UNC119

Summary

UNC119 (unc-119 lipid binding chaperone, HGNC:12565) is a protein-coding gene on chromosome 17q11.2, encoding Protein unc-119 homolog A (Q13432). Involved in synaptic functions in photoreceptor cells, the signal transduction in immune cells as a Src family kinase activator, endosome recycling, the uptake of bacteria and endocytosis, protein trafficking in sensory neurons and as lipid-binding chaperone with specificity for….

This gene is specifically expressed in the photoreceptors in the retina. The encoded product shares strong homology with the C. elegans unc119 protein and it can functionally complement the C. elegans unc119 mutation. It has been localized to the photoreceptor synapses in the outer plexiform layer of the retina, and suggested to play a role in the mechanism of photoreceptor neurotransmitter release through the synaptic vesicle cycle. Two transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 9094 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cone-rod dystrophy 24 (Moderate, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 211 total
• Phenotypes (HPO): 41
• Druggable target: yes
• MANE Select transcript: NM_005148

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12565
Approved symbol	UNC119
Name	unc-119 lipid binding chaperone
Location	17q11.2
Locus type	gene with protein product
Status	Approved
Aliases	HRG4, POC7, POC7A
Ensembl gene	ENSG00000109103
Ensembl biotype	protein_coding
OMIM	604011
Entrez	9094

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 2 retained_intron

ENST00000301032, ENST00000335765, ENST00000444148, ENST00000470125, ENST00000484980, ENST00000487844, ENST00000578434, ENST00000581945, ENST00000869304, ENST00000913791

RefSeq mRNA: 3 — MANE Select: NM_005148 NM_001330166, NM_005148, NM_054035

CCDS: CCDS11233, CCDS11234, CCDS82094

Canonical transcript exons

ENST00000335765 — 5 exons

Exon	Start	End
ENSE00000706544	28548592	28548705
ENSE00001865944	28546708	28547409
ENSE00001881694	28552338	28552624
ENSE00002771874	28547677	28547849
ENSE00002931030	28547999	28548101

Expression profiles

Bgee: expression breadth ubiquitous, 233 present calls, max score 96.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.5510 / max 721.2626, expressed in 1817 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
165023	30.4444	1817
165019	0.3615	149
165016	0.3012	93
165018	0.2924	132
165017	0.1190	57
165021	0.0253	3
165022	0.0040	2
165020	0.0032	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	96.92	gold quality
monocyte	CL:0000576	95.73	gold quality
mononuclear cell	CL:0000842	95.11	gold quality
leukocyte	CL:0000738	95.07	gold quality
right testis	UBERON:0004534	94.40	gold quality
left testis	UBERON:0004533	94.17	gold quality
right frontal lobe	UBERON:0002810	93.48	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.42	gold quality
cortical plate	UBERON:0005343	93.08	gold quality
spleen	UBERON:0002106	92.88	gold quality
cingulate cortex	UBERON:0003027	92.60	gold quality
anterior cingulate cortex	UBERON:0009835	92.50	gold quality
cerebellar hemisphere	UBERON:0002245	92.40	gold quality
cerebellar cortex	UBERON:0002129	92.27	gold quality
blood	UBERON:0000178	91.80	gold quality
lower esophagus mucosa	UBERON:0035834	91.64	gold quality
testis	UBERON:0000473	91.40	gold quality
Brodmann (1909) area 9	UBERON:0013540	91.26	gold quality
adenohypophysis	UBERON:0002196	91.17	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	91.04	gold quality
nucleus accumbens	UBERON:0001882	90.93	gold quality
lymph node	UBERON:0000029	90.82	gold quality
right adrenal gland	UBERON:0001233	90.79	gold quality
cerebellum	UBERON:0002037	90.63	gold quality
prefrontal cortex	UBERON:0000451	90.40	gold quality
right adrenal gland cortex	UBERON:0035827	90.40	gold quality
skin of abdomen	UBERON:0001416	90.19	gold quality
amygdala	UBERON:0001876	90.15	gold quality
left adrenal gland cortex	UBERON:0035825	90.14	gold quality
skin of leg	UBERON:0001511	90.11	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-11121	yes	3146.94
E-GEOD-98556	yes	1434.48
E-HCAD-13	yes	586.74
E-MTAB-7316	yes	69.89
E-GEOD-137537	yes	29.32
E-GEOD-135922	yes	14.90
E-GEOD-124858	no	61.92
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 22)

• identification as activator of SRC-type tyrosine kinases (PMID:12496276)
• The presence of ARL2 in the retina and co-localization with HRG4 was confirmed. Amino acid residues of PDEdelta involved in binding ARL2 and forming a hydrophobic pocket were shown to be highly conserved in HRG4 (PMID:12527357)
• Unc119 plays an important role in fibrotic processes through myofibroblast differentiation; Unc119 increases the kinase activity of Fyn and associates with it in coprecipitation and colocalization studies. (PMID:17579091)
• Unc119 orchestrates the recruitment of the actin-based motor protein, myosin 5B, and the organization of multiprotein complexes on endosomes. The Unc119-regulated pathway is essential for immunological synapse formation and T cell activation. (PMID:19592652)
• demonstrate a role for Unc119 in clathrin- and caveolae-based endocytosis as well as macropinocytosis. Depletion of Unc119 in fibroblasts increases FM4-64, albumin, viruses, and ligand-coated beads. (PMID:19781630)
• Heightened expression of Unc119 promotes T helper type (Th)2 cells, inhibits Th1 cell differentiation, and contributes to the pathogenesis of asthma in humans. (PMID:20220094)
• This study demonistrated that UNC119 is a Galpha subunit cofactor essential for G protein trafficking in sensory cilia. (PMID:21642972)
• Interaction of transducin with uncoordinated 119 protein (UNC119): implications for the model of transducin trafficking in rod photoreceptors. (PMID:21712387)
• The discovery of the UNC119 defect provides a molecular mechanism for a subset of patients with this previously unexplained disease. Here we review our recent findings on the UNC119 mutation in ICL. (PMID:22729960)
• Crystal structures of Arl3 in complex with UNC119a reveal the molecular basis of specificity. The N-terminal amphipathic helix of Arl3.GppNHp is not displaced by the interswitch toggle but remains bound on the surface of the protein (PMID:22960633)
• The profile of UNC119a subcellular distribution remained largely unchanged under all tested conditions of illumination, and correlated with the profile of Galpha(t1) following its light-dependent translocation. (PMID:23072788)
• UNC119a bridges the transmission of Fyn signals to Rab11, leading to the completion of cytokinesis. (PMID:23535298)
• Novel Biochemical and Structural Insights into the Interaction of Myristoylated Cargo with Unc119 Protein and Their Release by Arl2/3. (PMID:27481943)
• Studies indicate that the binding of UNC119 and PDE6D, to the lipid-modified ciliary cargo and the specific release of the cargo in the cilia by the ciliary small G-protein Arl3 in a GTP-dependent manner. (PMID:27911709)
• Data show that the solubilising factor UNC119 sequesters myristoylated Src family protein tyrosine kinases (SFKs) to maintain its enrichment at the plasma membrane to enable signal transduction. (PMID:28740133)
• This review will outline the trafficking pathways required for constructing the cilium by highlighting UNC119’s role and the complexities involved in ciliary trafficking. Finally, despite important roles for UNC119 in cilia, UNC119 proteins also interact with non-ciliary proteins to affect other cellular processes. (PMID:28935136)
• UNC119 was significantly up-regulated in liver cancer cells and tissues. It promoted cell growth and migration through the Wnt/beta-catenin and TGF-beta/EMT signaling pathways, respectively (PMID:29552781)
• UNC119 was significantly up-regulated in liver cancer cells and tissues. It promoted cell growth and migration through the Wnt/beta-catenin and TGF-beta/EMT signaling pathways, respectively. (PMID:29552782)
• The findings support that UNC119 is a regulator of the RASSF6-MDM2-p53 axis and functions as a tumor suppressor. (PMID:29931788)
• UNC119 is significantly up-regulated and promoted cell growth and migration in hepatic cancer cells and tissues via Wnt/b-catenin signal pathway and TGF-b/EMT signal pathway (PMID:30610799)
• UNC119 was significantly upregulated and promoted cell growth in hepatic cancer cells and tissues by the Wnt/beta-catenin signal pathway and migration by TGF-beta/EMT signal pathway. Curcumin treatment inhibited cell proliferation, growth, migration, and invasion by inhibition of those pathways. (PMID:31679307)
• The RAS-interacting chaperone UNC119 drives the RASSF6-MDM2-p53 axis and antagonizes RAS-mediated malignant transformation. (PMID:32554467)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	unc119a1	ENSDARG00000034453
danio_rerio	unc119a2	ENSDARG00000044362
mus_musculus	Unc119	ENSMUSG00000002058
rattus_norvegicus	Unc119	ENSRNOG00000011060
drosophila_melanogaster	unc-119	FBGN0025549
caenorhabditis_elegans		WBGENE00006843

Paralogs (1): UNC119B (ENSG00000175970)

Protein

Protein identifiers

Protein unc-119 homolog A — Q13432 (reviewed: Q13432)

Alternative names: Retinal protein 4

All UniProt accessions (5): Q13432, C9JSK0, J3QQT8, K7EJU3, K7EN86

UniProt curated annotations — full annotation on UniProt →

Function. Involved in synaptic functions in photoreceptor cells, the signal transduction in immune cells as a Src family kinase activator, endosome recycling, the uptake of bacteria and endocytosis, protein trafficking in sensory neurons and as lipid-binding chaperone with specificity for a diverse subset of myristoylated proteins. Specifically binds the myristoyl moiety of a subset of N-terminally myristoylated proteins and is required for their localization. Binds myristoylated GNAT1 and is required for G-protein localization and trafficking in sensory neurons. Probably plays a role in trafficking proteins in photoreceptor cells. Plays important roles in mediating Src family kinase signals for the completion of cytokinesis via RAB11A.

Subunit / interactions. Interacts with CABP4; in the absence of calcium. Interacts with DNM1; leading to a decrease of DNM1 GTPase activity. May interact with GTP-bound ARL1. Interacts with ARL2 and ARL3 (GTP-bound forms); this promotes the release of myyristoylated cargo proteins. Found in a complex with ARL3, RP2 and UNC119; RP2 induces hydrolysis of GTP ARL3 in the complex, leading to the release of UNC119. Interacts with NPHP3 (when myristoylated). Interacts with CYS1 (when myristoylated). Interacts with MACIR; interaction only takes place when UNC119 is not liganded with myristoylated proteins. Interacts with LCK; this interaction plays a crucial role in activation of LCK. Interacts with FYN. Interacts with RAB11A; in a cell cycle-dependent manner. Interacts with LYN (via SH2 and SH3 domains); leading to LYN activation. Found in a complex with ABL1, ABL2, CRK and UNC119; leading to the inhibition of CRK phosphorylation by ABL kinases. Interacts with CD44; leading to Shigella invasion. Interacts with KLHL18 (via kelch repeats). Interacts with PPP3CA, PPP3CB and PPP3CC. Interacts with USP48; this interaction promotes UNC119 stability.

Subcellular location. Cytoplasm. Cytoskeleton. Microtubule organizing center. Centrosome. Spindle pole. Spindle.

Tissue specificity. Abundantly expressed in retina, in photoreceptor synapses and inner segments. Expressed in a much lesser extent in several other tissues.

Post-translational modifications. Phosphorylation suppresses its interaction with KLHL18 and down-regulates its KLHL18-mediated degradation. Phosphorylated more under light conditions than dark conditions. Dephosphorylated by calcineurin.

Disease relevance. Immunodeficiency 13 (IMD13) [MIM:615518] A rare and heterogeneous syndrome defined by a reproducible reduction in the CD4 T-lymphocyte count (less than 300 cells per microliter or less than 20% of total T-cells) in the absence of HIV infection or other known causes of immunodeficiency. IMD13 predisposes to infections and malignancy. The disease may be caused by variants affecting the gene represented in this entry. Cone-rod dystrophy 24 (CORD24) [MIM:620342] An autosomal dominant form of cone-rod dystrophy, an inherited retinal dystrophy characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa, due to cone photoreceptors degenerating at a higher rate than rod photoreceptors. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Adopts an immunoglobulin-like beta-sandwich fold forming a hydrophobic cavity that captures N-terminally myristoylated target peptides. Phe residues within the hydrophobic beta sandwich are required for myristate binding.

Similarity. Belongs to the PDE6D/unc-119 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q13432-1	A	yes
Q13432-2	B

RefSeq proteins (3): NP_001317095, NP_005139, NP_473376 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008015	PDED_dom	Domain
IPR014756	Ig_E-set	Homologous_superfamily
IPR037036	PDED_dom_sf	Homologous_superfamily
IPR051519	PDE6D_unc-119_myristoyl-bd	Family

Pfam: PF05351

UniProt features (33 total): strand 9, mutagenesis site 4, helix 4, region of interest 3, sequence variant 3, turn 3, modified residue 3, chain 1, compositionally biased region 1, binding site 1, splice variant 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
3GQQ	X-RAY DIFFRACTION	1.95
3RBQ	X-RAY DIFFRACTION	2
6H6A	X-RAY DIFFRACTION	2
4GOJ	X-RAY DIFFRACTION	2.1
5L7K	X-RAY DIFFRACTION	2.1
9GKG	X-RAY DIFFRACTION	2.21
7UMO	X-RAY DIFFRACTION	2.3
9NEM	X-RAY DIFFRACTION	2.49
4GOK	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13432-F1	80.03	0.67

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 (1): 131

Post-translational modifications (3): 37, 39, 41

Mutagenesis-validated functional residues (4):

Position	Phenotype
29–32	impairs interaction with lck.
37	loss of phosphorylation; when associated with a-39 and a-41.
39	loss of phosphorylation; when associated with a-37 and a-41.
41	loss of phosphorylation; when associated with a-37 and a-39.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 339 (showing top): GOBP_MITOTIC_CYTOKINESIS, GOBP_REGULATION_OF_PROTEIN_TYROSINE_KINASE_ACTIVITY, MODULE_274, GOBP_REGULATION_OF_PHOSPHORYLATION, GCANCTGNY_MYOD_Q6, GOBP_NEGATIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_PHOTOTRANSDUCTION, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY, GOBP_VESICLE_MEDIATED_TRANSPORT, CAGCTG_AP4_Q5, chr17q11, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_POSITIVE_REGULATION_OF_PEPTIDYL_TYROSINE_PHOSPHORYLATION, GOBP_CELL_CELL_SIGNALING, GOLDRATH_ANTIGEN_RESPONSE

GO Biological Process (11): mitotic cytokinesis (GO:0000281), endocytosis (GO:0006897), chemical synaptic transmission (GO:0007268), nervous system development (GO:0007399), visual perception (GO:0007601), phototransduction (GO:0007602), lipoprotein transport (GO:0042953), positive regulation of protein tyrosine kinase activity (GO:0061098), negative regulation of clathrin-dependent endocytosis (GO:1900186), negative regulation of caveolin-mediated endocytosis (GO:2001287), protein transport (GO:0015031)

GO Molecular Function (2): lipid binding (GO:0008289), protein binding (GO:0005515)

GO Cellular Component (9): spindle pole (GO:0000922), centrosome (GO:0005813), cytosol (GO:0005829), intercellular bridge (GO:0045171), synapse (GO:0045202), spindle midzone (GO:0051233), cytoplasm (GO:0005737), spindle (GO:0005819), cytoskeleton (GO:0005856)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
binding	2
spindle	2
intracellular membraneless organelle	2
mitotic cell cycle	1
cytoskeleton-dependent cytokinesis	1
mitotic cell cycle process	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
anterograde trans-synaptic signaling	1
system development	1
sensory perception of light stimulus	1
signal transduction	1
detection of light stimulus	1
protein transport	1
lipoprotein localization	1
protein tyrosine kinase activity	1
positive regulation of protein kinase activity	1
positive regulation of peptidyl-tyrosine phosphorylation	1
regulation of protein tyrosine kinase activity	1
negative regulation of receptor-mediated endocytosis	1
clathrin-dependent endocytosis	1
regulation of clathrin-dependent endocytosis	1
negative regulation of endocytosis	1
caveolin-mediated endocytosis	1
regulation of caveolin-mediated endocytosis	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
centriole	1
microtubule organizing center	1
cytoplasm	1
cell junction	1
intracellular anatomical structure	1
microtubule cytoskeleton	1

Protein interactions and networks

STRING

1886 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UNC119	ARL2	P36404	903
UNC119	ARL3	P36405	866
UNC119	PPIE	Q9UNP9	839
UNC119	PITPNM3	Q9BZ71	813
UNC119	PDE6D	O43924	799
UNC119	SIDT1	Q9NXL6	780
UNC119	MYO1D	O94832	770
UNC119	AIPL1	Q9NZN9	756
UNC119	GUCY2D	Q02846	753
UNC119	NPHP3	Q7Z494	745
UNC119	AJM1	C9J069	741
UNC119	CNTD1	Q8N815	741
UNC119	IGDCC3	Q8IVU1	738
UNC119	RIMS1	Q86UR5	732
UNC119	IL5RA	Q01344	731

IntAct

211 interactions, top by confidence:

A	B	Type	Score
ARL3	UNC119	psi-mi:“MI:0915”(physical association)	0.940
UNC119	ARL3	psi-mi:“MI:0407”(direct interaction)	0.940
UNC119	ARL2	psi-mi:“MI:0915”(physical association)	0.920
ARL2	UNC119	psi-mi:“MI:0915”(physical association)	0.920
UNC119	ARL2	psi-mi:“MI:0914”(association)	0.920
UNC119	ARL2	psi-mi:“MI:0407”(direct interaction)	0.920
C16orf74	UNC119	psi-mi:“MI:0915”(physical association)	0.780
UNC119	C16orf74	psi-mi:“MI:0915”(physical association)	0.780
ARL3	UNC119B	psi-mi:“MI:0914”(association)	0.730
UNC119	ARL15	psi-mi:“MI:0915”(physical association)	0.670
UNC119	UNC119B	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
NPHP3	UNC119B	psi-mi:“MI:0914”(association)	0.590
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
UNC119	AMOT	psi-mi:“MI:0915”(physical association)	0.560
AMOT	UNC119	psi-mi:“MI:0915”(physical association)	0.560
UNC119	LRIF1	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (214): UNC119 (Two-hybrid), AMOT (Two-hybrid), C16orf74 (Two-hybrid), UNC119 (Affinity Capture-MS), UNC119 (Affinity Capture-MS), UNC119 (Affinity Capture-MS), PALD1 (Affinity Capture-MS), PDE9A (Affinity Capture-MS), NPHP3 (Affinity Capture-MS), NME2P1 (Affinity Capture-MS), C12orf75 (Affinity Capture-MS), PDE8A (Affinity Capture-MS), LIMK2 (Affinity Capture-MS), C5orf30 (Affinity Capture-MS), PRKG2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0F7YYX3, A1Z0Q5, A2TJ54, A7SIM4, B9G4M9, E9PVB5, F4JP36, O14187, O19177, O75503, P03172, P03474, P06476, P16191, P16195, P16199, P16201, P16203, P16205, P16207, P24872, P27907, P36318, P36552, P57083, P67907, P67923, Q05059, Q08989, Q0V9Z3, Q10128, Q13432, Q197C5, Q1ZYR0, Q2YDM0, Q3B7D0, Q3SYR2, Q3TBN1, Q3UMW8, Q5BKX0

Diamond homologs: A6NIH7, O19177, Q10658, Q13432, Q17297, Q3SYR2, Q62885, Q66JA9, Q6INE2, Q8C4B4, Q90Z08, Q9XYQ2, Q9Z2R6, O55057, Q95142, Q9XT54, O43924

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	119
Likely benign	60
Benign	11

Top pathogenic / likely-pathogenic (0)

SpliceAI

925 predictions. Top by Δscore:

Variant	Effect	Δscore
17:28547654:C:CA	donor_gain	1.0000
17:28547675:A:AC	donor_gain	1.0000
17:28547676:C:CC	donor_gain	1.0000
17:28547679:A:AC	donor_gain	1.0000
17:28547679:AGCT:A	donor_gain	1.0000
17:28547679:AGCTC:A	donor_gain	1.0000
17:28547680:G:C	donor_gain	1.0000
17:28547717:G:A	donor_gain	1.0000
17:28547845:CCACC:C	acceptor_gain	1.0000
17:28547846:CACC:C	acceptor_gain	1.0000
17:28547846:CACCC:C	acceptor_gain	1.0000
17:28547847:ACC:A	acceptor_gain	1.0000
17:28547848:CC:C	acceptor_gain	1.0000
17:28547848:CCC:C	acceptor_gain	1.0000
17:28547849:CC:C	acceptor_gain	1.0000
17:28547849:CCTGA:C	acceptor_loss	1.0000
17:28547850:C:CC	acceptor_gain	1.0000
17:28547850:C:T	acceptor_gain	1.0000
17:28547851:T:G	acceptor_loss	1.0000
17:28547855:C:CT	acceptor_gain	1.0000
17:28547856:A:T	acceptor_gain	1.0000
17:28547998:CGTGG:C	donor_gain	1.0000
17:28548097:CCGTT:C	acceptor_gain	1.0000
17:28548098:CGTTC:C	acceptor_gain	1.0000
17:28548588:TCA:T	donor_loss	1.0000
17:28548589:CA:C	donor_loss	1.0000
17:28548590:A:C	donor_loss	1.0000
17:28548591:C:CT	donor_loss	1.0000
17:28551972:AGCC:A	donor_gain	1.0000
17:28552337:CCA:C	donor_gain	1.0000

AlphaMissense

1585 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:28547314:A:G	Y236H	1.000
17:28547320:A:G	Y234H	1.000
17:28547326:C:G	A232P	1.000
17:28547327:T:A	K231N	1.000
17:28547327:T:G	K231N	1.000
17:28547329:T:C	K231E	1.000
17:28547330:A:C	N230K	1.000
17:28547330:A:T	N230K	1.000
17:28547357:G:C	F221L	1.000
17:28547357:G:T	F221L	1.000
17:28547358:A:G	F221S	1.000
17:28547359:A:G	F221L	1.000
17:28547362:A:C	Y220D	1.000
17:28547362:A:G	Y220H	1.000
17:28547363:G:C	F219L	1.000
17:28547363:G:T	F219L	1.000
17:28547364:A:G	F219S	1.000
17:28547365:A:G	F219L	1.000
17:28547366:G:C	S218R	1.000
17:28547366:G:T	S218R	1.000
17:28547368:T:G	S218R	1.000
17:28547370:T:A	D217V	1.000
17:28547370:T:C	D217G	1.000
17:28547371:C:G	D217H	1.000
17:28547373:G:A	S216F	1.000
17:28547373:G:T	S216Y	1.000
17:28547374:A:G	S216P	1.000
17:28547400:A:G	M207T	1.000
17:28547707:A:G	Y194H	1.000
17:28547723:G:C	N188K	1.000

dbSNP variants (sampled 300 via entrez): RS1000006422 (17:28546228 G>A), RS1000019876 (17:28550998 T>A,C), RS1000241430 (17:28548533 G>A,T), RS1000605605 (17:28547619 G>A,T), RS1000976211 (17:28547247 C>T), RS1001060460 (17:28553947 G>A), RS1001659985 (17:28551670 A>G), RS1001856196 (17:28549827 G>C), RS1002584052 (17:28552770 G>A), RS1003068672 (17:28550720 C>G), RS1003098508 (17:28551102 G>A), RS1004301864 (17:28550150 G>C), RS1004421601 (17:28548215 C>G,T), RS1004638543 (17:28546546 C>G), RS1004711099 (17:28548013 C>T)

Disease associations

OMIM: gene MIM:604011 | disease phenotypes: MIM:615518, MIM:620342, MIM:120970

GenCC curated gene-disease

Disease	Classification	Inheritance
cone-rod dystrophy 24	Moderate	Autosomal dominant
cone-rod dystrophy	Supportive	Autosomal dominant
idiopathic CD4 lymphocytopenia	Limited	Autosomal dominant

Mondo (3): idiopathic CD4 lymphocytopenia (MONDO:0014226), cone-rod dystrophy 24 (MONDO:0957240), cone-rod dystrophy (MONDO:0015993)

Orphanet (2): Idiopathic CD4 lymphocytopenia (Orphanet:228000), Cone rod dystrophy (Orphanet:1872)

HPO phenotypes

41 total (30 of 41 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000403	Recurrent otitis media
HP:0000505	Visual impairment
HP:0000529	Progressive visual loss
HP:0000543	Optic disc pallor
HP:0000545	Myopia
HP:0000548	Cone/cone-rod dystrophy
HP:0000551	Color vision defect
HP:0000575	Scotoma
HP:0000580	Pigmentary retinopathy
HP:0000603	Central scotoma
HP:0000608	Macular degeneration
HP:0000613	Photophobia
HP:0000639	Nystagmus
HP:0000662	Nyctalopia
HP:0001105	Retinal atrophy
HP:0001888	Decreased total lymphocyte count
HP:0002110	Bronchiectasis
HP:0002721	Immunodeficiency
HP:0002788	Recurrent upper respiratory tract infections
HP:0003596	Middle age onset
HP:0005403	Decreased total T cell count
HP:0006532	Recurrent pneumonia
HP:0007401	Macular atrophy
HP:0007641	Dyschromatopsia
HP:0007663	Reduced visual acuity
HP:0007703	Abnormal retinal pigmentation
HP:0007737	Spicular pigmentation of the retina
HP:0007761	Pericentral scotoma
HP:0007843	Attenuation of retinal blood vessels

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066441 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — Lipid binding chaperones

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
squarunkin A	Binding	8.0	pIC50

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.48	Kd	333.8	nM	CHEMBL3752910
6.34	ED50	459.9	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 4 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-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149732: Binding affinity to human UNC119 incubated for 45 mins by Kinobead based pull down assay	kd	0.3338	uM

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression	3
trichostatin A	decreases expression, affects expression	2
Zinc	affects expression, increases expression	2
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
beta-lapachone	decreases expression, increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Sunitinib	increases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Cisplatin	affects cotreatment, increases expression	1
Nicotine	decreases expression	1
Phthalic Acids	decreases expression	1
Tobacco Smoke Pollution	affects expression	1
Tretinoin	increases expression	1
Urethane	increases expression	1
Vincristine	increases expression	1
Cadmium Chloride	decreases expression	1
Zinc Sulfate	increases expression	1
Okadaic Acid	increases expression	1
Copper Sulfate	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
CHEMBL5652774	Binding	Binding affinity to human UNC119 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

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1R9	Abcam K-562 UNC119 KO	Cancer cell line	Female
CVCL_D2MW	Abcam Raji UNC119 KO	Cancer cell line	Male
CVCL_WQ78	Abcam Jurkat UNC119 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT06467344	PHASE1/PHASE2	RECRUITING	Study to Evaluate ACDN-01 in ABCA4-related Stargardt Retinopathy (STELLAR)
NCT06789445	PHASE1/PHASE2	RECRUITING	A Study to Investigate the Safety of OpCT-001 in Adults Who Have Primary Photoreceptor Disease (CLARICO)
NCT00427180	Not specified	UNKNOWN	IRIS PILOT - Extended Pilot Study With a Retinal Implant System
NCT01864486	Not specified	COMPLETED	Restoring Vision With the Intelligent Retinal Implant System (IRIS V1)in Patients With Retinal Dystrophy
NCT02435940	Not specified	RECRUITING	Inherited Retinal Degenerative Disease Registry
NCT02670980	Not specified	COMPLETED	Compensation for Blindness With the Intelligent Retinal Implant System (IRIS V2) in Patients With Retinal Dystrophy
NCT04658251	Not specified	TERMINATED	Study of New Mutations in Cone Disorders
NCT05355415	Not specified	RECRUITING	Adaptive Optics Imaging of Outer Retinal Diseases
NCT06445322	Not specified	RECRUITING	Prescreening Study to Identify Potential Stargardt Participants for ACDN-01 Clinical Trials (STARPATH)
NCT07548944	Not specified	RECRUITING	Observational Study to Investigate the Short-term Effects of Transcorneal Electrical Stimulation on Visual Performance
NCT00001319	Not specified	COMPLETED	Evaluation of HIV-Negative Patients With Low CD4+ T Lymphocyte Counts
NCT00001471	Not specified	COMPLETED	Tissue Biopsy and Imaging Studies in HIV-Infected Patients
NCT02113930	Not specified	COMPLETED	Idiopathic CD4 Lymphocytopenia
NCT07146737	Not specified	RECRUITING	Predictive Performance of a Generative Model for Corneal Tomography After ICL Implantation