CCBE1

Summary

CCBE1 (collagen and calcium binding EGF domains 1, HGNC:29426) is a protein-coding gene on chromosome 18q21.32, encoding Collagen and calcium-binding EGF domain-containing protein 1 (Q6UXH8). Required for lymphangioblast budding and angiogenic sprouting from venous endothelium during embryogenesis.

This gene is thought to function in extracellular matrix remodeling and migration. It is predominantly expressed in the ovary, but down regulated in ovarian cancer cell lines and primary carcinomas, suggesting its role as a tumour suppressor. Mutations in this gene have been associated with Hennekam lymphangiectasia-lymphedema syndrome, a generalized lymphatic dysplasia in humans.

Source: NCBI Gene 147372 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Hennekam lymphangiectasia-lymphedema syndrome 1 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 24
• Clinical variants (ClinVar): 572 total — 14 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 92
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_133459

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29426
Approved symbol	CCBE1
Name	collagen and calcium binding EGF domains 1
Location	18q21.32
Locus type	gene with protein product
Status	Approved
Aliases	FLJ30681, KIAA1983
Ensembl gene	ENSG00000183287
Ensembl biotype	protein_coding
OMIM	612753
Entrez	147372

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 5 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000439986, ENST00000589116, ENST00000589419, ENST00000649564, ENST00000650467, ENST00000695903, ENST00000695904, ENST00000915151

RefSeq mRNA: 1 — MANE Select: NM_133459 NM_133459

CCDS: CCDS32838

Canonical transcript exons

ENST00000439986 — 11 exons

Exon	Start	End
ENSE00001292732	59697212	59697423
ENSE00001327565	59696629	59696709
ENSE00003528624	59438111	59438146
ENSE00003563642	59469473	59469607
ENSE00003565504	59439543	59439578
ENSE00003586607	59480186	59480238
ENSE00003655309	59439677	59439816
ENSE00003669627	59466739	59466891
ENSE00003734653	59447983	59448103
ENSE00003739508	59454851	59454951
ENSE00003835575	59430939	59436141

Expression profiles

Bgee: expression breadth ubiquitous, 172 present calls, max score 92.42.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.4222 / max 256.7917, expressed in 1002 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172204	4.9585	945
172205	1.7626	436
172206	1.2919	395
172208	0.1592	78
172207	0.1082	56
172202	0.0499	22
172199	0.0306	20
172200	0.0205	11
172209	0.0174	7
172201	0.0145	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	92.42	gold quality
lower lobe of lung	UBERON:0008949	92.39	gold quality
oocyte	CL:0000023	89.74	gold quality
buccal mucosa cell	CL:0002336	87.20	gold quality
kidney epithelium	UBERON:0004819	86.85	silver quality
left ventricle myocardium	UBERON:0006566	84.14	gold quality
cardiac muscle of right atrium	UBERON:0003379	83.86	gold quality
muscle layer of sigmoid colon	UBERON:0035805	83.53	gold quality
left ovary	UBERON:0002119	83.34	gold quality
right lung	UBERON:0002167	82.61	gold quality
lung	UBERON:0002048	82.58	gold quality
ovary	UBERON:0000992	82.48	gold quality
left adrenal gland	UBERON:0001234	82.44	gold quality
left adrenal gland cortex	UBERON:0035825	82.02	gold quality
germinal epithelium of ovary	UBERON:0001304	81.86	gold quality
stromal cell of endometrium	CL:0002255	81.81	gold quality
cortical plate	UBERON:0005343	81.70	gold quality
adrenal gland	UBERON:0002369	81.46	gold quality
adrenal cortex	UBERON:0001235	81.44	gold quality
epithelial cell of pancreas	CL:0000083	81.37	silver quality
right adrenal gland	UBERON:0001233	81.29	gold quality
right adrenal gland cortex	UBERON:0035827	81.11	gold quality
right ovary	UBERON:0002118	79.90	gold quality
pigmented layer of retina	UBERON:0001782	79.78	gold quality
upper lobe of lung	UBERON:0008948	78.86	gold quality
adrenal tissue	UBERON:0018303	78.77	gold quality
endocervix	UBERON:0000458	78.76	gold quality
upper lobe of left lung	UBERON:0008952	78.25	gold quality
uterine cervix	UBERON:0000002	76.31	gold quality
seminal vesicle	UBERON:0000998	75.79	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	30.24
E-ANND-3	yes	5.37
E-MTAB-10290	no	211.66
E-MTAB-10137	no	9.65
E-MTAB-5061	no	2.17

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F7

miRNA regulators (miRDB)

168 targeting CCBE1, 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-3925-3P	100.00	69.95	1237
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4533	100.00	69.48	2758
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-3163	100.00	77.23	8605
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-507	99.97	70.11	1915

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 22)

• Homozygous cysteine to serine change and SNPS in CCBE1 were identified patients. (PMID:19911200)
• Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans (PMID:19935664)
• Loss of CCBE1 expression may promote ovarian carcinogenesis by enhancing migration & cell survival. CCBE1 is a new candidate tumour suppressor in ovarian cancer. (PMID:19935792)
• Human CCBE1 strongly enhances vascular endothelial growth factor-C-mediated lymphangiogenesis in a corneal micropocket assay (PMID:21778431)
• The study has shown that CCBE1 mutations are not a major contributor to non-immune hydrops fetalis. (PMID:22239599)
• Both siblings harbored a homozygous mutation in CCBE1. (PMID:24086631)
• CCBE1 enhances lymphangiogenesis via A disintegrin and metalloprotease with thrombospondin motifs-3-mediated vascular endothelial growth factor-C activation. (PMID:24552833)
• Collagen domains of CCBE1 are crucial for the activation of VEGFC in vitro and in vivo. The EGF domains of CCBE1 are dispensable for regulation of VEGFC processing in vitro, however, they are necessary for full lymphangiogenic activity of CCBE1 in vivo. (PMID:25814692)
• characterization of Hennekam Syndrome phenotypes in two Turkish siblings with protein mutation (PMID:26686525)
• these data indicated that CCBE1 may be served as a new predictor of prognosis in post-operative gastrointestinal stromal tumor patients and may play an important role in stimulating tumor progression (PMID:27506146)
• We identify CCBE1 as a direct target of miR-330-3p, and show that knockdown of CCBE1 results in a greater invasive capacity. Accordingly, in breast cancer patients CCBE1 is frequently downregulated, and its loss is associated with reduced distant relapse-free and overall survival. (PMID:28419078)
• Efficient activation of the lymphangiogenic growth factor VEGF-C requires the C-terminal domain of VEGF-C and the N-terminal domain of CCBE1. (PMID:28687807)
• the present results demonstrated that CCBE1 expression was downregulated in lung cancer, particularly in the presence of LNM. (PMID:29207117)
• Next-generation sequencing of 9 Chinese children with early-onset protein-losing enteropathy showed causative CCBE1 mutations (c.521C>T/c.271C>T) in 1 case. (PMID:30853196)
• A Novel RNA-Seq-Based Model for Preoperative Prediction of Lymph Node Metastasis in Oral Squamous Cell Carcinoma. (PMID:32934959)
• miR-942-5p Inhibits Proliferation, Metastasis, and Epithelial-Mesenchymal Transition in Colorectal Cancer by Targeting CCBE1. (PMID:33997050)
• The Lymphangiogenic Factor CCBE1 Promotes Angiogenesis and Tumor Growth in Colorectal Cancer. (PMID:34819004)
• Hsa_circ_0076931 suppresses malignant biological properties, down-regulates miR-6760-3p through direct binding, and up-regulates CCBE1 in glioma. (PMID:34931668)
• The YAP-TEAD4 complex promotes tumor lymphangiogenesis by transcriptionally upregulating CCBE1 in colorectal cancer. (PMID:36781122)
• CCBE1 promotes mitochondrial fusion by inhibiting the TGFbeta-DRP1 axis to prevent the progression of hepatocellular carcinoma. (PMID:36849082)
• Neovascularization directed by CAVIN1/CCBE1/VEGFC confers TMZ-resistance in glioblastoma. (PMID:38092144)
• The promotion of non-small cell lung cancer progression by collagen and calcium binding EGF domain 1 is mediated through the regulation of ERK/JNK/P38 phosphorylation by reactive oxygen species. (PMID:38726928)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ccbe1	ENSDARG00000086158
mus_musculus	Ccbe1	ENSMUSG00000046318
rattus_norvegicus	Ccbe1	ENSRNOG00000062986

Protein

Protein identifiers

Collagen and calcium-binding EGF domain-containing protein 1 — Q6UXH8 (reviewed: Q6UXH8)

Alternative names: Full of fluid protein homolog

All UniProt accessions (4): Q6UXH8, A0A3B3IRL6, A0A8Q3WKU1, A0A8Q3WKU2

UniProt curated annotations — full annotation on UniProt →

Function. Required for lymphangioblast budding and angiogenic sprouting from venous endothelium during embryogenesis.

Subcellular location. Secreted.

Tissue specificity. Detected in fibroblasts and urine (at protein level). Not expressed in blood or lymphatic endothelial cells.

Disease relevance. Hennekam lymphangiectasia-lymphedema syndrome 1 (HKLLS1) [MIM:235510] A form of Hennekam lymphangiectasia-lymphedema syndrome, a generalized lymph-vessels dysplasia characterized by intestinal lymphangiectasia with severe lymphedema of the limbs, genitalia and face. In addition, affected individuals have unusual facies and some manifest intellectual disability. HKLLS1 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the CCBE1 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q6UXH8-1	1	yes
Q6UXH8-2	2
Q6UXH8-3	3

RefSeq proteins (1): NP_597716* (*=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
IPR008160	Collagen	Repeat
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR049883	NOTCH1_EGF-like	Domain

Pfam: PF01391, PF07645

UniProt features (25 total): sequence variant 6, glycosylation site 3, disulfide bond 3, splice variant 3, domain 3, compositionally biased region 3, region of interest 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UXH8-F1	65.61	0.13

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 (3): 138–150, 146–159, 161–174

Glycosylation sites (3): 142, 182, 385

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 398 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, GOBP_POSITIVE_REGULATION_OF_PROTEIN_MATURATION, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, GOBP_VASCULAR_ENDOTHELIAL_GROWTH_FACTOR_SIGNALING_PATHWAY, MODULE_255, GOCC_COLLAGEN_TRIMER, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, MODULE_317, GOBP_RESPIRATORY_SYSTEM_PROCESS, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, TGACCTY_ERR1_Q2, GOBP_POSITIVE_REGULATION_OF_ENDOTHELIAL_CELL_MIGRATION, GOBP_PROTEIN_MATURATION, GOBP_SPROUTING_ANGIOGENESIS

GO Biological Process (16): lymphangiogenesis (GO:0001946), sprouting angiogenesis (GO:0002040), respiratory system process (GO:0003016), positive regulation of vascular endothelial growth factor production (GO:0010575), positive regulation of endothelial cell migration (GO:0010595), positive regulation of protein processing (GO:0010954), lung development (GO:0030324), positive regulation of angiogenesis (GO:0045766), venous blood vessel morphogenesis (GO:0048845), positive regulation of vascular endothelial growth factor signaling pathway (GO:1900748), positive regulation of lymphangiogenesis (GO:1901492), lymphatic endothelial cell migration (GO:1904977), angiogenesis (GO:0001525), lymph vessel development (GO:0001945), respiratory gaseous exchange by respiratory system (GO:0007585), endothelial cell migration (GO:0043542)

GO Molecular Function (4): protease binding (GO:0002020), calcium ion binding (GO:0005509), collagen binding (GO:0005518), protein binding (GO:0005515)

GO Cellular Component (4): collagen trimer (GO:0005581), obsolete extracellular space (GO:0005615), extracellular matrix (GO:0031012), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lymph vessel morphogenesis	2
anatomical structure formation involved in morphogenesis	2
angiogenesis	2
endothelial cell migration	2
blood vessel morphogenesis	2
anatomical structure morphogenesis	1
system process	1
respiratory gaseous exchange by respiratory system	1
positive regulation of cytokine production	1
vascular endothelial growth factor production	1
regulation of vascular endothelial growth factor production	1
regulation of endothelial cell migration	1
positive regulation of cell migration	1
protein processing	1
positive regulation of proteolysis	1
regulation of protein processing	1
positive regulation of protein maturation	1
respiratory tube development	1
animal organ development	1
respiratory system development	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
venous blood vessel development	1
positive regulation of signal transduction	1
vascular endothelial growth factor signaling pathway	1
regulation of vascular endothelial growth factor signaling pathway	1
lymphangiogenesis	1
positive regulation of developmental process	1
regulation of lymphangiogenesis	1
vasculature development	1
anatomical structure development	1
multicellular organismal process	1
cell migration	1
enzyme binding	1
metal ion binding	1
protein-containing complex binding	1
binding	1
protein-containing complex	1
external encapsulating structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

716 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CCBE1	VEGFC	P49767	928
CCBE1	ADAMTS2	O95450	852
CCBE1	ADAMTS3	O15072	825
CCBE1	SOX18	P35713	689
CCBE1	FLT4	P35916	663
CCBE1	FOXC2	Q99958	615
CCBE1	GJC2	Q5T442	613
CCBE1	VEGFD	O43915	610
CCBE1	FAT4	Q6V0I7	569
CCBE1	COL25A1	Q9BXS0	536
CCBE1	LYVE1	Q9Y5Y7	519
CCBE1	COLEC10	Q9Y6Z7	517
CCBE1	COL6A6	A6NMZ7	512
CCBE1	FCN3	O75636	499
CCBE1	COL15A1	P39059	497

IntAct

28 interactions, top by confidence:

A	B	Type	Score
MMP2	COL4A1	psi-mi:“MI:0914”(association)	0.640
CCBE1	CEP55	psi-mi:“MI:0915”(physical association)	0.560
STX11	CCBE1	psi-mi:“MI:0915”(physical association)	0.560
KLHL12	CCBE1	psi-mi:“MI:0915”(physical association)	0.560
CCBE1	STX11	psi-mi:“MI:0915”(physical association)	0.560
CEP55	CCBE1	psi-mi:“MI:0915”(physical association)	0.560
CLEC11A	VWA8	psi-mi:“MI:0914”(association)	0.530
KCTD17	CBX4	psi-mi:“MI:0914”(association)	0.530
LAIR2	LAMA5	psi-mi:“MI:0914”(association)	0.530
NOTCH2	ZNF316	psi-mi:“MI:0914”(association)	0.530
VEGFB	LAMB2	psi-mi:“MI:0914”(association)	0.530
CCBE1	H2BC5	psi-mi:“MI:0915”(physical association)	0.400
CCBE1	FXR1	psi-mi:“MI:0915”(physical association)	0.370
CCBE1	SIAH2	psi-mi:“MI:0915”(physical association)	0.370
CCBE1	TOX4	psi-mi:“MI:0915”(physical association)	0.370
CCBE1	POTEF	psi-mi:“MI:0914”(association)	0.350
CCBE1	FKBP15	psi-mi:“MI:0914”(association)	0.350
KLHL22	TRAV18	psi-mi:“MI:0914”(association)	0.350
ADIPOQ	AGRN	psi-mi:“MI:0914”(association)	0.350
C1QTNF1	CALU	psi-mi:“MI:0914”(association)	0.350
CHCHD4	PDHX	psi-mi:“MI:0914”(association)	0.350
EGFL7	LAMA5	psi-mi:“MI:0914”(association)	0.350
GRAMD1B	MYCBP2	psi-mi:“MI:0914”(association)	0.350

BioGRID (21): CCBE1 (Two-hybrid), CCBE1 (Two-hybrid), CCBE1 (Two-hybrid), CCBE1 (Biochemical Activity), CCBE1 (Two-hybrid), CCBE1 (Two-hybrid), CCBE1 (Two-hybrid), CCBE1 (Two-hybrid), CCBE1 (Two-hybrid), CCBE1 (Two-hybrid), INCA1 (Two-hybrid), CCBE1 (Proximity Label-MS), CCBE1 (Two-hybrid), POTEF (Affinity Capture-MS), VASP (Affinity Capture-MS)

ESM2 similar proteins: A0A060WQA3, A0MSJ1, A5PN28, A6NHN0, A8WGB1, A8WR59, B2RNN3, B7Z0K8, C7DZK3, O35167, O35348, O76368, O88207, P0C862, P12107, P13942, P20908, P20909, P23805, P25067, P25318, P25940, P42916, P83371, P98085, Q03637, Q07092, Q07563, Q0II24, Q0VF58, Q17RW2, Q30D77, Q32S24, Q3MI99, Q4ZJM7, Q4ZJN1, Q60467, Q61245, Q64739, Q6UXH8

Diamond homologs: A8WGB1, B3EWY9, B5DFC9, E1BMV3, G3V928, O19045, O43897, O57382, O73775, O75095, O88322, O88947, P00743, P07204, P07225, P10493, P13497, P14543, P15306, P21941, P23142, P25155, P25723, P35951, P37889, P48960, P51942, P53813, P98063, P98069, P98070, P98095, P98118, P98157, P98163, Q07954, Q08761, Q08879, Q09165, Q14112

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	5
Uncertain significance	264
Likely benign	180
Benign	75

Top pathogenic / likely-pathogenic (19)

Variant ID	HGVS	Classification
1954352	NM_133459.4(CCBE1):c.477C>A (p.Cys159Ter)	Pathogenic
2103625	NM_133459.4(CCBE1):c.886dup (p.His296fs)	Pathogenic
2427216	NC_000018.9:g.(?57363841)(57364574_?)del	Pathogenic
2728703	NM_133459.4(CCBE1):c.37_58del (p.Arg13fs)	Pathogenic
2994186	NM_133459.4(CCBE1):c.322C>T (p.Arg108Ter)	Pathogenic
3670927	NM_133459.4(CCBE1):c.262G>T (p.Glu88Ter)	Pathogenic
445	NM_133459.4(CCBE1):c.223T>A (p.Cys75Ser)	Pathogenic
446	NM_133459.4(CCBE1):c.305G>C (p.Cys102Ser)	Pathogenic
447	NM_133459.4(CCBE1):c.979G>C (p.Gly327Arg)	Pathogenic
448	NM_133459.4(CCBE1):c.683_684insT (p.Leu229fs)	Pathogenic
450	NM_133459.4(CCBE1):c.520T>C (p.Cys174Arg)	Pathogenic
4724097	NM_133459.4(CCBE1):c.294T>A (p.Cys98Ter)	Pathogenic
4753607	NM_133459.4(CCBE1):c.352C>T (p.Arg118Ter)	Pathogenic
4780331	NM_133459.4(CCBE1):c.3G>A (p.Met1Ile)	Pathogenic
1066181	NM_133459.4(CCBE1):c.400+1del	Likely pathogenic
2000978	NM_133459.4(CCBE1):c.916-2A>T	Likely pathogenic
2760753	NM_133459.4(CCBE1):c.265+1G>A	Likely pathogenic
3236090	NM_133459.4(CCBE1):c.293G>A (p.Cys98Tyr)	Likely pathogenic
3686999	NM_133459.4(CCBE1):c.951+1G>A	Likely pathogenic

SpliceAI

2697 predictions. Top by Δscore:

Variant	Effect	Δscore
18:59438109:A:AC	donor_gain	1.0000
18:59438110:C:CC	donor_gain	1.0000
18:59439576:ACCC:A	acceptor_loss	1.0000
18:59439577:CCCTG:C	acceptor_loss	1.0000
18:59439578:CCTG:C	acceptor_loss	1.0000
18:59439579:C:A	acceptor_loss	1.0000
18:59439580:T:C	acceptor_loss	1.0000
18:59466734:CTT:C	donor_loss	1.0000
18:59466735:TTACC:T	donor_loss	1.0000
18:59466736:TAC:T	donor_loss	1.0000
18:59466737:A:AC	donor_gain	1.0000
18:59466737:AC:A	donor_gain	1.0000
18:59466738:C:CT	donor_gain	1.0000
18:59466738:CC:C	donor_gain	1.0000
18:59466738:CCA:C	donor_gain	1.0000
18:59466738:CCAG:C	donor_gain	1.0000
18:59466738:CCAGT:C	donor_gain	1.0000
18:59466897:T:TC	acceptor_gain	1.0000
18:59466903:C:CT	acceptor_gain	1.0000
18:59466904:A:T	acceptor_gain	1.0000
18:59469462:T:A	donor_gain	1.0000
18:59469471:AC:A	donor_gain	1.0000
18:59469472:C:CA	donor_gain	1.0000
18:59469491:C:CA	donor_gain	1.0000
18:59469497:T:TA	donor_gain	1.0000
18:59469604:TAATC:T	acceptor_loss	1.0000
18:59469605:AATCT:A	acceptor_loss	1.0000
18:59469606:ATCTG:A	acceptor_loss	1.0000
18:59469607:TCT:T	acceptor_loss	1.0000
18:59469608:C:CA	acceptor_loss	1.0000

AlphaMissense

2605 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:59480197:C:G	C85S	1.000
18:59480198:A:T	C85S	1.000
18:59469568:C:G	C102S	0.999
18:59469569:A:T	C102S	0.999
18:59480196:G:C	C85W	0.999
18:59480198:A:G	C85R	0.999
18:59480230:C:G	C74S	0.999
18:59480231:A:T	C74S	0.999
18:59469478:C:G	C132S	0.998
18:59469479:A:G	C132R	0.998
18:59469479:A:T	C132S	0.998
18:59469534:A:C	C113W	0.998
18:59469535:C:T	C113Y	0.998
18:59469536:A:G	C113R	0.998
18:59469541:C:G	C111S	0.998
18:59469542:A:G	C111R	0.998
18:59469542:A:T	C111S	0.998
18:59469569:A:G	C102R	0.998
18:59469595:C:G	C93S	0.998
18:59469596:A:T	C93S	0.998
18:59480197:C:A	C85F	0.998
18:59480197:C:T	C85Y	0.998
18:59480229:G:C	C74W	0.998
18:59480231:A:G	C74R	0.998
18:59469477:A:C	C132W	0.997
18:59469535:C:A	C113F	0.997
18:59469567:G:C	C102W	0.997
18:59469478:C:T	C132Y	0.996
18:59469535:C:G	C113S	0.996
18:59469536:A:T	C113S	0.996

dbSNP variants (sampled 300 via entrez): RS1000005753 (18:59468254 G>A,C,T), RS1000017568 (18:59439462 C>T), RS1000017720 (18:59475962 G>A), RS1000036810 (18:59468420 G>A), RS1000040926 (18:59498587 G>T), RS1000045548 (18:59619631 A>C,G), RS1000054246 (18:59631721 A>G), RS1000071646 (18:59649326 G>A), RS1000096471 (18:59568749 G>A), RS1000115923 (18:59608741 C>G,T), RS1000143950 (18:59453818 C>A,T), RS1000148533 (18:59608940 A>G), RS1000159432 (18:59579148 C>T), RS1000166822 (18:59527437 G>A), RS1000182505 (18:59561288 C>A,G,T)

Disease associations

OMIM: gene MIM:612753 | disease phenotypes: MIM:235510, MIM:611590

GenCC curated gene-disease

Disease	Classification	Inheritance
Hennekam lymphangiectasia-lymphedema syndrome 1	Definitive	Autosomal recessive
Hennekam syndrome	Supportive	Autosomal recessive

Mondo (3): Hennekam lymphangiectasia-lymphedema syndrome 1 (MONDO:0009337), renal tubular acidosis, distal, 4, with hemolytic anemia (MONDO:0012700), Hennekam syndrome (MONDO:0016256)

Orphanet (2): Hennekam syndrome (Orphanet:2136), Distal renal tubular acidosis with anemia (Orphanet:93610)

HPO phenotypes

92 total (30 of 92 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000076	Vesicoureteral reflux
HP:0000085	Horseshoe kidney
HP:0000086	Ectopic kidney
HP:0000126	Hydronephrosis
HP:0000160	Narrow mouth
HP:0000189	Narrow palate
HP:0000212	Gingival overgrowth
HP:0000272	Malar flattening
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000322	Short philtrum
HP:0000337	Broad forehead
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000431	Wide nasal bridge
HP:0000501	Glaucoma
HP:0000677	Oligodontia
HP:0000684	Delayed eruption of teeth
HP:0000752	Hyperactivity
HP:0000767	Pectus excavatum
HP:0000774	Narrow chest
HP:0001004	Lymphedema
HP:0001007	Hirsutism
HP:0001055	Erysipelas

GWAS associations

24 associations (top):

Study	Trait	p-value
GCST002095_2	Major depressive disorder	3.000000e-06
GCST002491_27	Age-related hearing impairment	4.000000e-07
GCST008758_76	Pre-treatment viral load in HIV-1 infection	6.000000e-16
GCST010320_140	PR interval	7.000000e-12
GCST010321_63	PR interval	1.000000e-11
GCST010796_1869	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-08
GCST010796_1870	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST012297_2	Schizophrenia, bipolar disorder or major depressive disorder	7.000000e-06
GCST012310_11	Schizophrenia x sex interaction	3.000000e-06
GCST012490_242	Femur bone mineral density x serum urate levels interaction	9.000000e-10
GCST012490_502	Femur bone mineral density x serum urate levels interaction	3.000000e-08
GCST012490_91	Femur bone mineral density x serum urate levels interaction	3.000000e-10
GCST90000025_661	Appendicular lean mass	1.000000e-15
GCST90002385_290	High light scatter reticulocyte count	4.000000e-15
GCST90002386_88	High light scatter reticulocyte percentage of red cells	3.000000e-17
GCST90002387_214	Immature fraction of reticulocytes	4.000000e-09
GCST90002390_556	Mean corpuscular hemoglobin	6.000000e-14
GCST90002392_44	Mean corpuscular volume	6.000000e-09
GCST90002392_45	Mean corpuscular volume	5.000000e-10
GCST90002395_284	Mean platelet volume	1.000000e-09
GCST90002400_249	Plateletcrit	2.000000e-11
GCST90002402_627	Platelet count	2.000000e-15
GCST90002405_567	Reticulocyte count	3.000000e-12
GCST90002406_514	Reticulocyte fraction of red cells	1.000000e-14

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0010125	viral load
EFO:0004462	PR interval
EFO:0004327	electrocardiography
EFO:0008343	sex interaction measurement
EFO:0004531	urate measurement
EFO:0004980	appendicular lean mass
EFO:0007986	reticulocyte count
EFO:0004527	mean corpuscular hemoglobin
EFO:0007985	platelet crit
EFO:0004309	platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
sodium arsenite	increases abundance, decreases expression, affects cotreatment	3
mercuric bromide	decreases expression, affects cotreatment	2
Air Pollutants	increases expression, decreases expression, increases abundance	2
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
Tretinoin	decreases expression, increases expression	2
Cadmium Chloride	increases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	decreases expression	1
methyleugenol	decreases expression	1
propionaldehyde	increases expression	1
bisphenol A	decreases expression	1
trichostatin A	increases expression	1
methylparaben	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
benzo(e)pyrene	decreases methylation	1
didecyldimethylammonium	decreases expression	1
aflatoxin B2	decreases methylation	1
maleic acid	increases expression	1
4-nonylphenol	affects cotreatment, decreases expression	1
naphthenic acid	decreases expression	1
avobenzone	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-tert-octylphenol	affects cotreatment, decreases expression	1
3-nitrobenzanthrone	decreases expression	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1

Clinical trials (associated diseases)

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