UNC13A
Chr 19ADARunc-13 homolog A
Also known as: IDDSF, Munc13-1, NEDHES, NEDSMS
The protein binds to phorbol esters and diacylglycerol and regulates neurotransmitter release at synapses. Loss-of-function mutations cause neurodevelopmental disorders characterized by intellectual disability, seizures, hypotonia, absent or delayed speech, movement abnormalities, and dysmorphic features, with both autosomal dominant and autosomal recessive inheritance patterns reported. The gene is extremely intolerant to loss-of-function variation, consistent with its critical role in synaptic function.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Extremely missense-constrained (top ~0.01%)
The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).
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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
437 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 1 | 5 | 11 | 0 | 17 |
Likely Pathogenic | 0 | 2 | 1 | 0 | 3 |
VUS | 24 | 220 | 11 | 0 | 255 |
Likely Benign | 0 | 8 | 18 | 89 | 115 |
Benign | 0 | 4 | 6 | 18 | 28 |
Conflicting | — | 5 | |||
| Total | 25 | 239 | 47 | 107 | 423 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
UNC13A · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
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