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): 283 total — 17 pathogenic, 29 likely-pathogenic
• GTEx eGene: eQTL in 7 tissues, sQTL in 2 (q < 0.05)
• Phenotypes (HPO): 19
• Cancer dependency (DepMap): dependent in 29.2% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Constraint (gnomAD): pLI 0.01 (LoF-tolerant), LOEUF 1.71 (unconstrained)
• 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: 38 — 19 protein_coding, 17 nonsense_mediated_decay, 2 retained_intron

MANE Select: ENST00000370360

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 1, TSL 4: 1, TSL 5: 2

ENST00000370360, ENST00000463560, ENST00000471465, ENST00000487911, ENST00000495106, ENST00000495852, ENST00000896608, ENST00000896609, ENST00000896610, ENST00000896611, ENST00000896612, ENST00000931415, ENST00000931416, ENST00000931417, ENST00000931418, ENST00000931419, ENST00000931420, ENST00000931421, ENST00000946567, ENST00000991566, ENST00000991567, ENST00000991568, ENST00000991569, ENST00001015966, ENST00001063620, ENST00001063621, ENST00001063622, ENST00001063623, ENST00001063624, ENST00001063625, ENST00001063626, ENST00001063627, ENST00001063628, ENST00001092989, ENST00001092990, ENST00001108215, ENST00001108216, ENST00001144678

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.

Highest expression (Bgee): primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, cerebellar hemisphere, cerebellar cortex, hemisphere of cerebellum.

Genetic regulation across tissues (GTEx eQTL / sQTL)

GLMN is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 7 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

9 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	eqtl	2.4e-05	+0.10	1:92342777:T:C
Testis	eqtl	1.9e-03	-0.54	1:92067545:TAACAG:T
Colon Sigmoid	eqtl	4.6e-03	-0.29	1:91925921:C:T
Brain Anterior cingulate cortex BA24	eqtl	7.0e-03	+1.14	1:92711158:A:C
Brain Nucleus accumbens basal ganglia	eqtl	1.1e-02	-0.22	1:93020491:GGA:G
Heart Atrial Appendage	sqtl	3.7e-02	-0.41	1:92471140:C:T
Brain Hippocampus	eqtl	3.8e-02	-0.31	1:92770777:G:A
Artery Coronary	eqtl	4.6e-02	+0.54	1:91741128:C:T
Lung	sqtl	4.9e-02	+0.30	1:91889599:G:T

FANTOM5 promoters

2 alternative TSS:

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

Top tissues by expression

showing 100 of 279 tissues 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
esophagus mucosa	UBERON:0002469	83.26	gold quality
testis	UBERON:0000473	83.14	gold quality
adenohypophysis	UBERON:0002196	83.10	gold quality
prefrontal cortex	UBERON:0000451	82.99	gold quality
calcaneal tendon	UBERON:0003701	82.99	gold quality
lower esophagus	UBERON:0013473	82.98	gold quality
lower esophagus muscularis layer	UBERON:0035833	82.97	gold quality
muscle layer of sigmoid colon	UBERON:0035805	82.96	gold quality
esophagus	UBERON:0001043	82.93	gold quality
ovary	UBERON:0000992	82.89	gold quality
tibial nerve	UBERON:0001323	82.78	gold quality
nucleus accumbens	UBERON:0001882	82.68	gold quality
caudate nucleus	UBERON:0001873	82.49	gold quality
vagina	UBERON:0000996	82.47	gold quality
spleen	UBERON:0002106	82.37	gold quality
neocortex	UBERON:0001950	82.24	gold quality
small intestine Peyer’s patch	UBERON:0003454	82.12	gold quality
right uterine tube	UBERON:0001302	82.01	gold quality
frontal cortex	UBERON:0001870	81.99	gold quality
metanephros cortex	UBERON:0010533	81.98	gold quality
zone of skin	UBERON:0000014	81.96	gold quality
right adrenal gland cortex	UBERON:0035827	81.91	gold quality
left uterine tube	UBERON:0001303	81.69	gold quality
pituitary gland	UBERON:0000007	81.59	gold quality
putamen	UBERON:0001874	81.55	gold quality
right adrenal gland	UBERON:0001233	81.29	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	81.26	gold quality
ganglionic eminence	UBERON:0004023	81.14	gold quality
amygdala	UBERON:0001876	81.02	gold quality
cerebral cortex	UBERON:0000956	80.94	gold quality
omental fat pad	UBERON:0010414	80.87	gold quality
cortical plate	UBERON:0005343	80.84	gold quality
body of pancreas	UBERON:0001150	80.83	gold quality
peritoneum	UBERON:0002358	80.81	gold quality
upper lobe of left lung	UBERON:0008952	80.74	gold quality
telencephalon	UBERON:0001893	80.61	gold quality
mucosa of transverse colon	UBERON:0004991	80.60	gold quality
oviduct epithelium	UBERON:0004804	80.53	gold quality
brain	UBERON:0000955	80.45	gold quality
sigmoid colon	UBERON:0001159	80.42	gold quality
central nervous system	UBERON:0001017	80.39	gold quality
left adrenal gland cortex	UBERON:0035825	80.26	gold quality
forebrain	UBERON:0001890	80.25	gold quality
right atrium auricular region	UBERON:0006631	80.20	gold quality
adipose tissue of abdominal region	UBERON:0007808	80.18	gold quality
left adrenal gland	UBERON:0001234	80.14	gold quality
transverse colon	UBERON:0001157	80.13	gold quality
tibial artery	UBERON:0007610	80.11	gold quality
popliteal artery	UBERON:0002250	80.09	gold quality
gastrocnemius	UBERON:0001388	80.06	gold quality
leukocyte	CL:0000738	79.96	gold quality
right lung	UBERON:0002167	79.91	gold quality
monocyte	CL:0000576	79.85	gold quality
upper lobe of lung	UBERON:0008948	79.80	gold quality
mononuclear cell	CL:0000842	79.70	gold quality
apex of heart	UBERON:0002098	79.70	gold quality
muscle of leg	UBERON:0001383	79.66	gold quality
aorta	UBERON:0000947	79.61	gold quality
embryo	UBERON:0000922	79.49	gold quality
female reproductive system	UBERON:0000474	79.48	gold quality
prostate gland	UBERON:0002367	79.46	gold quality
left coronary artery	UBERON:0001626	79.43	gold quality
right coronary artery	UBERON:0001625	79.40	gold quality
ascending aorta	UBERON:0001496	79.36	gold quality
tendon	UBERON:0000043	79.35	gold quality
heart left ventricle	UBERON:0002084	79.28	gold quality
subcutaneous adipose tissue	UBERON:0002190	79.28	gold quality
thoracic aorta	UBERON:0001515	79.25	gold quality
adrenal gland	UBERON:0002369	79.20	gold quality
adrenal cortex	UBERON:0001235	79.19	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

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 78 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Retina	tissue	36.2
Cerebellum	tissue	20.1	low
Superior colliculi	tissue	19.0
Thalamus	tissue	18.7
Midbrain	tissue	18.2
Pons	tissue	18.0
Hippocampal formation	tissue	15.9
Putamen	tissue	15.7
Substantia nigra	tissue	15.6
Septum	tissue	15.6
Hypothalamus	tissue	15.5
Cerebral cortex	tissue	15.4	medium
Occipital cortex	tissue	15.4
Ventral forebrain	tissue	15.2
Retrosplenial and cingulate cortex	tissue	15.1
Retrosplenial cortex	tissue	15.1
Prefrontal cortex	tissue	14.9
Temporal cortex	tissue	14.9
Motor cortex	tissue	14.7
Entorhinal cortex	tissue	14.5
Spinal cord	tissue	14.4
Somatosensory cortex	tissue	14.4
Amygdala	tissue	14.2
Medulla oblongata	tissue	14.1
Basal ganglia	tissue	14.0	not detected
Insular cortex	tissue	13.9
Periaqueductal gray	tissue	13.7
Corpus callosum	tissue	13.0
Frontal cortex	tissue	11.9
Postcentral gyrus	tissue	11.9
Olfactory bulb	tissue	11.9
Choroid plexus	tissue	10.6
Nucleus accumbens	tissue	10.3
Caudate putamen	tissue	9.1
Skin 1	tissue	8.8	medium
Tonsil	tissue	8.2	high
Thymus	tissue	8.0
Lymph node	tissue	7.8	high
Testis	tissue	7.6	low
Bone marrow	tissue	7.1	medium
Breast	tissue	6.6	medium
Locus coeruleus	tissue	6.5
Hippocampus	tissue	6.2	not detected
Esophagus	tissue	6.1	medium
Thyroid gland	tissue	5.8	medium
Appendix	tissue	5.8	high
Endometrium 1	tissue	5.6	high
Epididymis	tissue	5.4	medium
Placenta	tissue	5.2	high
Urinary bladder	tissue	5.0	high
Heart muscle	tissue	4.9	medium
Ovary	tissue	4.9	not detected
Parathyroid gland	tissue	4.9	not detected
Prostate	tissue	4.8	high
Rectum	tissue	4.6	high
Skeletal muscle	tissue	4.6	not detected
Smooth muscle	tissue	4.4	not detected
Colon	tissue	4.4	high
Cervix	tissue	4.3	medium
Adrenal gland	tissue	4.3	medium

Brain sub-regions (HPA Brain Atlas): detected in 191; highest nTPM — Cerebellar cortex (16.1), Subiculum (15.9), Vermis (14.6), Ventral spinal cord (14.4), Ventral hippocampus (13.7).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MNT, MXI1

Functional genomics

gnomAD constraint: pLI 0.00624, LOEUF 1.71, missense Z 0.47 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000370360 — one region, missense o/e 0.89. 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.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): DU 145 (-1.824), MGH-ECC3 (-1.278), ABC-1 (-1.209), PACADD-119 (-1.203), NCI-H2887 (-1.074), HCC515 (-1.055), HCC-78 (-1.04), KPL-1 (-1.033), SHP-77 (-1.009), KP-N-SI9s (-1.005), SNU-1196 (-0.995), MEL-JUSO (-0.992), HD-MB03 (-0.972), YAPC (-0.962), CML-T1 (-0.946).

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

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:2141180) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 31 distinct phenotype terms.

Mouse phenotype (MP)	Records
hemorrhage	2
embryonic growth retardation	2
increased bone mineral density	1
abnormal heart morphology	1
abnormal heart looping	1
abnormal embryo development	1
abnormal somite shape	1
abnormal embryo size	1
abnormal embryo turning	1
incomplete embryo turning	1
abnormal visceral yolk sac morphology	1
pale yolk sac	1
disorganized yolk sac vascular plexus	1
abnormal neural tube morphology	1
delayed neural tube closure	1
abnormal chorioallantoic fusion	1
abnormal tail bud morphology	1
abnormal pharyngeal arch morphology	1
abnormal vitelline vasculature morphology	1
abnormal forebrain development	1
pallor	1
abnormal neural tube closure	1
abnormal midbrain development	1
pericardial effusion	1
increased apoptosis	1

+6 more (showing top 25).

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
BTBD8	protein-coding	284697
C1orf146	protein-coding	388649
RPAP2	protein-coding	79871
GFI1	protein-coding	2672
EVI5	protein-coding	7813

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 (57 total): helix 35, 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 by resolution:

PDB	Title	Method	Resolution (Å)
4F52	Structure of a Glomulin-RBX1-CUL1 complex	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Predicted intracellular proteins, Disease related genes, Human disease related genes, Congenital malformations, Congenital malformations of the circulatory system

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cytosol; nucleoplasm

Antibody reliability (HPA): IH approved · IF approved

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)

Type	Positions
N-acetylalanine	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 activity.
476	disrupts interaction with rbx1. loss of inhibition of scf (skp1-cullin-f-box protein) e3 ubiquitin-protein ligase activity.
567	disrupts interaction with rbx1. loss of inhibition of scf (skp1-cullin-f-box protein) e3 ubiquitin-protein ligase activity.
574	disrupts interaction with rbx1. loss of inhibition of scf (skp1-cullin-f-box protein) e3 ubiquitin-protein ligase activity.
219	loss of interaction with fkbp4 and fkbp1a.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-983168	Antigen processing: Ubiquitination & Proteasome degradation	curated
R-HSA-1280218	Adaptive Immune System	—
R-HSA-983169	Class I MHC mediated antigen processing & presentation	—
R-HSA-168256	Immune System	—

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 (10): vasculogenesis (GO:0001570), positive regulation of cytokine production (GO:0001819), 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)

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

3 top-level categories:

Category	Pathways
Class I MHC mediated antigen processing & presentation	1
Immune System	1
Adaptive Immune System	1

GO top-level categories

38 GO namespaces:

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
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
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
Cul4-RING E3 ubiquitin ligase complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 18 of 20 annotations. The rest are phylogenetic / computational / electronic (IEA).

18 experimentally-supported GO terms:

GO term	NS	Evidence
cell surface receptor signaling pathway	BP	direct assay
epigenetic regulation of gene expression	BP	mutant phenotype
muscle cell differentiation	BP	mutant phenotype
negative regulation of T cell proliferation	BP	direct assay
negative regulation of cell population proliferation	BP	direct assay
positive regulation of cytokine production	BP	mutant phenotype
positive regulation of interleukin-2 production	BP	direct assay
positive regulation of phosphorylation	BP	direct assay
regulation of proteasomal ubiquitin-dependent protein catabolic process	BP	mutant phenotype
vasculogenesis	BP	mutant phenotype
Cul2-RING ubiquitin ligase complex	CC	physical interaction
Cul3-RING ubiquitin ligase complex	CC	physical interaction
Cul4A-RING E3 ubiquitin ligase complex	CC	physical interaction
cullin-RING ubiquitin ligase complex	CC	physical interaction
hepatocyte growth factor receptor binding	MF	direct assay
signaling receptor binding	MF	direct assay
ubiquitin protein ligase binding	MF	direct assay
ubiquitin-protein transferase inhibitor activity	MF	genetic interaction

Protein interactions and networks

STRING

showing 15 of 883 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GLMN	FBXW8	Q8N3Y1	860
GLMN	CUL7	Q14999	845
GLMN	RBX1	P62877	833
GLMN	FKBP4	Q02790	769
GLMN	SKP1	P34991	731
GLMN	PHYH	O14832	716
GLMN	UBA3	Q8TBC4	715
GLMN	CUL1	Q13616	699
GLMN	FBXW11	Q9UKB1	667
GLMN	A0A087WY85	A0A087WY85	640
GLMN	FKBP1A	P20071	561
GLMN	KRIT1	O00522	469
GLMN	CDC34	P49427	464
GLMN	BTRC	Q9Y297	452
GLMN	CCM2	Q9BSQ5	442

IntAct

Human interaction partners of GLMN in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

13 partners by confidence:

Partner	Interaction type	MIscore	Records
FKBP4	physical association	0.740	3
RBX1	physical association	0.670	6
CUL2	association	0.640	1
FKBP5	association	0.640	1
EFS	physical association	0.560	3
PEX5	physical association	0.560	3
SNAI1	physical association	0.560	3
CUL1	association	0.530	1
MGST3	association	0.530	1
NEGR1	physical association	0.400	1
HSPB1	physical association	0.370	1
CAND2	association	0.350	1
NSFL1C	physical association	0.000	1

BioGRID (301 interactions; top human partners by supporting records): FKBP4 (Two-hybrid; 12 records), RBX1 (Affinity Capture-MS; 10 records), CUL3 (Affinity Capture-MS; 8 records), CUL1 (Affinity Capture-MS; 7 records), CUL4A (Affinity Capture-MS; 6 records), MET (Two-hybrid; 6 records), CUL7 (Affinity Capture-Western; 5 records), FKBP1A (FRET; 5 records), FKBP5 (FRET; 5 records), CUL2 (Affinity Capture-MS; 4 records), CUL4B (Affinity Capture-MS; 4 records), CUL9 (Affinity Capture-MS; 4 records), ARRDC1 (Affinity Capture-MS; 3 records), DCAF4 (Affinity Capture-MS; 3 records), ENPP6 (Affinity Capture-MS; 3 records)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
MET	down-regulates	GLMN	relocalization

Protein complexes (CORUM) (2)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

2 complexes by size:

Complex	Subunits	Members
Ubiquitin E3 ligase (GLMN, FBXW8, SKP1A, RBX1)	4	FBXW8, GLMN, RBX1, SKP1
★ FKBP1A-GLMN complex	2	FKBP1A, GLMN

Disease & clinical

Genetic variants

Variant evidence for GLMN: 283 ClinVar records (46 pathogenic / likely pathogenic); 5 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	29
Uncertain significance	132
Likely benign	17
Benign	32

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 46 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1323020	NM_053274.3(GLMN):c.1376del (p.Gly459fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
618145	NM_053274.3(GLMN):c.1720C>T (p.Arg574Ter)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
379875	NM_053274.3(GLMN):c.39+2T>C	Pathogenic	criteria provided, single submitter	1
420033	NM_053274.3(GLMN):c.1208T>G (p.Leu403Ter)	Pathogenic	criteria provided, single submitter	1
549853	NM_053274.3(GLMN):c.1630G>T (p.Glu544Ter)	Pathogenic	criteria provided, single submitter	1
1069620	NM_053274.3(GLMN):c.841C>T (p.Gln281Ter)	Pathogenic	criteria provided, single submitter	1
1073647	NM_053274.3(GLMN):c.1078_1079del (p.Ser360fs)	Pathogenic	criteria provided, single submitter	1
1691364	NM_053274.3(GLMN):c.336del (p.Glu112fs)	Pathogenic	criteria provided, single submitter	1
1691367	NM_053274.3(GLMN):c.1073del (p.Ile358fs)	Pathogenic	criteria provided, single submitter	1
1691368	NM_053274.3(GLMN):c.1319G>A (p.Trp440Ter)	Pathogenic	criteria provided, single submitter	1
1810259	NM_053274.3(GLMN):c.1406_1409del (p.Asp469fs)	Pathogenic	criteria provided, single submitter	1
2672116	NM_053274.3(GLMN):c.395-1G>C	Pathogenic	criteria provided, single submitter	1
3252358	NM_053274.3(GLMN):c.92del (p.Gln30_Leu31insTer)	Pathogenic	criteria provided, single submitter	1
3765556	NM_053274.3(GLMN):c.1268del (p.Asn423fs)	Pathogenic	criteria provided, single submitter	1
4279979	NM_053274.3(GLMN):c.1471C>T (p.Gln491Ter)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore GLMN’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 31 predictions of 1,895):

Position(s)	Effect	Δscore	Sites
1:92246647–92246648	acceptor_loss	1.0000	6
1:92247876–92247877	donor_loss	1.0000	5
1:92263626	donor_gain	1.0000
1:92297402–92297403	donor_loss	1.0000	5
1:92297535	acceptor_gain	1.0000
1:92297959–92297960	donor_loss	1.0000	2
1:92297964	donor_gain	1.0000
1:92298030–92298031	acceptor_gain	1.0000	3
1:92298030	acceptor_loss	1.0000
1:92247145–92247146	acceptor_loss	0.9900	6

AlphaMissense

713 missense substitutions predicted likely pathogenic (of 3,941 scored), across 259 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D469	8	0.838	0.918
D25	8	0.812	0.902
D485	8	0.752	0.940
R479	7	0.921	0.989
E101	7	0.912	0.930
W63	7	0.908	0.989
N476	7	0.901	0.983
W495	7	0.877	0.959
R381	7	0.875	0.975
E108	7	0.871	0.934
F441	7	0.871	0.954
D463	7	0.863	0.921
F183	7	0.834	0.959
F505	7	0.834	0.948
F565	7	0.825	0.922
H519	7	0.812	0.933
F29	7	0.809	0.968
D566	7	0.762	0.860
E577	7	0.752	0.865
K425	6	0.922	0.985

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	3.51e-07

Disease associations

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

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
glomuvenous malformation	Definitive	Autosomal dominant	5

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (4 panels, 3 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

4 panels:

Panel	Rating
DDG2P	green
Paediatric disorders	green
Vascular skin disorders	green
Fetal anomalies	amber

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 phenotypes (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:

Study	Trait	p-value
GCST004625_6	Monocyte count	7e-176
GCST004609_107	Monocyte percentage of white cells	5e-167
GCST004608_8	Granulocyte percentage of myeloid white cells	2e-99
GCST004632_8	Lymphocyte percentage of white cells	1e-20
GCST004626_130	Myeloid white cell count	2e-14

EFO canonical traits (from GWAS)

4 canonical traits:

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 disease descriptors:

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 (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 53 human assays (53 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5425473	IC50	3100 nM

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	affects cotreatment, decreases expression	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)

Via MONDO — disease-level, not drug-specific.

3 trials:

NCT	Phase	Status	Title
NCT03767660	Phase 4	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

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for GLMN across ~30M SureChEMBL compounds — explore on Sugi Predict.