UNC13D

Summary

UNC13D (unc-13 homolog D, HGNC:23147) is a protein-coding gene on chromosome 17q25.3, encoding Protein unc-13 homolog D (Q70J99). Plays a role in cytotoxic granule exocytosis in lymphocytes.

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.

Source: NCBI Gene 201294 — RefSeq curated summary.

At a glance

• Gene–disease (curated): familial hemophagocytic lymphohistiocytosis 3 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 9
• Clinical variants (ClinVar): 1,615 total — 108 pathogenic, 49 likely-pathogenic
• Phenotypes (HPO): 53
• MANE Select transcript: NM_199242

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23147
Approved symbol	UNC13D
Name	unc-13 homolog D
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Aliases	Munc13-4
Ensembl gene	ENSG00000092929
Ensembl biotype	protein_coding
OMIM	608897
Entrez	201294

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 15 protein_coding, 5 retained_intron, 4 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000207549, ENST00000412096, ENST00000585574, ENST00000586108, ENST00000586147, ENST00000586519, ENST00000586930, ENST00000587105, ENST00000587495, ENST00000587504, ENST00000588774, ENST00000589670, ENST00000590762, ENST00000590856, ENST00000591563, ENST00000591616, ENST00000592386, ENST00000699510, ENST00000699511, ENST00000699512, ENST00000699513, ENST00000868100, ENST00000868101, ENST00000965711, ENST00000965712

RefSeq mRNA: 1 — MANE Select: NM_199242 NM_199242

CCDS: CCDS11730

Canonical transcript exons

ENST00000207549 — 32 exons

Exon	Start	End
ENSE00001194682	75839839	75839942
ENSE00001361625	75844221	75844404
ENSE00001406672	75831098	75831169
ENSE00001410181	75831243	75831348
ENSE00001417723	75827225	75828086
ENSE00001418337	75830028	75830151
ENSE00003462137	75843484	75843519
ENSE00003475032	75835647	75835777
ENSE00003476975	75842433	75842613
ENSE00003494829	75840957	75841001
ENSE00003496780	75834325	75834531
ENSE00003506057	75836200	75836256
ENSE00003514081	75843159	75843266
ENSE00003514546	75840507	75840576
ENSE00003515185	75842857	75842923
ENSE00003530783	75834920	75835063
ENSE00003545792	75843014	75843073
ENSE00003546438	75835855	75835906
ENSE00003558858	75834075	75834143
ENSE00003561658	75836801	75836918
ENSE00003562057	75834618	75834716
ENSE00003575562	75836012	75836109
ENSE00003589504	75836339	75836429
ENSE00003605880	75840762	75840830
ENSE00003630475	75828787	75828983
ENSE00003643801	75832966	75833045
ENSE00003646128	75830578	75830661
ENSE00003653841	75835409	75835529
ENSE00003665342	75836572	75836696
ENSE00003685576	75830362	75830482
ENSE00003786468	75840018	75840110
ENSE00003787457	75840225	75840329

Expression profiles

Bgee: expression breadth ubiquitous, 195 present calls, max score 98.01.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.4208 / max 357.3428, expressed in 961 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
168107	5.4958	678
168102	2.6713	286
168110	2.4244	534
168108	2.2670	599
168109	0.6851	376
168111	0.6442	260
168106	0.3418	78
168103	0.2429	114
168100	0.2412	118
168105	0.2262	78

Top tissues by expression

236 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.01	gold quality
bone marrow cell	CL:0002092	96.89	gold quality
spleen	UBERON:0002106	96.04	gold quality
right lung	UBERON:0002167	95.56	gold quality
upper lobe of left lung	UBERON:0008952	95.24	gold quality
leukocyte	CL:0000738	95.01	gold quality
monocyte	CL:0000576	94.91	gold quality
sural nerve	UBERON:0015488	94.39	gold quality
blood	UBERON:0000178	93.99	gold quality
vermiform appendix	UBERON:0001154	93.41	gold quality
upper lobe of lung	UBERON:0008948	93.04	gold quality
lower esophagus mucosa	UBERON:0035834	92.97	gold quality
lymph node	UBERON:0000029	91.71	gold quality
upper arm skin	UBERON:0004263	91.71	gold quality
caecum	UBERON:0001153	91.52	gold quality
kidney epithelium	UBERON:0004819	91.20	gold quality
tibial nerve	UBERON:0001323	89.79	gold quality
right uterine tube	UBERON:0001302	89.68	gold quality
esophagus mucosa	UBERON:0002469	89.52	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.30	gold quality
left ovary	UBERON:0002119	88.48	gold quality
bone marrow	UBERON:0002371	88.37	gold quality
mucosa of transverse colon	UBERON:0004991	88.07	gold quality
right atrium auricular region	UBERON:0006631	87.98	gold quality
right lobe of liver	UBERON:0001114	87.67	gold quality
small intestine	UBERON:0002108	87.67	gold quality
cardiac atrium	UBERON:0002081	87.65	gold quality
cerebellar vermis	UBERON:0004720	87.60	gold quality
right ovary	UBERON:0002118	87.41	gold quality
vagina	UBERON:0000996	87.17	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.40
E-MTAB-5061	no	3.64

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

25 targeting UNC13D, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4639-5P	99.81	67.37	1028
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-6889-3P	98.84	67.35	1198
HSA-MIR-4451	98.82	68.17	1455
HSA-MIR-6529-3P	98.68	66.76	1020
HSA-MIR-3135B	98.61	65.33	1470
HSA-MIR-4536-5P	98.47	64.39	657
HSA-MIR-4736	97.96	65.89	1287
HSA-MIR-3652	97.71	65.43	1890
HSA-MIR-665	97.60	65.64	1781
HSA-MIR-4430	97.47	65.61	1813
HSA-MIR-1202	97.19	66.43	827
HSA-MIR-3972	97.19	66.46	808
HSA-MIR-6815-5P	96.05	65.55	662
HSA-MIR-6865-5P	96.05	65.58	675

Literature-anchored findings (GeneRIF, showing 40)

• HMunc13-4 mutations were shown to cause familial hemophagocytic lymphohistiocytosis; HMunc13-4 is essential for the priming step of cytolytic granules secretion preceding vesicle membrane fusion. (PMID:14622600)
• Rab27 regulates the dense core granule secretion in platelets by employing its binding protein, Munc13-4 (PMID:14699162)
• MUNC13-4 mutations play a role in the development of familial haemophagocytic lymphohistiocytosis subtype 3 through a defective cytotoxic pathway (PMID:15466010)
• A large group of 63 unrelated patients with Familial hemophagocytic lymphohistiocytosis (FHL) was analysed for mutations in STX11, PRF1, and UNC13D. (PMID:16278825)
• These observations decisively prove that Rab27a inhibits ENaC function through a complex mechanism that involves GTP/GDP status, and protein-protein interactions involving Munc13-4 and SLP-5 effector proteins. (PMID:16630545)
• CD107a surface expression has a role in Munc13-4 defect in familial hemophagocytic lymphohistiocytosis (PMID:16778144)
• 12 novel and 4 known Munc13-4 mutations spread throughout the gene were found in haemophagocytic lymphohistiocytosis patients. (PMID:16825436)
• Biallelic UNC13D mutations were found in 18% of the PRF1/STX11-negative familial haemophagocytic lymphohistiocytosis families. (PMID:17993578)
• girl with systemic juvenile arthritis without macrophage activation syndrome was found to have compound heterozygous mutations of UNC13D and reduced NK cell cytotoxic function (PMID:18240215)
• The genes PRF1, GZMB, UNC13D, and Rab27a involved in hemophagocytic lymphohistiocytosis do not confer a significant risk of association with systemic-onset juvenile idiopathic arthritis. (PMID:18311812)
• Fatal sibling cases of familial hemophagocytic lymphohistiocytosis (FHL) with MUNC13-4 mutations (PMID:18432499)
• a role for Munc13-4 as a component of the secretory machinery in neutrophils. (PMID:18453599)
• UNC13D mutations leading to splicing errors represent the majority of mutations observed in familial hemophagocytic lymphohistiocytosis (PMID:18492689)
• The data suggest an association between MUNC13-4 polymorphisms and macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis. (PMID:18759271)
• mutated in type III hemophagocytic lymphohistiocytosis, a severe inflammatory disease of infectious etiology with fatal outcome (PMID:19120489)
• UNC13D mutations are associated with primary hemophagocytic lymphohistiocytosis. (PMID:19131769)
• Rab27a or Munc13-4 recruitment to lytic granules is preferentially regulated by different receptor signals, demonstrating that individual target cell ligands regulate discrete molecular events for lytic granule maturation. (PMID:19704116)
• rRecurrent splicing mutations in UNC13D gene is associated with familial hemophagocytic lymphohistiocytosis. (PMID:20015888)
• Data show that all but one patient with atypical familial hemophagocytic lymphohistiocytosis carried at least one splice-site mutation in UNC13D or STXBP2. (PMID:20823128)
• Hemophagocytic lymphohistiocytosis with MUNC13-4 gene mutation or reduced natural killer cell function prior to onset of childhood leukemia. (PMID:21370424)
• study reports recurrent fetal hydrops caused by familial hemophagocytic lymphohistiocytosis with Munc13-4 mutation (PMID:21646258)
• Seven novel mutations in PRF1, UNC13D, and XIAP were identified in Chinese EBV-HLH patients. Only a fraction of Chinese children with EBV-HLH have genetic defects in PRF1, UNC13D, and XIAP. (PMID:21674762)
• Data show that point mutations in the binding motif of munc13-4 have severely impaired rab27a binding, allowing dissection of rab27a requirements in munc13-4 function. (PMID:21693760)
• novel Dutch founder mutation leads to severe early onset of FHL3 due to misfolding and degradation of munc13-4(1-899). (PMID:21755595)
• Missense and splice-site sequence variants in PRF1, MUNC13-4, and STXBP2 were found in 25 (14%) of the adult patients. The A91V-PRF1 genotype was found in 12 of these patients (48%). (PMID:21881043)
• Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D. (PMID:21931115)
• Data indicate that Munc13-4 reinternalization is required for the maintenance of an intracellular pool that is functional to guarantee the serial killing potential. (PMID:22271450)
• study reports that Munc13-4 bound Ca(2 ) and restored Ca(2 )-dependent granule exocytosis to permeable cells (platelets, mast, and neuroendocrine cells) dependent on putative Ca(2 )-binding residues in C2A and C2B. (PMID:22508512)
• The deep intronic mutation UNC13D:c.118-308C>T accounts for the majority of previously missing mutations and is the most frequent mutation in familial hemophagocytic lymphohistiocytosis type 3 in Korea. (PMID:23180437)
• Novel deep intronic and missense UNC13D mutations are reported in familial haemophagocytic lymphohistiocytosis type 3. (PMID:23672263)
• Defects in cargo trafficking caused by mutations in RAB27A and UNC13D genes, encoding Rab27a and its effector Munc13-4, cause severe immunodeficiencies in humans. (Review) (PMID:23810987)
• These data suggest that rare loss-of-function variations of UND13D are risk factors for autoimmune lymphoproliferative syndrome development. (PMID:23840885)
• this is the first report of HLH in association with EVC syndrome, and the IVS13+5G>A mutation that we believe is causative of EVC in our patient is also unreported. (PMID:23924873)
• This patient the patient carried mutations in FAS, XIAP, and UNC13D genes inherited from his mother who had rheumatoid arthritis; UNC13D is involved in familial hemophagocytic lymphohistiocytosis (PMID:24043286)
• The prevalence of a 253-kb inversion and two deep intronic mutations, c.118-308C > T and c.118-307G > A, in UNC13D was determined in 1709 North American patients with type 3 hemophagocytic lymphohistiocytosis. 8 new mutations were also found. (PMID:24470399)
• Data indicate that Munc13-4 is highly expressed in differentiated NK cells and effector CD8(+) T lymphocytes. (PMID:24842371)
• These studies highlight the need for RAB27A sequencing in patients with FHL with normal pigmentation and identify a critical binding site for Munc13-4 on Rab27a, revealing the molecular basis of this interaction. (PMID:25312756)
• These data support an important role for Munc13-4 in human platelet degranulation (PMID:25573973)
• Synergistic defects of UNC13D and AP3B1 leading to adult hemophagocytic lymphohistiocytosis. (PMID:25980904)
• A newly defined mutation in the UNC13D (c.175G>C; p.Ala59Pro) was found in an asymptomatic heterozygote father and his homozygous daughter who had hemophagocytic lymphohistiocytosis. (PMID:26377049)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	unc13d	ENSDARG00000078249
mus_musculus	Unc13d	ENSMUSG00000057948
rattus_norvegicus	Unc13d	ENSRNOG00000007439
caenorhabditis_elegans	aex-1	WBGENE00000084

Paralogs (1): BAIAP3 (ENSG00000007516)

Protein

Protein identifiers

Protein unc-13 homolog D — Q70J99 (reviewed: Q70J99)

Alternative names: Munc13-4

All UniProt accessions (14): Q70J99, A0A8V8TNE8, A0A8V8TNG5, A0A8V8TNT8, A0A8V8TPN4, A0A8V8TPP8, A0A8V8TQ40, K7EIH3, K7ELN2, K7EM66, K7EMK8, K7EN29, K7EN81, K7EQ37

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in cytotoxic granule exocytosis in lymphocytes. Required for both granule maturation and granule docking and priming at the immunologic synapse. Regulates assembly of recycling and late endosomal structures, leading to the formation of an endosomal exocytic compartment that fuses with perforin-containing granules at the immunologic synapse and licences them for exocytosis. Regulates Ca(2+)-dependent secretory lysosome exocytosis in mast cells.

Subunit / interactions. Interacts with DOC2A. Interacts with RAB27A. Interacts with RHOG; the interaction increases RhoG affinity to the membrane lipids, targets UNC13D to membrane lipids and facilitates cytotoxic granule (CG) docking to the plasma membrane.

Subcellular location. Cytoplasm. Membrane. Late endosome. Recycling endosome. Lysosome.

Tissue specificity. Expressed at high levels in spleen, thymus and leukocytes. Also expressed in lung and placenta, and at very low levels in brain, heart, skeletal muscle and kidney. Expressed in cytotoxic T-lymphocytes (CTL) and mast cells.

Disease relevance. Hemophagocytic lymphohistiocytosis, familial, 3 (FHL3) [MIM:608898] A rare disorder characterized by immune dysregulation with hypercytokinemia, defective function of natural killer cell, and massive infiltration of several organs by activated lymphocytes and macrophages. The clinical features of the disease include fever, hepatosplenomegaly, cytopenia, and less frequently neurological abnormalities ranging from irritability and hypotonia to seizures, cranial nerve deficits and ataxia. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The MHD1 and MHD2 domains mediate localization on recycling endosomes and lysosome.

Similarity. Belongs to the unc-13 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q70J99-1	1	yes
Q70J99-2	2
Q70J99-3	3

RefSeq proteins (1): NP_954712* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR010439	MUN_dom	Domain
IPR014770	Munc13_1	Domain
IPR014772	Munc13_dom-2	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR052095	UNC-13_domain	Family

Pfam: PF00168, PF06292

UniProt features (33 total): binding site 13, domain 4, splice variant 4, sequence conflict 4, sequence variant 3, region of interest 2, chain 1, modified residue 1, mutagenesis site 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
9LA9	ELECTRON MICROSCOPY	4.38

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q70J99-F1	85.04	0.63

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (13): 208; 940; 941; 941; 947; 1005; 1005; 1007; 1007; 1013; 127; 133 …

Post-translational modifications (1): 150

Mutagenesis-validated functional residues (1):

Position	Phenotype
608–611	abolishes localization to lysosomes and interaction with rab27a.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 310 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOCC_SECRETORY_GRANULE, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, GOBP_VESICLE_MEDIATED_TRANSPORT, GOMF_GTPASE_BINDING, GOBP_POSITIVE_REGULATION_OF_SUBSTRATE_ADHESION_DEPENDENT_CELL_SPREADING, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, SREBP1_02, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, NFKB_Q6, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_MAST_CELL_ACTIVATION

GO Biological Process (12): granuloma formation (GO:0002432), germinal center formation (GO:0002467), phagocytosis (GO:0006909), regulation of mast cell degranulation (GO:0043304), natural killer cell degranulation (GO:0043320), positive regulation of exocytosis (GO:0045921), secretion (GO:0046903), defense response to virus (GO:0051607), positive regulation of substrate adhesion-dependent cell spreading (GO:1900026), positive regulation of regulated secretory pathway (GO:1903307), exocytosis (GO:0006887), establishment of localization in cell (GO:0051649)

GO Molecular Function (3): small GTPase binding (GO:0031267), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (11): extracellular region (GO:0005576), lysosome (GO:0005764), late endosome (GO:0005770), cytosol (GO:0005829), membrane (GO:0016020), Weibel-Palade body (GO:0033093), azurophil granule lumen (GO:0035578), recycling endosome (GO:0055037), exocytic vesicle (GO:0070382), cytoplasm (GO:0005737), endosome (GO:0005768)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
endosome	2
immune effector process	1
chronic inflammatory response	1
adaptive immune response based on somatic recombination of immune receptors built from immunoglobulin superfamily domains	1
anatomical structure formation involved in morphogenesis	1
endocytosis	1
regulation of myeloid leukocyte mediated immunity	1
regulation of leukocyte degranulation	1
mast cell degranulation	1
natural killer cell activation involved in immune response	1
natural killer cell mediated cytotoxicity	1
leukocyte degranulation	1
exocytosis	1
regulation of exocytosis	1
positive regulation of secretion by cell	1
transport	1
defense response	1
response to virus	1
positive regulation of cell-substrate adhesion	1
substrate adhesion-dependent cell spreading	1
regulation of substrate adhesion-dependent cell spreading	1
regulated exocytosis	1
positive regulation of exocytosis	1
regulation of regulated secretory pathway	1
vesicle-mediated transport	1
secretion by cell	1
vesicle fusion to plasma membrane	1
establishment of localization	1
cellular localization	1
GTPase binding	1
cation binding	1
binding	1
lytic vacuole	1
cytoplasm	1
clathrin-coated vesicle	1
secretory granule	1
vacuolar lumen	1
secretory granule lumen	1
azurophil granule	1

Protein interactions and networks

STRING

836 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UNC13D	RAB27A	P51159	999
UNC13D	STX11	O75558	989
UNC13D	STXBP2	Q15833	967
UNC13D	PRF1	P14222	902
UNC13D	RAB27B	O00194	895
UNC13D	STX19	Q8N4C7	870
UNC13D	FHL2	Q14192	838
UNC13D	LYST	Q99698	822
UNC13D	S100A10	P08206	802
UNC13D	SH2D1A	O60880	763
UNC13D	AP3B1	O00203	720
UNC13D	GNLY	P09325	689
UNC13D	VAMP7	P51809	645
UNC13D	MYO5A	Q9Y4I1	609
UNC13D	XIAP	P98170	601

IntAct

41 interactions, top by confidence:

A	B	Type	Score
	RHOG	psi-mi:“MI:0915”(physical association)	0.660
UNC13D	RAB27A	psi-mi:“MI:0915”(physical association)	0.570
UNC13D	RHOG	psi-mi:“MI:0915”(physical association)	0.540
	RHOG	psi-mi:“MI:0915”(physical association)	0.540
UNC13D	RHOG	psi-mi:“MI:0403”(colocalization)	0.540
BSG	BTAF1	psi-mi:“MI:0914”(association)	0.530
CMKLR1	SC5D	psi-mi:“MI:0914”(association)	0.530
GALNT16	IPO8	psi-mi:“MI:0914”(association)	0.530
	PLG	psi-mi:“MI:0914”(association)	0.350
	NBAS	psi-mi:“MI:0914”(association)	0.350
RHOG	COPE	psi-mi:“MI:0914”(association)	0.350
MAGEA9	MED19	psi-mi:“MI:0914”(association)	0.350
APLNR	TTI1	psi-mi:“MI:0914”(association)	0.350
ARMC6	DDX39A	psi-mi:“MI:0914”(association)	0.350
ATP6V1H	ATP6V1B1	psi-mi:“MI:0914”(association)	0.350
CD200R1	KIF2A	psi-mi:“MI:0914”(association)	0.350
CD40	IPO5	psi-mi:“MI:0914”(association)	0.350
CHRNB2	SNX2	psi-mi:“MI:0914”(association)	0.350
CXCR4	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (30): ANXA5 (Co-fractionation), DPYSL2 (Co-fractionation), UNC13D (Co-fractionation), UNC13D (Co-fractionation), UNC13D (Co-fractionation), RAB27A (Reconstituted Complex), UNC13D (Proximity Label-MS), UNC13D (Negative Genetic), UNC13D (Proximity Label-MS), UNC13D (Affinity Capture-RNA), UNC13D (Affinity Capture-MS), UNC13D (Negative Genetic), UNC13D (Negative Genetic), UNC13D (Co-fractionation), UNC13D (Co-fractionation)

ESM2 similar proteins: A1IGU3, A1IGU4, A1IGU5, A6QP29, B1AVH7, B2RUP2, B5DFA1, D2H0G5, D3ZFJ3, O15068, O55043, P00530, P07332, P14238, P16879, P55194, P98171, Q0GNC1, Q14155, Q15052, Q27J81, Q3U5C8, Q3UMR0, Q58EX7, Q5VV41, Q5XXR3, Q5ZLR6, Q60I26, Q63406, Q64096, Q6PFY1, Q6PGG2, Q70J99, Q7TNH6, Q80TT2, Q80VK6, Q86WN1, Q8C2K1, Q8C6B2, Q8CJ00

