TM4SF20
Chr 2ADtransmembrane 4 L six family member 20
Also known as: PRO994, SLI5, TCCE518
The encoded protein is a four-transmembrane protein that regulates CREB3L1 activation and collagen synthesis through regulated intramembrane proteolysis, with high expression in multiple brain regions including parietal and occipital lobes, hippocampus, and cerebellum. Mutations cause specific language impairment-5 with autosomal dominant inheritance. The gene shows tolerance to loss-of-function variants (low pLI score), suggesting the pathogenic variants may work through alternative mechanisms.
Primary Disease Associations & Inheritance
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Tolerant to missense variation
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
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
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
TM4SF20 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools