UNC13C

Chr 15

unc-13 homolog C

NCBI Gene: 440279 ENSG00000137766 UniProt: Q8NB66 OMIM: 614568

The protein functions in vesicle maturation during exocytosis and regulates synaptic transmission at parallel fiber-Purkinje cell synapses in the cerebellum. Mutations cause autosomal recessive cerebellar ataxia, mental retardation, and disequilibrium syndrome, characterized by early-onset cerebellar dysfunction with intellectual disability and balance problems. The gene shows tolerance to loss-of-function variants in the general population.

OMIM ResearchSummary from UniProt

Predicted to enable calmodulin binding activity. Predicted to be involved in glutamatergic synaptic transmission and regulated exocytosis. Predicted to be located in presynaptic active zone. Predicted to be active in several cellular components, including axon terminus; presynaptic membrane; and synaptic vesicle membrane. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.54

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.54LOEUF

pLI 0.000

Z-score 5.53

OE 0.42 (0.33–0.54)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-0.14Z-score

OE missense 1.01 (0.96–1.06)

1105 obs / 1091.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.42 (0.33–0.54)

0≤0.351.4

Missense OE?1.01 (0.96–1.06)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 44 / 105.3Missense obs/exp: 1105 / 1091.7Syn Z: -1.50

Background carrier burden — how many people carry a rare variant somewhere in UNC13C?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 26

3,039 rare PASS variants

Rare truncating (LoF)

1 in 370

357 rare PASS variants

Rare synonymous (reference)

1 in 48

1,066 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for UNC13C. 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 34	1 in 400
South Asian	~43k	1 in 18	1 in 520
Remaining (unassigned)	~30k	1 in 21	1 in 320
European (Finnish)	~27k	1 in 68	1 in 470
Admixed American	~22k	1 in 23	1 in 330
African / African American	~21k	1 in 18	1 in 510
East Asian	~20k	1 in 24	1 in 390
Ashkenazi Jewish	~13k	1 in 120	1 in 640
Middle Eastern	~2,884	1 in 21	1 in 320

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 23 of 32 coding exons well covered in gnomAD exomes; exons 6, 11, 12, 15, 23 and 4 more marginal. Genomes: all 32.? see exons ↓