LAMTOR3

Summary

LAMTOR3 (late endosomal/lysosomal adaptor, MAPK and MTOR activator 3, HGNC:15606) is a protein-coding gene on chromosome 4q23, encoding Ragulator complex protein LAMTOR3 (Q9UHA4). As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. It is a selective cancer dependency (DepMap: 58.3% of cell lines).

This gene encodes a scaffold protein that functions in the extracellular signal-regulated kinase (ERK) cascade. The protein is localized to late endosomes by the mitogen-activated protein-binding protein-interacting protein, and binds specifically to MAP kinase kinase MAP2K1/MEK1, MAP kinase MAPK3/ERK1, and MAP kinase MAPK1/ERK2. Studies of the orthologous gene in mouse indicate that it regulates late endosomal traffic and cell proliferation. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. A pseudogene of this gene is located on the long arm of chromosome 13.

Source: NCBI Gene 8649 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 26 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 58.3% of screened cell lines
• MANE Select transcript: NM_021970

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15606
Approved symbol	LAMTOR3
Name	late endosomal/lysosomal adaptor, MAPK and MTOR activator 3
Location	4q23
Locus type	gene with protein product
Status	Approved
Aliases	MP1, MAPBP, Ragulator3
Ensembl gene	ENSG00000109270
Ensembl biotype	protein_coding
OMIM	603296
Entrez	8649

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000226522, ENST00000499666, ENST00000515100, ENST00000871285, ENST00000871286, ENST00000928219

RefSeq mRNA: 2 — MANE Select: NM_021970 NM_001243736, NM_021970

CCDS: CCDS3652, CCDS58920

Canonical transcript exons

ENST00000499666 — 7 exons

Exon	Start	End
ENSE00001343088	99893955	99894000
ENSE00001343093	99894335	99894427
ENSE00001965395	99878336	99882067
ENSE00003510525	99887296	99887354
ENSE00003610343	99884062	99884125
ENSE00003617099	99885542	99885675
ENSE00003678182	99892000	99892034

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 97.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.8287 / max 601.8499, expressed in 1810 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53296	42.9868	1810
53297	0.8419	555

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of sigmoid colon	UBERON:0004993	97.04	gold quality
colonic mucosa	UBERON:0000317	96.84	gold quality
oocyte	CL:0000023	96.82	gold quality
pigmented layer of retina	UBERON:0001782	96.44	gold quality
retina	UBERON:0000966	96.42	gold quality
ventricular zone	UBERON:0003053	96.17	gold quality
islet of Langerhans	UBERON:0000006	96.06	gold quality
calcaneal tendon	UBERON:0003701	95.93	gold quality
secondary oocyte	CL:0000655	95.84	gold quality
eye	UBERON:0000970	95.84	gold quality
palpebral conjunctiva	UBERON:0001812	95.69	gold quality
rectum	UBERON:0001052	95.52	gold quality
ganglionic eminence	UBERON:0004023	95.46	gold quality
esophagus squamous epithelium	UBERON:0006920	95.19	gold quality
corpus epididymis	UBERON:0004359	95.16	gold quality
oral cavity	UBERON:0000167	94.91	gold quality
gall bladder	UBERON:0002110	94.71	gold quality
germinal epithelium of ovary	UBERON:0001304	94.61	gold quality
jejunal mucosa	UBERON:0000399	94.59	gold quality
gingiva	UBERON:0001828	94.58	gold quality
esophagus mucosa	UBERON:0002469	94.57	gold quality
gingival epithelium	UBERON:0001949	94.49	gold quality
adrenal tissue	UBERON:0018303	94.47	gold quality
lower esophagus mucosa	UBERON:0035834	94.45	gold quality
epithelium of esophagus	UBERON:0001976	94.28	gold quality
upper leg skin	UBERON:0004262	94.25	gold quality
parietal pleura	UBERON:0002400	94.16	gold quality
cortical plate	UBERON:0005343	94.16	gold quality
skin of hip	UBERON:0001554	94.07	gold quality
bone marrow	UBERON:0002371	94.05	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6911	no	250.16
E-HCAD-5	no	2.19
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

127 targeting LAMTOR3, 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-4795-3P	100.00	74.62	4024
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3924	100.00	72.09	2394
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-145-5P	99.92	71.13	1836

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 58.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 10)

• We investigated the neuroprotective effect of glial-derived neurotrophic factor (GDNF) upon alcohol-exposed B92 cultures, as well as the role of the cytoskeleton and mitogen-activated protein kinase (MAPK) pathways in this effect. (PMID:17113937)
• A complex encoded by the MAPKSP1, ROBLD3, and c11orf59 genes interacts with the Rag GTPases, recruits them to lysosomes, and is essential for mTORC1 activation (PMID:20381137)
• identified polymorphisms in LAMTOR2 and LAMTOR3 do not seem to play a relevant role in breast cancer (PMID:23341997)
• we demonstrate that the MAPK scaffold protein MEK partner 1 (MP1) is important for gastrin-induced phosphorylation of ERK1 and ERK2 and that MP1 promotes gastrin-induced proliferation of AGS-GR cells (PMID:23408059)
• The present study was aimed at investigating whether the miR-29c binding site single nucleotide polymorphisms within the 3’-UTRs of LAMTOR3 gene affected the gastric cancer risk. (PMID:25661340)
• BCL2 expression in mesennchymal lung cancer cells was induced by ERK1 activity through the upregulation of the MEK1/ERK1 scaffold protein MEK partner-1. Interfering with the MEK1/MP1/ERK1 axis using a MEK1 inhibitor or MP1 depletion repressed BCL2 expression and sensitized MLCCs to chemoradiotherapy. (PMID:28606806)
• Studied role of MEK partner-1 (LAMTOR3) in driving MEK/ERK pathway in EGFRviii-expressing glioma cells. (PMID:28830458)
• LAMTOR3 is highly expressed in bladder carcinoma cell lines and tissues and plays a key role in the development and progression of bladder carcinoma. (PMID:31699189)
• Circ_0075829 facilitates the progression of pancreatic carcinoma by sponging miR-1287-5p and activating LAMTOR3 signalling. (PMID:33184989)
• LAMTOR3 is a prognostic biomarker in kidney renal clear cell carcinoma. (PMID:36082464)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	lamtor3	ENSDARG00000057075
mus_musculus	Lamtor3	ENSMUSG00000091512
rattus_norvegicus	Lamtor3	ENSRNOG00000088035
drosophila_melanogaster	Lamtor3	FBGN0032642
caenorhabditis_elegans		WBGENE00007390

Protein

Protein identifiers

Ragulator complex protein LAMTOR3 — Q9UHA4 (reviewed: Q9UHA4)

Alternative names: Late endosomal/lysosomal adaptor and MAPK and MTOR activator 3, MEK-binding partner 1, Mitogen-activated protein kinase kinase 1-interacting protein 1, Mitogen-activated protein kinase scaffold protein 1

All UniProt accessions (1): Q9UHA4

UniProt curated annotations — full annotation on UniProt →

Function. As part of the Ragulator complex it is involved in amino acid sensing and activation of mTORC1, a signaling complex promoting cell growth in response to growth factors, energy levels, and amino acids. Activated by amino acids through a mechanism involving the lysosomal V-ATPase, the Ragulator plays a dual role for the small GTPases Rag (RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and/or RagD/RRAGD): it (1) acts as a guanine nucleotide exchange factor (GEF), activating the small GTPases Rag and (2) mediates recruitment of Rag GTPases to the lysosome membrane. Activated Ragulator and Rag GTPases function as a scaffold recruiting mTORC1 to lysosomes where it is in turn activated. Adapter protein that enhances the efficiency of the MAP kinase cascade facilitating the activation of MAPK2.

Subunit / interactions. Part of the Ragulator complex composed of LAMTOR1, LAMTOR2, LAMTOR3, LAMTOR4 and LAMTOR5. LAMTOR4 and LAMTOR5 form a heterodimer that interacts, through LAMTOR1, with a LAMTOR2, LAMTOR3 heterodimer. Interacts with LAMTOR1 and LAMTOR2; the interaction is direct. The Ragulator complex interacts with both the mTORC1 complex and heterodimers constituted of the Rag GTPases RagA/RRAGA, RagB/RRAGB, RagC/RRAGC and RagD/RRAGD; regulated by amino acid availability. The Ragulator complex interacts with SLC38A9; the probable amino acid sensor. Component of the lysosomal folliculin complex (LFC), composed of FLCN, FNIP1 (or FNIP2), RagA/RRAGA or RagB/RRAGB GDP-bound, RagC/RRAGC or RagD/RRAGD GTP-bound, and Ragulator. Interacts with MAP2K1/MEK1 and MAPK2. Interacts with MORG1.

Subcellular location. Late endosome membrane.

Similarity. Belongs to the LAMTOR3 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UHA4-1	1	yes
Q9UHA4-2	2

RefSeq proteins (2): NP_001230665, NP_068805* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR015019	LAMTOR3	Family

Pfam: PF08923

UniProt features (19 total): strand 7, helix 6, chain 1, region of interest 1, splice variant 1, mutagenesis site 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

25 structures.

PDB	Method	Resolution (Å)
6B9X	X-RAY DIFFRACTION	1.42
3CPT	X-RAY DIFFRACTION	1.9
1SKO	X-RAY DIFFRACTION	2
2ZL1	X-RAY DIFFRACTION	2
5X6V	X-RAY DIFFRACTION	2.02
6EHP	X-RAY DIFFRACTION	2.3
5X6U	X-RAY DIFFRACTION	2.4
5Y39	X-RAY DIFFRACTION	2.65
6EHR	X-RAY DIFFRACTION	2.9
5Y3A	X-RAY DIFFRACTION	2.9
7UX2	ELECTRON MICROSCOPY	2.9
5YK3	X-RAY DIFFRACTION	3.01
6U62	ELECTRON MICROSCOPY	3.18
6WJ2	ELECTRON MICROSCOPY	3.2
7UXC	ELECTRON MICROSCOPY	3.2
7UXH	ELECTRON MICROSCOPY	3.2
9ED4	ELECTRON MICROSCOPY	3.23
6ULG	ELECTRON MICROSCOPY	3.31
8DHB	ELECTRON MICROSCOPY	3.53
6NZD	ELECTRON MICROSCOPY	3.6
6WJ3	ELECTRON MICROSCOPY	3.9
7T3B	ELECTRON MICROSCOPY	3.9
9ED6	ELECTRON MICROSCOPY	3.98
7T3A	ELECTRON MICROSCOPY	4
7T3C	ELECTRON MICROSCOPY	4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UHA4-F1	95.53	0.92

Functional residue map

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

Mutagenesis-validated functional residues (1):

Position	Phenotype
59–62	in m5 mutant; impaired association with rag gtpases.

Function

Pathways and Gene Ontology

Reactome pathways

26 pathways

ID	Pathway
R-HSA-1632852	Macroautophagy
R-HSA-165159	MTOR signalling
R-HSA-166208	mTORC1-mediated signalling
R-HSA-380972	Energy dependent regulation of mTOR by LKB1-AMPK
R-HSA-5628897	TP53 Regulates Metabolic Genes
R-HSA-5674135	MAP2K and MAPK activation
R-HSA-6798695	Neutrophil degranulation
R-HSA-8943724	Regulation of PTEN gene transcription
R-HSA-9639288	Amino acids regulate mTORC1
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-162582	Signal Transduction
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-212436	Generic Transcription Pathway
R-HSA-2262752	Cellular responses to stress
R-HSA-3700989	Transcriptional Regulation by TP53
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-5683057	MAPK family signaling cascades
R-HSA-5684996	MAPK1/MAPK3 signaling
R-HSA-6807070	PTEN Regulation
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9006925	Intracellular signaling by second messengers
R-HSA-9612973	Autophagy
R-HSA-9711097	Cellular response to starvation

MSigDB gene sets: 212 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_ACID_CHEMICAL, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, KEGG_MAPK_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_TOR_SIGNALING, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, TGACCTY_ERR1_Q2, TACAATC_MIR508, GOBP_CELLULAR_RESPONSE_TO_ACID_CHEMICAL, GOMF_KINASE_ACTIVATOR_ACTIVITY, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, AFP1_Q6, GOBP_TOR_SIGNALING

GO Biological Process (9): intracellular protein localization (GO:0008104), positive regulation of TOR signaling (GO:0032008), TORC1 signaling (GO:0038202), positive regulation of MAPK cascade (GO:0043410), cellular response to amino acid stimulus (GO:0071230), protein localization to cell junction (GO:1902414), positive regulation of TORC1 signaling (GO:1904263), regulation of TOR signaling (GO:0032006), positive regulation of intracellular signal transduction (GO:1902533)

GO Molecular Function (4): kinase activator activity (GO:0019209), guanyl-nucleotide exchange factor activity (GO:0005085), protein binding (GO:0005515), molecular adaptor activity (GO:0060090)

GO Cellular Component (14): lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), focal adhesion (GO:0005925), endosome membrane (GO:0010008), late endosome membrane (GO:0031902), specific granule membrane (GO:0035579), extracellular exosome (GO:0070062), tertiary granule membrane (GO:0070821), Ragulator complex (GO:0071986), FNIP-folliculin RagC/D GAP (GO:1990877), cytoplasm (GO:0005737), endosome (GO:0005768), late endosome (GO:0005770), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Signal Transduction	2
MTOR signalling	2
Autophagy	1
Transcriptional Regulation by TP53	1
RAF/MAP kinase cascade	1
Innate Immune System	1
PTEN Regulation	1
Cellular response to starvation	1
Intracellular signaling by second messengers	1
Immune System	1
RNA Polymerase II Transcription	1
Cellular responses to stimuli	1
Generic Transcription Pathway	1
MAPK1/MAPK3 signaling	1
MAPK family signaling cascades	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
TOR signaling	3
positive regulation of intracellular signal transduction	2
regulation of intracellular signal transduction	2
binding	2
endosome	2
secretory granule membrane	2
cellular anatomical structure	2
macromolecule localization	1
regulation of TOR signaling	1
MAPK cascade	1
regulation of MAPK cascade	1
response to amino acid	1
cellular response to acid chemical	1
intracellular protein localization	1
positive regulation of TOR signaling	1
TORC1 signaling	1
regulation of TORC1 signaling	1
positive regulation of signal transduction	1
intracellular signal transduction	1
enzyme activator activity	1
kinase activity	1
kinase regulator activity	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
molecular_function	1
lysosome	1
lytic vacuole membrane	1
membrane	1
cell periphery	1
cell-substrate junction	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
late endosome	1
endosome membrane	1
specific granule	1
extracellular vesicle	1
tertiary granule	1
vacuolar membrane	1
guanyl-nucleotide exchange factor complex	1

Protein interactions and networks

STRING

1242 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LAMTOR3	LAMTOR2	Q9Y2Q5	999
LAMTOR3	LAMTOR1	Q6IAA8	997
LAMTOR3	LAMTOR4	Q0VGL1	996
LAMTOR3	LAMTOR5	O43504	995
LAMTOR3	MAP2K1	Q02750	974
LAMTOR3	KSR1	Q8IVT5	815
LAMTOR3	CDKN2A	P42771	811
LAMTOR3	RRAGC	Q9HB90	788
LAMTOR3	RRAGA	Q7L523	769
LAMTOR3	RAF1	P04049	713
LAMTOR3	WDR83	Q9BRX9	709
LAMTOR3	MAPK3	P27361	682
LAMTOR3	RRAGB	Q5VZM2	633
LAMTOR3	SLC38A9	Q8NBW4	593
LAMTOR3	RRAGD	Q9NQL2	592

IntAct

143 interactions, top by confidence:

A	B	Type	Score
LAMTOR3	LAMTOR2	psi-mi:“MI:0915”(physical association)	0.960
LAMTOR2	LAMTOR3	psi-mi:“MI:0915”(physical association)	0.960
LAMTOR3	LAMTOR2	psi-mi:“MI:2364”(proximity)	0.960
LAMTOR2	LAMTOR3	psi-mi:“MI:2364”(proximity)	0.960
LAMTOR4	LAMTOR5	psi-mi:“MI:0914”(association)	0.960
LAMTOR5	LAMTOR4	psi-mi:“MI:0914”(association)	0.960

BioGRID (208): LAMTOR2 (Two-hybrid), NIF3L1 (Two-hybrid), LAMTOR3 (Affinity Capture-RNA), LAMTOR3 (Affinity Capture-MS), LAMTOR3 (Affinity Capture-MS), LAMTOR3 (Affinity Capture-Western), LAMTOR3 (Affinity Capture-Western), LAMTOR3 (Affinity Capture-Western), LAMTOR3 (Affinity Capture-MS), LAMTOR3 (Two-hybrid), LAMTOR3 (Affinity Capture-MS), LAMTOR3 (Affinity Capture-MS), LAMTOR2 (Co-crystal Structure), LAMTOR3 (Proximity Label-MS), LAMTOR3 (Proximity Label-MS)

ESM2 similar proteins: A0JN39, A8WGF4, B0BN93, B4F6Y3, B5G0G8, D2SW95, O54956, O88653, P23514, P53618, P84169, Q05B56, Q0JNK5, Q13889, Q17QQ1, Q28C65, Q3SX43, Q4SSF5, Q503S6, Q53PC7, Q5E964, Q5FVD6, Q5R3Z6, Q5R922, Q5U204, Q5XGS8, Q5ZIA5, Q5ZIP2, Q5ZKR4, Q63486, Q6GNI4, Q6NWV3, Q6PC62, Q6Y228, Q6Z844, Q7L523, Q7T0T2, Q7T0V2, Q80X95, Q84LG4

Diamond homologs: B4F6Y3, B5G0G8, O88653, Q17QQ1, Q4SSF5, Q503S6, Q5R3Z6, Q5U204, Q5ZIP2, Q6Y228, Q7T0T2, Q7T0V2, Q9UHA4, Q9VJD2, Q86J23

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
LAMTOR3	up-regulates	MAP2K1	binding
LAMTOR3	“form complex”	LAMTOR	binding
LAMTOR3	up-regulates	MEK1/2	binding
LAMTOR3	up-regulates	MAPK3	binding
ARHGAP8	“up-regulates activity”	LAMTOR3	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 75 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
mTORC1-mediated signalling	9	77.9×	2e-13
Energy dependent regulation of mTOR by LKB1-AMPK	9	64.4×	9e-13
MTOR signalling	9	43.5×	2e-11
PTEN Regulation	9	37.4×	7e-11
Amino acids regulate mTORC1	10	36.4×	1e-11
Cellular response to starvation	10	30.1×	4e-11
Regulation of PTEN gene transcription	9	29.2×	6e-10
Autophagy	9	24.3×	3e-09

GO biological processes:

GO term	Partners	Fold	FDR
protein localization to lysosome	5	81.0×	4e-07
positive regulation of TOR signaling	8	61.0×	9e-11
positive regulation of TORC1 signaling	10	45.5×	6e-12
cellular response to amino acid stimulus	9	42.4×	9e-11
lysosome localization	5	40.5×	1e-05
intracellular protein localization	6	9.7×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	17
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

824 predictions. Top by Δscore:

Variant	Effect	Δscore
4:99881976:A:AC	donor_gain	1.0000
4:99881977:C:CC	donor_gain	1.0000
4:99881983:C:CT	donor_gain	1.0000
4:99882004:T:TA	donor_gain	1.0000
4:99884122:CCAC:C	acceptor_gain	1.0000
4:99884123:CACC:C	acceptor_gain	1.0000
4:99884123:CACCT:C	acceptor_loss	1.0000
4:99884124:ACCTA:A	acceptor_loss	1.0000
4:99884125:CCTAA:C	acceptor_loss	1.0000
4:99884126:CTA:C	acceptor_loss	1.0000
4:99885538:TTACC:T	donor_loss	1.0000
4:99885539:TACCT:T	donor_loss	1.0000
4:99885540:A:AC	donor_gain	1.0000
4:99885540:AC:A	donor_gain	1.0000
4:99885540:ACCT:A	donor_loss	1.0000
4:99885541:C:CC	donor_gain	1.0000
4:99885541:CC:C	donor_gain	1.0000
4:99885541:CCTG:C	donor_gain	1.0000
4:99885671:TGCCA:T	acceptor_gain	1.0000
4:99885673:CCA:C	acceptor_gain	1.0000
4:99885674:CA:C	acceptor_gain	1.0000
4:99885674:CAC:C	acceptor_gain	1.0000
4:99885676:C:CC	acceptor_gain	1.0000
4:99885676:CTA:C	acceptor_loss	1.0000
4:99885677:T:A	acceptor_loss	1.0000
4:99887290:TTTTA:T	donor_loss	1.0000
4:99887291:TTTA:T	donor_loss	1.0000
4:99887292:TTA:T	donor_loss	1.0000
4:99887293:TA:T	donor_loss	1.0000
4:99887294:A:AG	donor_loss	1.0000

