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…

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

—

P/LP missense

0.74

LOEUF

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in VGLL3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 170

495 rare PASS variants

Rare truncating (LoF)

1 in 6,100

45 rare PASS variants

Rare synonymous (reference)

1 in 270

201 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for VGLL3. 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 260	1 in 5,700
South Asian	~43k	1 in 91	1 in 5,100
Remaining (unassigned)	~30k	1 in 140	≈ 1 in 30,000
European (Finnish)	~27k	1 in 310	≈ 1 in 13,000
Admixed American	~22k	1 in 140	≈ 1 in 7,500
African / African American	~21k	1 in 130	≈ 1 in 6,400
East Asian	~20k	1 in 130	≈ 1 in 18,000
Ashkenazi Jewish	~13k	1 in 680	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 110	≈ 1 in 2,900

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): 2 of 4 coding exons well covered in gnomAD exomes; exon 4 poorly covered; exon 1 marginal. Genomes: all 4.? see exons ↓