EPB41L3

Summary

EPB41L3 (erythrocyte membrane protein band 4.1 like 3, HGNC:3380) is a protein-coding gene on chromosome 18p11.31, encoding Band 4.1-like protein 3 (Q9Y2J2). Tumor suppressor that inhibits cell proliferation and promotes apoptosis.

Predicted to enable cytoskeletal protein-membrane anchor activity. Predicted to be a structural constituent of cytoskeleton. Predicted to be involved in several processes, including nervous system development; paranodal junction maintenance; and protein localization to axon. Located in several cellular components, including cell-cell junction; ciliary basal body; and cytosol. Implicated in esophagus squamous cell carcinoma. Biomarker of meningioma.

Source: NCBI Gene 23136 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities (Strong, GenCC)
• GWAS associations: 17
• Clinical variants (ClinVar): 181 total — 1 pathogenic
• MANE Select transcript: NM_012307

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3380
Approved symbol	EPB41L3
Name	erythrocyte membrane protein band 4.1 like 3
Location	18p11.31
Locus type	gene with protein product
Status	Approved
Aliases	DAL1, KIAA0987, 4.1B
Ensembl gene	ENSG00000082397
Ensembl biotype	protein_coding
OMIM	605331
Entrez	23136

Gene structure

Transcript identifiers

Ensembl transcripts: 77 — 65 protein_coding, 7 protein_coding_CDS_not_defined, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000341928, ENST00000342933, ENST00000400111, ENST00000540638, ENST00000542652, ENST00000544123, ENST00000545076, ENST00000578196, ENST00000578395, ENST00000578431, ENST00000578432, ENST00000578503, ENST00000578524, ENST00000578618, ENST00000579271, ENST00000579951, ENST00000580179, ENST00000580308, ENST00000580316, ENST00000580647, ENST00000580866, ENST00000580989, ENST00000581292, ENST00000581387, ENST00000581454, ENST00000581757, ENST00000581833, ENST00000582592, ENST00000582703, ENST00000582729, ENST00000584015, ENST00000584055, ENST00000584651, ENST00000584670, ENST00000585142, ENST00000637651, ENST00000866142, ENST00000866143, ENST00000866144, ENST00000866145, ENST00000866146, ENST00000866147, ENST00000866148, ENST00000866149, ENST00000866150, ENST00000866151, ENST00000866152, ENST00000866153, ENST00000866154, ENST00000866155, ENST00000866156, ENST00000866157, ENST00000866158, ENST00000866159, ENST00000866160, ENST00000936512, ENST00000936513, ENST00000936514, ENST00000936515, ENST00000971990, ENST00000971991, ENST00000971992, ENST00000971993, ENST00000971994, ENST00000971995, ENST00000971996, ENST00000971997, ENST00000971998, ENST00000971999, ENST00000972000, ENST00000972001, ENST00000972002, ENST00000972003, ENST00000972004, ENST00000972005, ENST00000972006, ENST00000972007

RefSeq mRNA: 30 — MANE Select: NM_012307 NM_001281533, NM_001281534, NM_001281535, NM_001330557, NM_001384682, NM_001384683, NM_001384684, NM_001384685, NM_001384686, NM_001384687, NM_001384688, NM_001384689, NM_001384690, NM_001384691, NM_001384692, NM_001384693, NM_001384694, NM_001384695, NM_001384696, NM_001384697, NM_001384698, NM_001384699, NM_001384700, NM_001384701, NM_001384702, NM_001384703, NM_001384704, NM_001384705, NM_001384706, NM_012307

CCDS: CCDS11838, CCDS62381, CCDS62382, CCDS82236, CCDS82237

Canonical transcript exons

ENST00000341928 — 23 exons

Exon	Start	End
ENSE00000665284	5415818	5416378
ENSE00001357890	5543913	5543997
ENSE00002265390	5392386	5393478
ENSE00003464036	5438035	5438110
ENSE00003465054	5406777	5406968
ENSE00003471179	5443838	5443880
ENSE00003479959	5398021	5398143
ENSE00003529708	5428313	5428465
ENSE00003544735	5424262	5424359
ENSE00003548492	5423378	5423553
ENSE00003564310	5394677	5394793
ENSE00003572917	5395609	5395707
ENSE00003575557	5419711	5419877
ENSE00003592469	5433469	5433556
ENSE00003606517	5407701	5407736
ENSE00003616370	5410566	5410619
ENSE00003630680	5433903	5434121
ENSE00003646904	5395067	5395147
ENSE00003650515	5397058	5397426
ENSE00003785177	5396201	5396332
ENSE00003786047	5445140	5445244
ENSE00003789583	5478241	5478438
ENSE00003791859	5489001	5489194

Expression profiles

Bgee: expression breadth ubiquitous, 285 present calls, max score 98.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.1738 / max 922.6606, expressed in 1267 samples.

FANTOM5 promoters (25 alternative TSS)

Promoter ID	TPM avg	Samples expressed
171121	14.3365	1146
171129	4.0095	612
171105	3.7510	92
171122	2.9551	946
171107	1.3760	102
171120	1.3691	626
171119	0.5042	267
171099	0.3829	174
171108	0.3616	63
171115	0.3379	121

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pons	UBERON:0000988	98.85	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.75	gold quality
Brodmann (1909) area 10	UBERON:0013541	98.62	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.58	gold quality
sperm	CL:0000019	98.56	gold quality
frontal pole	UBERON:0002795	98.51	gold quality
spinal cord	UBERON:0002240	98.50	gold quality
middle frontal gyrus	UBERON:0002702	98.26	gold quality
dorsal root ganglion	UBERON:0000044	98.24	gold quality
prefrontal cortex	UBERON:0000451	98.12	gold quality
dorsal plus ventral thalamus	UBERON:0001897	98.11	gold quality
subthalamic nucleus	UBERON:0001906	98.01	gold quality
paraflocculus	UBERON:0005351	97.92	gold quality
superior vestibular nucleus	UBERON:0007227	97.84	gold quality
inferior vagus X ganglion	UBERON:0005363	97.78	gold quality
corpus callosum	UBERON:0002336	97.76	gold quality
male germ cell	CL:0000015	97.72	gold quality
cerebellar vermis	UBERON:0004720	97.72	gold quality
ganglionic eminence	UBERON:0004023	97.53	gold quality
medulla oblongata	UBERON:0001896	97.50	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.45	gold quality
substantia nigra pars compacta	UBERON:0001965	97.35	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.27	gold quality
cortical plate	UBERON:0005343	97.13	gold quality
midbrain	UBERON:0001891	97.09	gold quality
substantia nigra	UBERON:0002038	97.06	gold quality
jejunal mucosa	UBERON:0000399	97.00	gold quality
sural nerve	UBERON:0015488	97.00	gold quality
primary visual cortex	UBERON:0002436	96.96	gold quality
cerebellar cortex	UBERON:0002129	96.95	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	42.77
E-MTAB-8142	yes	36.49
E-GEOD-83139	yes	8.60
E-MTAB-8060	no	365.56
E-MTAB-6142	no	131.76
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ERG

miRNA regulators (miRDB)

107 targeting EPB41L3, 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-7110-3P	100.00	73.18	2486
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4776-3P	100.00	68.73	1340
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-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-1271-5P	99.91	71.99	1972

Literature-anchored findings (GeneRIF, showing 40)

• Results show that three 14-3-3 isoforms, beta, gamma and eta, are DAL-1/Protein 4.1B-binding proteins. (PMID:11996670)
• DAL-1 protein functions at the interface between cell adhesion and apoptosis in suppressing breast cancer cell growth (PMID:12115567)
• TSLC1 and DAL-1, two distinct tumor suppressor proteins, directly associate in lung cancer. (PMID:12234973)
• DAL-1 has a role in the development of multiple meningioma and does not function as a tumor suppressor (PMID:12478663)
• Mechanisms such as genetic imprinting and monoallelic expression in combination with los os heterozygosity may be responsible for loss of EPB41L3 protein in early breast tumors. (PMID:15138999)
• DAL-1/4.1B protein significantly inhibits PRMT3 methylation of cellular substrates, which may affect mechanism through which DAL-1/4.1B affects tumor cell growth. (PMID:15334060)
• protein 4.1B in mouse small intestine & DAL-1 in human colon showed similar distributions in normal intestinal epithelial cells; expression reduced in intestinal carcinoma; may function in preventing malignant transformation of intestinal epithelial cells (PMID:15517334)
• U2 domain, when properly targeted to the plasma membrane, contains all the residues necessary for mediating Protein 4.1B growth suppression. (PMID:15688033)
• 4.1B gene deletion was statistically more common in ependymomas. (PMID:15731777)
• DAL-1 methylation is involved in the development and progression of non-small cell lung cancers and provides an indicator for poor prognosis. (PMID:15837747)
• The low mutational frequency in the study discounts sequence variations in DAL-1/4.1B as the main mechanism underlying participation of this gene in the neoplastic transformation of meningiomas. (PMID:16142420)
• promoter methylation of the 4.1B is one of the most frequent epigenetic alterations in RCCC and could predict the metastatic recurrence of the surgically resected RCCC (PMID:16152585)
• methylation of DAL-1 leading to loss of the expression, is an important event in the pathogenesis of non-small-cell lung cancer (PMID:16205641)
• These studies implicate the DAL-1/4.1B locus in sporadic meningiomas less commonly than reported previously, and suggest that it is a progression rather than an initiation locus. (PMID:16213361)
• These results suggest that protein methylation cooperates with DAL-1/4.1B-associated caspase 8-specific activation to induce apoptosis in breast cancer cells. (PMID:16420693)
• TSLC1 and DAL-1 are involved in the pathogenesis of breast cancer and are frequently inactivated by methylation (PMID:17260099)
• suggest a more general role for Protein 4.1B as a negative regulator of cancer progression to metastatic disease (PMID:17640904)
• A growing body of evidence supports a role for loss of EPB41L3 in tumor progression, including in prostate cancer [review] (PMID:18554153)
• Our results demonstrate a frequent, predominant epigenetic silencing of CADM1 and DAL-1 in nasal NK/T-cell lymphoma (NL), which likely play a synergic role in NL pathogenesis. (PMID:19115211)
• Using shotgun mass spectrometry, we found this protein differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19165527)
• Identify Golgi-specific protein 4.1 that appears to have an essential role in maintaining the structure of the Golgi and in assembly of a subset of membrane proteins. (PMID:19299464)
• Results identify erythrocyte protein band 4.1-like 3 (protein 4.1B) as an intracellular effector molecule of Synaptic Cell Adhesion Molecule 1 (SynCAM1) that is sufficient to recruit NMDA-type receptors (NMDARs) to SynCAM1 adhesion sites in COS7 cells. (PMID:19796685)
• An inducible model of EPB41L3 expression in three-dimensional spheroids confirmed that reexpression of EPB41L3 induces extensive apoptotic cell death in ovarian cancers. (PMID:20651987)
• The expressions of TSLC1 and 4.1B in non-small cell lung cancer tissues were significantly lower than that in adjacent lung tissues. (PMID:21081044)
• Structural basis of tumor suppressor in lung cancer 1 (TSLC1) binding to differentially expressed in adenocarcinoma of the lung (DAL-1/4.1B). (PMID:21131357)
• aberrant CADM1 and 4.1B expression is involved in progression of breast cancer, especially in invasion into the stroma and metastasis (PMID:21526423)
• miR-223, induced by the transcription factor Twist, posttranscriptionally downregulates EPB41L3 expression by directly targeting its 3’-untranslated regions. (PMID:21628394)
• Data suggest that the four-gene methylation panel might provide an alternative triage test after primary high-risk papillomavirus (hr-HPV) testing. (PMID:21796628)
• Loss of expression of the differentially expressed in adenocarcinoma of the lung protein is associated with metastasis of non-small cell lung carcinoma. (PMID:22782504)
• In granulosa cells, there are significant changes in expression during follicular maturation. (PMID:24828608)
• Studies indicate that tumor suppressor protein 4.1B/DAL-1 plays a crucial regulatory role in cell growth and differentiation. (PMID:25183197)
• The results suggest that tumor suppressor DAL-1 could also attenuate epithelial-to mesenchymal transition and be important for tumor metastasis in the early transformation process in lung cancer. (PMID:25609022)
• We conclude that EPB41L3, RASSF2 and TSP-1 genes are involved in the pathogenesis of diffuse gliomas (PMID:25621889)
• a central role of CADM1 in stabilizing the complex with 4.1B and MPP3 (PMID:25780926)
• Our study demonstrates for the first time that platelet-secreted miR-223 via P-MVs can promote lung cancer cell invasion via targeting tumor suppressor EPB41L3. (PMID:25881295)
• Downregulation of DAL-1/4.1B expression effectively suppresses DAL-1/4.1B protein expression in lung cancer cells. (PMID:26300315)
• findings reveal that EPB41L3 suppresses tumour cell invasion and inhibits MMP2 and MMP9 expression in esophageal squamous cell carcinoma cells (PMID:26916087)
• aberrant expression of DAL-1 by hypermethylation in the promoter region results in tumor suppressor gene behavior that plays important roles in the malignancy of gastric cancers (PMID:26923709)
• 4.1B gene deletion was sufficient to transform SV40T antigen-immortalized mouse embryonic fibroblasts (iMEFs), as reflected by the ability of 4.1B(-/-) iMEFs to growth in the environments that were growth restrictive for 4.1B(+/+) iMEFs and to form tumors in nude mice, whereas 4.1B(+/+) iMEFs were unable to form tumors in vivo. (PMID:27312663)
• We revealed that DAL-1 was downregulated while HSPA5 was upregulated in NSCLC and found the protein of DAL-1 and HSPA5 co-localized in the cytoplasm and nucleus. We demonstrated that DAL-1 can suppress the expression of HSPA5 on mRNA and protein levels, and decrease EMT, migration, invasion and proliferation abilities by down-regulating HSPA5 (PMID:29048640)

Cross-species orthologs

11 orthologs

Organism	Symbol	Gene ID
danio_rerio	epb41l3a	ENSDARG00000002255
danio_rerio	epb41l3b	ENSDARG00000019917
mus_musculus	Epb41l3	ENSMUSG00000024044
rattus_norvegicus	Epb41l3	ENSRNOG00000016724
drosophila_melanogaster	yrt	FBGN0004049
drosophila_melanogaster	cora	FBGN0010434
drosophila_melanogaster	Frmd5	FBGN0032225
caenorhabditis_elegans	erm-1	WBGENE00001333
caenorhabditis_elegans	frm-1	WBGENE00001488
caenorhabditis_elegans		WBGENE00001489
caenorhabditis_elegans	frm-4	WBGENE00001491

Paralogs (10): MYLIP (ENSG00000007944), EPB41L2 (ENSG00000079819), EPB41L1 (ENSG00000088367), EPB41L4B (ENSG00000095203), EPB41L5 (ENSG00000115109), EPB41L4A (ENSG00000129595), FRMD6 (ENSG00000139926), EPB41 (ENSG00000159023), FRMD5 (ENSG00000171877), FRMD3 (ENSG00000172159)

Protein

Protein identifiers

Band 4.1-like protein 3 — Q9Y2J2 (reviewed: Q9Y2J2)

Alternative names: 4.1B, Differentially expressed in adenocarcinoma of the lung protein 1, Erythrocyte membrane protein band 4.1-like 3

All UniProt accessions (22): Q9Y2J2, A0A0A0MRA8, A0A0A0MSA4, A0A0J9YW26, A0A0J9YW31, A0A0J9YWE1, A0A0J9YWN0, A0A0J9YWS4, A0A0J9YY18, A0A0U1RR92, A0A1B0GTF8, A8K968, J3KRD1, J3KS70, J3KT37, J3QKK4, J3QKY2, J3QLU5, J3QR33, J3QRQ6, J3QS55, J3QS83

UniProt curated annotations — full annotation on UniProt →

Function. Tumor suppressor that inhibits cell proliferation and promotes apoptosis. Modulates the activity of protein arginine N-methyltransferases, including PRMT3 and PRMT5.

Subunit / interactions. Interacts (via FERM domain) with CADM1. Interacts (via FERM domain) with PRMT3; the interaction is direct and inhibits the protein-arginine N-methyltransferase activity of PRMT3. Interacts with PRMT5. Interacts with PRMT6.

Subcellular location. Cytoplasm. Cytoskeleton. Cell junction. Cell membrane.

Tissue specificity. Expressed at high levels in brain, with lower levels in kidney, intestine, and testis. Detected in lung.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9Y2J2-1	1	yes
Q9Y2J2-2	2
Q9Y2J2-3	3
Q9Y2J2-4	4

RefSeq proteins (30): NP_001268462, NP_001268463, NP_001268464, NP_001317486, NP_001371611, NP_001371612, NP_001371613, NP_001371614, NP_001371615, NP_001371616, NP_001371617, NP_001371618, NP_001371619, NP_001371620, NP_001371621, NP_001371622, NP_001371623, NP_001371624, NP_001371625, NP_001371626, NP_001371627, NP_001371628, NP_001371629, NP_001371630, NP_001371631, NP_001371632, NP_001371633, NP_001371634, NP_001371635, NP_036439* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000299	FERM_domain	Domain
IPR000798	Ez/rad/moesin-like	Family
IPR007477	SAB_dom	Domain
IPR008379	Band_4.1_C	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR014352	FERM/acyl-CoA-bd_prot_sf	Homologous_superfamily
IPR014847	FA	Domain
IPR018979	FERM_N	Domain
IPR018980	FERM_PH-like_C	Domain
IPR019747	FERM_CS	Conserved_site
IPR019748	FERM_central	Domain
IPR019749	Band_41_domain	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR030691	Band4.1-L3_FERM_F1	Domain
IPR035963	FERM_2	Homologous_superfamily

Pfam: PF00373, PF04382, PF05902, PF08736, PF09379, PF09380

UniProt features (72 total): modified residue 13, strand 13, helix 10, region of interest 8, splice variant 7, compositionally biased region 6, turn 5, sequence variant 3, sequence conflict 3, chain 2, initiator methionine 1, domain 1

Structure

Experimental structures (PDB)

54 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6IBE	X-RAY DIFFRACTION	1.45
5RYO	X-RAY DIFFRACTION	1.58
5RZB	X-RAY DIFFRACTION	1.59
5RYZ	X-RAY DIFFRACTION	1.61
5RZ4	X-RAY DIFFRACTION	1.61
5RZ1	X-RAY DIFFRACTION	1.62
5RZW	X-RAY DIFFRACTION	1.62
5RYP	X-RAY DIFFRACTION	1.63
5RYU	X-RAY DIFFRACTION	1.63
5RYX	X-RAY DIFFRACTION	1.63
5RZ5	X-RAY DIFFRACTION	1.63
5RYM	X-RAY DIFFRACTION	1.64
5RYQ	X-RAY DIFFRACTION	1.64
5RZ6	X-RAY DIFFRACTION	1.64
5RYW	X-RAY DIFFRACTION	1.66
5RZ8	X-RAY DIFFRACTION	1.66
5RZU	X-RAY DIFFRACTION	1.66
5RZJ	X-RAY DIFFRACTION	1.68
5RYV	X-RAY DIFFRACTION	1.69
5RYY	X-RAY DIFFRACTION	1.69
5RZE	X-RAY DIFFRACTION	1.69
5RZS	X-RAY DIFFRACTION	1.69
5RZG	X-RAY DIFFRACTION	1.7
5RZP	X-RAY DIFFRACTION	1.7
5RZL	X-RAY DIFFRACTION	1.71
5RZM	X-RAY DIFFRACTION	1.71
5RYT	X-RAY DIFFRACTION	1.72
5RZ0	X-RAY DIFFRACTION	1.74
5RZ3	X-RAY DIFFRACTION	1.74
5RZX	X-RAY DIFFRACTION	1.74

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2J2-F1	59.53	0.25

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 (13): 1, 2, 88, 420, 443, 460, 469, 492, 706, 708, 960, 962, 1081

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6794361	Neurexins and neuroligins
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea
R-HSA-9662361	Sensory processing of sound by outer hair cells of the cochlea

MSigDB gene sets: 363 (showing top): RNGTGGGC_UNKNOWN, MODULE_52, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, PEREZ_TP63_TARGETS, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOBP_NEUROGENESIS, KEGG_TIGHT_JUNCTION, MODULE_16, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, SENESE_HDAC1_AND_HDAC2_TARGETS_DN, MODULE_66, MODULE_118, NKX62_Q2, GOBP_CELL_JUNCTION_ORGANIZATION

GO Biological Process (13): protein localization to paranode region of axon (GO:0002175), apoptotic process (GO:0006915), regulation of cell shape (GO:0008360), cortical cytoskeleton organization (GO:0030865), cortical actin cytoskeleton organization (GO:0030866), paranodal junction assembly (GO:0030913), actomyosin structure organization (GO:0031032), myelin maintenance (GO:0043217), neuron projection morphogenesis (GO:0048812), protein localization to juxtaparanode region of axon (GO:0071205), protein localization to plasma membrane (GO:0072659), regulation of neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0098696), biological_process (GO:0008150)

GO Molecular Function (6): actin binding (GO:0003779), structural constituent of cytoskeleton (GO:0005200), cytoskeletal protein-membrane anchor activity (GO:0106006), structural molecule activity (GO:0005198), protein binding (GO:0005515), cytoskeletal protein binding (GO:0008092)

GO Cellular Component (15): cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), cilium (GO:0005929), cell junction (GO:0030054), paranode region of axon (GO:0033270), ciliary basal body (GO:0036064), juxtaparanode region of axon (GO:0044224), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), membrane (GO:0016020), axolemma (GO:0030673), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Sensory processing of sound	2
Protein-protein interactions at synapses	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
main axon	3
protein localization to axon	2
regulation of biological quality	2
cytoskeleton organization	2
actin cytoskeleton organization	2
synapse	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
regulation of cell morphogenesis	1
cortical cytoskeleton organization	1
cell-cell junction assembly	1
cellular component assembly involved in morphogenesis	1
myelin assembly	1
plasma membrane organization	1
myelination	1
neuron projection development	1
plasma membrane bounded cell projection morphogenesis	1
protein localization to membrane	1
protein localization to cell periphery	1
neurotransmitter receptor localization to postsynaptic specialization membrane	1
regulation of protein localization to synapse	1
regulation of receptor localization to synapse	1
regulation of protein localization to cell periphery	1
regulation of protein localization to membrane	1
cytoskeletal protein binding	1
structural molecule activity	1
cytoskeleton	1
cytoskeletal adaptor activity	1
lipid binding	1
protein-membrane adaptor activity	1
molecular_function	1
binding	1
protein binding	1
cytoplasm	1
intracellular membraneless organelle	1
membrane	1
cell periphery	1
anchoring junction	1

Protein interactions and networks

STRING

1326 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EPB41L3	PRMT3	O60678	914
EPB41L3	CADM1	Q9BY67	857
EPB41L3	RUBCNL	Q9H714	645
EPB41L3	TAFA4	Q96LR4	582
EPB41L3	MPP3	Q13368	574
EPB41L3	PRMT1	Q99873	564
EPB41L3	PRMT5	O14744	530
EPB41L3	JAM3	Q9BX67	506
EPB41L3	C1QBP	Q07021	494
EPB41L3	NINJ2	Q9NZG7	486
EPB41L3	ZNF582	Q96NG8	474
EPB41L3	PAX1	P15863	474
EPB41L3	RBFOX2	O43251	469
EPB41L3	CNTNAP2	Q9UHC6	461
EPB41L3	EPB41	P11171	448

IntAct

134 interactions, top by confidence:

A	B	Type	Score
GSK3B	AXIN1	psi-mi:“MI:0914”(association)	0.980
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
EPB41L3	YWHAG	psi-mi:“MI:0915”(physical association)	0.870
YWHAB	EPB41L3	psi-mi:“MI:0915”(physical association)	0.810
YWHAZ	EPB41L3	psi-mi:“MI:0915”(physical association)	0.750
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SNRPB	PRMT5	psi-mi:“MI:0914”(association)	0.670
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
PNN	CASC3	psi-mi:“MI:0914”(association)	0.640
YWHAB	BLTP3B	psi-mi:“MI:0914”(association)	0.610
YWHAE	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
TUBB3	POTEF	psi-mi:“MI:0914”(association)	0.530
SYNGAP1	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
CACNG5	ZNF316	psi-mi:“MI:0914”(association)	0.530
EPB41L1	AP3B1	psi-mi:“MI:0914”(association)	0.530
AP3S1	AP3B1	psi-mi:“MI:0914”(association)	0.530
EPB41L3	AP3B1	psi-mi:“MI:0914”(association)	0.530
SNRPN	PRMT5	psi-mi:“MI:0914”(association)	0.530
DDAH2	OGT	psi-mi:“MI:0914”(association)	0.530
PRICKLE3	SIAH2	psi-mi:“MI:0914”(association)	0.530
MISP	OBSL1	psi-mi:“MI:0914”(association)	0.530
PALS1	AMOTL1	psi-mi:“MI:0914”(association)	0.530

BioGRID (357): EPB41L3 (Affinity Capture-MS), EPB41L3 (Two-hybrid), EPB41L3 (Affinity Capture-MS), EPB41L3 (Affinity Capture-MS), MBIP (Two-hybrid), YWHAB (Affinity Capture-MS), YWHAE (Affinity Capture-MS), YWHAH (Affinity Capture-MS), YWHAG (Affinity Capture-MS), YWHAQ (Affinity Capture-MS), ACIN1 (Affinity Capture-MS), MLLT3 (Affinity Capture-MS), PRMT5 (Affinity Capture-MS), AP3B1 (Affinity Capture-MS), AP3D1 (Affinity Capture-MS)

ESM2 similar proteins: A2ASS6, A8DYP0, E9QMW4, G4SLH0, J7M799, M9MRD1, O15061, O43491, O55103, O70318, O75952, O77788, P07197, P08553, P08855, P11799, P12839, P16053, P27321, P51125, P54938, P57786, P82179, P83741, Q06637, Q13061, Q23551, Q28820, Q4R3X7, Q63425, Q66H38, Q696W0, Q6TS35, Q70IV5, Q7Z589, Q7ZUV7, Q86TC9, Q8BMB0, Q8TC56, Q8WZ42

Diamond homologs: A2A2Y4, A2AD83, A2ALK8, B2RYE5, F1LYQ8, F1P065, F8VPU2, O43491, O57457, O70318, O94887, P11171, P11434, P26045, P28191, P29074, P48193, P52963, Q0P4Q4, Q54K81, Q58CU2, Q5FVG2, Q5R803, Q5RAB8, Q6P5H6, Q6Q7P4, Q6ZUT3, Q7Z6J6, Q8BGS1, Q8BHD4, Q91VS8, Q9H329, Q9H4G0, Q9HCM4, Q9HCS5, Q9JMC8, Q9MYU8, Q9N179, Q9V8R9, Q9WTP0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ERG	“down-regulates quantity by repression”	EPB41L3	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 149 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
Activation of BAD and translocation to mitochondria	6	43.5×	7e-07
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	38.4×	1e-06
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	38.4×	1e-06
Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants	6	29.7×	4e-06
Activation of BH3-only proteins	6	28.4×	4e-06
Downstream signal transduction	6	21.8×	1e-05
RHO GTPases activate PKNs	7	21.1×	4e-06
Signaling by high-kinase activity BRAF mutants	7	21.1×	4e-06

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	14.0×	9e-03
Ras protein signal transduction	6	9.4×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	146
Likely benign	8
Benign	6

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
815967	GRCh37/hg19 18p11.32-11.31(chr18:544117-5679224)x1	Pathogenic

SpliceAI

5015 predictions. Top by Δscore:

Variant	Effect	Δscore
18:5394811:C:CT	acceptor_gain	1.0000
18:5394812:A:T	acceptor_gain	1.0000
18:5396333:C:CC	acceptor_gain	1.0000
18:5396335:G:C	acceptor_gain	1.0000
18:5396339:C:CT	acceptor_gain	1.0000
18:5396339:C:T	acceptor_gain	1.0000
18:5396340:A:T	acceptor_gain	1.0000
18:5397053:GTTAC:G	donor_loss	1.0000
18:5397054:TTA:T	donor_loss	1.0000
18:5397055:TACC:T	donor_loss	1.0000
18:5406772:CTGA:C	donor_loss	1.0000
18:5406773:TGACC:T	donor_loss	1.0000
18:5406774:GAC:G	donor_loss	1.0000
18:5406775:A:AG	donor_loss	1.0000
18:5406776:CCT:C	donor_gain	1.0000
18:5406964:AGCTC:A	acceptor_gain	1.0000
18:5406965:GCTC:G	acceptor_gain	1.0000
18:5406966:CTC:C	acceptor_gain	1.0000
18:5406966:CTCC:C	acceptor_gain	1.0000
18:5406967:TC:T	acceptor_gain	1.0000
18:5406967:TCCT:T	acceptor_gain	1.0000
18:5406968:CC:C	acceptor_gain	1.0000
18:5406969:C:A	acceptor_loss	1.0000
18:5406969:C:CC	acceptor_gain	1.0000
18:5406970:T:A	acceptor_loss	1.0000
18:5410658:C:CT	acceptor_gain	1.0000
18:5419775:T:TA	donor_gain	1.0000
18:5419932:C:CC	acceptor_gain	1.0000
18:5423372:GCCTA:G	donor_loss	1.0000
18:5423373:CCTA:C	donor_loss	1.0000

AlphaMissense

7072 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:5394769:C:G	A1060P	1.000
18:5394781:C:G	A1056P	1.000
18:5394789:A:G	L1053P	1.000
18:5395107:C:G	R1038P	1.000
18:5423500:A:G	F406S	1.000
18:5424265:A:G	F387S	1.000
18:5424285:A:C	C380W	1.000
18:5424286:C:T	C380Y	1.000
18:5424287:A:G	C380R	1.000
18:5424294:C:A	W377C	1.000
18:5424294:C:G	W377C	1.000
18:5424296:A:G	W377R	1.000
18:5424296:A:T	W377R	1.000
18:5424298:A:G	L376S	1.000
18:5424307:G:T	A373D	1.000
18:5424325:A:G	L367P	1.000
18:5424330:A:C	F365L	1.000
18:5424330:A:T	F365L	1.000
18:5424331:A:G	F365S	1.000
18:5424332:A:G	F365L	1.000
18:5424334:C:T	G364E	1.000
18:5424335:C:G	G364R	1.000
18:5424335:C:T	G364R	1.000
18:5428332:A:C	I349S	1.000
18:5428332:A:T	I349N	1.000
18:5428337:A:C	F347L	1.000
18:5428337:A:T	F347L	1.000
18:5428338:A:G	F347S	1.000
18:5428339:A:G	F347L	1.000
18:5428359:A:C	I340S	1.000

dbSNP variants (sampled 300 via entrez): RS1000005067 (18:5458837 G>A), RS1000011232 (18:5506630 G>A), RS1000015743 (18:5498567 C>A,T), RS1000033492 (18:5534545 A>G), RS1000040442 (18:5529002 G>C), RS1000046498 (18:5617553 C>T), RS1000086142 (18:5493151 T>G), RS1000088806 (18:5498780 A>G), RS1000089954 (18:5607114 T>C), RS1000099817 (18:5617365 C>T), RS1000135823 (18:5441946 C>T), RS1000140764 (18:5431321 C>G,T), RS1000156492 (18:5412830 T>C), RS1000156682 (18:5541217 C>T), RS1000167540 (18:5524061 A>T)

Disease associations

OMIM: gene MIM:605331 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities	Strong	Autosomal recessive

Mondo (1): neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities (MONDO:0030063)

Orphanet (0):

HPO phenotypes

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

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST002367_3	Social communication problems	2.000000e-06
GCST002711_11	Sleep duration	6.000000e-06
GCST003073_8	Cerebral amyloid deposition (PET imaging)	3.000000e-07
GCST004292_48	Glomerular filtration rate (creatinine)	7.000000e-09
GCST006387_2	Thyroid nodules	5.000000e-06
GCST006479_22	Diverticular disease	9.000000e-06
GCST007344_124	Estimated glomerular filtration rate	2.000000e-11
GCST007876_68	Estimated glomerular filtration rate	8.000000e-14
GCST008058_68	Estimated glomerular filtration rate	2.000000e-25
GCST008059_67	Estimated glomerular filtration rate	4.000000e-23
GCST008064_15	Chronic kidney disease	4.000000e-06
GCST008747_149	Estimated glomerular filtration rate	5.000000e-14
GCST008747_88	Estimated glomerular filtration rate	5.000000e-12
GCST009412_22	Vertical cup-disc ratio	7.000000e-06
GCST009416_4	Optic nerve head parameters (multi-trait analysis)	3.000000e-07
GCST90014122_5	Lacunar stroke	1.000000e-06
GCST90014123_5	Lacunar stroke	2.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0005427	social communication impairment
EFO:0007707	cerebral amyloid deposition measurement
EFO:1001436	thyroid nodule
EFO:0009959	diverticular disease
EFO:0006939	cup-to-disc ratio measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	8
trichostatin A	increases expression, affects cotreatment	3
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
entinostat	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Arsenic	increases abundance, increases expression, affects expression	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	decreases expression, affects expression	2
Aflatoxin B1	increases methylation, decreases methylation	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	increases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	increases expression	1
lead acetate	affects cotreatment, decreases expression	1
arsenite	affects binding, decreases reaction	1
chromous chloride	affects cotreatment, decreases expression	1
cobaltous chloride	decreases expression	1
chromic oxide	affects cotreatment, decreases expression	1
zinc chromate	affects expression, increases abundance	1
hydroquinone	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, decreases expression	1
mercuric bromide	affects cotreatment, increases expression	1
chromium hexavalent ion	affects expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	affects methylation	1
monomethylarsonous acid	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

Clinical trials (associated diseases)

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