AlphaMissense

803 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:99885593:T:A	K62N	1.000
4:99885593:T:G	K62N	1.000
4:99885594:T:A	K62I	1.000
4:99885595:T:C	K62E	1.000
4:99885618:G:T	A54D	1.000
4:99887313:C:A	G29V	1.000
4:99887313:C:T	G29E	1.000
4:99887314:C:G	G29R	1.000
4:99887314:C:T	G29R	1.000
4:99884062:C:G	G101R	0.999
4:99884062:C:T	G101R	0.999
4:99884082:G:T	A94D	0.999
4:99884083:C:G	A94P	0.999
4:99884085:A:T	I93K	0.999
4:99884090:A:C	S91R	0.999
4:99884090:A:T	S91R	0.999
4:99884092:T:G	S91R	0.999
4:99884121:A:T	V81D	0.999
4:99885562:A:G	C73R	0.999
4:99885575:A:C	N68K	0.999
4:99885575:A:T	N68K	0.999
4:99885585:A:G	L65P	0.999
4:99885588:C:T	G64E	0.999
4:99885591:A:G	L63P	0.999
4:99885591:A:T	L63H	0.999
4:99885594:T:G	K62T	0.999
4:99885595:T:G	K62Q	0.999
4:99885600:C:T	G60E	0.999
4:99885601:C:G	G60R	0.999
4:99885601:C:T	G60R	0.999

dbSNP variants (sampled 300 via entrez): RS1000414722 (4:99879958 T>C), RS1000449431 (4:99888461 T>C), RS1000537062 (4:99882705 T>C), RS1000880981 (4:99885460 A>G), RS1001055056 (4:99889983 G>C), RS1001069164 (4:99892387 A>G), RS1001153606 (4:99878475 G>T), RS1001191967 (4:99889170 C>A), RS1001274973 (4:99880954 G>A,C,T), RS1001327338 (4:99881260 C>T), RS1001438617 (4:99892646 C>T), RS10016741 (4:99886064 T>A,C,G), RS1001689216 (4:99878897 G>C), RS1001698959 (4:99895286 T>A,C), RS10018046 (4:99879893 C>A,T)

Disease associations

OMIM: gene MIM:603296 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001032_3	Caffeine consumption	6.000000e-07
GCST90002396_228	Mean reticulocyte volume	1.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004330	coffee consumption
EFO:0010701	mean reticulocyte volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465366 (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
6.09	Kd	816.1	nM	CHEMBL3752910
6.09	ED50	816.1	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 3 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	2149878: Binding affinity to human LAMTOR3 incubated for 45 mins by Kinobead based pull down assay	kd	0.8161	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Air Pollutants	affects expression, increases abundance, decreases expression	3
Copper	affects binding, increases expression, decreases expression	3
Valproic Acid	affects expression, increases expression	3
Cadmium Chloride	increases abundance, increases expression	3
Tobacco Smoke Pollution	increases expression	2
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
potassium chromate(VI)	decreases expression	1
beta-methylcholine	affects expression	1
abrine	increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
bisphenol S	increases expression	1
jinfukang	decreases expression	1
NSC 689534	increases expression, affects binding	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Sunitinib	increases expression	1
Glyphosate	increases expression	1
Air Pollutants, Occupational	affects expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Cadmium	increases abundance, increases expression	1
Chelating Agents	affects binding, increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Disulfiram	affects binding, decreases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5342230	Binding	Inhibition of N terminal 6 his tagged human MAPKSP1 expressed in E-coli at 1 uM in presence of ATP relative to control	Discovery of C-5 Pyrazole-Substituted Pyrrolopyridine Derivatives as Potent and Selective Inhibitors for Janus Kinase 1. — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1VN	Abcam HeLa LAMTOR3 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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