GPN2

Chr 1

GPN-loop GTPase 2

Also known as: ATPBD1B

NCBI Gene: 54707 ENSG00000142751 UniProt: Q9H9Y4 OMIM: 621544

GPN2 is a small GTPase that ensures proper nuclear import and assembly of RNA polymerase II and III complexes. Mutations cause autosomal recessive developmental and epileptic encephalopathy with microcephaly, typically presenting in early infancy with severe intellectual disability, seizures, and progressive brain atrophy. The gene shows moderate constraint against loss-of-function variants, consistent with its essential role in RNA polymerase function.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable GTPase activity. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.85

Clinical Summary— GPN2

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 55 VUS of 63 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.85LOEUF

pLI 0.014

Z-score 1.94

OE 0.41 (0.21–0.85)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.17Z-score

OE missense 0.96 (0.85–1.09)

175 obs / 181.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.41 (0.21–0.85)

0≤0.351.4

Missense OE?0.96 (0.85–1.09)

0≤0.61.4

Synonymous OE?1.15

0≤1.21.6

LoF obs/exp: 5 / 12.3Missense obs/exp: 175 / 181.5Syn Z: -1.02

This gene — mechanism propensity

0.74top 25%

GOF

0.6541th %ile

LOF

0.2583th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

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.

ClinVar Variant Classifications

63 submitted variants in ClinVar

ClinVar

Classification Summary

Likely Pathogenic1

VUS55

Likely Benign1

Likely Pathogenic

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	1	1
VUS	55	55
Likely Benign	1	1
Benign	0	0
Total	57	57

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

View in ClinVar →

5 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap GPN2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →