #611890

Lethal congenital contracture syndrome 1MIM #253310

Active trials

172

Pathogenic / LP

718

ClinVar variants

Pubs (1 yr)

0.8

Missense Z

0.75

LOEUF

Clinical Summary— GLE1

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Gene-Disease Validity (ClinGen)

amyotrophic lateral sclerosis · ADLimited

Limited evidence — not for standalone diagnostic reporting

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

172 Pathogenic / Likely Pathogenic· 119 VUS of 718 total submissions

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GeneReview available — GLE1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

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.

0.75LOEUF

pLI 0.000

Z-score 2.86

OE 0.53 (0.38–0.75)

Tolerant

Typical tolerance to LoF variation

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.

0.81Z-score

OE missense 0.88 (0.81–0.97)

335 obs / 379.1 exp

Tolerant

Mild missense constraint

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.0.53 (0.38–0.75)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.88 (0.81–0.97)

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.0.91

0≤1.21.6

LoF obs/exp: 23 / 43.3Missense obs/exp: 335 / 379.1Syn Z: 0.83

0.6163th %ile

GOF

0.6639th %ile

LOF

0.3358th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.