VGLL3

Chr 3

vestigial like family member 3

Also known as: VGL-3, VGL3

NCBI Gene: 389136 ENSG00000206538 UniProt: A8MV65 OMIM: 609980

The protein acts as a coactivator for mammalian transcription enhancer factors (TEFs), regulating gene transcription in the nucleus. Mutations cause autosomal recessive developmental and epileptic encephalopathy with variable features including intellectual disability, seizures, and developmental delays. The gene shows moderate constraint against loss-of-function variants, suggesting some intolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, UniProt

Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.74

Clinical Summary— VGLL3

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.33) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.74LOEUF

pLI 0.070

Z-score 2.19

OE 0.33 (0.16–0.74)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.22Z-score

OE missense 0.95 (0.84–1.08)

175 obs / 183.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.33 (0.16–0.74)

0≤0.351.4

Missense OE?0.95 (0.84–1.08)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 4 / 12.3Missense obs/exp: 175 / 183.3Syn Z: -0.87

This gene — mechanism propensity

0.6455th %ile

GOF

0.3590th %ile

LOF

0.60top 25%

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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.