EEA1

Summary

EEA1 (early endosome antigen 1, HGNC:3185) is a protein-coding gene on chromosome 12q22, encoding Early endosome antigen 1 (Q15075). Binds phospholipid vesicles containing phosphatidylinositol 3-phosphate and participates in endosomal trafficking.

Enables 1-phosphatidylinositol binding activity; GTP-dependent protein binding activity; and protein homodimerization activity. Involved in endocytosis and vesicle fusion. Located in cytosol and early endosome membrane.

Source: NCBI Gene 8411 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 173 total
• Druggable target: yes
• MANE Select transcript: NM_003566

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3185
Approved symbol	EEA1
Name	early endosome antigen 1
Location	12q22
Locus type	gene with protein product
Status	Approved
Aliases	ZFYVE2
Ensembl gene	ENSG00000102189
Ensembl biotype	protein_coding
OMIM	605070
Entrez	8411

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000322349, ENST00000418984, ENST00000547833, ENST00000549790, ENST00000553019, ENST00000931425, ENST00000962097

RefSeq mRNA: 1 — MANE Select: NM_003566 NM_003566

CCDS: CCDS31874

Canonical transcript exons

ENST00000322349 — 29 exons

Exon	Start	End
ENSE00000921600	92776844	92776942
ENSE00000921601	92777543	92777663
ENSE00000921602	92777941	92778179
ENSE00000921603	92779115	92779300
ENSE00000921604	92780280	92780411
ENSE00000921605	92781950	92782135
ENSE00000921606	92787867	92788049
ENSE00000921607	92798892	92799086
ENSE00000921608	92801600	92801701
ENSE00001198267	92770637	92776133
ENSE00002396241	92802404	92802734
ENSE00003466872	92816200	92816400
ENSE00003502372	92891629	92891721
ENSE00003524392	92857275	92857340
ENSE00003527221	92809017	92809156
ENSE00003533311	92852175	92852296
ENSE00003541182	92929043	92929295
ENSE00003556718	92811279	92811434
ENSE00003563771	92832512	92832850
ENSE00003570513	92842465	92842581
ENSE00003585393	92827912	92828061
ENSE00003607769	92819308	92819511
ENSE00003618346	92826166	92826285
ENSE00003624093	92852912	92853025
ENSE00003631990	92851111	92851266
ENSE00003649921	92853915	92853954
ENSE00003650865	92857431	92857485
ENSE00003656064	92812980	92813093
ENSE00003660560	92864860	92864987

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 95.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.2662 / max 2000.8820, expressed in 1813 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
132649	25.5705	1811
132644	4.7983	1202
132648	0.5712	323
132643	0.3262	149

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	95.51	gold quality
upper leg skin	UBERON:0004262	94.68	gold quality
biceps brachii	UBERON:0001507	94.48	gold quality
tendon	UBERON:0000043	94.07	gold quality
oral cavity	UBERON:0000167	94.04	gold quality
gingival epithelium	UBERON:0001949	93.82	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.77	gold quality
gingiva	UBERON:0001828	93.67	gold quality
cauda epididymis	UBERON:0004360	93.58	gold quality
penis	UBERON:0000989	93.49	gold quality
skin of hip	UBERON:0001554	93.44	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	93.14	gold quality
esophagus squamous epithelium	UBERON:0006920	93.11	gold quality
urethra	UBERON:0000057	92.79	gold quality
tendon of biceps brachii	UBERON:0008188	92.62	gold quality
synovial joint	UBERON:0002217	92.50	gold quality
jejunal mucosa	UBERON:0000399	92.40	gold quality
jejunum	UBERON:0002115	91.98	gold quality
mammary duct	UBERON:0001765	91.76	gold quality
mucosa of paranasal sinus	UBERON:0005030	91.61	gold quality
heart right ventricle	UBERON:0002080	91.47	gold quality
mammalian vulva	UBERON:0000997	91.34	gold quality
epithelium of nasopharynx	UBERON:0001951	91.26	gold quality
superficial temporal artery	UBERON:0001614	91.07	gold quality
pericardium	UBERON:0002407	90.95	gold quality
germinal epithelium of ovary	UBERON:0001304	90.52	gold quality
sural nerve	UBERON:0015488	90.06	gold quality
caput epididymis	UBERON:0004358	90.05	gold quality
parietal pleura	UBERON:0002400	89.92	gold quality
tibia	UBERON:0000979	89.51	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-36552	no	242.57
E-MTAB-6678	no	3.63
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

271 targeting EEA1, 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-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-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-10401-5P	99.99	65.79	948

Literature-anchored findings (GeneRIF, showing 23)

• activation of p38 MAPK caused a decrease in EEA1 colocalization with phagosomes, arresting maturation into the phagolysosome (PMID:12963735)
• macropinosomes do not mature to late endosomes or fuse with lysosomes. EEA1 continuously mediates homotypic fusion as long as the macropinosomes persist. (PMID:15052657)
• These results suggest that EEA1 is involved in neuronal synaptic vesicle function and axonal transport and growth. EEA1 may undergo calcium-dependent conformational changes that are required for binding to SNAP-25. (PMID:15451443)
• Results describe the geometry of the micelle penetration of the early endosome antigen 1 FYVE domain. (PMID:16331966)
• PIKfyve is distributed in microdomains that are distinct from those occupied by EEA1 and Hrs (PMID:16448788)
• Impairment of internalization of specific glutamate receptors and their subsequent accumulation in the synapse may account for the neurological deficits observed in some patients developing EEA1 autoantibodies. (PMID:17113235)
• results suggest that the local production of PtdIns(3)P implicates the fusion of macropinosomes via EEA1 as well as conventional early endosomes (PMID:17146146)
• crystal structure of Rab5A in complex with the EEA1 C(2)H(2) zinc finger (PMID:20534488)
• The knockdown of STEAP4 inhibits insulin-stimulated glucose transport and GLUT4 translocation via the attenuated phosphorylation of Akt, independent of the effects of EEA1. (PMID:21468601)
• p97 inhibition causes increased EEA1 self-association at the endosome membrane. (PMID:21556036)
• EEA1 interacts with Phafin2 and colocolizes with Phafin2 in endosome membrane. (PMID:22816767)
• NMR analyses of the interaction between the FYVE domain of early endosome antigen 1 (EEA1) and phosphoinositide embedded in a lipid bilayer. (PMID:22915584)
• We therefore propose that the N1072K variant of the EEA1 gene is a candidate mutation for susceptibility to diabetes in the Japanese population. (PMID:23499280)
• nuclear uptake of Abeta involves the dynamin-dependent EEA1 and TGF-beta/Smad signaling pathways. (PMID:24491918)
• Data indicate that early endosome antigen 1 (EEA1) is important for the small GTPase Rab31-mediated enhancement of ligand-bound EGF receptor (EGFR) endocytic trafficking. (PMID:24644286)
• In serum-deprivated HeLa cells with low endocytic activity there two types of EEA1-vesicles: the first one carries the both EEA1 and Rab5 at high levels; the second consists of weakly decorated EEA1-vesicles that can be both Rab5-positive and -negative. (PMID:25711083)
• Under the regulation of Rab5, the fused vesicles are targeted to early endosomes and thus deliver the internalized TbetaRI to the caveolin-1 and EEA1 double-positive early endosomes (caveolin-1-positive early endosomes). (PMID:25998683)
• EEA1 mobility on endosomes is decreased upon stimulation of EGF receptor endocytosis in HeLa cells (PMID:26993163)
• results suggest a new mechanism in which Rab5 induces a change in flexibility of EEA1, generating an entropic collapse force that pulls the captured vesicle towards the target membrane to initiate docking and membrane fusion (PMID:27556945)
• Rab5C and EEA1 in the early endosomal pathway, and Rab7A and lysobisphosphatidic acid in the late endosomal pathway, are important for trafficking of phosphorothioate Antisense oligonucleotides and facilitate their escape from endolysosomal compartments after Stabilin-mediated internalization. (PMID:29437530)
• identification of allergic bronchopulmonary aspergillosis -associated variants in EEA that have functional effects on macrophage phagocytosis and phagolysosome acidification of A. fumigatus conidia. (PMID:29547649)
• This also suggests that this pathway is involved in EEA1-vesicles biogenesis. (PMID:30188634)
• Here, using EGF/EGFR endocytosis as a model and confocal microscopy of fixed and live cells, we provide evidence favoring EEA1-vesicles being pre-existed vesicular compartment, that maintains its resident proteins’ level and is sensitive to biosynthetic, but not endocytic pathway disturbance. (PMID:32357161)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	eea1	ENSDARG00000062868
mus_musculus	Eea1	ENSMUSG00000036499
rattus_norvegicus	Eea1	ENSRNOG00000021681
drosophila_melanogaster	Rbpn-5	FBGN0034585
caenorhabditis_elegans		WBGENE00011696

Protein

Protein identifiers

Early endosome antigen 1 — Q15075 (reviewed: Q15075)

Alternative names: Endosome-associated protein p162, Zinc finger FYVE domain-containing protein 2

All UniProt accessions (4): Q15075, F8VUZ7, F8W119, F8WE79

UniProt curated annotations — full annotation on UniProt →

Function. Binds phospholipid vesicles containing phosphatidylinositol 3-phosphate and participates in endosomal trafficking.

Subunit / interactions. Homodimer. Binds STX6. Binds RAB5A, RAB5B, RAB5C and RAB22A that have been activated by GTP-binding. Interacts with RAB31. Interacts with ERBB2. Interacts with SAMD9 and SAMD9L. May interact with PLEKHF2.

Subcellular location. Early endosome membrane. Cytoplasm.

Domain organisation. The FYVE-type zinc finger domain mediates interactions with phosphatidylinositol 3-phosphate in membranes of early endosomes and penetrates bilayers. The FYVE domain insertion into PtdIns(3)P-enriched membranes is substantially increased in acidic conditions.

Miscellaneous. Antibodies against EEA1 are found in sera from patients with subacute cutaneous lupus erythematosus and other autoimmune diseases.

RefSeq proteins (1): NP_003557* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000306	Znf_FYVE	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR013087	Znf_C2H2_type	Domain
IPR017455	Znf_FYVE-rel	Domain

Pfam: PF01363

UniProt features (69 total): mutagenesis site 23, sequence conflict 9, binding site 8, strand 8, helix 6, turn 4, zinc finger region 2, modified residue 2, region of interest 2, compositionally biased region 2, chain 1, sequence variant 1, coiled-coil region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
3MJH	X-RAY DIFFRACTION	2.03
1JOC	X-RAY DIFFRACTION	2.2
1HYI	SOLUTION NMR
1HYJ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15075-F1	73.53	0.06

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 (8): 1374; 1377; 1382; 1385; 1402; 1405; 1358; 1361

Post-translational modifications (2): 52, 70

Mutagenesis-validated functional residues (23):

Position	Phenotype
39	strongly reduces interaction with rab5c.
41	strongly reduces interaction with rab5c.
42	strongly reduces interaction with rab5c.
44	strongly reduces interaction with rab5c.
47	strongly reduces interaction with rab5c.
60	strongly reduces interaction with rab5c.
1349	reduces phosphatidylinositol 3-phosphate binding and endosomal location.
1352	reduces phosphatidylinositol 3-phosphate binding and endosomal location.
1357	reduces phosphatidylinositol 3-phosphate binding and endosomal location.
1358	abolishes phosphatidylinositol 3-phosphate binding and endosomal location.
1365	strongly reduces phosphatidylinositol 3-phosphate binding and endosomal location.
1367–1368	abolishes phosphatidylinositol 3-phosphate binding and endosomal location.
1370	abolishes endosomal location.
1371	abolishes phosphatidylinositol 3-phosphate binding and endosomal location.
1372	abolishes endosomal location. abolishes ph sensitivity of the fyve-type zinc finger domain; when associated with a-1373.
1373	abolishes phosphatidylinositol 3-phosphate binding and endosomal location. abolishes ph sensitivity of the fyve-type zin
1374	abolishes phosphatidylinositol 3-phosphate binding and endosomal location.
1375	abolishes phosphatidylinositol 3-phosphate binding and endosomal location.
1377	abolishes phosphatidylinositol 3-phosphate binding and endosomal location.
1378	abolishes phosphatidylinositol 3-phosphate binding and endosomal location.
1385	abolishes phosphatidylinositol 3-phosphate binding and endosomal location.
1400	strongly reduces phosphatidylinositol 3-phosphate binding and abolishes endosomal location.
1405	abolishes phosphatidylinositol 3-phosphate binding and endosomal location.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade

MSigDB gene sets: 0 (showing top):

GO Biological Process (6): endocytosis (GO:0006897), vesicle fusion (GO:0006906), synaptic vesicle to endosome fusion (GO:0016189), host-mediated perturbation of viral process (GO:0044788), early endosome to late endosome transport (GO:0045022), chemical synaptic transmission, postsynaptic (GO:0099565)

GO Molecular Function (7): calmodulin binding (GO:0005516), 1-phosphatidylinositol binding (GO:0005545), zinc ion binding (GO:0008270), GTP-dependent protein binding (GO:0030742), protein homodimerization activity (GO:0042803), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (14): early endosome (GO:0005769), cytosol (GO:0005829), early endosome membrane (GO:0031901), axonal spine (GO:0044308), recycling endosome (GO:0055037), extracellular exosome (GO:0070062), Schaffer collateral - CA1 synapse (GO:0098685), presynaptic endosome (GO:0098830), postsynaptic early endosome (GO:0098842), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), endosome (GO:0005768), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Toll-like Receptor Cascades	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
endosome	3
cellular anatomical structure	3
vesicle-mediated transport	2
postsynapse	2
protein binding	2
early endosome	2
synapse	2
vesicle budding from membrane	1
membrane invagination	1
import into cell	1
vesicle organization	1
organelle membrane fusion	1
endosome organization	1
organelle fusion	1
synaptic vesicle endosomal processing	1
host-mediated perturbation of symbiont process	1
vesicle-mediated transport between endosomal compartments	1
cell surface receptor signaling pathway	1
chemical synaptic transmission	1
nervous system process	1
phospholipid binding	1
transition metal ion binding	1
identical protein binding	1
protein dimerization activity	1
binding	1
cation binding	1
endosome membrane	1
axon	1
neuron spine	1
extracellular vesicle	1
presynapse	1
postsynaptic endosome	1
intracellular anatomical structure	1
endomembrane system	1
cytoplasmic vesicle	1
intracellular vesicle	1

Protein interactions and networks

STRING

3046 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EEA1	RAB5A	P20339	999
EEA1	RABGEF1	Q9UJ41	975
EEA1	RABEP1	Q15276	966
EEA1	STX6	O43752	960
EEA1	LAMP1	P11279	919
EEA1	TFRC	P02786	913
EEA1	RAB11A	P24410	896
EEA1	CLTC	Q00610	857
EEA1	VPS45	Q9NRW7	857
EEA1	LAMP2	P13473	853
EEA1	RAB4A	P20338	849
EEA1	RAB5C	P51148	832
EEA1	APPL1	Q9UKG1	820
EEA1	TGOLN2	O43493	785
EEA1	GAPVD1	Q14C86	777

IntAct

144 interactions, top by confidence:

A	B	Type	Score
RAB5A	EEA1	psi-mi:“MI:0915”(physical association)	0.830
EEA1	RAB5A	psi-mi:“MI:0915”(physical association)	0.830
RAB5C	EEA1	psi-mi:“MI:0915”(physical association)	0.730
EEA1	RAB5C	psi-mi:“MI:0403”(colocalization)	0.730
EEA1	RAB5C	psi-mi:“MI:0915”(physical association)	0.730
EEA1	RAB5C	psi-mi:“MI:0407”(direct interaction)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
EEA1	RAB22A	psi-mi:“MI:0915”(physical association)	0.650
RAB22A	EEA1	psi-mi:“MI:0915”(physical association)	0.650
PPP2R3A	WTIP	psi-mi:“MI:0914”(association)	0.640
Axin1	LRP6	psi-mi:“MI:0403”(colocalization)	0.600
Stx6	EEA1	psi-mi:“MI:0915”(physical association)	0.580
EEA1	Stx6	psi-mi:“MI:0915”(physical association)	0.580
ERBB2	EEA1	psi-mi:“MI:0403”(colocalization)	0.570
EEA1	ERBB2	psi-mi:“MI:0914”(association)	0.570
ERBB2	KPNB1	psi-mi:“MI:0915”(physical association)	0.570
EEA1	ERBB2	psi-mi:“MI:0915”(physical association)	0.570
Dctn2	DCTN6	psi-mi:“MI:0914”(association)	0.560
PCNA	POM121C	psi-mi:“MI:0914”(association)	0.550

BioGRID (805): EEA1 (Co-fractionation), EEA1 (Co-crystal Structure), EEA1 (Reconstituted Complex), EEA1 (Affinity Capture-MS), EEA1 (Affinity Capture-MS), EEA1 (Affinity Capture-MS), EEA1 (Affinity Capture-MS), EEA1 (Affinity Capture-MS), EEA1 (Co-fractionation), EEA1 (Affinity Capture-MS), EEA1 (Affinity Capture-MS), EEA1 (Affinity Capture-MS), EEA1 (Affinity Capture-MS), EEA1 (Affinity Capture-MS), EEA1 (Affinity Capture-MS)

ESM2 similar proteins: D3ZZL9, E9Q1U1, F4I9A2, O75330, O97961, P49454, P61430, P97779, Q00547, Q03410, Q0VBY1, Q13439, Q14789, Q15075, Q15643, Q28628, Q4R7H3, Q53EZ4, Q5M7B7, Q5RI56, Q5T9S5, Q60563, Q61595, Q62209, Q640L5, Q6TFL3, Q70FJ1, Q7FAD5, Q861Q8, Q86UP2, Q8BL66, Q8CDI7, Q8CHG3, Q8HYY4, Q8IWJ2, Q8NB25, Q8NCX0, Q8R5M4, Q90631, Q90Z16

Diamond homologs: A0A0D1E015, A0JMD2, A1CEK1, A1DFP5, A2QWA2, A4QTV1, A8QCE4, A8XJZ8, B0G126, B0WAQ0, B3MT31, B3P851, B4G2G5, B4IC49, B4JHI7, B4K982, B4M140, B4NFJ7, B4PRU6, D2H5P6, D3ZVP7, D4A8G9, E1BLZ4, F1MM41, F7EP40, O13821, O14964, O59722, O76902, O95405, O96838, P0CS26, P0CS27, P34756, P40343, Q05B78, Q08CN9, Q0CJV3, Q0P4S0, Q0U4Z8

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
MAPK14	up-regulates	EEA1	phosphorylation
EEA1	“form complex”	“Early Endosome”	binding
MAPK14	“up-regulates activity”	EEA1	phosphorylation
RAB5C	“up-regulates activity”	EEA1	binding
PLEKHF2	“up-regulates activity”	EEA1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 131 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
RAB geranylgeranylation	5	10.8×	6e-03
RAB GEFs exchange GTP for GDP on RABs	6	9.3×	5e-03
Clathrin-mediated endocytosis	7	7.5×	5e-03
Membrane Trafficking	11	5.1×	3e-03
Vesicle-mediated transport	11	4.8×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
endosomal transport	9	20.9×	3e-07
positive regulation of canonical Wnt signaling pathway	8	11.8×	1e-04
endocytosis	10	9.1×	6e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	139
Likely benign	7
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

5904 predictions. Top by Δscore:

Variant	Effect	Δscore
12:92775986:A:AC	donor_gain	1.0000
12:92775990:CT:C	donor_gain	1.0000
12:92776010:ATTAT:A	donor_gain	1.0000
12:92776013:AT:A	donor_gain	1.0000
12:92776132:TG:T	acceptor_gain	1.0000
12:92776134:C:CC	acceptor_gain	1.0000
12:92776843:CCCGT:C	donor_gain	1.0000
12:92776851:A:AC	donor_gain	1.0000
12:92776852:C:CC	donor_gain	1.0000
12:92777538:CTGA:C	donor_loss	1.0000
12:92777539:TGACC:T	donor_loss	1.0000
12:92777540:GAC:G	donor_loss	1.0000
12:92777541:A:C	donor_loss	1.0000
12:92777659:GACAT:G	acceptor_gain	1.0000
12:92777661:CAT:C	acceptor_gain	1.0000
12:92777662:AT:A	acceptor_gain	1.0000
12:92777664:C:CC	acceptor_gain	1.0000
12:92777664:CTGGA:C	acceptor_loss	1.0000
12:92777674:T:TC	acceptor_gain	1.0000
12:92777937:TCA:T	donor_loss	1.0000
12:92777938:CA:C	donor_loss	1.0000
12:92777940:C:CG	donor_loss	1.0000
12:92777944:T:A	donor_gain	1.0000
12:92777957:T:A	donor_gain	1.0000
12:92778178:TG:T	acceptor_gain	1.0000
12:92778179:GC:G	acceptor_loss	1.0000
12:92778180:C:CA	acceptor_loss	1.0000
12:92778180:C:CC	acceptor_gain	1.0000
12:92779094:T:TA	donor_gain	1.0000
12:92779095:C:A	donor_gain	1.0000

AlphaMissense

9335 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:92776127:A:G	C1374R	1.000
12:92776130:G:C	H1373D	1.000
12:92776133:G:C	H1372D	1.000
12:92776910:C:A	W1349C	1.000
12:92776910:C:G	W1349C	1.000
12:92776912:A:G	W1349R	1.000
12:92776912:A:T	W1349R	1.000
12:92776034:A:G	C1405R	0.999
12:92776043:A:G	C1402R	0.999
12:92776045:A:T	V1401D	0.999
12:92776049:G:T	R1400S	0.999
12:92776094:A:G	C1385R	0.999
12:92776103:A:G	C1382R	0.999
12:92776114:C:A	G1378V	0.999
12:92776114:C:T	G1378E	0.999
12:92776118:A:G	C1377R	0.999
12:92776125:G:C	C1374W	0.999
12:92776126:C:G	C1374S	0.999
12:92776126:C:T	C1374Y	0.999
12:92776127:A:T	C1374S	0.999
12:92776128:G:C	H1373Q	0.999
12:92776128:G:T	H1373Q	0.999
12:92776131:A:C	H1372Q	0.999
12:92776131:A:T	H1372Q	0.999
12:92776847:T:A	R1370S	0.999
12:92776847:T:G	R1370S	0.999
12:92776848:C:G	R1370T	0.999
12:92776862:A:C	F1365L	0.999
12:92776862:A:T	F1365L	0.999
12:92776863:A:G	F1365S	0.999

dbSNP variants (sampled 300 via entrez): RS1000041492 (12:92854101 T>C), RS1000104186 (12:92803939 A>G), RS1000121938 (12:92896739 T>C,G), RS1000131189 (12:92782655 T>C), RS1000135584 (12:92832003 C>T), RS1000149015 (12:92799858 A>G), RS1000165940 (12:92876694 T>C), RS1000185480 (12:92782229 A>G), RS1000237475 (12:92876365 T>A), RS1000244806 (12:92773299 A>G), RS1000252027 (12:92926228 G>A), RS1000262631 (12:92792821 A>C), RS1000295099 (12:92835479 T>C), RS1000316097 (12:92891879 T>C), RS1000329105 (12:92835173 G>A)

Disease associations

OMIM: gene MIM:605070 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): congenital portosystemic shunt (MONDO:0018811)

Orphanet (1): Congenital portosystemic shunt (Orphanet:480531)

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004640_10	Western dietary pattern	4.000000e-06
GCST006193_5	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	3.000000e-11
GCST006194_7	Diastolic blood pressure x smoking status (current vs non-current) interaction (1df test)	3.000000e-07
GCST006195_90	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	3.000000e-08
GCST009310_22	Sensorimotor dexterity	8.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0008111	diet measurement
EFO:0006336	diastolic blood pressure
EFO:0006527	smoking status measurement
EFO:0006335	systolic blood pressure
EFO:0008354	cognitive function measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067333 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

42 measured of 42 human assays (42 total across all organisms); most potent 42 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine	IC50	55 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
5-methoxy-6-(3-(1-methyl-H-pyrazol-3-yl)phenyl)-N-(pyridin-3-yl)-2-(pyridin-4-yl)pyrimidin-4-amine	IC50	55 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
2-di(pyridin-4-yl)pyrimidin-4-amine	IC50	55 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
5-methoxy-2-morpholino-6-(3-(oxazol-2-yl)phenyl)-N-(pyridin-4-yl)pyrimidin-4-amine	IC50	55 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)ethyl]naphthalene-2-carboxamide	IC50	55 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
5-methoxy-6-[3-(1-methylpyrazol-3-yl)phenyl]-2-morpholin-4-yl-N-pyridin-3-ylpyrimidin-4-amine	IC50	550 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
5-methoxy-6-(2-(1-methyl-1H-pyrazol-3-yl)pyridin-4-yl)-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine	IC50	550 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
1-(3-(5-methoxy-2-morpholino-6-(pyridin-4-ylamino)pyrimidin-4-yl)phenyl)piperidin-4-ol	IC50	550 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
6-(3-(1H-pyrazol-1-yl)phenyl)-5-chloro-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine	IC50	550 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
6-(5,6-dimethoxypyridin-2-yl)-5-methoxy-2-morpholino-N-(pyridin-4-yl)pyrimidin-4-amine	IC50	550 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
5-methoxy-2’-(I-methyl-1H-pyrazol-3-yl)-2-morpholino-N-(pyridin-4-yl)-4,4’-bipyrimidin-4-amine	IC50	550 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
4-(5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(quinolin-6-yl)pyrimidin-2-yl)morpholine	IC50	550 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
6-methyl-9-(1-methylpyrazol-3-yl)-2-morpholino-4-(4-pyridylamino)pyrimido[5,4-c]quinolin-one	IC50	550 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
pyrimidin-4-yl)morpholine	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
4-[5-methoxy-6-[3-(1-methylpyrazol-3-yl)phenyl]-2-(2-pyridin-2-ylethoxy)pyrimidin-4-yl]morpholine	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
6-(5,6-dimethoxypyridin-3-yl)-5-methoxy-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
5-methoxy-2-morpholin-4-yl-6-(3-pyridazin-3-ylphenyl)-N-pyridin-3-ylpyrimidin-4-amine	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
6-(3,4-dimethoxyphenyl)-5-methoxy-2-morpholin-4-yl-N-pyridin-3-ylpyrimidin-4-amine	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
3-[5-methoxy-2-morpholin-4-yl-6-(pyridin-3-ylamino)pyrimidin-4-yl]benzonitrile	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
3-[5-methoxy-2-morpholin-4-yl-6-(pyridin-3-ylamino)pyrimidin-4-yl]-N,N-dimethylbenzamide	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
1-(3-(5-methoxy-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)phenyl)pyrrolidin-3-ol	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
4-(3-(5-methoxy-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)phenyl)-1-methylpiperazin-2-one	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
4-(3-(5-methoxy-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)phenyl)morpholin-3-one	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
1-(3-(5-methoxy-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)phenyl)pyrrolidin-2-one	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholino-N-(pyridazin-3-ylmethyl)pyrimidin-4-amine	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
4-((1-methylpiperidin-3-yl)oxy)-2-morpholino-8-phenyl-6H-pyrazolo[1,5-d]pyrimido[5,4-b][1,4]oxazine	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
4-[5-methoxy-6-morpholin-4-yl-2-(3-pyrazol-1-ylphenyl)pyrimidin-4-yl]-1-methylpiperazin-2-one	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
4-[5-methoxy-4-morpholino-6-(3-pyrazol-1-ylphenyl)pyrimidin-2-yl]-1-methyl-piperazin-2-one	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
(R)-5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-(morpholin-3-ylmethoxy)-N-(pyridin-4-yl)pyrimidin-4-amine	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
pyrimidin-2-yl)morpholin-3-yl)methanol	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
oxide	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
4-(5-methoxy-4-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl)morpholine	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
1-(3-(5-methoxy-2-morpholino-6-(pyridin-3-ylamino)pyrimidin-4-yl)phenyl)piperidin-4-ol	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-6-(methylsulfinyl)-2-morpholino-N-(pyridin-3-yl)pyrimidin-4-amine	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
4-(5-methoxy-6-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-2-morpholinopyrimidin-4-yl)-1-methylpiperazin-2-one	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
4-(4-(3-(1H-pyrazol-1-yl)phenyl)-6-methoxy-6-(4-phenyl-1H-imidazol-2-yl)pyrimidin-2-yl)morpholine	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
5-methoxy-2-(3-(1-methyl-1H-pyrazol-3-yl)phenyl)-N-(pyridin-3-ylmethyl)-6-(pyridin-4-yl)pyrimidin-4-amine	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
2-morpholin-4-yl-9-pyrazol-1-yl-4-(pyridin-4-ylamino)-6H-pyrimido[5,4-c]quinolin-5-one	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
4-(3-cyanophenyl)-N,N-dimethyl-2-morpholino-6-(4-pyridylamino)pyrimidine-6-carboxamide	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
N,N-dimethyl-2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(3-pyridylamino)pyrimidine-6-carboxamide	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
[2-morpholino-4-(3-pyrazol-1-ylphenyl)-6-(3-pyridylamino)pyrimidin-6-yl]methanol	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE
6-[3-(1-methylpyrazol-3-yl)phenyl]-2-morpholin-4-yl-5-(1,3-oxazol-2-yl)-N-pyridin-4-ylpyrimidin-4-amine	IC50	5500 nM	US-20250197375: PYRIMIDINES AND METHODS OF THEIR USE

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects cotreatment	4
Tobacco Smoke Pollution	affects expression, decreases expression	2
Cadmium Chloride	increases abundance, increases palmitoylation, increases expression, decreases reaction	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
geldanamycin	increases expression	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
deoxynivalenol	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
trichostatin A	increases expression	1
arsenite	affects binding, decreases reaction	1
cobaltous chloride	affects cotreatment, increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
lead chloride	affects cotreatment, increases expression	1
cadmium sulfate	affects cotreatment, increases expression	1
nivalenol	increases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
deguelin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol B	increases expression	1
thifluzamide	increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pyrachlostrobin	increases expression	1
dorsomorphin	affects cotreatment, increases 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
CHEMBL5651326	Binding	Binding affinity to human EEA1 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

5 cell lines: 3 transformed cell line, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1QQ	Abcam HeLa EEA1 KO	Cancer cell line	Female
CVCL_C0I7	293EL	Transformed cell line	Female
CVCL_C0I8	293EL-APP-/-	Transformed cell line	Female
CVCL_C0I9	293EL-APP*	Transformed cell line	Female
CVCL_SL41	HAP1 EEA1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06041906	Not specified	ENROLLING_BY_INVITATION	International Registry of Congenital Portosystemic Shunt (IRCPSS)
NCT07314814	Not specified	NOT_YET_RECRUITING	Genetic Hallmarks of Patients With Congenital Portosystemic Shunts and Portopulmonary Hypertension