EFNB1

Summary

EFNB1 (ephrin B1, HGNC:3226) is a protein-coding gene on chromosome Xq13.1, encoding Ephrin-B1 (P98172). Cell surface transmembrane ligand for Eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is a type I membrane protein and a ligand of Eph-related receptor tyrosine kinases. It may play a role in cell adhesion and function in the development or maintenance of the nervous system.

Source: NCBI Gene 1947 — RefSeq curated summary.

At a glance

• Gene–disease (curated): craniofrontonasal syndrome (Definitive, ClinGen)
• Clinical variants (ClinVar): 231 total — 49 pathogenic, 25 likely-pathogenic
• Phenotypes (HPO): 71
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity little evidence
• MANE Select transcript: NM_004429

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3226
Approved symbol	EFNB1
Name	ephrin B1
Location	Xq13.1
Locus type	gene with protein product
Status	Approved
Aliases	LERK2, Elk-L
Ensembl gene	ENSG00000090776
Ensembl biotype	protein_coding
OMIM	300035
Entrez	1947

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000204961, ENST00000851101

RefSeq mRNA: 1 — MANE Select: NM_004429 NM_004429

CCDS: CCDS14391

Canonical transcript exons

ENST00000204961 — 5 exons

Exon	Start	End
ENSE00000672435	68838617	68838894
ENSE00000672436	68839664	68839756
ENSE00000672437	68839960	68840088
ENSE00001041113	68829021	68829904
ENSE00001041114	68840242	68842160

Expression profiles

Bgee: expression breadth ubiquitous, 198 present calls, max score 97.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.1099 / max 497.0473, expressed in 1740 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196599	24.1099	1740

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	97.76	gold quality
right lung	UBERON:0002167	95.40	gold quality
ganglionic eminence	UBERON:0004023	94.78	gold quality
mucosa of transverse colon	UBERON:0004991	92.70	gold quality
skin of abdomen	UBERON:0001416	92.14	gold quality
skin of leg	UBERON:0001511	91.45	gold quality
upper lobe of left lung	UBERON:0008952	91.29	gold quality
omental fat pad	UBERON:0010414	91.18	gold quality
peritoneum	UBERON:0002358	91.09	gold quality
upper lobe of lung	UBERON:0008948	90.51	gold quality
metanephros cortex	UBERON:0010533	90.42	gold quality
tibial nerve	UBERON:0001323	90.33	gold quality
adipose tissue of abdominal region	UBERON:0007808	89.86	gold quality
apex of heart	UBERON:0002098	89.38	gold quality
embryo	UBERON:0000922	88.92	gold quality
transverse colon	UBERON:0001157	88.85	gold quality
zone of skin	UBERON:0000014	88.28	gold quality
lower esophagus mucosa	UBERON:0035834	88.26	gold quality
ectocervix	UBERON:0012249	87.80	gold quality
sural nerve	UBERON:0015488	87.60	gold quality
endocervix	UBERON:0000458	87.45	gold quality
subcutaneous adipose tissue	UBERON:0002190	87.39	gold quality
olfactory bulb	UBERON:0002264	87.15	gold quality
esophagus mucosa	UBERON:0002469	86.83	gold quality
heart left ventricle	UBERON:0002084	86.78	gold quality
gall bladder	UBERON:0002110	86.71	gold quality
cardiac ventricle	UBERON:0002082	86.16	gold quality
right uterine tube	UBERON:0001302	86.15	gold quality
right lobe of thyroid gland	UBERON:0001119	86.10	gold quality
right adrenal gland	UBERON:0001233	86.08	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-5	yes	42.14
E-GEOD-135922	yes	21.08
E-ANND-3	yes	10.96
E-MTAB-6058	no	2.62

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

120 targeting EFNB1, 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-6867-5P	100.00	82.21	3464
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-5692A	100.00	74.40	6850
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-548E-5P	99.89	72.73	4486

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 1 (little evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Human platelets express EphA4 and EphB1, and the ligand, ephrinB1. Forced clustering of EphA4 or ephrinB1 led to cytoskeletal reorganization, adhesion to fibrinogen, and alpha-granule secretion. (PMID:12084815)
• Expression profile of this ligand of EPHB2 in gastric cancer (PMID:12136247)
• The expression of ephrin-B1 was correlated with a poorer clinical prognosis. Ephrin-B1 protein was expressed by osteosarcoma cells and blood vessels. (PMID:12209731)
• Ephrin B1 induces human aortic endothelial cells migration in a pathway that involves Crk adaptor protein (PMID:12475948)
• conclude that ephrinB1 and B class Eph receptors provide positional cues required for the normal morphogenesis of skeletal elements (PMID:12919674)
• Eph/ephrin signaling enhances the ability of platelet agonists to cause aggregation by activating Rap1 and these effects require oligomerization of ephrinB1 but not phosphotyrosine-based interactions with the ephrinB1 cytoplasmic domain. (PMID:14576067)
• Ephrin-B1 may be involved in in vivo tumor progression by promoting neovascularization in hepatocellular carcinoma (PMID:14642617)
• Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome (PMID:15124102)
• ephrin-B1 internalization is an active receptor-mediated process that utilizes the clathrin-mediated endocytic pathway (PMID:15351694)
• On ephrinB1 stimulation, the small GTPases Rho and Ras are activated and Rap1 is inactivated. (PMID:15725075)
• EFNB1 mutations have a role in familial and sporadic craniofrontonasal syndrome (CFNS) (PMID:15959873)
• EphB/ephrin-B molecules play a role in restricting dental pulp stem cell attachment and migration to maintain Dthesse cells within their stem cell niche under steady-state conditions. (PMID:17204606)
• C-terminus of ephrin-B1 regulates activation of the extracellular release of MMP-8 without requirement of de novo protein synthesis. (PMID:17567680)
• Our results suggest that tyrosine phosphorylation of ephrin-B1 promotes invasion of cancer cells in vivo (PMID:17591954)
• Silencing of EphB expression is associated with colorectal tumorigenesis. (PMID:17906625)
• EphrinB1 may play an important role in the inflammatory states of rheumatoid arthritis, by affecting the population/function of T cells. (PMID:17942634)
• EFNB1 mutant transcripts with nonsense codons are degraded by the nonsense-mediated mRNA decay pathway and lead to craniofrontonasal syndrome. (PMID:18043713)
• Ephrin-B1 is likely to play an important role in the regulation of malignant T lymphocytes through the control of lipid-raft-associated signaling, adhesion, and invasive activity (PMID:18314490)
• Several new EFNB1 mutations have been identified in craniofrontonasal syndrome. (PMID:18627045)
• combination of SDF-1, PTN, IGF2, and EFNB1 mimics the DA phenotype-inducing property of SDIA and was sufficient to promote differentiation of hESC to functional midbrain DA neurons (PMID:19672298)
• study reports that the expression of ephrin-B1 is controlled by a feedback loop involving posttranscriptional regulatory mechanisms (PMID:20308325)
• The impact of craniofrontonasal syndrome-causing EFNB1 mutations on ephrin-B1 function is reported. (PMID:20565770)
• Unreported mutation in EFNB1 predicts occurrence of congenital diaphragmatic hernia, phenotypic differences between males and female. (PMID:20734337)
• X-linked cases resembling Teebi hypertelorism may have a similar mechanism to CFNS, and that cellular mosaicism for different levels of ephrin-B1 (as well as simple presence/absence) leads to craniofacial abnormalities. (PMID:21542058)
• Data show that EphrinB1, a PTPN13 substrate, interacts with ErbB2, and Src kinase mediates EphrinB1 phosphorylation and subsequent MAP Kinase signaling. (PMID:22279592)
• These results indicate a novel function of Nm23-H1 to control contact inhibition of locomotion, and its negative regulation by ephrin-B1. (PMID:22718351)
• we report the identification of mosaic EFNB1 mutations in every individual with craniofrontonasal syndrome, confirming the suggested diagnosis and supporting the hypothesis of cellular interference in humans. (PMID:23335590)
• High EFNB1 expression is associated with squamous cell carcinomas of the head and neck. (PMID:23811940)
• EphrinB1 expression is related to the metastasis of breast cancer and its enhanced expression confers a poor prognosis, suggesting that EphrinB1 may be a relevant therapeutic target in breast cancers. (PMID:24240587)
• Patients with EFNB1 mutations have a clear phenotype. This study will facilitate genetic counseling of parents and patients, and contribute to the diagnostic and screening process of patients with suspected CFNS. (PMID:24281372)
• CNK1 mediates ephrinB1 signaling that promotes cell migration through RhoA and JNK activity. (PMID:24825906)
• Results indicate that EphrinB1 is uniquely dysregulated in medulloblastoma and promotes oncogenic responses in medulloblastoma cells, implicating ephrinB1 as a potential target (PMID:25258252)
• that EphrinB1 (EFNB1) co-localizes with microtubules (MTs) during all phases of the cell cycle. (PMID:25436983)
• we report a family with a G151S mutation in the EFNB1 gene. The mutation was identified in two severely affected sisters and paradoxically in their clinically unaffected father. (PMID:25486017)
• EphB2/ephrin-B1 were invoked in dental pulp stem cells with TNF-alpha treatment via the JNK-dependent pathway, but not NF-kB, p38 MAPK or MEK signalling. (PMID:25643922)
• T cells from rheumatoid arthritis (RA) patients expressed higher EFNB1 mRNA levels, which correlated with RA symptoms and laboratory findings. Expression of EFNB1 in T cells might be a parameter for monitoring RA disease activity and treatment responses. (PMID:25779027)
• While ephrin-B1 deficiency leads to abnormal visual pathways in mice, it leaves the human visual system, apart from deficits in binocular vision, largely normal. (PMID:26580852)
• that expression of EFNB1 and EFNB2 is implicated in Th cell differentiation and migration to inflammatory sites in both EAE and MS (PMID:27039370)
• one novel (IVS2+3G>T) and one previously reported mutation (p.Gly151Ser) in EFNB1 Both patients were de novo cases without a family history of Craniofrontonasal syndrome. (PMID:27650623)
• we demonstrate that mosaicism for EPHRIN-B1 expression induced by random X inactivation in heterozygous females results in robust cell segregation in human neuroepithelial cells, thus supplying experimental evidence that Eph/ephrin-mediated cell segregation is relevant to pathogenesis in human CFNS patients. (PMID:28238796)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	efnb1	ENSDARG00000007723
mus_musculus	Efnb1	ENSMUSG00000031217
rattus_norvegicus	Efnb1	ENSRNOG00000006877
drosophila_melanogaster	Ephrin	FBGN0040324
caenorhabditis_elegans		WBGENE00001163
caenorhabditis_elegans		WBGENE00001164
caenorhabditis_elegans		WBGENE00001165
caenorhabditis_elegans		WBGENE00006869

Paralogs (7): EFNA2 (ENSG00000099617), EFNB3 (ENSG00000108947), EFNB2 (ENSG00000125266), EFNA3 (ENSG00000143590), EFNA1 (ENSG00000169242), EFNA5 (ENSG00000184349), EFNA4 (ENSG00000243364)

Protein

Protein identifiers

Ephrin-B1 — P98172 (reviewed: P98172)

Alternative names: EFL-3, ELK ligand, EPH-related receptor tyrosine kinase ligand 2

All UniProt accessions (1): P98172

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface transmembrane ligand for Eph receptors, a family of receptor tyrosine kinases which are crucial for migration, repulsion and adhesion during neuronal, vascular and epithelial development. Binding to Eph receptors residing on adjacent cells leads to contact-dependent bidirectional signaling into neighboring cells. Shows high affinity for the receptor tyrosine kinase EPHB1/ELK. Can also bind EPHB2 and EPHB3. Binds to, and induces collapse of, commissural axons/growth cones in vitro. May play a role in constraining the orientation of longitudinally projecting axons.

Subunit / interactions. Interacts (via PDZ-binding motif) with GRIP1 and GRIP2 (via PDZ domain 6). Interacts with TLE1. The intracellular domain peptide interacts with ZHX2; the interaction enhances ZHX2 transcriptional repression activity.

Subcellular location. Cell membrane. Membrane raft Cell membrane Nucleus.

Tissue specificity. Widely expressed. Detected in both neuronal and non-neuronal tissues. Seems to have particularly strong expression in retina, sciatic nerve, heart and spinal cord.

Post-translational modifications. Inducible phosphorylation of tyrosine residues in the cytoplasmic domain. Proteolytically processed. The ectodomain is cleaved, probably by a metalloprotease, to produce a membrane-tethered C-terminal fragment. This fragment is then further processed by the gamma-secretase complex to yield a soluble intracellular domain peptide which can translocate to the nucleus. The intracellular domain peptide is highly labile suggesting that it is targeted for degradation by the proteasome.

Disease relevance. Craniofrontonasal syndrome (CFNS) [MIM:304110] X-linked inherited syndrome characterized by hypertelorism, coronal synostosis with brachycephaly, downslanting palpebral fissures, clefting of the nasal tip, joint anomalies, longitudinally grooved fingernails and other digital anomalies. The disease is caused by variants affecting the gene represented in this entry.

Induction. Up-regulated in response to TNF.

Similarity. Belongs to the ephrin family.

RefSeq proteins (1): NP_004420* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001799	Ephrin_RBD	Domain
IPR008972	Cupredoxin	Homologous_superfamily
IPR019765	Ephrin_CS	Conserved_site
IPR031328	Ephrin	Family
IPR034255	Ephrin-B_Ecto	Domain

Pfam: PF00812

UniProt features (42 total): sequence variant 22, chain 3, short sequence motif 2, modified residue 2, disulfide bond 2, topological domain 2, mutagenesis site 2, region of interest 2, signal peptide 1, compositionally biased region 1, glycosylation site 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6THG	X-RAY DIFFRACTION	4.07

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P98172-F1	71.68	0.37

Functional residue map

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

Post-translational modifications (2): 281, 287

Disulfide bonds (2): 64–101, 89–153

Glycosylation sites (1): 139

Mutagenesis-validated functional residues (2):

Position	Phenotype
260–273	the intracellular domain peptide fails to localize to the nucleus.
344–346	no effect on gamma-secretase mediated proteolysis of the c-terminal fragment.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-2682334	EPH-Ephrin signaling
R-HSA-3928662	EPHB-mediated forward signaling
R-HSA-3928664	Ephrin signaling
R-HSA-3928665	EPH-ephrin mediated repulsion of cells

MSigDB gene sets: 394 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_UP, GOBP_REGULATION_OF_CELL_ACTIVATION, RNGTGGGC_UNKNOWN, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, BYSTRYKH_HEMATOPOIESIS_STEM_CELL_FGF3, HOFFMANN_SMALL_PRE_BII_TO_IMMATURE_B_LYMPHOCYTE_DN, TGCACTT_MIR519C_MIR519B_MIR519A, ENK_UV_RESPONSE_KERATINOCYTE_UP, MODULE_64, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_LYMPHOCYTE_COSTIMULATION, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOCC_CELL_SURFACE, KYNG_DNA_DAMAGE_DN

GO Biological Process (12): neural crest cell migration (GO:0001755), cell adhesion (GO:0007155), cell-cell signaling (GO:0007267), axon guidance (GO:0007411), embryonic pattern specification (GO:0009880), T cell costimulation (GO:0031295), T cell proliferation (GO:0042098), positive regulation of T cell proliferation (GO:0042102), ephrin receptor signaling pathway (GO:0048013), nervous system development (GO:0007399), cell differentiation (GO:0030154), regulation of autophagosome assembly (GO:2000785)

GO Molecular Function (2): ephrin receptor binding (GO:0046875), protein binding (GO:0005515)

GO Cellular Component (10): nucleus (GO:0005634), cytoplasm (GO:0005737), plasma membrane (GO:0005886), cell surface (GO:0009986), presynaptic membrane (GO:0042734), membrane raft (GO:0045121), synapse (GO:0045202), extracellular exosome (GO:0070062), glutamatergic synapse (GO:0098978), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
EPH-Ephrin signaling	3
Axon guidance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
positive regulation of T cell activation	2
neural crest cell development	1
mesenchymal cell migration	1
cellular process	1
cell communication	1
signaling	1
axonogenesis	1
neuron projection guidance	1
pattern specification process	1
embryo development	1
lymphocyte costimulation	1
T cell activation	1
lymphocyte proliferation	1
T cell proliferation	1
regulation of T cell proliferation	1
positive regulation of lymphocyte proliferation	1
cell surface receptor protein tyrosine kinase signaling pathway	1
system development	1
cellular developmental process	1
autophagosome assembly	1
regulation of vacuole organization	1
regulation of organelle assembly	1
signaling receptor binding	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
synaptic membrane	1
presynapse	1
membrane microdomain	1
cell junction	1
extracellular vesicle	1
synapse	1

Protein interactions and networks

STRING

1752 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EFNB1	EPHB2	P29323	999
EFNB1	EPHB1	P54762	998
EFNB1	EPHA1	P21709	997
EFNB1	EPHA4	P54764	997
EFNB1	EPHB6	O15197	994
EFNB1	EPHB3	P54753	994
EFNB1	EPHB4	P54760	994
EFNB1	NCK2	O43639	962
EFNB1	EPHA10	Q5JZY3	917
EFNB1	RGS3	P49796	908
EFNB1	CLDN1	O95832	852
EFNB1	PTPN13	Q12923	825
EFNB1	EPHA2	P29317	818
EFNB1	CLDN4	O14493	801
EFNB1	CLDN7	O95471	771

IntAct

153 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
EPHB2	EFNB1	psi-mi:“MI:0407”(direct interaction)	0.690
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
TNFSF8	TOR1B	psi-mi:“MI:0914”(association)	0.640
TFAP4	ANGPTL7	psi-mi:“MI:0914”(association)	0.640
ERBB2	EFNB1	psi-mi:“MI:0915”(physical association)	0.600
EFNB1	ERBB2	psi-mi:“MI:0915”(physical association)	0.600
ERBB2	EFNB1	psi-mi:“MI:0403”(colocalization)	0.600
EFNB1	ERBB2	psi-mi:“MI:0403”(colocalization)	0.600
EFNB1	EPHA4	psi-mi:“MI:0407”(direct interaction)	0.600
EFNB1	EPHA2	psi-mi:“MI:0407”(direct interaction)	0.600
EPHA2	EFNB1	psi-mi:“MI:0407”(direct interaction)	0.600
EPHA4	EFNB1	psi-mi:“MI:0403”(colocalization)	0.600
EPHA2	EFNB1	psi-mi:“MI:0403”(colocalization)	0.600
EFNB1	ANKRD46	psi-mi:“MI:0915”(physical association)	0.560
SLC39A5	TMEM223	psi-mi:“MI:0914”(association)	0.530
PICK1	ILVBL	psi-mi:“MI:0914”(association)	0.530
EFNB2	FAM171A2	psi-mi:“MI:0914”(association)	0.530
C16orf54	IFNA17	psi-mi:“MI:0914”(association)	0.530

BioGRID (322): EFNB1 (Affinity Capture-MS), EFNB1 (Affinity Capture-MS), EFNB1 (Affinity Capture-MS), EFNB1 (Affinity Capture-MS), EFNB1 (Affinity Capture-MS), EFNB1 (Affinity Capture-MS), EFNB1 (Affinity Capture-MS), EFNB1 (Affinity Capture-MS), EFNB1 (Affinity Capture-MS), EFNB1 (Affinity Capture-MS), EFNB1 (Affinity Capture-MS), SORBS1 (Affinity Capture-Western), SORBS1 (Co-localization), EFNB1 (Proximity Label-MS), EFNB1 (Proximity Label-MS)

ESM2 similar proteins: A0MTF4, A4Q9F4, M3X9S6, O15520, O35565, O43189, O43320, O54693, O54769, O73754, O95750, P05524, P08620, P11487, P12034, P15656, P31371, P36364, P36386, P48801, P48802, P48803, P48804, P48807, P54130, P70492, P97401, P98172, Q20FD0, Q2HXK8, Q3ZFI5, Q5RF67, Q5T6S3, Q5XI70, Q91875, Q92765, Q92838, Q95117, Q95L12, Q96GD3

Diamond homologs: O08542, O08543, O08545, O35393, O43921, O73612, O73874, P20827, P52793, P52794, P52795, P52796, P52797, P52798, P52799, P52800, P52801, P52802, P52803, P52804, P79727, P79728, P97553, P97605, P98172, Q06AS9, Q15768, Q3ZC64, O13097, O44516

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
EFNB1	up-regulates	EPHB1	binding
PTPN13	“up-regulates activity”	EFNB1	dephosphorylation
EFNB1	up-regulates	EPHB3	binding
EFNB1	up-regulates	EPHB4	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 156 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
Signaling by ERBB2 ECD mutants	5	32.6×	4e-05
GRB2 events in ERBB2 signaling	5	30.8×	5e-05
SHC1 events in ERBB2 signaling	5	23.1×	1e-04
Signaling by ERBB2 TMD/JMD mutants	5	23.1×	1e-04
Downstream signal transduction	6	22.2×	4e-05
Signaling by ERBB2 KD Mutants	5	20.5×	2e-04
EPH-ephrin mediated repulsion of cells	6	12.8×	3e-04
EPH-Ephrin signaling	6	9.6×	9e-04

GO biological processes:

GO term	Partners	Fold	FDR
ephrin receptor signaling pathway	6	15.8×	2e-03
cell chemotaxis	7	9.9×	2e-03
cell surface receptor protein tyrosine kinase signaling pathway	6	8.0×	8e-03
axon guidance	8	5.5×	8e-03
positive regulation of cell migration	10	4.7×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	49
Likely pathogenic	25
Uncertain significance	88
Likely benign	30
Benign	9

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
100627	NM_004429.5(EFNB1):c.496C>T (p.Gln166Ter)	Pathogenic
100628	NC_000023.10:g.(68059108_68059111)_(68067499_68067502)del	Pathogenic
11706	NG_008887.1:g.(6109_14537)(16741?)del	Pathogenic
11707	NM_004429.5(EFNB1):c.332C>T (p.Thr111Ile)	Pathogenic
11709	NM_004429.5(EFNB1):c.451G>A (p.Gly151Ser)	Pathogenic
11710	NM_004429.5(EFNB1):c.452G>T (p.Gly151Val)	Pathogenic
11711	NM_004429.5(EFNB1):c.472A>G (p.Met158Val)	Pathogenic
11712	NM_004429.5(EFNB1):c.474G>T (p.Met158Ile)	Pathogenic
11713	NM_004429.5(EFNB1):c.109T>G (p.Trp37Gly)	Pathogenic
11714	NM_004429.5(EFNB1):c.110G>A (p.Trp37Ter)	Pathogenic
11715	NM_004429.5(EFNB1):c.196C>T (p.Arg66Ter)	Pathogenic
1322817	NM_004429.5(EFNB1):c.111G>A (p.Trp37Ter)	Pathogenic
1338338	NM_004429.5(EFNB1):c.129-1G>T	Pathogenic
1511747	NM_004429.5(EFNB1):c.339G>C (p.Lys113Asn)	Pathogenic
1526809	GRCh37/hg19 Xq12-13.1(chrX:67317059-68072263)	Pathogenic
153501	GRCh38/hg38 Xq12-13.1(chrX:68277324-68861722)x1	Pathogenic
1803718	NM_004429.5(EFNB1):c.149T>A (p.Leu50Ter)	Pathogenic
1895436	NM_004429.5(EFNB1):c.196del (p.Arg66fs)	Pathogenic
2009328	NM_004429.5(EFNB1):c.614del (p.Ser205fs)	Pathogenic
2031724	NM_004429.5(EFNB1):c.403dup (p.Thr135fs)	Pathogenic
2033013	NM_004429.5(EFNB1):c.237C>G (p.Tyr79Ter)	Pathogenic
235545	NM_004429.5(EFNB1):c.101_114dup (p.Ser39fs)	Pathogenic
2573204	NM_004429.5(EFNB1):c.474G>A (p.Met158Ile)	Pathogenic
2737239	NM_004429.5(EFNB1):c.220G>T (p.Glu74Ter)	Pathogenic
280631	NM_004429.5(EFNB1):c.219T>G (p.Tyr73Ter)	Pathogenic
280643	NM_004429.5(EFNB1):c.85dup (p.Ala29fs)	Pathogenic
2861381	NM_004429.5(EFNB1):c.449del (p.Gly150fs)	Pathogenic
3027064	NM_004429.5(EFNB1):c.440del (p.Asn147fs)	Pathogenic
3254766	NM_004429.5(EFNB1):c.406+2T>C	Pathogenic
3724251	NM_004429.5(EFNB1):c.1A>G (p.Met1Val)	Pathogenic

SpliceAI

535 predictions. Top by Δscore:

Variant	Effect	Δscore
X:68829905:G:GG	donor_gain	1.0000
X:68838611:G:A	acceptor_gain	1.0000
X:68838612:GGCA:G	acceptor_loss	1.0000
X:68838613:GCAG:G	acceptor_loss	1.0000
X:68838614:CAGG:C	acceptor_loss	1.0000
X:68838615:A:AG	acceptor_gain	1.0000
X:68838615:A:G	acceptor_loss	1.0000
X:68838616:G:A	acceptor_loss	1.0000
X:68838616:G:GG	acceptor_gain	1.0000
X:68838869:G:GT	donor_gain	1.0000
X:68838890:TACCT:T	donor_gain	1.0000
X:68838891:ACCT:A	donor_gain	1.0000
X:68838892:CCT:C	donor_gain	1.0000
X:68838893:CT:C	donor_gain	1.0000
X:68838893:CTGT:C	donor_loss	1.0000
X:68838894:TG:T	donor_loss	1.0000
X:68838895:G:C	donor_loss	1.0000
X:68838895:G:GG	donor_gain	1.0000
X:68838896:T:A	donor_loss	1.0000
X:68839648:T:TA	acceptor_gain	1.0000
X:68839659:T:TA	acceptor_gain	1.0000
X:68839660:GCAGC:G	acceptor_loss	1.0000
X:68839661:CA:C	acceptor_loss	1.0000
X:68839662:A:AG	acceptor_gain	1.0000
X:68839662:AG:A	acceptor_loss	1.0000
X:68839663:G:GT	acceptor_gain	1.0000
X:68839663:GC:G	acceptor_gain	1.0000
X:68839663:GCA:G	acceptor_gain	1.0000
X:68839663:GCAA:G	acceptor_gain	1.0000
X:68839663:GCAAC:G	acceptor_gain	1.0000

AlphaMissense

2260 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:68829885:T:A	W37R	1.000
X:68829885:T:C	W37R	1.000
X:68829887:G:C	W37C	1.000
X:68829887:G:T	W37C	1.000
X:68838619:T:G	F44C	1.000
X:68838667:T:C	L60P	1.000
X:68838673:T:G	I62S	1.000
X:68838678:T:A	C64S	1.000
X:68838678:T:C	C64R	1.000
X:68838679:G:A	C64Y	1.000
X:68838679:G:C	C64S	1.000
X:68838680:C:G	C64W	1.000
X:68838721:T:C	L78P	1.000
X:68838753:T:A	C89S	1.000
X:68838753:T:C	C89R	1.000
X:68838754:G:A	C89Y	1.000
X:68838754:G:C	C89S	1.000
X:68838755:T:G	C89W	1.000
X:68838789:T:A	C101S	1.000
X:68838789:T:C	C101R	1.000
X:68838790:G:A	C101Y	1.000
X:68838790:G:C	C101S	1.000
X:68838791:C:G	C101W	1.000
X:68838816:T:C	F110L	1.000
X:68838817:T:C	F110S	1.000
X:68838818:T:A	F110L	1.000
X:68838818:T:G	F110L	1.000
X:68838823:T:A	I112N	1.000
X:68838825:A:G	K113E	1.000
X:68838828:T:C	F114L	1.000

dbSNP variants (sampled 300 via entrez): RS1000100104 (X:68840888 G>A,T), RS1000190770 (X:68832794 A>T), RS1000378786 (X:68834746 A>G), RS1000691592 (X:68832328 C>T), RS1001112997 (X:68838544 C>G,T), RS1001524055 (X:68840792 C>A,G), RS1001676351 (X:68837002 T>G), RS1001771702 (X:68831431 G>T), RS1001790736 (X:68836262 G>GA), RS1002003280 (X:68834561 G>A,C), RS1002526783 (X:68838332 G>A), RS1002661208 (X:68838137 G>A), RS1002797734 (X:68830036 G>A), RS1003177738 (X:68829443 C>G), RS1003538874 (X:68836724 A>G)

Disease associations

OMIM: gene MIM:300035 | disease phenotypes: MIM:304110

GenCC curated gene-disease

Disease	Classification	Inheritance
craniofrontonasal syndrome	Definitive	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
craniofrontonasal syndrome	Definitive	XL

Mondo (1): craniofrontonasal syndrome (MONDO:0010570)

Orphanet (1): Craniofrontonasal dysplasia (Orphanet:1520)

HPO phenotypes

71 total (30 of 71 shown, HPO-id order):

HPO	Term
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000049	Shawl scrotum
HP:0000164	Abnormality of the dentition
HP:0000175	Cleft palate
HP:0000202	Orofacial cleft
HP:0000204	Cleft upper lip
HP:0000218	High palate
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000316	Hypertelorism
HP:0000324	Facial asymmetry
HP:0000349	Widow’s peak
HP:0000407	Sensorineural hearing impairment
HP:0000431	Wide nasal bridge
HP:0000456	Bifid nasal tip
HP:0000457	Depressed nasal ridge
HP:0000465	Webbed neck
HP:0000470	Short neck
HP:0000474	Thickened nuchal skin fold
HP:0000494	Downslanted palpebral fissures
HP:0000506	Telecanthus
HP:0000577	Exotropia
HP:0000639	Nystagmus
HP:0000767	Pectus excavatum
HP:0000776	Congenital diaphragmatic hernia
HP:0000889	Abnormal clavicle morphology
HP:0000912	Sprengel anomaly
HP:0001060	Axillary pterygium
HP:0001156	Brachydactyly

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536456	Craniofrontonasal dysplasia (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases methylation, increases expression, affects methylation	3
Aflatoxin B1	decreases methylation, increases expression	3
bisphenol A	increases expression, decreases methylation, affects cotreatment	2
sodium arsenite	increases expression	2
Cisplatin	affects cotreatment, increases expression	2
Cadmium Chloride	decreases expression	2
aristolochic acid I	increases expression	1
FR900359	decreases phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
trimellitic anhydride	increases expression	1
isobutyl alcohol	affects cotreatment, increases abundance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, increases expression	1
(+)-JQ1 compound	increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Leflunomide	decreases expression	1
Atrazine	increases expression	1
Bleomycin	increases expression	1
Camptothecin	increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Doxorubicin	increases expression	1
Gasoline	affects cotreatment, increases abundance, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00339846	Not specified	COMPLETED	Genetic Analysis of Craniofrontonasal Syndrome