GMEB2

Chr 20

glucocorticoid modulatory element binding protein 2

Also known as: GMEB-2, P79PIF, PIF79

NCBI Gene: 26205 ENSG00000101216 UniProt: Q9UKD1

The GMEB2 protein is a transcriptional regulator that binds to glucocorticoid modulatory elements and enhances glucocorticoid sensitivity, and also serves as an essential factor for parvovirus replication. Mutations in GMEB2 cause neurodevelopmental disorders with intellectual disability, typically presenting in early childhood. The gene shows autosomal dominant inheritance and is highly constrained against loss-of-function mutations.

ResearchSummary from RefSeq, UniProt

This gene is a member of KDWK gene family. The product of this gene associates with GMEB1 protein, and the complex is essential for parvovirus DNA replication. Study of rat homolog implicates the role of this gene in modulation of transactivation by the glucocorticoid receptor bound to glucocorticoid response elements. This gene appears to use multiple polyadenylation sites. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.24

Clinical Summary— GMEB2

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

60 VUS of 74 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.24LOEUF

pLI 0.995

Z-score 3.95

OE 0.05 (0.02–0.24)

Highly constrained

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

Missense Constraint?

2.20Z-score

OE missense 0.66 (0.59–0.74)

220 obs / 333.1 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.24)

0≤0.351.4

Missense OE?0.66 (0.59–0.74)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 1 / 20.1Missense obs/exp: 220 / 333.1Syn Z: -0.16

This gene — mechanism propensity

0.2698th %ile

GOF

0.2398th %ile

LOF

0.79top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.24

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

74 submitted variants in ClinVar

ClinVar

Classification Summary

VUS60

Likely Benign6

VUS

Likely 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	60	0	60
Likely Benign	4	2	6
Benign	0	0	0
Total	64	2	66

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

View in ClinVar →

54 pathogenic / likely-pathogenic (of 79) ClinVar copy-number / structural variants overlap GMEB2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →