UNC13A

Chr 19ADAR

unc-13 homolog A

NCBI Gene: 23025ENSG00000130477UniProt: Q9UPW8

Plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway. Involved in neurotransmitter release by acting in synaptic vesicle priming prior to vesicle fusion and participates in the activity-dependent refilling of readily releasable vesicle pool (RRP). Essential for synaptic vesicle maturation in most excitatory/glutamatergic but not inhibitory/GABA-mediated synapses. Facilitates neuronal dense core vesicles fusion as well as controls the location and efficiency of their synaptic release (By similarity). Also involved in secretory granule priming in insulin secretion. Plays a role in dendrite formation by melanocytes (PubMed:23999003)

Primary Disease Associations & Inheritance

?Intellectual development disorder with seizures and dysmorphic faciesMIM #621457
AD
Neurodevelopmental disorder with hypotonia, epilepsy, and absent speechMIM #621455
AR
Neurodevelopmental disorder with speech delay, movement abnormalities, and seizuresMIM #621456
AD
430
ClinVar variants
20
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— UNC13A
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
20 Pathogenic / Likely Pathogenic· 250 VUS of 430 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.16LOEUF
pLI 1.000
Z-score 8.39
OE 0.09 (0.05–0.16)
Highly constrained

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

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
5.63Z-score
OE missense 0.50 (0.47–0.54)
513 obs / 1018.3 exp
Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.09 (0.05–0.16)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.50 (0.47–0.54)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.00
0≤1.21.6
LoF obs/exp: 9 / 99.1Missense obs/exp: 513 / 1018.3Syn Z: -0.03

ClinVar Variant Classifications

430 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
Likely Pathogenic3
VUS250
Likely Benign112
Benign29
Conflicting5
17
Pathogenic
3
Likely Pathogenic
250
VUS
112
Likely Benign
29
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
5
12
0
17
Likely Pathogenic
0
2
1
0
3
VUS
19
215
16
0
250
Likely Benign
0
8
18
86
112
Benign
0
3
6
20
29
Conflicting
—5
Total1923353106416

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.

Gene2Phenotype Curations

UNC13A-related congenital epileptic encephalopathy and severe neuromuscular disorder

moderate
ARLoss Of FunctionDecreased Gene Product Level
Dev. Disorders
G2P ↗
splice donor variantframeshift variantstop gainedmissense variantintron variant

UNC13A-related neurodevelopmental disorder with ataxia and tremor or dyskinetic movements

moderate
ADGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variant

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
UNC13 HOMOLOG A; UNC13A
MIM #609894 · *

?Intellectual development disorder with seizures and dysmorphic facies

MIM #621457

Molecular basis of disorder known

Autosomal dominant

Neurodevelopmental disorder with hypotonia, epilepsy, and absent speech

MIM #621455

Molecular basis of disorder known

Autosomal recessive

Neurodevelopmental disorder with speech delay, movement abnormalities, and seizures

MIM #621456

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review.
Ohno K et al.·Int J Mol Sci
2023Review
UNC13A in amyotrophic lateral sclerosis: from genetic association to therapeutic target.
Willemse SW et al.·J Neurol Neurosurg Psychiatry
2023Review
Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function.
Asadollahi R et al.·Nat Genet
2025
Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.
Lionel AC et al.·Genet Med
2018
C9orf72 and UNC13A are shared risk loci for amyotrophic lateral sclerosis and frontotemporal dementia: a genome-wide meta-analysis.
Diekstra FP et al.·Ann Neurol
2014Meta-analysis
UNC13A variant rs12608932 is associated with increased risk of amyotrophic lateral sclerosis and reduced patient survival: a meta-analysis.
Yang B et al.·Neurol Sci
2019Meta-analysis
Genetic variability in sporadic amyotrophic lateral sclerosis.
Van Daele SH et al.·Brain
2023
Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing.
Pottier C et al.·Nat Commun
2025
The era of cryptic exons: implications for ALS-FTD.
Mehta PR et al.·Mol Neurodegener
2023Review
Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder.
Lipstein N et al.·J Clin Invest
2017
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools