GLMN

Summary

GLMN (glomulin, FKBP associated protein, HGNC:14373) is a protein-coding gene on chromosome 1p22.1, encoding Glomulin (Q92990). Regulatory component of cullin-RING-based SCF (SKP1-Cullin-F-box protein) E3 ubiquitin-protein ligase complexes. It is a selective cancer dependency (DepMap: 29.2% of cell lines) and haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a phosphorylated protein that is a member of a Skp1-Cullin-F-box-like complex. The protein is essential for normal development of the vasculature and mutations in this gene have been associated with glomuvenous malformations, also called glomangiomas. Multiple splice variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 11146 — RefSeq curated summary.

At a glance

• Gene–disease (curated): glomuvenous malformation (Definitive, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 264 total — 17 pathogenic, 23 likely-pathogenic
• Phenotypes (HPO): 19
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 29.2% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_053274

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14373
Approved symbol	GLMN
Name	glomulin, FKBP associated protein
Location	1p22.1
Locus type	gene with protein product
Status	Approved
Aliases	FAP48, FAP68, GLML, GVM, FKBPAP
Ensembl gene	ENSG00000174842
Ensembl biotype	protein_coding
OMIM	601749
Entrez	11146

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 16 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay

ENST00000370360, ENST00000463560, ENST00000471465, ENST00000487911, ENST00000495106, ENST00000495852, ENST00000896608, ENST00000896609, ENST00000896610, ENST00000896611, ENST00000896612, ENST00000931415, ENST00000931416, ENST00000931417, ENST00000931418, ENST00000931419, ENST00000931420, ENST00000931421, ENST00000946567

RefSeq mRNA: 2 — MANE Select: NM_053274 NM_001319683, NM_053274

CCDS: CCDS738

Canonical transcript exons

ENST00000370360 — 19 exons

Exon	Start	End
ENSE00001067534	92290198	92290306
ENSE00001207026	92288914	92289151
ENSE00001207034	92291418	92291537
ENSE00001207039	92297404	92297529
ENSE00001708229	92246402	92246646
ENSE00001898939	92298925	92298987
ENSE00002159430	92297961	92298029
ENSE00003042006	92268105	92268135
ENSE00003078835	92266700	92266741
ENSE00003132370	92286490	92286592
ENSE00003145022	92266419	92266492
ENSE00003173612	92267913	92268002
ENSE00003175276	92269723	92269776
ENSE00003187600	92271465	92271652
ENSE00003192504	92264554	92264638
ENSE00003620454	92262863	92262926
ENSE00003674725	92247878	92247989
ENSE00003685219	92263623	92263732
ENSE00003790474	92247062	92247144

Expression profiles

Bgee: expression breadth ubiquitous, 257 present calls, max score 90.85.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.6659 / max 200.9506, expressed in 1626 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13259	7.3001	1609
13260	0.3658	194

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.85	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.85	gold quality
cerebellar hemisphere	UBERON:0002245	89.67	gold quality
cerebellar cortex	UBERON:0002129	89.48	gold quality
right hemisphere of cerebellum	UBERON:0014890	89.11	gold quality
cerebellum	UBERON:0002037	87.15	gold quality
mucosa of stomach	UBERON:0001199	86.95	gold quality
lower esophagus mucosa	UBERON:0035834	86.74	gold quality
Brodmann (1909) area 9	UBERON:0013540	86.70	gold quality
right frontal lobe	UBERON:0002810	86.63	gold quality
granulocyte	CL:0000094	86.16	gold quality
left ovary	UBERON:0002119	85.78	gold quality
right ovary	UBERON:0002118	85.62	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	85.30	gold quality
left lobe of thyroid gland	UBERON:0001120	85.28	gold quality
right lobe of thyroid gland	UBERON:0001119	85.17	gold quality
skin of abdomen	UBERON:0001416	84.60	gold quality
right testis	UBERON:0004534	84.60	gold quality
cingulate cortex	UBERON:0003027	84.48	gold quality
thyroid gland	UBERON:0002046	84.46	gold quality
anterior cingulate cortex	UBERON:0009835	84.41	gold quality
left testis	UBERON:0004533	84.22	gold quality
ectocervix	UBERON:0012249	84.16	gold quality
adrenal tissue	UBERON:0018303	83.87	gold quality
endocervix	UBERON:0000458	83.84	gold quality
Brodmann (1909) area 10	UBERON:0013541	83.78	gold quality
skin of leg	UBERON:0001511	83.76	gold quality
body of uterus	UBERON:0009853	83.63	gold quality
ventricular zone	UBERON:0003053	83.56	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	83.45	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-6386	no	105.26
E-ANND-3	no	3.70

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MNT, MXI1

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 29.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 11)

• Describes the characterizations of 14 different mutations in the glomulin gene in patients with glomuvenous malformations. (PMID:11845407)
• FAP48-FKBP complexes increase IL2 production (PMID:12604780)
• A novel GLMN mutation is described in an Italian family with glomuvenous malformations in which some members present with the less commonly observed phenotype of solitary lesions. (PMID:22092580)
• These data identify glomulin as a permissivity factor for VACV infection and as a potential therapeutic target for inhibition of vaccinia virus (VACV) infection. (PMID:22280104)
• The glomuvenous malformation protein Glomulin binds Rbx1 and regulates cullin-1 RING ligase-mediated turnover of Fbw7. (PMID:22405651)
• FAP48 adipocyte expression plays a key role in HIV-associated lipodystrophy. (PMID:22678819)
• Structural and biochemical analyses reveal that GLMN adopts a HEAT-like repeat fold that tightly binds the E2-interacting surface of RBX1, inhibiting CRL-mediated chain formation by the E2 CDC34. (PMID:22748924)
• Our report contributes to document the possible association between the c.395-1G>C mutation of GLMN gene and glomuvenous malformations. (PMID:24961656)
• In summary, we present a case of congenital plaquetype GVM and a case of familial disseminated cutaneous GVM, both with the same glomulin gene mutation (c.157_161delAAGAA), but with different clinical expression. (PMID:30325312)
• GLMN causing vascular malformations: the clinical and genetic differentiation of cutaneous venous malformations. (PMID:35732373)
• Loss-of-function variants in GLMN are associated with generalized skin hyperpigmentation with or without glomuvenous malformation. (PMID:38489583)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	glmnb	ENSDARG00000010958
danio_rerio	glmna	ENSDARG00000058267
mus_musculus	Glmn	ENSMUSG00000029276
rattus_norvegicus	Glmn	ENSRNOG00000002054
drosophila_melanogaster	CG30496	FBGN0050496

Protein

Protein identifiers

Glomulin — Q92990 (reviewed: Q92990)

Alternative names: FK506-binding protein-associated protein, FKBP-associated protein

All UniProt accessions (3): Q92990, M0QX84, M0QXG8

UniProt curated annotations — full annotation on UniProt →

Function. Regulatory component of cullin-RING-based SCF (SKP1-Cullin-F-box protein) E3 ubiquitin-protein ligase complexes. Inhibits E3 ubiquitin ligase activity by binding to RBX1 (via RING domain) and inhibiting its interaction with the E2 ubiquitin-conjugating enzyme CDC34. Inhibits RBX1-mediated neddylation of CUL1. Required for normal stability and normal cellular levels of key components of SCF ubiquitin ligase complexes, including FBXW7, RBX1, CUL1, CUL2, CUL3, CUL4A, and thereby contributes to the regulation of CCNE1 and MYC levels. Essential for normal development of the vasculature. Contributes to the regulation of RPS6KB1 phosphorylation.

Subunit / interactions. Interacts with FKBP4 and FKBP1A. Isoform 1: Interacts with RBX1 (via RING domain). Identified in complexes that contain RBX1 plus one of the cullins CUL1, CUL2, CUL3, and CUL4A. Identified in a SCF complex composed of CUL1, RBX1, SKP1, FBXW7 and GLMN. Component of a SCF-like complex consisting of CUL7, RBX1, SKP1, FBXW8 and GLMN. Interacts with unphosphorylated MET and is released upon MET phosphorylation.

Tissue specificity. Ubiquitous.

Post-translational modifications. Phosphorylated on tyrosine residues.

Disease relevance. Glomuvenous malformations (GVMs) [MIM:138000] Characterized by the presence of smooth-muscle-like glomus cells in the media surrounding distended vascular lumens. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The C-terminal half of the protein is important for interaction with RBX1.

Isoforms (2)

UniProt ID	Names	Canonical?
Q92990-1	1, FAP68, FKBP-associated protein 68 kDa	yes
Q92990-2	2, FAP48, FKBP-associated protein 48 kDa

RefSeq proteins (2): NP_001306612, NP_444504* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR013877	YAP-bd/ALF4/Glomulin	Family
IPR019516	Glomulin/ALF4	Family

Pfam: PF08568

UniProt features (54 total): helix 32, mutagenesis site 5, turn 5, strand 3, region of interest 2, splice variant 2, sequence variant 2, initiator methionine 1, chain 1, modified residue 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4F52	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92990-F1	88.41	0.72

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 (1): 2

Mutagenesis-validated functional residues (5):

Position	Phenotype
425	disrupts interaction with rbx1. loss of inhibition of scf (skp1-cullin-f-box protein) e3 ubiquitin-protein ligase activi
476	disrupts interaction with rbx1. loss of inhibition of scf (skp1-cullin-f-box protein) e3 ubiquitin-protein ligase activi
567	disrupts interaction with rbx1. loss of inhibition of scf (skp1-cullin-f-box protein) e3 ubiquitin-protein ligase activi
574	disrupts interaction with rbx1. loss of inhibition of scf (skp1-cullin-f-box protein) e3 ubiquitin-protein ligase activi
219	loss of interaction with fkbp4 and fkbp1a.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation

MSigDB gene sets: 231 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, REACTOME_ANTIGEN_PROCESSING_UBIQUITINATION_PROTEASOME_DEGRADATION, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GTCTACC_MIR379, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION

GO Biological Process (12): vasculogenesis (GO:0001570), positive regulation of cytokine production (GO:0001819), neural tube closure (GO:0001843), cell surface receptor signaling pathway (GO:0007166), negative regulation of cell population proliferation (GO:0008285), regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032434), positive regulation of interleukin-2 production (GO:0032743), epigenetic regulation of gene expression (GO:0040029), negative regulation of T cell proliferation (GO:0042130), positive regulation of phosphorylation (GO:0042327), muscle cell differentiation (GO:0042692), circulatory system development (GO:0072359)

GO Molecular Function (5): signaling receptor binding (GO:0005102), hepatocyte growth factor receptor binding (GO:0005171), ubiquitin protein ligase binding (GO:0031625), ubiquitin-protein transferase inhibitor activity (GO:0055105), protein binding (GO:0005515)

GO Cellular Component (5): cytoplasm (GO:0005737), cullin-RING ubiquitin ligase complex (GO:0031461), Cul2-RING ubiquitin ligase complex (GO:0031462), Cul3-RING ubiquitin ligase complex (GO:0031463), Cul4A-RING E3 ubiquitin ligase complex (GO:0031464)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell differentiation	2
cullin-RING ubiquitin ligase complex	2
blood vessel morphogenesis	1
cytokine production	1
regulation of cytokine production	1
positive regulation of gene expression	1
positive regulation of multicellular organismal process	1
primary neural tube formation	1
tube closure	1
signal transduction	1
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
regulation of proteasomal protein catabolic process	1
regulation of ubiquitin-dependent protein catabolic process	1
positive regulation of cytokine production	1
interleukin-2 production	1
regulation of interleukin-2 production	1
chromatin remodeling	1
regulation of gene expression	1
T cell proliferation	1
regulation of T cell proliferation	1
negative regulation of lymphocyte proliferation	1
negative regulation of T cell activation	1
phosphorylation	1
regulation of phosphorylation	1
positive regulation of phosphate metabolic process	1
muscle structure development	1
system development	1
protein binding	1
growth factor receptor binding	1
ubiquitin-like protein ligase binding	1
ubiquitin-protein transferase activity	1
enzyme inhibitor activity	1
ubiquitin-protein transferase regulator activity	1
binding	1
intracellular anatomical structure	1
cellular anatomical structure	1
ubiquitin ligase complex	1

Protein interactions and networks

STRING

1125 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GLMN	RBX1	P62877	949
GLMN	CUL7	Q14999	909
GLMN	FBXW8	Q8N3Y1	903
GLMN	FKBP4	Q02790	895
GLMN	CUL1	Q13616	841
GLMN	SKP1	P34991	740
GLMN	UBA3	Q8TBC4	715
GLMN	PHYH	O14832	713
GLMN	FKBP1A	P20071	711
GLMN	FBXW11	Q9UKB1	675
GLMN	CDC34	P49427	668
GLMN	A0A087WY85	A0A087WY85	626
GLMN	CUL9	Q8IWT3	527
GLMN	BIRC3	Q13489	525
GLMN	FKBP5	Q13451	505

IntAct

143 interactions, top by confidence:

A	B	Type	Score
CUL9	TP53	psi-mi:“MI:0914”(association)	0.920
FKBP4	GLMN	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
RBX1	GLMN	psi-mi:“MI:0915”(physical association)	0.670
ENPP6	SCAMP1	psi-mi:“MI:0914”(association)	0.640
MILR1	INPPL1	psi-mi:“MI:0914”(association)	0.640
VSIG1	TTI1	psi-mi:“MI:0914”(association)	0.640
ARRDC1	NEDD4	psi-mi:“MI:0914”(association)	0.640
GLMN	FKBP5	psi-mi:“MI:0914”(association)	0.640
GLMN	CUL2	psi-mi:“MI:0914”(association)	0.640
SAV1	SEC16A	psi-mi:“MI:2364”(proximity)	0.570
SNAI1	GLMN	psi-mi:“MI:0915”(physical association)	0.560
EFS	GLMN	psi-mi:“MI:0915”(physical association)	0.560
	GLMN	psi-mi:“MI:0915”(physical association)	0.560
PEX5	GLMN	psi-mi:“MI:0915”(physical association)	0.560
C3AR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
HTR2C	KLRG2	psi-mi:“MI:0914”(association)	0.530
APLNR	METTL15	psi-mi:“MI:0914”(association)	0.530
KIR3DL2	METTL15	psi-mi:“MI:0914”(association)	0.530
VASN	AP3B1	psi-mi:“MI:0914”(association)	0.530
MGST3	GAPDHS	psi-mi:“MI:0914”(association)	0.530
FZD10	NRP1	psi-mi:“MI:0914”(association)	0.530

BioGRID (298): MET (Two-hybrid), GLMN (Affinity Capture-MS), GLMN (Affinity Capture-MS), GLMN (Affinity Capture-MS), GLMN (Affinity Capture-MS), GLMN (Affinity Capture-MS), GLMN (Affinity Capture-MS), GLMN (Affinity Capture-MS), GLMN (Two-hybrid), GLMN (Co-fractionation), IMPDH2 (Co-fractionation), GLMN (Affinity Capture-Western), GLMN (Affinity Capture-MS), GLMN (Proximity Label-MS), GLMN (Proximity Label-MS)

ESM2 similar proteins: A1A535, A2AIV2, A8XSV3, F1QJX5, F1QN74, O75691, O75800, P50748, Q0KK59, Q14D04, Q16X15, Q19317, Q3UHQ6, Q3URV1, Q4R6I5, Q4R7B1, Q5FWU8, Q5JWR5, Q5PQS3, Q5RHR6, Q5SPP5, Q5U430, Q5ZLS8, Q640K1, Q642P2, Q69YN4, Q6AXZ5, Q6GN08, Q6IV68, Q6TNU3, Q6ZQ18, Q6ZT12, Q86XI2, Q8BG67, Q8BL99, Q8BZM1, Q8C6S9, Q8IQV9, Q8K2A7, Q8K368

Diamond homologs: Q8BZM1, Q92990

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MET	down-regulates	GLMN	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	23
Uncertain significance	132
Likely benign	8
Benign	34

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069620	NM_053274.3(GLMN):c.841C>T (p.Gln281Ter)	Pathogenic
1073647	NM_053274.3(GLMN):c.1078_1079del (p.Ser360fs)	Pathogenic
1323020	NM_053274.3(GLMN):c.1376del (p.Gly459fs)	Pathogenic
1691364	NM_053274.3(GLMN):c.336del (p.Glu112fs)	Pathogenic
1691367	NM_053274.3(GLMN):c.1073del (p.Ile358fs)	Pathogenic
1691368	NM_053274.3(GLMN):c.1319G>A (p.Trp440Ter)	Pathogenic
1810259	NM_053274.3(GLMN):c.1406_1409del (p.Asp469fs)	Pathogenic
2672116	NM_053274.3(GLMN):c.395-1G>C	Pathogenic
3252358	NM_053274.3(GLMN):c.92del (p.Gln30_Leu31insTer)	Pathogenic
3765556	NM_053274.3(GLMN):c.1268del (p.Asn423fs)	Pathogenic
379875	NM_053274.3(GLMN):c.39+2T>C	Pathogenic
420033	NM_053274.3(GLMN):c.1208T>G (p.Leu403Ter)	Pathogenic
4279979	NM_053274.3(GLMN):c.1471C>T (p.Gln491Ter)	Pathogenic
4685667	NM_053274.3(GLMN):c.35_36del (p.Arg12fs)	Pathogenic
549853	NM_053274.3(GLMN):c.1630G>T (p.Glu544Ter)	Pathogenic
7805	NM_053274.3(GLMN):c.980_984del	Pathogenic
7806	NM_053274.3(GLMN):c.157_161del (p.Glu52_Lys53insTer)	Pathogenic
1066531	NM_053274.3(GLMN):c.632+1G>A	Likely pathogenic
1324482	NM_053274.3(GLMN):c.1473+2T>A	Likely pathogenic
1334667	NM_053274.3(GLMN):c.1141-1G>A	Likely pathogenic
1709641	NM_053274.3(GLMN):c.465_468del (p.Leu156fs)	Likely pathogenic
2440517	NM_053274.3(GLMN):c.148C>T (p.Gln50Ter)	Likely pathogenic
2672221	NM_053274.3(GLMN):c.1585+1G>A	Likely pathogenic
3340816	NM_053274.3(GLMN):c.923+2dup	Likely pathogenic
3376169	NM_053274.3(GLMN):c.920T>G (p.Leu307Ter)	Likely pathogenic
3382812	NM_053274.3(GLMN):c.1573A>T (p.Lys525Ter)	Likely pathogenic
3600442	NM_053274.3(GLMN):c.598del (p.Glu200fs)	Likely pathogenic
3767101	NM_053274.3(GLMN):c.1585G>T (p.Glu529Ter)	Likely pathogenic
3779702	NM_053274.3(GLMN):c.1470_1473dup (p.Thr492fs)	Likely pathogenic
3899333	NM_053274.3(GLMN):c.1405_1406del (p.Ser468_Asp469insTer)	Likely pathogenic

SpliceAI

2838 predictions. Top by Δscore:

Variant	Effect	Δscore
1:92246643:GGACC:G	acceptor_loss	1.0000
1:92246645:ACCTG:A	acceptor_loss	1.0000
1:92246646:CCT:C	acceptor_loss	1.0000
1:92246647:C:T	acceptor_loss	1.0000
1:92246648:T:G	acceptor_loss	1.0000
1:92247145:C:CC	acceptor_gain	1.0000
1:92247874:CAA:C	donor_loss	1.0000
1:92247875:AAC:A	donor_loss	1.0000
1:92247876:A:AG	donor_loss	1.0000
1:92247877:C:CA	donor_loss	1.0000
1:92247985:CCAGT:C	acceptor_gain	1.0000
1:92247986:CAGTC:C	acceptor_gain	1.0000
1:92247987:AGTC:A	acceptor_loss	1.0000
1:92247988:GTC:G	acceptor_loss	1.0000
1:92247989:TCTGT:T	acceptor_loss	1.0000
1:92247990:C:CC	acceptor_gain	1.0000
1:92263622:CCTAT:C	donor_gain	1.0000
1:92263626:T:C	donor_gain	1.0000
1:92297399:CGCA:C	donor_loss	1.0000
1:92297400:GCAC:G	donor_loss	1.0000
1:92297401:CACC:C	donor_loss	1.0000
1:92297402:A:T	donor_loss	1.0000
1:92297403:C:A	donor_loss	1.0000
1:92297526:TTTG:T	acceptor_gain	1.0000
1:92297527:TTG:T	acceptor_gain	1.0000
1:92297534:C:CT	acceptor_gain	1.0000
1:92297535:A:T	acceptor_gain	1.0000
1:92297955:ACTT:A	donor_loss	1.0000
1:92297958:TA:T	donor_loss	1.0000
1:92297959:A:AC	donor_gain	1.0000

AlphaMissense

3941 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:92246594:C:G	R574P	0.993
1:92247925:A:G	L513P	0.993
1:92247937:A:G	L509P	0.992
1:92246605:A:C	S570R	0.991
1:92246605:A:T	S570R	0.991
1:92246607:T:G	S570R	0.991
1:92246600:A:G	L572P	0.989
1:92247937:A:T	L509H	0.989
1:92262899:C:A	R479S	0.989
1:92262899:C:G	R479S	0.989
1:92291509:A:G	L65P	0.989
1:92291516:A:G	W63R	0.989
1:92291516:A:T	W63R	0.989
1:92246582:A:G	L578P	0.988
1:92247917:A:G	S516P	0.988
1:92264578:T:A	K425N	0.985
1:92264578:T:G	K425N	0.985
1:92246633:G:T	A561D	0.984
1:92262908:A:C	N476K	0.983
1:92262908:A:T	N476K	0.983
1:92247899:C:G	A522P	0.982
1:92267998:A:G	L338P	0.982
1:92246634:C:G	A561P	0.981
1:92262900:C:G	R479T	0.981
1:92291518:C:T	G62D	0.981
1:92247937:A:C	L509R	0.980
1:92268110:C:G	G335R	0.980
1:92268110:C:T	G335R	0.980
1:92291519:C:G	G62R	0.980
1:92286580:G:C	S215R	0.979

dbSNP variants (sampled 300 via entrez): RS1000007584 (1:92249990 GC>G,GCC), RS1000034267 (1:92268228 A>G), RS1000035534 (1:92259990 C>G,T), RS1000046069 (1:92295038 A>G), RS1000073331 (1:92342408 G>A), RS1000077876 (1:92310826 G>A), RS1000143339 (1:92362129 A>G), RS1000187867 (1:92350839 G>A), RS1000198436 (1:92354501 A>C), RS1000233490 (1:92334223 A>G), RS1000265197 (1:92301132 G>A), RS1000272061 (1:92354977 C>G,T), RS1000280777 (1:92256164 A>C), RS1000304260 (1:92256683 G>C), RS1000307406 (1:92318754 C>A)

Disease associations

OMIM: gene MIM:601749 | disease phenotypes: MIM:138000, MIM:112200

GenCC curated gene-disease

Disease	Classification	Inheritance
glomuvenous malformation	Definitive	Autosomal dominant

Mondo (2): glomuvenous malformation (MONDO:0007672), blue rubber bleb nevus (MONDO:0007203)

Orphanet (2): Glomuvenous malformation (Orphanet:83454), Blue rubber bleb nevus (Orphanet:1059)

HPO phenotypes

19 total (19 of 19 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000951	Abnormality of the skin
HP:0001939	Abnormality of metabolism/homeostasis
HP:0002629	Gastrointestinal arteriovenous malformation
HP:0002778	Abnormal tracheal morphology
HP:0002814	Abnormality of the lower limb
HP:0002817	Abnormality of the upper limb
HP:0010640	Abnormal nasal cavity morphology
HP:0011297	Abnormal digit morphology
HP:0011354	Generalized abnormality of skin
HP:0011355	Localized skin lesion
HP:0012210	Abnormal renal morphology
HP:0012721	Venous malformation
HP:0031445	Oral mucosa nodule
HP:0045026	Abnormal mediastinum morphology
HP:0100026	Arteriovenous malformation
HP:0200034	Papule
HP:0200035	Skin plaque
HP:0200036	Skin nodule

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004608_8	Granulocyte percentage of myeloid white cells	2.000000e-99
GCST004609_177	Monocyte percentage of white cells	5.000000e-167
GCST004625_6	Monocyte count	7.000000e-176
GCST004626_1	Myeloid white cell count	2.000000e-14
GCST004632_91	Lymphocyte percentage of white cells	1.000000e-20

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007997	granulocyte percentage of myeloid white cells
EFO:0007989	monocyte percentage of leukocytes
EFO:0005091	monocyte count
EFO:0007993	lymphocyte percentage of leukocytes

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C536240	Blue rubber bleb nevus syndrome (supp.)
C536827	Glomus vagale tumors (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465342 (SINGLE PROTEIN)

