UNC13C

Chr 15

unc-13 homolog C

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.

OMIMResearchSummary from UniProt
MultiplemechanismLOEUF 0.54
Clinical SummaryUNC13C
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
1 unique Pathogenic / Likely Pathogenic· 96 VUS of 100 total submissions
Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Moderate LoF intolerance
LoF Constraint
0.54LOEUF
pLI 0.000
Z-score 5.53
OE 0.42 (0.330.54)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint
-0.14Z-score
OE missense 1.01 (0.961.06)
1105 obs / 1091.7 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.42 (0.330.54)
00.351.4
Missense OE1.01 (0.961.06)
00.61.4
Synonymous OE1.10
01.21.6
LoF obs/exp: 44 / 105.3Missense obs/exp: 1105 / 1091.7Syn Z: -1.50
DN
0.6551th %ile
GOF
0.6736th %ile
LOF
0.4136th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median
DNprediction above median

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.

ClinVar Variant Classifications

100 submitted variants in ClinVar

Classification Summary

Pathogenic1
VUS96
Likely Benign3
1
Pathogenic
96
VUS
3
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
1
0
1
Likely Pathogenic
0
0
0
0
0
VUS
0
95
1
0
96
Likely Benign
0
2
0
1
3
Benign
0
0
0
0
0
Total09721100

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

UNC13C · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
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