UNC13A

protein-coding

unc-13 homolog A, the group of UNC13 homologs

Gene summary

This gene encodes a member of the UNC13 family. UNC13 proteins bind to phorbol esters and diacylglycerol and play important roles in neurotransmitter release at synapses. Single nucleotide polymorphisms in this gene may be associated with sporadic amyotrophic lateral sclerosis. [provided by RefSeq, Feb 2012]

MANE transcript

NM_001080421.3

Inheritance

AD, AR

ClinVar variants

P:11U:251B:110

Top phenotype

neurodevelopmental disorder with hypotonia, epilepsy, and absent speech

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr19:17,601,336-17,688,365

External References & Databases

Ensembl (ENSG00000130477)

Transcript & Mutation Effects

hg38 • Region Span ~87.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

congenital myasthenic syndromeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0018940

Submitter: PanelApp Australia

neurodevelopmental disorder with hypotonia, epilepsy, and absent speechDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0980940

Submitter: ClinGen

The *UNC13A* gene is located on chromosome 19 at 19p13.11 and encodes unc-13 homolog A, or Munc13-1, which is one of four genes in the UNC13 homolog gene family. *UNC13A* was first reported in association with an autosomal recessive congenital nervous system disorder by Engel et al. (2016), who described a proband with a homozygous stop-gained variant presenting with microcephaly, cortical hyperexcitability, and myasthenia (PMID 27648472). Probands with this condition exhibit a neurodevelopmental syndrome characterized by profound global developmental delay and early-onset seizures. Evidence supporting this gene-disease relationship includes case-level data and experimental data. 12 variants (4 missense, 1 nonsense, 2 frameshift, and 5 splice region) that have been reported in ten probands were included in this curation (PMIDs: 27648472, 28771251, 36447687, 39039281, 41125872). The mechanism of pathogenicity appears to be loss of function. This gene-disease association is supported by animal models, expression studies, and in vitro functional assays. Munc13-1 is highly expressed in the brain and at the neuromuscular junction, where it localizes to presynaptic terminals and plays a critical role in synaptic transmission by regulating release site assembly, synaptic vesicle priming, activity-dependent replenishment of the releasable vesicle pool, calcium channel proximity, and short-term synaptic plasticity (PMIDs: 17167095, 30690332). In vivo and in vitro experiments have demonstrated that loss of *UNC13A* can alter various properties of neuronal and neuromuscular synaptic transmission and lead to muscle weakness, respiratory insufficiency, and perinatal lethality (PMIDs: 10440375, 27648472, 33771998, 37243591, 39634123). Gene editing studies have demonstrated that *UNC13A* recessive variants reduce gene expression, fail to localize to the synapse, and alter synaptic plasticity in neuronal cell models (PMID: 41125872). In summary, there is definitive evidence to support this gene-disease relationship. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date April 17, 2026 (SOP Version 12).

neurodevelopmental disorder with speech delay, movement abnormalities, and seizuresDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0980941

Submitter: ClinGen

The *UNC13A* gene is located on chromosome 19 at 19p13.11 and encodes unc-13 homolog A, or Munc13-1, which is one of four genes in the UNC13 homolog gene family. *UNC13A* was first reported in association with an autosomal dominant congenital nervous system disorder by Lipstein et al. (2017), who described a proband with a de novo missense variant, p.(Pro814Leu), presenting with developmental delay, dyskinetic movement disorder and tremors (PMID: 28192369). Evidence supporting this gene-disease relationship includes case-level data and experimental data. The p.(Pro814Leu) variant has since been demonstrated to be a common recurrent de novo disease-causing variant in multiple publications (PMID: 33057194, 39634123, 41125872). Eight variants (7 missense, and 1 two amino acid in frame substitution) have since been reported in association with developmental delay (especially speech delay), ataxia, tremor or dyskinetic movements in 18 unrelated probands are included in this curation (PMID: 31130284, 39634123, 41125872). Asadollahi et al. (2025) also reported a familial missense variant, p.(Cys587Phe), and proposed a subtype of *UNC13A*-related autosomal dominant disease characterized by mild-to-moderate intellectual disability and seizures (PMID: 41125872) (not scored). The mechanism of pathogenicity appears to be gain of function. This gene-disease association is supported by animal models, expression studies, and in vitro functional assays. Munc13-1 is highly expressed in the brain and at the neuromuscular junction, where it localizes to presynaptic terminals and plays a critical role in synaptic transmission by regulating release site assembly, synaptic vesicle priming, activity-dependent refilling of the releasable vesicle pool, calcium channel proximity, and short-term synaptic plasticity (PMIDs: 17167095, 30690332). Overexpression of patient variants in cell culture has demonstrated increased calcium signaling, and gene editing of both mouse hippocampal neurons and C. elegans has shown a gain-of-function phenotype with respect to synaptic vesicle release, vesicle depletion, and neuromuscular paralysis (PMID: 39634123, 41125872). In summary, there is definitive evidence to support this gene-disease relationship. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date April 17, 2026 (SOP Version 12).

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0100038

Submitter: G2P

complex neurodevelopmental disorderMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: G2P

congenital nervous system disorderLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0002320

Submitter: Illumina

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UNC13A variants in ClinVar

18 Conditions Cataloged

not specifiedTotal: 157

not providedTotal: 148

UNC13A-related disorderTotal: 126

Neurodevelopmental disorderTotal: 3

UNC13A-related Neurodevelopmental and Movement disorderTotal: 3

Neurodevelopmental disorder with hypotonia, epilepsy, and absent speechTotal: 3

Neurodevelopmental disorder with speech delay, movement abnormalities, and seizuresTotal: 3

TremorTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001080421.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	90 clinvar	9 clinvar	101
missense	5 clinvar	4 clinvar	225 clinvar	9 clinvar	2 clinvar	245
nonsense		1 clinvar	3 clinvar			4
start loss						0
frameshift	1 clinvar		11 clinvar			12
splice donor/acceptor (+/-2bp)			10 clinvar			10
Total	6	5	251	99	11	372

Highest pathogenic variant AF is 0.0000012405748

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001080421.3	RefSeq	NP_001073890.2	44	MANE Select
ENST00000519716.7	Ensembl	ENSP00000429562.2	44	MANE Select
NM_001387021.1	RefSeq	NP_001373950.1	42	Standard
NM_001387022.1	RefSeq	NP_001373951.1	42	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Synaptic vesicle cycle - Homo sapiens (human)
Synaptic Vesicle Pathway

Biological Process

positive regulation of neurotransmitter secretion
neurotransmitter secretion
neuromuscular junction development
synaptic vesicle docking
synaptic vesicle priming

Molecular Function

calcium ion binding
calmodulin binding
phospholipid binding
syntaxin-1 binding
diacylglycerol binding

Cellular Component

plasma membrane
cell junction
synaptic vesicle membrane
neuromuscular junction
presynaptic membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000519716
Coding exons: 44
Length: 87265
Individuals with no LoFs: 125167
Homozygous LoFs: 0
Heterozygous LoFs: 29
Defined: 125196
p: 0.000116

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	5.63	513	1.02e+3	0.504	0.0000641	11229
Missense (PolyPhen)		174	467.09	0.37252		4933
Synonymous	-0.0310	428	427	1.00	0.0000311	3085
Loss of Function	8.39	9	99.1	0.0908	0.00000513	1103

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00071	0.00071	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000056	0.000055	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.00010	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: 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 (By similarity). Also involved in secretory granule priming in insulin secretion (By similarity). Interacts with FBXO45 (via SRY domain); leading to the degradation of UNC13A by the proteasome (By similarity). Plays a role in dendrite formation by melanocytes (PubMed:23999003). {ECO:0000250, ECO:0000269|PubMed:23999003}.;

Intolerance Scores

RVIS EVS: -1.7
RVIS percentile EVS: 2.58

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.875

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium