UNC93B1

Summary

UNC93B1 (unc-93B1 regulator of TLR signaling, HGNC:13481) is a protein-coding gene on chromosome 11q13.2, encoding Protein unc-93 homolog B1 (Q9H1C4). Plays an important role in innate and adaptive immunity by regulating nucleotide-sensing Toll-like receptor (TLR) signaling.

This gene encodes a protein that is involved in innate and adaptive immune response by regulating toll-like receptor signaling. The encoded protein traffics nucleotide sensing toll-like receptors to the endolysosome from the endoplasmic reticulum. Deficiency of the encoded protein has been associated with herpes simplex encephalitis.

Source: NCBI Gene 81622 — RefSeq curated summary.

At a glance

• Gene–disease (curated): herpes simplex encephalitis, susceptibility to, 1 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 429 total — 5 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 33
• Druggable target: yes
• MANE Select transcript: NM_030930

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13481
Approved symbol	UNC93B1
Name	unc-93B1 regulator of TLR signaling
Location	11q13.2
Locus type	gene with protein product
Status	Approved
Aliases	UNC93, UNC-93B
Ensembl gene	ENSG00000110057
Ensembl biotype	protein_coding
OMIM	608204
Entrez	81622

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 8 protein_coding, 6 retained_intron, 1 nonsense_mediated_decay

ENST00000227471, ENST00000524455, ENST00000525368, ENST00000528096, ENST00000528423, ENST00000530138, ENST00000531152, ENST00000533424, ENST00000622364, ENST00000864506, ENST00000864507, ENST00000864508, ENST00000864509, ENST00000930952, ENST00000959345

RefSeq mRNA: 1 — MANE Select: NM_030930 NM_030930

CCDS: CCDS73334

Canonical transcript exons

ENST00000227471 — 11 exons

Exon	Start	End
ENSE00000824041	67997675	67997799
ENSE00003531573	67993676	67993794
ENSE00003597638	67996602	67996784
ENSE00003644518	68003657	68003798
ENSE00003650035	67999173	67999305
ENSE00003655820	68003948	68004097
ENSE00003663353	68003022	68003175
ENSE00003665994	67995611	67995884
ENSE00003679014	67991100	67991857
ENSE00003682505	67999519	67999680
ENSE00003692215	67998359	67998452

Expression profiles

Bgee: expression breadth ubiquitous, 174 present calls, max score 97.21.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.3676 / max 319.7694, expressed in 1786 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
120982	20.7254	1784
120981	0.3944	208
120980	0.2478	147

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	97.21	gold quality
monocyte	CL:0000576	97.15	gold quality
leukocyte	CL:0000738	97.06	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.35	gold quality
spleen	UBERON:0002106	95.58	gold quality
bone marrow cell	CL:0002092	95.35	gold quality
vermiform appendix	UBERON:0001154	92.36	gold quality
right lung	UBERON:0002167	92.17	gold quality
right uterine tube	UBERON:0001302	91.70	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.57	gold quality
upper lobe of left lung	UBERON:0008952	90.71	gold quality
minor salivary gland	UBERON:0001830	90.66	gold quality
mucosa of transverse colon	UBERON:0004991	89.54	gold quality
gall bladder	UBERON:0002110	89.30	gold quality
upper lobe of lung	UBERON:0008948	89.27	gold quality
small intestine	UBERON:0002108	88.82	gold quality
stromal cell of endometrium	CL:0002255	88.61	gold quality
lymph node	UBERON:0000029	88.51	gold quality
transverse colon	UBERON:0001157	88.11	gold quality
right adrenal gland cortex	UBERON:0035827	87.89	gold quality
right coronary artery	UBERON:0001625	87.43	gold quality
right adrenal gland	UBERON:0001233	87.36	gold quality
mucosa of stomach	UBERON:0001199	87.25	gold quality
body of stomach	UBERON:0001161	87.12	gold quality
left adrenal gland cortex	UBERON:0035825	86.94	gold quality
left adrenal gland	UBERON:0001234	86.81	gold quality
rectum	UBERON:0001052	86.59	gold quality
blood	UBERON:0000178	86.46	gold quality
endocervix	UBERON:0000458	86.34	gold quality
metanephros cortex	UBERON:0010533	85.81	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-9467	yes	12.28
E-MTAB-9067	yes	11.69
E-ANND-3	yes	11.58
E-CURD-53	no	158.79

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

9 targeting UNC93B1, 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-1250-3P	99.96	70.04	4038
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-4725-5P	98.67	65.42	628
HSA-MIR-504-5P	98.67	65.40	631
HSA-MIR-216B-5P	97.16	66.76	1126

Literature-anchored findings (GeneRIF, showing 27)

• Haplotype H3 of the hUNC-93B1 gene seems related to E/A-ratio in elderly men. The relationship between the hUNC-93B1 gene and the age at onset of heart failure and mortality support a view of a clinically relevant impact of the gene. (PMID:16111919)
• findings elucidate a genetic etiology for herpes simplex virus encephalitis in two children with autosomal recessive deficiency in the intracellular protein UNC-93B, resulting in impaired cellular interferon-alpha/beta and -lambda antiviral responses (PMID:16973841)
• study confirms the function of UNC-93B for innate immunity in human beings, and extends the knowledge for this molecule to the analysis of its regulation and the subcellular localization of the endogenous protein (PMID:18082565)
• No UNC-93B1 mutations were foundin patients with MRS. (PMID:18241724)
• IRAK-4-, MyD88-, and UNC-93B-deficient patients did not display autoreactive antibodies in their serum or develop autoimmune diseases, suggesting that IRAK-4, MyD88, and UNC-93B pathway blockade may thwart autoimmunity in humans. (PMID:19006693)
• regulates ligand-induced trafficking of TLR7 and TLR9 from the ER to endolysosomes, potential therapeutic target for controlling dysregulated TLR7/9 responses in autoimmune diseases (PMID:19120473)
• Individuals with congenital mutations develop severe HSV-1 encephalitis (PMID:19120481)
• To date only 2 children with UNC-93B deficiencies have been identified after isolated HSV-1 encephalitis. (PMID:21173679)
• UNC93B1 physically associates with human TLR8 and regulates TLR8-mediated signaling (PMID:22164301)
• UNC93B1 expression is required for TLR3 cleavage and signaling. (PMID:22611194)
• IgM(+)IgD(+)CD27(+) but not switched B cells were strongly reduced in MYD88-, IRAK-4-, and TIRAP-deficient patients, but not UNC-93B-deficient patients. (PMID:23002119)
• TLR3 is the important regulator of UNC93B1 that in turn governs the responsiveness of all TLR3 as the important regulator of UNC93B1 that in turn governs the responsiveness of all NAS Toll-like receptors (PMID:23166319)
• the UNC93B1 tyrosine-based motif regulates trafficking and TLR responses via separate mechanisms. (PMID:25187660)
• Endosomal localization of endogenous TLR3 was decreased by silencing of LRRC59, suggesting that LRRC59 promotes UNC93B1-mediated translocation of NA-sensing TLRs from the ER upon infection. (PMID:26466955)
• Expression of a constitutively active STIM1 mutant, which no longer binds UNC93B1, restores antigen degradation and cross-presentation in 3d-mutated dendritic cells. (PMID:29158474)
• Our results suggest that rare protein-altering variants in the C10orf88 and UNC93B1 genes are associated with a worse response to anti-VEGF therapy in patients with neovascular age-related macular degeneration, but these results require further validation in other cohorts. (PMID:29852030)
• UNC93B1 regulates cell-cycle arrest at the G1 phase in oral squamous cell carcinoma. Down-regulated UNC93B1 stops granulocyte macrophage colony-stimulating factor. UNC93B1 may control tumors via granulocyte macrophage colony-stimulating factor. (PMID:30935694)
• Cryo-EM structures of Toll-like receptors in complex with UNC93B1. (PMID:33432245)
• Donor UNC-93 Homolog B1 genetic polymorphism predicts survival outcomes after unrelated bone marrow transplantation. (PMID:33627833)
• UNC93B1 curbs cytosolic DNA signaling by promoting STING degradation. (PMID:33837956)
• Dynamic control of nucleic-acid-sensing Toll-like receptors by the endosomal compartment. (PMID:34223897)
• Variants Affecting the C-Terminal Tail of UNC93B1 Are Not a Common Risk Factor for Systemic Lupus Erythematosus. (PMID:34440442)
• UNC93B1 attenuates the cGAS-STING signaling pathway by targeting STING for autophagy-lysosome degradation. (PMID:35577759)
• UNC93B1 variants underlie TLR7-dependent autoimmunity. (PMID:38207055)
• Large-scale mutational analysis identifies UNC93B1 variants that drive TLR-mediated autoimmunity in mice and humans. (PMID:38780621)
• Genetic variants in UNC93B1 predispose to childhood-onset systemic lupus erythematosus. (PMID:38831104)
• Gain-of-function human UNC93B1 variants cause systemic lupus erythematosus and chilblain lupus. (PMID:38869500)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	unc93b1	ENSDARG00000069114
mus_musculus	Unc93b1	ENSMUSG00000036908
rattus_norvegicus	Unc93b1	ENSRNOG00000017703
drosophila_melanogaster	CG3078	FBGN0023524

Paralogs (1): UNC93A (ENSG00000112494)

Protein

Protein identifiers

Protein unc-93 homolog B1 — Q9H1C4 (reviewed: Q9H1C4)

All UniProt accessions (3): Q9H1C4, E9PNE5, E9PR93

UniProt curated annotations — full annotation on UniProt →

Function. Plays an important role in innate and adaptive immunity by regulating nucleotide-sensing Toll-like receptor (TLR) signaling. Required for the transport of a subset of TLRs (including TLR3, TLR7 and TLR9) from the endoplasmic reticulum to endolysosomes where they can engage pathogen nucleotides and activate signaling cascades. May play a role in autoreactive B-cells removal.

Subunit / interactions. Interacts with TLR3, TLR5, TLR7, and TLR9 (probably via transmembrane domain).

Subcellular location. Endoplasmic reticulum membrane. Endosome. Lysosome. Cytoplasmic vesicle. Phagosome.

Tissue specificity. Expressed in plasmocytoid dendritic cells (at protein level). Highly expressed in antigen-presenting cells. Expressed in heart, and at lower level in kidney. Expressed at low level in other tissues.

Post-translational modifications. N-glycosylated.

Disease relevance. Encephalopathy, acute, infection-induced, 1, herpes-specific (IIAE1) [MIM:610551] A rare complication of human herpesvirus 1 (HHV-1) infection, occurring in only a small minority of HHV-1 infected individuals. It is characterized by hemorrhagic necrosis of parts of the temporal and frontal lobes. Onset is over several days and involves fever, headache, seizures, stupor, and often coma, frequently with a fatal outcome. Disease susceptibility is associated with variants affecting the gene represented in this entry. Mutations in UNC93B1 resulting in autosomal recessive UNC93B1 deficiency predispose otherwise healthy individuals to isolated herpes simplex encephalitis due to impaired IFNs production. UNC93B1 deficiency, however, does not compromise immunity to most pathogens, unlike most known primary immunodeficiencies.

Induction. Up-regulated by TLRs agonists.

Similarity. Belongs to the unc-93 family.

RefSeq proteins (1): NP_112192* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR043268	UNC93B1	Family

UniProt features (53 total): helix 24, transmembrane region 12, turn 4, glycosylation site 3, strand 3, region of interest 2, modified residue 2, chain 1, sequence variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7C76	ELECTRON MICROSCOPY	3.4
7CYN	ELECTRON MICROSCOPY	4.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H1C4-F1	80.12	0.49

Functional residue map

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

Post-translational modifications (2): 547, 550

Glycosylation sites (3): 251, 272, 449

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-1679131	Trafficking and processing of endosomal TLR
R-HSA-5602415	UNC93B1 deficiency - HSE

MSigDB gene sets: 277 (showing top): GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_OR_POLYSACCHARIDE_ANTIGEN_VIA_MHC_CLASS_II, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_TOLL_LIKE_RECEPTOR_9_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION_OF_PEPTIDE_ANTIGEN, chr11q13, GOBP_TOLL_LIKE_RECEPTOR_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_POSITIVE_REGULATION_OF_INTERLEUKIN_12_PRODUCTION, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A4, GOBP_CYTOKINE_PRODUCTION

GO Biological Process (15): cell morphogenesis (GO:0000902), toll-like receptor signaling pathway (GO:0002224), T cell antigen processing and presentation (GO:0002457), intracellular protein transport (GO:0006886), antigen processing and presentation of exogenous peptide antigen via MHC class II (GO:0019886), positive regulation of interleukin-12 production (GO:0032735), positive regulation of interleukin-6 production (GO:0032755), toll-like receptor 3 signaling pathway (GO:0034138), toll-like receptor 7 signaling pathway (GO:0034154), toll-like receptor 9 signaling pathway (GO:0034162), innate immune response (GO:0045087), defense response to virus (GO:0051607), adaptive immune response (GO:0002250), immune system process (GO:0002376), antigen processing and presentation (GO:0019882)

GO Molecular Function (2): Toll-like receptor binding (GO:0035325), protein binding (GO:0005515)

GO Cellular Component (9): Golgi membrane (GO:0000139), lysosome (GO:0005764), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), early phagosome (GO:0032009), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), phagocytic vesicle (GO:0045335)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Toll-like Receptor Cascades	1
Diseases associated with the TLR signaling cascade	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endolysosomal toll-like receptor signaling pathway	3
positive regulation of cytokine production	2
immune response	2
endomembrane system	2
cytoplasm	2
anatomical structure morphogenesis	1
pattern recognition receptor signaling pathway	1
T cell mediated immunity	1
antigen processing and presentation	1
intracellular protein localization	1
protein transport	1
intracellular transport	1
antigen processing and presentation of exogenous peptide antigen	1
antigen processing and presentation of peptide antigen via MHC class II	1
interleukin-12 production	1
regulation of interleukin-12 production	1
interleukin-6 production	1
regulation of interleukin-6 production	1
defense response to symbiont	1
defense response	1
response to virus	1
biological_process	1
immune system process	1
signaling receptor binding	1
binding	1
Golgi apparatus	1
bounding membrane of organelle	1
lytic vacuole	1
cytoplasmic vesicle	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
phagocytic vesicle	1
cellular anatomical structure	1
intracellular vesicle	1
endocytic vesicle	1

Protein interactions and networks

STRING

1340 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UNC93B1	TLR3	O15455	995
UNC93B1	TLR7	Q9NYK1	956
UNC93B1	TLR9	Q9NR96	929
UNC93B1	TLR8	Q9NR97	801
UNC93B1	MYD88	P78397	794
UNC93B1	IFNB1	P01574	749
UNC93B1	TBK1	Q9UHD2	715
UNC93B1	SDCBP2	Q9H190	712
UNC93B1	IFNL1	Q8IU54	699
UNC93B1	SDCBP	O00560	694
UNC93B1	CNPY3	Q9BT09	692
UNC93B1	IRAK4	Q9NWZ3	614
UNC93B1	IRF7	Q92985	600
UNC93B1	TRAF3	Q13114	591
UNC93B1	IRF3	Q14653	580

IntAct

151 interactions, top by confidence:

A	B	Type	Score
TLR8	UNC93B1	psi-mi:“MI:0915”(physical association)	0.600
TLR8	UNC93B1	psi-mi:“MI:0403”(colocalization)	0.600
UNC93B1	SSMEM1	psi-mi:“MI:0915”(physical association)	0.560
MFF	UNC93B1	psi-mi:“MI:0915”(physical association)	0.560
FATE1	UNC93B1	psi-mi:“MI:0915”(physical association)	0.560
CREB3L1	UNC93B1	psi-mi:“MI:0915”(physical association)	0.560
LDLRAD1	UNC93B1	psi-mi:“MI:0915”(physical association)	0.560
	UNC93B1	psi-mi:“MI:0915”(physical association)	0.560
KLRC1	UNC93B1	psi-mi:“MI:0915”(physical association)	0.560
UNC93B1	SYNDIG1	psi-mi:“MI:0915”(physical association)	0.560
TMEM237	UNC93B1	psi-mi:“MI:0915”(physical association)	0.560
UNC93B1	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560
UNC93B1	SLC35C2	psi-mi:“MI:0915”(physical association)	0.560
BEST2	UNC93B1	psi-mi:“MI:0915”(physical association)	0.560
CLDN7	UNC93B1	psi-mi:“MI:0915”(physical association)	0.560
SSMEM1	UNC93B1	psi-mi:“MI:0915”(physical association)	0.560
FFAR3	UNC93B1	psi-mi:“MI:0915”(physical association)	0.560
GPR101	UNC93B1	psi-mi:“MI:0915”(physical association)	0.560
UNC93B1	GPRC5D	psi-mi:“MI:0915”(physical association)	0.560
TM4SF18	UNC93B1	psi-mi:“MI:0915”(physical association)	0.560
GPR37L1	UNC93B1	psi-mi:“MI:0915”(physical association)	0.560
UNC93B1	REEP1	psi-mi:“MI:0915”(physical association)	0.560
LEUTX	UNC93B1	psi-mi:“MI:0915”(physical association)	0.560
CD79A	UNC93B1	psi-mi:“MI:0915”(physical association)	0.560
EBP	UNC93B1	psi-mi:“MI:0915”(physical association)	0.560
UNC93B1	HHLA2	psi-mi:“MI:0915”(physical association)	0.560
UNC93B1	LIME1	psi-mi:“MI:0915”(physical association)	0.560
CCDC107	UNC93B1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (546): UNC93B1 (Affinity Capture-RNA), UNC93B1 (Proximity Label-MS), UNC93B1 (Affinity Capture-MS), UNC93B1 (Affinity Capture-MS), UNC93B1 (Affinity Capture-MS), UNC93B1 (Affinity Capture-MS), UNC93B1 (Affinity Capture-MS), AAAS (Affinity Capture-MS), ABCB7 (Affinity Capture-MS), ABCC1 (Affinity Capture-MS), ACAD9 (Affinity Capture-MS), ADCK3 (Affinity Capture-MS), ADCK4 (Affinity Capture-MS), AGPAT2 (Affinity Capture-MS), AGPAT4 (Affinity Capture-MS)

ESM2 similar proteins: A4IFN5, A6NDV4, B1AWJ5, B1AZA5, B2LYG4, P59266, Q05B45, Q0VCJ8, Q3KRC4, Q3UMZ3, Q5EA70, Q5H8A4, Q5QJU3, Q5RBJ7, Q5U3C3, Q5VTY9, Q5ZMH6, Q6PHN7, Q6TCH4, Q6W5G4, Q6ZVK1, Q7Z7J7, Q865K8, Q86WK9, Q8BHH9, Q8BMT9, Q8BWB6, Q8C1E7, Q8K3J9, Q8N6M3, Q8NBT3, Q8NEB5, Q8NFT2, Q8VCW4, Q8VCY8, Q8VD53, Q8VDI9, Q96GM1, Q9BSA9, Q9BXJ8

Diamond homologs: Q8VCW4, Q9H1C4

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 113 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of chemokine production	5	18.7×	1e-03
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	8	17.5×	6e-06
positive regulation of cytosolic calcium ion concentration	10	11.7×	6e-06
phospholipase C-activating G protein-coupled receptor signaling pathway	8	10.5×	2e-04
G protein-coupled receptor signaling pathway	12	4.3×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	6
Uncertain significance	179
Likely benign	204
Benign	17

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
1440823	NM_030930.4(UNC93B1):c.702C>A (p.Cys234Ter)	Pathogenic
1443637	NM_030930.4(UNC93B1):c.1038_1041del (p.Phe346fs)	Pathogenic
1999060	NM_030930.4(UNC93B1):c.341_351del (p.Gly114fs)	Pathogenic
2027491	NM_030930.4(UNC93B1):c.668_671del (p.Ile223fs)	Pathogenic
3671733	NM_030930.4(UNC93B1):c.800del (p.Ile267fs)	Pathogenic
2705350	NM_030930.4(UNC93B1):c.1345_1363+52del	Likely pathogenic
2710002	NM_030930.4(UNC93B1):c.781+1G>A	Likely pathogenic
3338157	NM_030930.4(UNC93B1):c.1632_1644delinsCAACTCGGAG (p.Glu544_Asp548delinsAspAsnSerGlu)	Likely pathogenic
3359228	NM_030930.4(UNC93B1):c.1006C>T (p.Arg336Cys)	Likely pathogenic
3685903	NM_030930.4(UNC93B1):c.1364-2A>G	Likely pathogenic
4277368	NM_030930.4(UNC93B1):c.1574G>C (p.Arg525Pro)	Likely pathogenic

SpliceAI

1467 predictions. Top by Δscore:

Variant	Effect	Δscore
11:67993671:CTCA:C	donor_loss	1.0000
11:67993672:TCA:T	donor_loss	1.0000
11:67993673:CACCT:C	donor_loss	1.0000
11:67993674:A:C	donor_loss	1.0000
11:67993675:CCTT:C	donor_gain	1.0000
11:67993803:A:T	acceptor_gain	1.0000
11:67993806:CAG:C	acceptor_gain	1.0000
11:67993807:A:T	acceptor_gain	1.0000
11:67993808:G:C	acceptor_gain	1.0000
11:67993808:G:GC	acceptor_gain	1.0000
11:67993811:C:CT	acceptor_gain	1.0000
11:67995609:A:AC	donor_gain	1.0000
11:67995610:C:CC	donor_gain	1.0000
11:67995709:C:CT	acceptor_gain	1.0000
11:67997700:G:GA	donor_gain	1.0000
11:67998357:A:AC	donor_gain	1.0000
11:67998358:C:CC	donor_gain	1.0000
11:67998363:G:C	donor_gain	1.0000
11:67999167:ACTC:A	donor_loss	1.0000
11:67999168:CTCA:C	donor_loss	1.0000
11:67999169:TCACA:T	donor_loss	1.0000
11:67999170:CA:C	donor_loss	1.0000
11:67999171:A:AC	donor_gain	1.0000
11:67999171:A:T	donor_loss	1.0000
11:67999172:C:CC	donor_gain	1.0000
11:67999312:C:CT	acceptor_gain	1.0000
11:67999514:CTCA:C	donor_loss	1.0000
11:67999515:TCA:T	donor_loss	1.0000
11:67999516:CA:C	donor_loss	1.0000
11:67999517:A:AC	donor_gain	1.0000

AlphaMissense

3845 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:67999301:C:G	A187P	0.997
11:68003691:G:C	S68R	0.997
11:68003691:G:T	S68R	0.997
11:68003693:T:G	S68R	0.997
11:67996681:T:A	D337V	0.996
11:67998447:G:C	S231R	0.996
11:67998447:G:T	S231R	0.996
11:67998449:T:G	S231R	0.996
11:67999568:C:G	G169R	0.996
11:68003657:C:G	G80R	0.996
11:67997711:G:C	S290R	0.995
11:67997711:G:T	S290R	0.995
11:67997713:T:G	S290R	0.995
11:67999567:C:T	G169D	0.995
11:67999614:G:C	N153K	0.995
11:67999614:G:T	N153K	0.995
11:67996681:T:G	D337A	0.994
11:67996682:C:G	D337H	0.994
11:67996692:C:A	K333N	0.994
11:67996692:C:G	K333N	0.994
11:67999579:G:T	A165D	0.994
11:68003022:C:A	R131M	0.994
11:68003130:C:G	R95P	0.994
11:68003151:A:G	L88P	0.994
11:68003172:A:G	L81P	0.994
11:67993756:C:G	D468H	0.993
11:67999580:C:G	A165P	0.993
11:67999591:A:G	L161P	0.993
11:67995612:G:C	S454R	0.992
11:67995612:G:T	S454R	0.992

dbSNP variants (sampled 300 via entrez): RS1000119825 (11:67996742 T>C), RS1000234206 (11:67997004 C>G), RS1000291135 (11:67991704 T>C), RS1000652932 (11:68003349 G>A), RS1001078952 (11:68001508 A>G), RS1001362927 (11:67997504 A>G,T), RS1001476837 (11:67992813 T>C), RS1001529451 (11:68004988 C>G,T), RS1001631720 (11:68003529 C>A,G,T), RS1002587106 (11:68002299 C>T), RS1002633157 (11:68000394 G>A), RS1002897511 (11:68005031 C>G), RS1003170956 (11:68005705 C>T), RS1003789692 (11:68003346 C>A,T), RS1003969031 (11:67994308 G>A)

Disease associations

OMIM: gene MIM:608204 | disease phenotypes: MIM:610551, MIM:300755

GenCC curated gene-disease

Disease	Classification	Inheritance
herpes simplex encephalitis, susceptibility to, 1	Strong	Autosomal recessive
autoinflammatory syndrome	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
systemic lupus erythematosus	Moderate	SD

Mondo (4): herpes simplex encephalitis, susceptibility to, 1 (MONDO:0024563), immunodeficiency disease (MONDO:0021094), type 1 interferonopathy (MONDO:0700264), autoinflammatory syndrome (MONDO:0019751)

Orphanet (2): Herpes simplex virus encephalitis (Orphanet:1930), Type 1 interferonopathy (Orphanet:477647)

HPO phenotypes

33 total (30 of 33 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001250	Seizure
HP:0001259	Coma
HP:0001262	Excessive daytime somnolence
HP:0001347	Hyperreflexia
HP:0001945	Fever
HP:0001974	Increased total leukocyte count
HP:0002017	Nausea and vomiting
HP:0002133	Status epilepticus
HP:0002167	Abnormal speech pattern
HP:0002181	Cerebral edema
HP:0002315	Headache
HP:0002349	Focal aware seizure
HP:0002353	EEG abnormality
HP:0002384	Focal impaired awareness seizure
HP:0002721	Immunodeficiency
HP:0002902	Hyponatremia
HP:0002922	Increased CSF protein concentration
HP:0004302	Functional motor deficit
HP:0004372	Reduced consciousness
HP:0004887	Respiratory failure requiring assisted ventilation
HP:0005353	Recurrent herpes
HP:0007185	Loss of consciousness
HP:0011227	Elevated circulating C-reactive protein concentration
HP:0011897	Increased total neutrophil count
HP:0011972	Hypoglycorrhachia
HP:0012302	Herpes simplex encephalitis
HP:0012378	Fatigue
HP:0012443	Abnormal brain morphology
HP:0025143	Chills

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST012226_304	Waist circumference adjusted for body mass index	2.000000e-09
GCST012310_12	Schizophrenia x sex interaction	3.000000e-06
GCST012311_2	Schizophrenia x sex interaction	1.000000e-05

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007789	BMI-adjusted waist circumference
EFO:0008343	sex interaction measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067426 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.87	Kd	136.2	nM	CHEMBL5653589
6.77	ED50	169.7	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149733: Binding affinity to human UNC93B1 incubated for 45 mins by Kinobead based pull down assay	kd	0.1362	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects cotreatment	2
sodium arsenite	decreases expression, increases expression	2
Air Pollutants	increases expression, decreases expression, increases abundance	2
Nickel	affects expression, decreases expression, decreases reaction	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
lead acetate	decreases expression	1
trichostatin A	affects expression, decreases reaction	1
perfluorooctanoic acid	decreases expression	1
manganese chloride	decreases expression, increases abundance	1
cupric chloride	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Bortezomib	decreases expression	1
Temozolomide	decreases expression	1
Air Pollutants, Occupational	decreases expression	1
Cadmium	increases expression	1
Cisplatin	increases expression, affects cotreatment	1
Dexamethasone	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Manganese	decreases expression, increases abundance	1
Niclosamide	increases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652775	Binding	Binding affinity to human UNC93B1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D4RC	HCT116-UNC93B1-KO-c20	Cancer cell line	Male
CVCL_D4RD	HCT116-UNC93B1-KO-c24	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00001542	PHASE4	COMPLETED	Fluconazole Prophylaxis of Thrush in AIDS
NCT00144157	PHASE4	COMPLETED	Open Label Study of NVP+CBV Treatment in Women Who Have Received sdNVP for the pMTCT of HIV
NCT00162643	PHASE4	UNKNOWN	PI Vs. NNRTI Based Therapy for HIV Advanced Disease
NCT00273988	PHASE4	COMPLETED	Pharmacokinetic Study of Interaction Between Nevirapine and Methadone in HIV-1 Infected, Opioid-dependent Adults
NCT00981318	PHASE4	TERMINATED	Pilot Assessment of Lopinavir/Ritonavir and Maraviroc
NCT01086878	PHASE4	COMPLETED	Safety of Cotrimoxazole in HIV- and HAART-exposed Infants
NCT01090102	PHASE4	COMPLETED	Mesalamine to Reduce T Cell Activation in HIV Infection
NCT01147042	PHASE4	TERMINATED	Biochemical Response to Interferon-Gamma in Subjects With Specific Gene Mutation in Chronic Granulomatous Disease
NCT01230580	PHASE4	UNKNOWN	Protease Inhibitor Monotherapy Versus Ongoing Triple-therapy in the Long Term Management of HIV Infection (PIVOT)
NCT01465958	PHASE4	COMPLETED	Pharmacokinetics, Safety, and Tolerability of Subcutaneous GAMUNEX-C in Pediatric Subjects With Primary Immunodeficiency
NCT02274662	PHASE4	COMPLETED	Expanded Access Protocol Thymus Transplantation
NCT02348177	PHASE4	COMPLETED	Pharmacokinetics of Lopinavir/Ritonavir Superboosting in Infants and Young Children Co-infected With HIV and TB
NCT02396979	PHASE4	COMPLETED	Intervention of HIV, Drug Use and the Criminal Justice System in Malaysia
NCT02490956	PHASE4	UNKNOWN	Diagnostic Immunization With Rabies Vaccine in Patients With PID
NCT02503293	PHASE4	COMPLETED	A Study to Compare Quality of Life and Satisfaction in Primary Immunodeficient Patients Treated With Subcutaneous Injections of Gammanorm® 165 mg/mL Administered With Two Different Delivery Devices: Injections Using Pump or Rapid Push
NCT02881437	PHASE4	COMPLETED	IgG Level in Primary Immunodeficiency Switching From Standard SCIG to Every Other Week HyQvia
NCT03033745	PHASE4	COMPLETED	Safety and Tolerability of Higher Infusion Parameters of IgPro20 (Hizentra) in Subjects With Primary Immunodeficiency (PID)
NCT03677557	PHASE4	UNKNOWN	Safety, Tolerability, Patient Satisfaction and Cost of 16.5% Subcutaneous Immunoglobulin (Cutaquig®) Treatment
NCT04192487	PHASE4	COMPLETED	Effects of Crofelemer on the Gut Microbiome in Healthy Volunteers and in HIV+ Patients With Non-Infectious Diarrhea
NCT04566692	PHASE4	COMPLETED	A Study to Evaluate IGSC 20% Biweekly Dosing in Treatment-Experienced Participants and Loading/Maintenance Dosing in Treatment-Naïve Participants With Primary Immunodeficiency
NCT05493969	PHASE4	NOT_YET_RECRUITING	Efficacy and Tolerability of DTG Plus 3TC in HIV Infected Adults With Virologically Suppression and TDF Toxicity
NCT06576024	PHASE4	COMPLETED	Immunogenicity and Safety of Inactivated Hepatitis A Vaccine in HIV-infected People
NCT06634641	PHASE4	RECRUITING	Clozapine-related Immunodeficiency in Parkinsons Disease
NCT07076446	PHASE4	ACTIVE_NOT_RECRUITING	An Open-label, Multicenter Study to Assess the Pharmacokinetics (PK), Safety, and Tolerability of Subcutaneous IgPro20 in Immunoglobulin (IG) Treatment-naïve Participants With Primary Immunodeficiency (PID)
NCT00000118	PHASE3	COMPLETED	Ganciclovir Implant Study for Cytomegalovirus Retinitis
NCT00000134	PHASE3	COMPLETED	Studies of the Ocular Complications of AIDS (SOCA)–Cytomegalovirus Retinitis Retreatment Trial (CRRT)
NCT00000590	PHASE3	COMPLETED	Anti-HIV Immunoglobulin (HIVIG) in Prevention of Maternal-Fetal HIV Transmission (Pediatric ACTG Protocol 185)
NCT00001267	PHASE3	COMPLETED	A Randomized Pilot Study for the Treatment of AIDS or AIDS Related Complex With an Alternating or Simultaneous Combination Regimen of AZT and 2’,3’-Dideoxyinosine
NCT00001646	PHASE3	COMPLETED	Voriconazole vs. Amphotericin B in the Treatment of Invasive Aspergillosis
NCT00144183	PHASE3	COMPLETED	A Study of Single Dose Nevirapine (NVP) Combined With Combivir® for the Prevention of Mother to Child Transmission (pMTCT) - Treatment Options Preservation Study (TOPS)
NCT00243568	PHASE3	WITHDRAWN	Vicriviroc, a CCR5 Inhibitor, Added to an Optimized Antiretroviral Therapy for Previously Treated HIV (VICTOR-E2) (Study P04285
NCT00278954	PHASE3	COMPLETED	Efficacy, Safety and Pharmacokinetics of Gammaplex in Primary Immunodeficiency Diseases.
NCT00474370	PHASE3	COMPLETED	Vicriviroc in HIV-Treatment Experienced Subjects (Study P04889AM8)(COMPLETED)
NCT00478231	PHASE3	COMPLETED	Multicenter, Safety Study Of Maraviroc
NCT00523211	PHASE3	COMPLETED	Vicriviroc in HIV-Treatment Experienced Subjects (Study P04405AM5)
NCT00698334	PHASE3	COMPLETED	Efficacy of Thrice Weekly Directly Observed Treatment, Short-course (DOTS) in HIV-associated Tuberculosis
NCT00966160	PHASE3	COMPLETED	CD4 Cell Recovery in HIV-1 Patients Comparing 2 Treatment Regimes
NCT01363011	PHASE3	COMPLETED	Cobicistat-containing Highly Active Antiretroviral Regimens in HIV-1 Infected Patients With Mild to Moderate Renal Impairment
NCT01440569	PHASE3	COMPLETED	Safety and Efficacy of Cobicistat-boosted Darunavir in HIV Infected Adults
NCT01475838	PHASE3	COMPLETED	Study to Evaluate Switching From Regimens Consisting of a Ritonavir-boosted Protease Inhibitor Plus Emtricitabine/Tenofovir Fixed-Dose Combination to the Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF Single-Tablet Regimen in Virologically Suppressed, HIV-1 Infected Patients