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

ChEMBL bioactivities

5 potent at pChembl≥5 of 5 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.85	IC50	1400	nM	CHEMBL5438345
5.64	IC50	2310	nM	CHEMBL5431503
5.48	IC50	3300	nM	CHEMBL5402025
5.06	IC50	8800	nM	CHEMBL5423199
5.02	IC50	9500	nM	CHEMBL5408398

PubChem BioAssay actives

5 with measured affinity, of 53 total; 5 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-[[[3-[[2-(1,3-dihydroisoindol-2-yl)-2-oxoethyl]amino]-1-adamantyl]amino]methyl]benzonitrile	2015039: Inhibition of C-terminal His-tagged human recombinant FAP (27 to 760 residues) expressed in Sf9 insect cells using Z-Gly-Pro-7-amino-4-methylcoumarine as substrate incubated for 15 mins by fluorescence based analysis	ic50	1.4000	uM
[3-[[2-(1,3-dihydroisoindol-2-yl)-2-oxoethyl]amino]-1-adamantyl] N-(3-azidopropyl)carbamate	2015039: Inhibition of C-terminal His-tagged human recombinant FAP (27 to 760 residues) expressed in Sf9 insect cells using Z-Gly-Pro-7-amino-4-methylcoumarine as substrate incubated for 15 mins by fluorescence based analysis	ic50	2.3100	uM
1-(1,3-dihydroisoindol-2-yl)-2-[[3-[[2-(1,3-dihydroisoindol-2-yl)-2-oxoethyl]amino]-1-adamantyl]amino]ethanone	2015039: Inhibition of C-terminal His-tagged human recombinant FAP (27 to 760 residues) expressed in Sf9 insect cells using Z-Gly-Pro-7-amino-4-methylcoumarine as substrate incubated for 15 mins by fluorescence based analysis	ic50	3.3000	uM
[3-[[2-(1,3-dihydroisoindol-2-yl)-2-oxoethyl]amino]-1-adamantyl] N-(pyridin-2-ylmethyl)carbamate	2015039: Inhibition of C-terminal His-tagged human recombinant FAP (27 to 760 residues) expressed in Sf9 insect cells using Z-Gly-Pro-7-amino-4-methylcoumarine as substrate incubated for 15 mins by fluorescence based analysis	ic50	8.8000	uM
[3-[[2-(1,3-dihydroisoindol-2-yl)-2-oxoethyl]amino]-1-adamantyl] N-(1-adamantyl)carbamate	2015039: Inhibition of C-terminal His-tagged human recombinant FAP (27 to 760 residues) expressed in Sf9 insect cells using Z-Gly-Pro-7-amino-4-methylcoumarine as substrate incubated for 15 mins by fluorescence based analysis	ic50	9.5000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	4
bisphenol A	decreases methylation, increases expression, decreases expression	3
dicrotophos	decreases expression	1
trichostatin A	increases expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
perfluorooctane sulfonic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
abrine	decreases expression	1
jinfukang	decreases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	decreases expression	1
Coumestrol	increases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Formaldehyde	decreases expression	1
Ivermectin	decreases expression	1
Phthalic Acids	decreases methylation	1
Plant Extracts	affects cotreatment, increases expression	1
Quercetin	decreases expression	1
Ribonucleotides	affects binding	1
Rotenone	increases expression	1
Selenium	decreases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Tobacco Smoke Pollution	increases expression	1
Vitamin E	decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5368772	Binding	Inhibition of C-terminal His-tagged human recombinant FAP (27 to 760 residues) expressed in Sf9 insect cells using Z-Gly-Pro-7-amino-4-methylcoumarine as substrate incubated for 15 mins by fluorescence based analysis	Highly Selective Inhibitors of Dipeptidyl Peptidase 9 (DPP9) Derived from the Clinically Used DPP4-Inhibitor Vildagliptin. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03767660	PHASE4	UNKNOWN	Efficacy of Rapamycin (Sirolimus) in the Treatment of BRBNS, Hereditary or Sporadic Venous Malformation
NCT02399527	Not specified	RECRUITING	Lymphatic Anomalies Registry for the Assessment of Outcome Data
NCT06642051	Not specified	ACTIVE_NOT_RECRUITING	Safety of the Sonablate HIFU System for the Ablation of Incompetent Veins of the Periphery