Diamond homologs: A0FGR8, A0FGR9, A0JJX5, A1ZBD6, A2X479, A6QQP7, A8KBH6, B2RUP2, D4ABL6, E9PV86, K8FE10, O00445, O75923, O94812, O95294, P04409, P05126, P05128, P05129, P05130, P05696, P05771, P05772, P10102, P10829, P13677, P17252, P20444, P21521, P24505, P27715, P34693, P41885, P46097, P46935, P47708, P47709, P47861, P63318, P63319

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1615 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	108
Likely pathogenic	49
Uncertain significance	547
Likely benign	739
Benign	50

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068466	NM_199242.3(UNC13D):c.2258_2259insA (p.His754fs)	Pathogenic
1068528	NM_199242.3(UNC13D):c.82_83insCTCT (p.Asp28fs)	Pathogenic
1070830	NM_199242.3(UNC13D):c.3018C>G (p.Tyr1006Ter)	Pathogenic
1073330	NM_199242.3(UNC13D):c.1792C>T (p.Gln598Ter)	Pathogenic
1074647	NM_199242.3(UNC13D):c.779G>A (p.Trp260Ter)	Pathogenic
1074705	NM_199242.3(UNC13D):c.2037_2038insG (p.Arg680fs)	Pathogenic
1074706	NM_199242.3(UNC13D):c.177_178del (p.Tyr61fs)	Pathogenic
1074707	NM_199242.3(UNC13D):c.1545-2A>G	Pathogenic
1076211	NM_199242.3(UNC13D):c.883C>T (p.Gln295Ter)	Pathogenic
1299415	NM_199242.3(UNC13D):c.118-307G>A	Pathogenic
1299416	NM_199242.3(UNC13D):c.754-1G>C	Pathogenic
1323739	NM_199242.3(UNC13D):c.2381del (p.Leu794fs)	Pathogenic
1333524	NM_199242.3(UNC13D):c.751C>T (p.Gln251Ter)	Pathogenic
1400833	NM_199242.3(UNC13D):c.817C>T (p.Arg273Ter)	Pathogenic
1412812	NM_199242.3(UNC13D):c.859del (p.Arg287fs)	Pathogenic
1454697	NM_199242.3(UNC13D):c.640C>T (p.Arg214Ter)	Pathogenic
1455815	NM_199242.3(UNC13D):c.1072dup (p.Ser358fs)	Pathogenic
1687358	NM_199242.3(UNC13D):c.1612C>T (p.Gln538Ter)	Pathogenic
1694206	NM_199242.3(UNC13D):c.1947G>A (p.Trp649Ter)	Pathogenic
1996	NM_199242.3(UNC13D):c.1828_1839del (p.Arg610_Gln613del)	Pathogenic
1997	NM_199242.3(UNC13D):c.216del (p.Asn73fs)	Pathogenic
1998	NM_199242.3(UNC13D):c.1754dup (p.His586fs)	Pathogenic
1999	NM_199242.3(UNC13D):c.1389+1G>A	Pathogenic
2001	NM_199242.3(UNC13D):c.753+1G>T	Pathogenic
2002	NM_199242.3(UNC13D):c.1208T>C (p.Leu403Pro)	Pathogenic
2003	NM_199242.3(UNC13D):c.2570T>G (p.Phe857Cys)	Pathogenic
2030809	NM_199242.3(UNC13D):c.2434G>T (p.Glu812Ter)	Pathogenic
2077622	NM_199242.3(UNC13D):c.708del (p.Asp236fs)	Pathogenic
2103306	NM_199242.3(UNC13D):c.1953_1959del (p.Asp651fs)	Pathogenic
2138107	NM_199242.3(UNC13D):c.755_756dup (p.Leu253fs)	Pathogenic

SpliceAI

4179 predictions. Top by Δscore:

Variant	Effect	Δscore
17:75828084:CCC:C	acceptor_gain	1.0000
17:75828085:CC:C	acceptor_gain	1.0000
17:75828085:CCC:C	acceptor_gain	1.0000
17:75828086:CC:C	acceptor_gain	1.0000
17:75828086:CCTG:C	acceptor_loss	1.0000
17:75828087:C:CC	acceptor_gain	1.0000
17:75828088:T:A	acceptor_loss	1.0000
17:75828855:AG:A	donor_gain	1.0000
17:75828979:CCAGG:C	acceptor_gain	1.0000
17:75828980:CAGGC:C	acceptor_gain	1.0000
17:75828981:AGG:A	acceptor_gain	1.0000
17:75828982:GG:G	acceptor_gain	1.0000
17:75828984:C:CC	acceptor_gain	1.0000
17:75830024:TCACA:T	donor_loss	1.0000
17:75830026:A:AC	donor_gain	1.0000
17:75830026:ACAAT:A	donor_loss	1.0000
17:75830027:C:CA	donor_gain	1.0000
17:75830027:CA:C	donor_gain	1.0000
17:75830027:CAA:C	donor_gain	1.0000
17:75830027:CAATT:C	donor_gain	1.0000
17:75830357:CTCA:C	donor_loss	1.0000
17:75830358:TCA:T	donor_loss	1.0000
17:75830359:CACCA:C	donor_loss	1.0000
17:75830360:A:AC	donor_gain	1.0000
17:75830360:AC:A	donor_gain	1.0000
17:75830360:ACCA:A	donor_loss	1.0000
17:75830361:C:CA	donor_gain	1.0000
17:75830361:C:G	donor_loss	1.0000
17:75830361:CC:C	donor_gain	1.0000
17:75830361:CCA:C	donor_gain	1.0000

AlphaMissense

7073 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:75830133:A:T	V950D	0.998
17:75842452:A:G	W184R	0.998
17:75842452:A:T	W184R	0.998
17:75842450:C:A	W184C	0.997
17:75842450:C:G	W184C	0.997
17:75836914:A:G	W354R	0.996
17:75836914:A:T	W354R	0.996
17:75840250:A:G	L278P	0.995
17:75842606:G:C	S132R	0.995
17:75842606:G:T	S132R	0.995
17:75842608:T:G	S132R	0.995
17:75840529:C:T	G244E	0.993
17:75842895:A:T	V117E	0.993
17:75828886:C:G	A1018P	0.992
17:75834967:A:G	W649R	0.992
17:75834967:A:T	W649R	0.992
17:75835031:G:C	S627R	0.992
17:75835031:G:T	S627R	0.992
17:75835033:T:G	S627R	0.992
17:75835471:A:G	W596R	0.992
17:75835471:A:T	W596R	0.992
17:75836619:G:C	F417L	0.992
17:75836619:G:T	F417L	0.992
17:75836621:A:G	F417L	0.992
17:75840257:A:G	C276R	0.992
17:75842907:A:G	L113P	0.992
17:75830412:A:G	L927P	0.991
17:75840529:C:A	G244V	0.991
17:75842451:C:G	W184S	0.991
17:75842594:G:C	C136W	0.991

dbSNP variants (sampled 300 via entrez): RS1000119122 (17:75839560 AGTGTTG>A), RS1000448534 (17:75843382 C>A), RS1000464591 (17:75844807 T>C,G), RS1000551360 (17:75843612 G>A), RS1000874712 (17:75833386 G>A), RS1000886861 (17:75829389 G>A), RS1000921615 (17:75832553 T>TGGTTAC), RS1001082489 (17:75838963 G>A), RS1001265793 (17:75838926 C>G,T), RS1001318299 (17:75839018 T>G), RS1001427619 (17:75833449 T>G), RS1001431876 (17:75839262 C>A,T), RS1001532957 (17:75828606 G>A), RS1001766122 (17:75834430 C>G,T), RS1001818378 (17:75834238 A>C,T)

Disease associations

OMIM: gene MIM:608897 | disease phenotypes: MIM:608898, MIM:267700

GenCC curated gene-disease

Disease	Classification	Inheritance
familial hemophagocytic lymphohistiocytosis 3	Definitive	Autosomal recessive
hereditary hemophagocytic lymphohistiocytosis	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
familial hemophagocytic lymphohistiocytosis 3	Definitive	AR

Mondo (4): familial hemophagocytic lymphohistiocytosis 3 (MONDO:0012146), hereditary hemophagocytic lymphohistiocytosis (MONDO:0015541), autoinflammatory syndrome (MONDO:0019751), intellectual disability (MONDO:0001071)

Orphanet (4): Familial hemophagocytic lymphohistiocytosis (Orphanet:540), Primary hemophagocytic lymphohistiocytosis (Orphanet:158038), Autoinflammatory syndrome (Orphanet:93665), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

53 total (30 of 53 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000707	Abnormality of the nervous system
HP:0000952	Jaundice
HP:0000967	Petechiae
HP:0000978	Bruising susceptibility
HP:0000979	Purpura
HP:0000988	Skin rash
HP:0001019	Erythroderma
HP:0001250	Seizure
HP:0001259	Coma
HP:0001410	Decreased liver function
HP:0001433	Hepatosplenomegaly
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001903	Anemia
HP:0001913	Decreased total granulocyte count
HP:0001945	Fever
HP:0002086	Abnormality of the respiratory system
HP:0002155	Hypertriglyceridemia
HP:0002240	Hepatomegaly
HP:0002383	Infectious encephalitis
HP:0002500	Abnormal cerebral white matter morphology
HP:0002583	Colitis
HP:0002611	Cholestatic liver disease
HP:0002716	Lymphadenopathy
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0002958	Immune dysregulation
HP:0003073	Hypoalbuminemia

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST003013_1	White matter hyperintensity burden	5.000000e-19
GCST003013_15	White matter hyperintensity burden	3.000000e-19
GCST004606_28	Eosinophil count	3.000000e-09
GCST005547_10	Major depressive disorder	7.000000e-07
GCST007267_246	Systolic blood pressure	1.000000e-13
GCST010043_38	Asthma	4.000000e-08
GCST010241_306	Apolipoprotein A1 levels	2.000000e-08
GCST90002404_177	Red cell distribution width	3.000000e-12
GCST90014325_68	Asthma	3.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0005665	white matter hyperintensity measurement
EFO:0004842	eosinophil count
EFO:0006335	systolic blood pressure
EFO:0004614	apolipoprotein A 1 measurement
EFO:0009188	Red cell distribution width

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C537251	Hemophagocytic lymphohistiocytosis, familial, 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

38 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, affects binding, increases reaction, increases expression	4
(+)-JQ1 compound	decreases expression	2
Air Pollutants	increases abundance, increases oxidation, affects expression, affects cotreatment	2
Benzo(a)pyrene	decreases methylation, increases mutagenesis	2
Ozone	increases abundance, affects expression, affects cotreatment, increases oxidation	2
Cadmium Chloride	increases expression	2
aristolochic acid I	increases expression	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
2,2’-methylenebis(4-methyl-6-tert-butylphenol)	affects response to substance, affects expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
perfluorooctanoic acid	decreases expression	1
benzo(e)pyrene	decreases methylation	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
bisphenol S	decreases expression	1
MT19c compound	decreases expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	increases expression	1
Acrolein	increases abundance, affects cotreatment, increases oxidation	1
Cisplatin	decreases expression	1
Doxorubicin	decreases expression	1
Methapyrilene	decreases methylation	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1

Clinical trials (associated diseases)

208 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05744063	PHASE4	COMPLETED	A Post-authorization Study to Describe the Safety and Efficacy of Emapalumab for the Treatment of pHLH in Treatment Experienced Chinese Patients
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT03312751	PHASE3	COMPLETED	Study to Assess the Efficacy and Safety of Emapalumab in Primary Haemophagocytic Lymphohistiocytosis
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00368355	PHASE2	COMPLETED	T Cell Depletion for Recipients of HLA Haploidentical Related Donor Stem Cell Grafts
NCT00442182	PHASE2	UNKNOWN	The Efficacy and Safety of ITF2357 in AIS
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT01494103	PHASE1	ACTIVE_NOT_RECRUITING	Administration of Donor T Cells With the Caspase-9 Suicide Gene
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT06736080	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of Gene Therapy of FHL Type 3 Caused by Mutations in the Human UNC13D Gene by Transplantation of a Single Dose of Autologous CD34+ Cells Transduced ex Vivo With the UNC13D LV Vector Expressing the UNC13D cDNA
NCT03827343	Not specified	ACTIVE_NOT_RECRUITING	Retrospective Study of Immunotherapy Related Toxicities and Factors Impacting Outcomes in Children and Adults With Cancer
NCT06587191	Not specified	ACTIVE_NOT_RECRUITING	Emapalumab Efficacy in Children With Primary Hemophagocytic Lymphohistiocytosis
NCT00887939	Not specified	COMPLETED	Pathogenesis of Physical Induced Urticarial Syndromes
NCT03510442	Not specified	RECRUITING	Natural History, Genetics, and Pathophysiology of Systemic Juvenile Idiopathic Arthritis, Adult-Onset Still’s Disease, and Related Conditions
NCT06248957	Not specified	RECRUITING	SYSTEMS-LEVEL ANALYSES OF IMMUNE DYSREGULATION
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability