UNC13A

Chr 19ADAR

unc-13 homolog A

Also known as: IDDSF, Munc13-1, NEDHES, NEDSMS

NCBI Gene: 23025 ENSG00000130477 UniProt: Q9UPW8 OMIM: 609894

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

?Intellectual development disorder with seizures and dysmorphic faciesMIM #621457

Neurodevelopmental disorder with hypotonia, epilepsy, and absent speechMIM #621455

Neurodevelopmental disorder with speech delay, movement abnormalities, and seizuresMIM #621456

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

The dominant disease is caused by gain-of-function changes and the recessive disease by loss of function (Gene2Phenotype). A single heterozygous truncating variant therefore fits the recessive disease and does not by itself explain a dominant presentation; a novel missense has to be read against the dominant mechanism.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.16

LOEUF· LoF intol.

Multiple*

Mechanism· G2P

📖

GeneReview available — UNC13A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.09 (0.05–0.16)

0≤0.351.4

Missense OE?0.50 (0.47–0.54)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 9 / 99.1Missense obs/exp: 513 / 1018.3Syn Z: -0.03

Background carrier burden — how many people carry a rare variant somewhere in UNC13A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 48

1,620 rare PASS variants

Rare truncating (LoF)

1 in 2,000

150 rare PASS variants

Rare synonymous (reference)

1 in 32

974 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for UNC13A. 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 61	1 in 2,000
South Asian	~43k	1 in 46	1 in 3,700
Remaining (unassigned)	~30k	1 in 38	1 in 2,300
European (Finnish)	~27k	1 in 110	1 in 1,600
Admixed American	~22k	1 in 55	1 in 770
African / African American	~21k	1 in 45	1 in 670
East Asian	~20k	1 in 55	1 in 3,200
Ashkenazi Jewish	~13k	1 in 150	none seen
Middle Eastern	~2,884	1 in 44	none seen

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): 41 of 44 coding exons well covered in gnomAD exomes; exon 36 poorly covered; exons 1, 7 marginal. Genomes: 43 of 44 (exon 36 below).? see exons ↓