EFEMP1

Summary

EFEMP1 (EGF-like fibulin extracellular matrix protein 1, HGNC:3218) is a protein-coding gene on chromosome 2p16.1, encoding EGF-containing fibulin-like extracellular matrix protein 1 (Q12805). Binds EGFR, the EGF receptor, inducing EGFR autophosphorylation and the activation of downstream signaling pathways.

This gene encodes a member of the fibulin family of extracellular matrix glycoproteins. Like all members of this family, the encoded protein contains tandemly repeated epidermal growth factor-like repeats followed by a C-terminus fibulin-type domain. This gene is upregulated in malignant gliomas and may play a role in the aggressive nature of these tumors. Mutations in this gene are associated with Doyne honeycomb retinal dystrophy. Alternatively spliced transcript variants that encode the same protein have been described.

Source: NCBI Gene 2202 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Doyne honeycomb retinal dystrophy (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 165
• Clinical variants (ClinVar): 423 total — 9 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 88
• MANE Select transcript: NM_001039348

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3218
Approved symbol	EFEMP1
Name	EGF-like fibulin extracellular matrix protein 1
Location	2p16.1
Locus type	gene with protein product
Status	Approved
Aliases	S1-5, FBLN3, MTLV
Ensembl gene	ENSG00000115380
Ensembl biotype	protein_coding
OMIM	601548
Entrez	2202

Gene structure

Transcript identifiers

Ensembl transcripts: 54 — 50 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000355426, ENST00000394555, ENST00000421664, ENST00000424207, ENST00000429909, ENST00000438672, ENST00000439193, ENST00000440439, ENST00000452161, ENST00000452337, ENST00000480016, ENST00000497698, ENST00000634374, ENST00000635671, ENST00000881450, ENST00000881451, ENST00000881452, ENST00000881453, ENST00000881454, ENST00000881455, ENST00000881456, ENST00000881457, ENST00000881458, ENST00000881459, ENST00000881460, ENST00000881461, ENST00000881462, ENST00000881463, ENST00000951477, ENST00000951478, ENST00000951479, ENST00000951480, ENST00000951481, ENST00000951482, ENST00000951483, ENST00000951484, ENST00000951485, ENST00000951486, ENST00000951487, ENST00000951488, ENST00000951489, ENST00000951490, ENST00000951491, ENST00000951492, ENST00000951493, ENST00000951494, ENST00000951495, ENST00000951496, ENST00000951497, ENST00000951498, ENST00000951499, ENST00000951500, ENST00000951501, ENST00000951502

RefSeq mRNA: 2 — MANE Select: NM_001039348 NM_001039348, NM_001039349

CCDS: CCDS1857

Canonical transcript exons

ENST00000355426 — 12 exons

Exon	Start	End
ENSE00000932698	55870720	55870915
ENSE00000932699	55871000	55871123
ENSE00000932700	55874946	55875065
ENSE00000932701	55876623	55876742
ENSE00000932702	55877746	55877865
ENSE00001266691	55881612	55881734
ENSE00001433884	55922899	55922939
ENSE00001592219	55923711	55923782
ENSE00001952333	55865967	55867234
ENSE00003485817	55922360	55922447
ENSE00003530933	55917665	55918051
ENSE00003638839	55918219	55918267

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 99.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 170.9055 / max 4107.5513, expressed in 1304 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
28511	142.2172	1291
28510	23.7906	1043
28495	0.9310	382
28498	0.8450	362
28501	0.7379	328
28509	0.7004	365
28507	0.4863	231
28499	0.3531	205
28496	0.2091	114
28497	0.1191	49

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right coronary artery	UBERON:0001625	99.81	gold quality
thoracic aorta	UBERON:0001515	99.75	gold quality
descending thoracic aorta	UBERON:0002345	99.75	gold quality
ascending aorta	UBERON:0001496	99.74	gold quality
germinal epithelium of ovary	UBERON:0001304	99.71	gold quality
synovial joint	UBERON:0002217	99.71	gold quality
parietal pleura	UBERON:0002400	99.61	gold quality
choroid plexus epithelium	UBERON:0003911	99.57	gold quality
pigmented layer of retina	UBERON:0001782	99.55	gold quality
pericardium	UBERON:0002407	99.55	gold quality
aorta	UBERON:0000947	99.54	gold quality
left coronary artery	UBERON:0001626	99.51	gold quality
coronary artery	UBERON:0001621	99.50	gold quality
popliteal artery	UBERON:0002250	99.38	gold quality
tibial artery	UBERON:0007610	99.38	gold quality
skin of hip	UBERON:0001554	99.17	gold quality
urethra	UBERON:0000057	99.15	gold quality
placenta	UBERON:0001987	99.15	gold quality
gall bladder	UBERON:0002110	99.01	gold quality
saphenous vein	UBERON:0007318	99.01	gold quality
adipose tissue of abdominal region	UBERON:0007808	99.00	gold quality
pleura	UBERON:0000977	98.99	gold quality
cauda epididymis	UBERON:0004360	98.99	gold quality
omental fat pad	UBERON:0010414	98.99	gold quality
peritoneum	UBERON:0002358	98.98	gold quality
lateral globus pallidus	UBERON:0002476	98.96	gold quality
adipose tissue	UBERON:0001013	98.89	gold quality
mammary duct	UBERON:0001765	98.88	gold quality
lower lobe of lung	UBERON:0008949	98.86	gold quality
left ovary	UBERON:0002119	98.81	gold quality

Single-cell (SCXA)

Detected in 18 experiment(s), a significant marker in 18.

Experiment	Marker?	Max mean expression
E-MTAB-8322	yes	2824.43
E-MTAB-10137	yes	2570.32
E-MTAB-8410	yes	1795.16
E-MTAB-6701	yes	1394.98
E-MTAB-10662	yes	246.24
E-HCAD-1	yes	89.27
E-CURD-114	yes	68.53
E-GEOD-135922	yes	61.69
E-MTAB-8142	yes	43.92
E-MTAB-6678	yes	27.55
E-MTAB-9543	yes	24.04
E-HCAD-25	yes	22.08
E-MTAB-10287	yes	16.78
E-CURD-46	yes	16.57
E-GEOD-84465	yes	11.71

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI2

miRNA regulators (miRDB)

99 targeting EFEMP1, 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-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
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-144-3P	99.94	73.98	2698
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-4779	99.86	66.50	1583
HSA-LET-7G-3P	99.85	70.43	1929

Literature-anchored findings (GeneRIF, showing 40)

• EFEMP1 has a role in retinal drusen formation and is involved in the etiology of macular degeneration and Malattia Leventinese. (PMID:12242346)
• The Arg345Trp disease-associated allele of the EFEMP1 gene does not appear to be associated with cases of early onset drusen, nor does it appear to play a role in familial age-related macular degeneration. (PMID:12427233)
• The 5’ end of the FBLN3 gene has been characterized, and the important upstream motifs regulating its transcription have been identified. (PMID:14578376)
• TIMP-3 is a binding partner of epithelial growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) (PMID:15123717)
• A new genetic locus (GLC1H) for adult-onset POAG (primary open-angle glaucoma) maps to the 2p15-p16 region. (PMID:17210857)
• The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice. (PMID:17666404)
• EFEMP1 is silenced by promoter hypermethylation in lung cancer (PMID:17671114)
• Expression and cell compartmentalization of EFEMP1, a protein associated with Malattia Leventienese, is reported. (PMID:18188955)
• the transcripts upregulated according to disease progression were associated with signaling pathway/transcription, including tumor-associated calcium signal transducer 1 and chemokine ligand 19, and with cell communication, such as collagen. (PMID:19012040)
• a possible predictive impact of EFEMP1 expression in primary breast cancer (PMID:19115204)
• Up-Regulation of EFEMP1 is associated with pancreatic adenocarcinoma. (PMID:19208748)
• show that EFEMP1 binds EGF receptor (EGFR) in a competitive manner relative to epidermal growth factor (EGF), implicating that EFEMP1 and EGF share the same or adjacent binding sites on the EGFR. (PMID:19804359)
• This is the first report to describe a Japanese family with variable expressivity of Malattia leventinese (ML)/Doyne honeycomb retinal dystrophy (DHRD), in which a novel disease haplotype was identified. (PMID:19850834)
• FIB-3 mRNA expression and FIB-3 staining intensity was similar in the uteroscaral ligaments of women with and without uterine prolapse (PMID:19862539)
• EFEMP1 is highly expressed in malignant gliomas and promotes tumor invasion in the brain. (PMID:19887559)
• Fibulin-3 is upregulated in gliomas and cultured glioma cells; the protein was undetectable in normal brain or astrocytes. Fibulin-3 did not seem to affect glioma cell morphology or proliferation, but enhanced cell adhesion and promoted motility. (PMID:19887559)
• Loss of EFEMP1 is associated with hepatocellular carcinoma. (PMID:19898900)
• Aberrant promoter methylation and loiss of expression in non-small cell lung carcinoma (PMID:19913326)
• These findings suggest that fibulin-3 may play an important role as a negative regulator of chondrocyte differentiation. (PMID:20005202)
• EFEMP1 promotes angiogenesis and associates with lymph node metastasis, vascular invasion and poor prognosis of cervical carcinoma. (PMID:20378157)
• the expression level of EFEMP1 was significantly different between PCa and BPH. (PMID:21571867)
• Downregulation of fibulin-3 gene by promoter methylation is associated with colorectal cancer. (PMID:21744999)
• FLBN3 gene methylation is associated with colorectal cancer. (PMID:21796503)
• fibulin-3 negatively modulates the invasiveness of lung cancer cells via regulation of MMP-7 and MMP-2 and its expression is regulated by hypermethylation of the promoter region (PMID:21901248)
• EEFEMP1 suppresses glioma growth in vivo, both by modulating the tumor extracellular microenvironment and by altering critical intracellular oncogenic signaling pathways (PMID:21955618)
• This study highlights the mechanisms underlying the inefficient secretion of R345W EFEMP1 (PMID:22031286)
• Choroid neovascularization in doyne honeycomb retinal dystrophy is sensitive to treatment with intravitreal bevacizumab, providing indirect evidence that vascular endothelial growth factor may play a role in this disease. (PMID:22159686)
• Our findings indicate that Fib3-1 and Fib3-2 are potential biochemical markers for the diagnosis of osteoarthritis (PMID:22275171)
• The expressions of fibulin-3 mRNA and protein were not different between the prolapse and no prolapse groups. It is unlikely that abnormal expression of fibulin-3 has a major role in the pathogenesis of anterior vaginal wall prolapse. (PMID:22519482)
• Fibulin-3 promotes glioma growth and resistance through a novel paracrine regulation of Notch signaling. (PMID:22665268)
• Low-energy laser treatment is safe and may be effective in the treatment of autosomal dominant drusen. (PMID:23036572)
• The top three inhibitory compounds reduced R345W fibulin-3 secretion. (PMID:23230284)
• Cell model for age-related macular degeneration indicates that mitochondrial DNA variants mediate energy production and expression levels for CFH, C3 and EFEMP1 genes. (PMID:23365660)
• Define the Efemp1-p27(Kip1) axis as a potential marker module of PDAC cell sensitivity towards dual PI3K-mTOR inhibitors. (PMID:23470560)
• Solid phase binding assays detected strong calcium-dependent binding of the short fibulins to immobilized heparin, suggesting that these fibulins may bind cell surface-located heparan sulfate (PMID:23782690)
• EFEMP1 decreased secretion of MMPs and inhibited tumor cell proliferation. (PMID:23840707)
• Fibulin-3 exhibits antitumor effects towards hepatocellular carcinoma (PMID:23936443)
• FBLN3 suppresses both epithelial-to-mesenchymal transition and self-renewal of lung cancer stem cells by modulating the IGF1R pathway. (PMID:24013232)
• Subtype-independent loss of EFEMP1 expression in the majority of primary adenomas should prompt more detailed investigation in this tumor type. (PMID:24080855)
• fibulin-3 negatively modulates the invasiveness of lung cancer cells via regulation of p38-MAPK and MMP-2/9. (PMID:24142183)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	efemp1	ENSDARG00000059121
danio_rerio	si:ch73-173h19.3	ENSDARG00000104210
mus_musculus	Efemp1	ENSMUSG00000020467
rattus_norvegicus	Efemp1	ENSRNOG00000003553

Paralogs (6): FBLN1 (ENSG00000077942), FBLN5 (ENSG00000140092), VWDE (ENSG00000146530), FBLN2 (ENSG00000163520), EFEMP2 (ENSG00000172638), EYS (ENSG00000188107)

Protein

Protein identifiers

EGF-containing fibulin-like extracellular matrix protein 1 — Q12805 (reviewed: Q12805)

Alternative names: Extracellular protein S1-5, Fibrillin-like protein, Fibulin-3

All UniProt accessions (11): Q12805, A0A0S2Z4F1, A0A0U1RQV3, A0A0U1RRL0, C9J4H7, C9J4J8, C9J8S9, C9JPZ9, C9JQX7, C9JUM4, Q580Q6

UniProt curated annotations — full annotation on UniProt →

Function. Binds EGFR, the EGF receptor, inducing EGFR autophosphorylation and the activation of downstream signaling pathways. May play a role in cell adhesion and migration. May function as a negative regulator of chondrocyte differentiation. In the olfactory epithelium, it may regulate glial cell migration, differentiation and the ability of glial cells to support neuronal neurite outgrowth.

Subunit / interactions. Interacts with ECM1. Interacts with TIMP3.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. In the eye, associated with photoreceptor outer and inner segment regions, the nerve fiber layer, outer nuclear layer and inner and outer plexiform layers of the retina.

Disease relevance. Doyne honeycomb retinal dystrophy (DHRD) [MIM:126600] An autosomal dominant, progressive, ocular disorder characterized by yellow-white deposits known as drusen that accumulate beneath the retinal pigment epithelium. With age, drusen increase in size and number, and eventually cause visual symptoms, including decreased visual acuity, metamorphopsia, photophobia, and paracentral scotoma. The disease is caused by variants affecting the gene represented in this entry. Cutis laxa, autosomal recessive, 1D (ARCL1D) [MIM:620780] A connective tissue disorder characterized by loose, hyperextensible skin with decreased resilience and elasticity leading to a premature aged appearance. Face, hands, feet, joints, and torso may be differentially affected. The clinical spectrum of autosomal recessive cutis laxa is highly heterogeneous with respect to organ involvement and severity. ARCL1D features include skin laxity, thin and translucent skin with easy bruising, facial dysmorphism, joint hypermobility, muscle hypotonia, and multiple severe herniations. Skin laxity may progress with age. The disease is caused by variants affecting the gene represented in this entry. Glaucoma 1, open angle, H (GLC1H) [MIM:611276] A form of primary open angle glaucoma (POAG). POAG is characterized by a specific pattern of optic nerve and visual field defects. The angle of the anterior chamber of the eye is open, and usually the intraocular pressure is increased. However, glaucoma can occur at any intraocular pressure. The disease is generally asymptomatic until the late stages, by which time significant and irreversible optic nerve damage has already taken place. GLC1H is an autosomal dominant form manifesting at age between 3 and 40 years, in most patients. Some affected individuals present with glaucoma after age 35 or 40 years. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Up-regulated in malignant gliomas. May increase glioma cell adhesiveness and invasive properties.

Similarity. Belongs to the fibulin family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q12805-1	1	yes
Q12805-2	2
Q12805-3	3
Q12805-4	4
Q12805-5	5

RefSeq proteins (2): NP_001034437, NP_001034438 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR026823	cEGF	Domain
IPR049883	NOTCH1_EGF-like	Domain
IPR052235	Nephronectin_domain	Family
IPR055088	Fibulin_C	Domain

Pfam: PF07645, PF12662, PF22914

UniProt features (45 total): disulfide bond 15, sequence variant 8, mutagenesis site 7, domain 6, splice variant 5, signal peptide 1, chain 1, region of interest 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12805-F1	77.67	0.47

Functional residue map

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

Disulfide bonds (15): 177–190, 184–199, 201–212, 218–228, 224–237, 239–252, 258–268, 264–277, 279–292, 298–309, 305–318, 320–332, 338–350, 344–359, 365–377

Glycosylation sites (1): 249

Mutagenesis-validated functional residues (7):

Position	Phenotype
29	produces extracellular disulfide-linked homodimers similar as cys55arg mutation.
42	produces extracellular disulfide-linked homodimers similar as cys55arg mutation.
48	produces extracellular disulfide-linked homodimers similar as cys55arg mutation.
61	produces extracellular disulfide-linked homodimers similar as cys55arg mutation.
70	produces extracellular disulfide-linked homodimers similar as cys55arg mutation.
159	produces extracellular disulfide-linked homodimers similar as cys55arg mutation.
171	produces extracellular disulfide-linked homodimers similar as cys55arg mutation.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2129379	Molecules associated with elastic fibres

MSigDB gene sets: 491 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, MODULE_52, TSUNODA_CISPLATIN_RESISTANCE_UP, LEE_NEURAL_CREST_STEM_CELL_DN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_CARTILAGE_DEVELOPMENT, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_CARTILAGE_DEVELOPMENT, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, GOZGIT_ESR1_TARGETS_DN, GNF2_PTX3

GO Biological Process (9): regulation of DNA-templated transcription (GO:0006355), epidermal growth factor receptor signaling pathway (GO:0007173), visual perception (GO:0007601), peptidyl-tyrosine phosphorylation (GO:0018108), negative regulation of chondrocyte differentiation (GO:0032331), camera-type eye development (GO:0043010), embryonic eye morphogenesis (GO:0048048), post-embryonic eye morphogenesis (GO:0048050), signal transduction (GO:0007165)

GO Molecular Function (6): epidermal growth factor receptor activity (GO:0005006), epidermal growth factor receptor binding (GO:0005154), extracellular matrix structural constituent (GO:0005201), calcium ion binding (GO:0005509), growth factor activity (GO:0008083), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), extracellular matrix (GO:0031012), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Elastic fibre formation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
eye morphogenesis	2
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
ERBB signaling pathway	1
sensory perception of light stimulus	1
protein phosphorylation	1
peptidyl-tyrosine modification	1
chondrocyte differentiation	1
regulation of chondrocyte differentiation	1
negative regulation of cell differentiation	1
negative regulation of cartilage development	1
eye development	1
embryonic organ morphogenesis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
transmembrane receptor protein tyrosine kinase activity	1
epidermal growth factor receptor signaling pathway	1
epidermal growth factor binding	1
growth factor receptor binding	1
structural molecule activity	1
extracellular matrix	1
metal ion binding	1
receptor ligand activity	1
binding	1
cellular anatomical structure	1
external encapsulating structure	1
extracellular vesicle	1

Protein interactions and networks

STRING

2630 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EFEMP1	TIMP3	P35625	953
EFEMP1	EGFR	P00533	851
EFEMP1	ECM1	Q16610	747
EFEMP1	CFH	P08603	740
EFEMP1	ELN	P15502	638
EFEMP1	LOXL1	Q08397	631
EFEMP1	MMP7	P09237	625
EFEMP1	LUM	P51884	618
EFEMP1	PLEKHA1	Q9HB21	605
EFEMP1	MSLN	Q13421	598
EFEMP1	FN1	P02751	586
EFEMP1	PCDHGA12	O60330	584
EFEMP1	COL1A1	P02452	575
EFEMP1	TIMP1	P01033	571
EFEMP1	ARMS2	P0C7Q2	557

IntAct

181 interactions, top by confidence:

A	B	Type	Score
EFEMP1	SGTA	psi-mi:“MI:0915”(physical association)	0.930
SGTA	EFEMP1	psi-mi:“MI:0915”(physical association)	0.930
EFEMP1	TRAF2	psi-mi:“MI:0915”(physical association)	0.860
TRAF2	EFEMP1	psi-mi:“MI:0915”(physical association)	0.860
EFEMP1	MEOX2	psi-mi:“MI:0915”(physical association)	0.720
BAG6	EFEMP1	psi-mi:“MI:0915”(physical association)	0.670
EFEMP1	BAG6	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (177): SGTA (Two-hybrid), TRAF2 (Two-hybrid), BAG6 (Two-hybrid), RIC8A (Two-hybrid), TXNDC5 (Two-hybrid), EFEMP1 (Affinity Capture-RNA), EFEMP1 (Affinity Capture-RNA), EFEMP1 (Affinity Capture-RNA), EFEMP1 (Affinity Capture-RNA), SGTA (Two-hybrid), SGTA (Two-hybrid), EFEMP1 (Two-hybrid), EFEMP1 (Two-hybrid), MEOX2 (Two-hybrid), SGTA (Two-hybrid)

ESM2 similar proteins: A2VCU8, A6QR11, O35568, O42182, O55058, O73775, O95967, P07224, P23142, P31515, P35555, P35556, P53813, P60755, P60756, P98118, P98133, Q01974, Q03610, Q08761, Q08879, Q0WYX8, Q12805, Q2VWQ2, Q5EA62, Q5R3Z7, Q5RA73, Q5RC26, Q61220, Q61554, Q61555, Q62918, Q62919, Q7YQD7, Q7Z553, Q7ZXL5, Q8BPB5, Q8MJJ9, Q8UVJ7, Q90827

Diamond homologs: A0A6I8RMG7, B3EWY9, B5DFC9, O35568, O55058, O70244, O73775, O88322, O95967, P10493, P14543, P15306, P23142, P27590, P35444, P35445, P35555, P48960, P49747, Q08879, Q12805, Q14112, Q19267, Q28178, Q2KIT5, Q2Q426, Q2VWQ2, Q4G063, Q4V7F2, Q4V7M2, Q5EA46, Q5EA62, Q5G872, Q5RC26, Q5W7P8, Q60438, Q62919, Q66PY1, Q6NZL8, Q6UXH1

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 84 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.

GO biological processes:

GO term	Partners	Fold	FDR
keratinization	5	17.2×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	4
Uncertain significance	208
Likely benign	127
Benign	54

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
1048805	NM_001039348.3(EFEMP1):c.1201C>T (p.Arg401Ter)	Pathogenic
1294421	NM_001039348.3(EFEMP1):c.238A>T (p.Asn80Tyr)	Pathogenic
1294422	NM_001039348.3(EFEMP1):c.1480T>C (p.Ter494Gln)	Pathogenic
1356856	NM_001039348.3(EFEMP1):c.603C>A (p.Cys201Ter)	Pathogenic
1460322	NC_000002.11:g.(?55863372)(56149575_?)del	Pathogenic
2819332	NM_001039348.3(EFEMP1):c.690_693dup (p.Pro232fs)	Pathogenic
691884	NM_001039348.3(EFEMP1):c.320_324del (p.Met107fs)	Pathogenic
691885	NM_001039348.3(EFEMP1):c.615T>A (p.Tyr205Ter)	Pathogenic
965353	NM_001039348.3(EFEMP1):c.156del (p.Asp53fs)	Pathogenic
1294423	NM_001039348.3(EFEMP1):c.1429C>T (p.Arg477Cys)	Likely pathogenic
3376736	NM_001039348.3(EFEMP1):c.121C>T (p.Gln41Ter)	Likely pathogenic
3384188	NM_001039348.3(EFEMP1):c.1084C>T (p.Arg362Ter)	Likely pathogenic
523395	NM_001039348.3(EFEMP1):c.1189T>C (p.Tyr397His)	Likely pathogenic

SpliceAI

1905 predictions. Top by Δscore:

Variant	Effect	Δscore
2:55870711:GATAC:G	donor_loss	1.0000
2:55870712:ATAC:A	donor_loss	1.0000
2:55870713:TACT:T	donor_loss	1.0000
2:55870714:ACTT:A	donor_loss	1.0000
2:55870716:TTACT:T	donor_loss	1.0000
2:55870717:TACTC:T	donor_loss	1.0000
2:55870718:A:AC	donor_gain	1.0000
2:55870718:ACT:A	donor_gain	1.0000
2:55870718:ACTC:A	donor_loss	1.0000
2:55870719:C:CA	donor_gain	1.0000
2:55870719:CT:C	donor_gain	1.0000
2:55870719:CTC:C	donor_gain	1.0000
2:55870719:CTCG:C	donor_gain	1.0000
2:55870719:CTCGT:C	donor_gain	1.0000
2:55870912:TCGG:T	acceptor_gain	1.0000
2:55870913:CGGC:C	acceptor_gain	1.0000
2:55870916:C:CC	acceptor_gain	1.0000
2:55870999:CTTCT:C	donor_gain	1.0000
2:55874943:TA:T	donor_loss	1.0000
2:55874944:ACCTT:A	donor_loss	1.0000
2:55875062:ATGT:A	acceptor_gain	1.0000
2:55875066:C:CC	acceptor_gain	1.0000
2:55875069:T:C	acceptor_gain	1.0000
2:55875074:T:C	acceptor_gain	1.0000
2:55875074:T:TC	acceptor_gain	1.0000
2:55881745:CA:C	acceptor_gain	1.0000
2:55881746:A:AC	acceptor_gain	1.0000
2:55881746:A:C	acceptor_gain	1.0000
2:55870911:ATCGG:A	acceptor_gain	0.9900
2:55870913:CGG:C	acceptor_gain	0.9900

AlphaMissense

3245 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:55871111:C:G	C338S	1.000
2:55871112:A:T	C338S	1.000
2:55875020:C:G	C309S	1.000
2:55875021:A:T	C309S	1.000
2:55875053:C:G	C298S	1.000
2:55875054:A:G	C298R	1.000
2:55875054:A:T	C298S	1.000
2:55875065:T:A	D294V	1.000
2:55875065:T:C	D294G	1.000
2:55875065:T:G	D294A	1.000
2:55876623:C:G	D294H	1.000
2:55876628:C:G	C292S	1.000
2:55876628:C:T	C292Y	1.000
2:55876629:A:G	C292R	1.000
2:55876629:A:T	C292S	1.000
2:55876667:C:G	C279S	1.000
2:55876668:A:G	C279R	1.000
2:55876668:A:T	C279S	1.000
2:55876673:C:G	C277S	1.000
2:55876673:C:T	C277Y	1.000
2:55876674:A:G	C277R	1.000
2:55876674:A:T	C277S	1.000
2:55876683:A:G	S274P	1.000
2:55876685:C:A	G273V	1.000
2:55876686:C:A	G273C	1.000
2:55876693:G:C	N270K	1.000
2:55876693:G:T	N270K	1.000
2:55876694:T:A	N270I	1.000
2:55876700:C:G	C268S	1.000
2:55876701:A:T	C268S	1.000

dbSNP variants (sampled 300 via entrez): RS1000008646 (2:55924050 C>A,T), RS1000016023 (2:55878844 G>C), RS1000136716 (2:55902788 A>C,T), RS1000222743 (2:55887233 C>T), RS1000262447 (2:55919825 C>A,G), RS1000287058 (2:55894712 C>G,T), RS1000292301 (2:55875932 G>T), RS1000384749 (2:55900592 T>C), RS1000391660 (2:55882332 T>C), RS1000418408 (2:55880703 G>A), RS1000435435 (2:55900404 C>T), RS1000466669 (2:55882057 G>A,C,T), RS1000498647 (2:55921622 C>T), RS1000593188 (2:55921237 G>T), RS1000615431 (2:55877248 C>A,G,T)

Disease associations

OMIM: gene MIM:601548 | disease phenotypes: MIM:126600, MIM:620780, MIM:109820

GenCC curated gene-disease

Disease	Classification	Inheritance
Doyne honeycomb retinal dystrophy	Definitive	Autosomal dominant
autosomal recessive cutis laxa type 1	Strong	Autosomal recessive
juvenile open angle glaucoma	Strong	Autosomal dominant
cutis laxa, autosomal recessive, type 1d	Moderate	Autosomal recessive
cutis laxa	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
open-angle glaucoma	Moderate	AD
Doyne honeycomb retinal dystrophy	Definitive	AD

Mondo (13): Doyne honeycomb retinal dystrophy (MONDO:0007471), cutis laxa, autosomal recessive, type 1d (MONDO:0958335), cutis laxa (MONDO:0016175), juvenile open angle glaucoma (MONDO:0020367), optic atrophy (MONDO:0003608), inherited retinal dystrophy (MONDO:0019118), connective tissue disorder (MONDO:0003900), optic disk drusen (MONDO:0001746), blindness (disorder) (MONDO:0001941), night blindness (MONDO:0004588), scoliosis (MONDO:0005392), bladder diverticulum (MONDO:0007197), autosomal recessive cutis laxa type 1 (MONDO:0019572)

Orphanet (4): Familial drusen (Orphanet:75376), Cutis laxa (Orphanet:209), Juvenile glaucoma (Orphanet:98977), OBSOLETE: Inherited retinal disorder (Orphanet:71862)

HPO phenotypes

88 total (30 of 88 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000015	Bladder diverticulum
HP:0000023	Inguinal hernia
HP:0000098	Tall stature
HP:0000189	Narrow palate
HP:0000218	High palate
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000343	Long philtrum
HP:0000400	Macrotia
HP:0000483	Astigmatism
HP:0000494	Downslanted palpebral fissures
HP:0000505	Visual impairment
HP:0000506	Telecanthus
HP:0000508	Ptosis
HP:0000525	Abnormality iris morphology
HP:0000556	Retinal dystrophy
HP:0000572	Visual loss
HP:0000587	Abnormal optic nerve morphology
HP:0000593	Abnormal anterior chamber morphology
HP:0000603	Central scotoma
HP:0000613	Photophobia
HP:0000678	Dental crowding
HP:0000689	Dental malocclusion
HP:0000767	Pectus excavatum
HP:0000776	Congenital diaphragmatic hernia
HP:0000963	Thin skin
HP:0000973	Cutis laxa
HP:0000978	Bruising susceptibility

GWAS associations

165 associations (top):

Study	Trait	p-value
GCST000174_13	Height	2.000000e-12
GCST000175_37	Height	6.000000e-11
GCST000380_4	Height	2.000000e-09
GCST000406_4	Amyotrophic lateral sclerosis	1.000000e-06
GCST000522_10	Height	4.000000e-06
GCST000611_4	Height	6.000000e-09
GCST000644_7	Height	3.000000e-07
GCST000817_20	Height	4.000000e-08
GCST000817_74	Height	3.000000e-35
GCST001956_71	Height	8.000000e-16
GCST002483_1	Lung function (forced vital capacity)	2.000000e-12
GCST002483_6	Lung function (forced vital capacity)	2.000000e-07
GCST002647_26	Height	2.000000e-67
GCST002702_32	Height	1.000000e-38
GCST002764_10	Optic cup area	8.000000e-07
GCST002764_3	Optic cup area	4.000000e-08
GCST003013_20	White matter hyperintensity burden	3.000000e-07
GCST003013_6	White matter hyperintensity burden	2.000000e-08
GCST003198_1	Inguinal hernia	1.000000e-17
GCST003225_20	Pelvic organ prolapse (moderate/severe)	3.000000e-07
GCST003336_1	Waist circumference adjusted for body mass index	2.000000e-19
GCST003336_3	Waist circumference adjusted for body mass index	2.000000e-10
GCST003336_4	Waist circumference adjusted for body mass index	6.000000e-07
GCST003336_6	Waist circumference adjusted for body mass index	5.000000e-14
GCST003991_7	Childhood ear infection	2.000000e-10
GCST003998_17	Joint mobility (Beighton score)	1.000000e-07
GCST004063_80	Waist circumference adjusted for body mass index	2.000000e-19
GCST004063_93	Waist circumference adjusted for body mass index	3.000000e-21
GCST004067_178	Hip circumference adjusted for BMI	5.000000e-15
GCST004067_195	Hip circumference adjusted for BMI	6.000000e-10

EFO canonical traits (22, from GWAS)

EFO ID	Trait name
EFO:0004312	vital capacity
EFO:0005665	white matter hyperintensity measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0007904	susceptibility to childhood ear infection measurement
EFO:0007905	joint hypermobility measurement
EFO:0008039	BMI-adjusted hip circumference
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0004695	intraocular pressure measurement
EFO:0004847	age at onset
EFO:0009959	diverticular disease
EFO:0005763	pulse pressure measurement
EFO:0006336	diastolic blood pressure
EFO:0004341	body fat distribution
EFO:0004713	FEV/FVC ratio
EFO:0004314	forced expiratory volume
EFO:0010360	lysophosphatidylcholine 18:1 measurement
EFO:0010361	lysophosphatidylcholine 18:2 measurement
EFO:0010436	triacylglycerol 56:9 measurement
EFO:0006939	cup-to-disc ratio measurement
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004980	appendicular lean mass

MeSH disease descriptors (10)

Descriptor	Name	Tree numbers
D001766	Blindness	C10.597.751.941.162; C11.966.075; C23.888.592.763.941.162
D003240	Connective Tissue Diseases	C17.300
D003483	Cutis Laxa	C16.320.850.180; C17.300.230; C17.800.827.180
D009755	Night Blindness	C11.966.671
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D015594	Optic Disk Drusen	C10.292.700.450; C11.640.513
D058499	Retinal Dystrophies	C11.768.585.658
D012600	Scoliosis	C05.116.900.800.875
C562406	Bladder Diverticulum (supp.)
C536225	Cutis laxa, recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases methylation	9
Particulate Matter	decreases expression, increases abundance, affects cotreatment	5
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression, increases expression	4
Estradiol	affects cotreatment, increases expression, decreases expression, decreases reaction	4
sodium arsenite	decreases expression, increases abundance	3
cobaltous chloride	decreases expression, decreases secretion	3
Tobacco Smoke Pollution	affects expression, decreases expression	3
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	2
Resveratrol	affects secretion, affects cotreatment, decreases expression	2
Acrolein	affects cotreatment, increases oxidation, increases abundance	2
Arsenic	decreases expression, increases abundance	2
Benzo(a)pyrene	increases expression, increases methylation	2
Copper	affects binding, increases expression	2
Dexamethasone	decreases expression, affects cotreatment, increases expression	2
Doxorubicin	decreases expression, increases expression	2
Ozone	affects cotreatment, increases oxidation, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	2
Tretinoin	decreases expression, increases expression	2
Raloxifene Hydrochloride	affects expression, decreases expression, decreases reaction	2
aristolochic acid I	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
propionaldehyde	increases expression	1
bisphenol A	increases methylation	1
lead acetate	decreases expression	1
decabromobiphenyl ether	decreases expression	1
trichostatin A	increases expression	1
3,4-dichloroaniline	decreases expression	1
arsenite	decreases secretion, increases secretion, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07396441	PHASE4	RECRUITING	Supplementary Kelulut Honey Therapy in Juvenile Open-Angle Glaucoma: Effects on IL-6, RNFL and Dry Eye
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04197050	PHASE4	UNKNOWN	Effect of Sacubitril/Valsartan on Reduced Right Ventricular Ejection Fraction in Patients With CTD
NCT04928586	PHASE4	UNKNOWN	Immunosuppressant Combined With Pirfenidone in CTD-ILD
NCT05440240	PHASE4	RECRUITING	Percutaneous Needle Fasciotomy +/- Corticosteroid Injection for Dupuytren’s Contracture
NCT05505409	PHASE4	UNKNOWN	Efficacy and Safety of Pirfenidone in CTD-ILD
NCT06499233	PHASE4	RECRUITING	Efficacy and Safety of Prophylactic Treatment for Pneumocystis Jirovecii Pneumonia in Patients With Autoimmune Inflammatory Rheumatic Disease
NCT00508066	PHASE4	COMPLETED	Continuous Local Infusion of Anesthetic at the Incisional Site for Scoliosis Surgery
NCT00510575	PHASE4	COMPLETED	Surgical Outcomes Using Variable Rod Diameters in the Treatment of Idiopathic Scoliosis
NCT00768313	PHASE4	WITHDRAWN	Phase IV Comparing Rods of Yield Strengths to Correct Adolescent Idiopathic Scoliosis.
NCT00880607	PHASE4	COMPLETED	Intrathecal Morphine Versus Epidural Extended Release Morphine for Pediatric Patients Undergoing Spinal Fusion
NCT00958581	PHASE4	COMPLETED	Tranexamic Acid (TXA) Versus Epsilon Aminocaproic Acid (EACA) Versus Placebo for Spine Surgery
NCT01852747	PHASE4	TERMINATED	Comparison of Actifuse ABX and Local Bone in Spinal Surgery
NCT02464813	PHASE4	COMPLETED	Effect of Pregabalin on Immediate Post-operative and Longterm Pain
NCT02465099	PHASE4	TERMINATED	Posterior Spinal Fusion With Two Energy Dissection Techniques
NCT06540885	PHASE4	RECRUITING	A Comparison Between Palonosetron Versus Granisetron as PONV Prophylaxis in Scoliotic Patients Undergoing Spine Surgery
NCT06616220	PHASE4	COMPLETED	Dexamethasone for ESPB in Pain Management After Pediatric Idiopathic Scoliosis Surgery
NCT06789016	PHASE4	COMPLETED	Dexmedetomidine for ESPB in Pain Management After Pediatric Idiopathic Scoliosis Surgery
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT00864201	PHASE3	UNKNOWN	A Study to Evaluate the Use of Bosentan in Patients With Exercise Induced Pulmonary Arterial Hypertension Associated With Connective Tissue Disease
NCT01196091	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01205438	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01488708	PHASE3	TERMINATED	On Open-Label Study in Participants With Systemic Lupus Erythematosus
NCT03626688	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients
NCT03683186	PHASE3	ENROLLING_BY_INVITATION	A Study Evaluating the Long-Term Efficacy and Safety of Ralinepag in Subjects With PAH Via an Open-Label Extension
NCT04084678	PHASE3	TERMINATED	A Study of Ralinepag to Evaluate Effects on Exercise Capacity by CPET in Subjects With WHO Group 1 PH
NCT06716606	PHASE3	RECRUITING	A Study to Investigate the Long-term Safety and Efficacy of Belimumab in Adults With Interstitial Lung Disease (ILD) Associated With Systemic Sclerosis (SSc) and Other Connective Tissue Diseases (CTD) (BLISSconneCTD-OLE)
NCT06917690	PHASE3	RECRUITING	A Study to Learn About the Safety and Efficacy of the Drug Oleogel-S10 in Japanese Patients With Epidermolysis Bullosa
NCT00323752	PHASE3	COMPLETED	Recombinant Human Erythropoietin Compared to Autologous Pre-Donation Prior to Scoliosis Surgery in Children.
NCT00684112	PHASE3	COMPLETED	Analgesic Effects of Gabapentin After Scoliosis Surgery in Children
NCT00737997	PHASE3	COMPLETED	Effect of Early Morphine Administration on the Development of Acute Opioid Tolerance During Pediatric Scoliosis Surgery
NCT01103115	PHASE3	COMPLETED	Calcium + Vitamin D Supplementation for Low Bone Mass in Adolescent Idiopathic Scoliosis (AIS)
NCT01108211	PHASE3	COMPLETED	Improving Low Bone Mass With Vibration Therapy in Adolescent Idiopathic Scoliosis (AIS)
NCT01205256	PHASE3	COMPLETED	IRB-HSR# 14145 R,S Methadone: Analgesia and Pharmacokinetics in Adolescents Undergoing Scoliosis Correction
NCT02558010	PHASE3	COMPLETED	Perioperative Methadone Use to Decrease Opioid Requirement in Pediatric Spinal Fusion Patients
NCT03537612	PHASE3	TERMINATED	Sensorial and Physiological Mechanism-based Assessments of Perioperative Pain
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy