UNC13D

Chr 17AR

unc-13 homolog D

Also known as: HLH3, HPLH3, Munc13-4

NCBI Gene: 201294ENSG00000092929UniProt: Q70J99

This gene encodes a protein that is a member of the UNC13 family, containing similar domain structure as other family members but lacking an N-terminal phorbol ester-binding C1 domain present in other Munc13 proteins. The protein appears to play a role in vesicle maturation during exocytosis and is involved in regulation of cytolytic granules secretion. Mutations in this gene are associated with familial hemophagocytic lymphohistiocytosis type 3, a genetically heterogeneous, rare autosomal recessive disorder. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Hemophagocytic lymphohistiocytosis, familial, 3MIM #608898
AR
1
Active trials
59
Pathogenic / LP
500
ClinVar variants
31
Pubs (1 yr)
-0.2
Missense Z
0.77
LOEUF
Clinical Summary— UNC13D
🧬
Gene-Disease Validity (ClinGen)
familial hemophagocytic lymphohistiocytosis 3 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
59 Pathogenic / Likely Pathogenic· 109 VUS of 500 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
📖
GeneReview available — UNC13D
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.77LOEUF
pLI 0.000
Z-score 3.09
OE 0.59 (0.46–0.77)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
-0.24Z-score
OE missense 1.03 (0.96–1.09)
662 obs / 644.8 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE0.59 (0.46–0.77)
0≤0.351.4
Missense OE1.03 (0.96–1.09)
0≤0.61.4
Synonymous OE0.96
0≤1.21.6
LoF obs/exp: 40 / 67.3Missense obs/exp: 662 / 644.8Syn Z: 0.50
GOFDN
DN
0.6455th %ile
GOF
0.6931th %ile
LOF
0.2874th %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

500 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29
Likely Pathogenic30
VUS109
Likely Benign314
Benign2
Conflicting16
29
Pathogenic
30
Likely Pathogenic
109
VUS
314
Likely Benign
2
Benign
16
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
19
0
10
0
29
Likely Pathogenic
23
0
7
0
30
VUS
0
99
10
0
109
Likely Benign
0
0
156
158
314
Benign
0
0
2
0
2
Conflicting
—16
Total4299185158500

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

View in ClinVar →

UNC13D · protein map & ClinVar variants

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

Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Genetic and clinical characteristics of 54 pediatric lymphoma patients with variant mutation sites of UNC13D.
Duan Y et al.·Haematologica
2026Cohort
Single-cell analysis of UNC13D-mediated immune and dedifferentiation heterogeneity in acute myeloid leukemia and development of a prognostic model.
Wang Z et al.·Transl Cancer Res
2026Functional
Human herpesvirus 6B infection in an adult with hemophagocytic lymphohistiocytosis carrying an UNC13D mutation: a case report and literature review.
Xiao P et al.·Front Immunol
2025Open AccessReview
A Nationwide Analysis of the Phenotype/Genotype Landscape of Hemophagocytic Lymphohistiocytosis: UNC13D Associates with Poor Prognosis.
Brik Simon D et al.·Genes (Basel)
2025Open Access
Hemophagocytic lymphohistiocytosis caused by dual mutations in UNC13D and STX11 induced by HHV-7: a case report and review of the literature.
Wang X et al.·Ann Hematol
2025Open AccessReview
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients