LMAN1

Summary

LMAN1 (lectin, mannose binding 1, HGNC:6631) is a protein-coding gene on chromosome 18q21.32, encoding Protein ERGIC-53 (P49257). Mannose-specific lectin.

The protein encoded by this gene is a membrane mannose-specific lectin that cycles between the endoplasmic reticulum, endoplasmic reticulum-Golgi intermediate compartment, and cis-Golgi, functioning as a cargo receptor for glycoprotein transport. The protein has an N-terminal signal sequence, a calcium-dependent and pH-sensitive carbohydrate recognition domain, a stalk region that functions in oligomerization, a transmembrane domain, and a short cytoplasmic domain required for organelle targeting. Allelic variants of this gene are associated with the autosomal recessive disorder combined factor V-factor VIII deficiency.

Source: NCBI Gene 3998 — RefSeq curated summary.

At a glance

• Gene–disease (curated): factor V and factor VIII, combined deficiency of, type 1 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 234 total — 9 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 20
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_005570

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6631
Approved symbol	LMAN1
Name	lectin, mannose binding 1
Location	18q21.32
Locus type	gene with protein product
Status	Approved
Aliases	MR60, ERGIC-53, ERGIC53, gp58, MCFD1, FMFD1
Ensembl gene	ENSG00000074695
Ensembl biotype	protein_coding
OMIM	601567
Entrez	3998

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 3 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000251047, ENST00000587561, ENST00000587918, ENST00000587940, ENST00000592562, ENST00000904707, ENST00000963587

RefSeq mRNA: 1 — MANE Select: NM_005570 NM_005570

CCDS: CCDS11974

Canonical transcript exons

ENST00000251047 — 13 exons

Exon	Start	End
ENSE00000807273	59345919	59346051
ENSE00000914733	59353202	59353301
ENSE00001011718	59338760	59338953
ENSE00001011720	59331418	59331539
ENSE00001011721	59333091	59333244
ENSE00001011722	59338557	59338627
ENSE00001011723	59327823	59331129
ENSE00002852923	59359031	59359265
ENSE00003541207	59354519	59354580
ENSE00003567134	59355504	59355658
ENSE00003609027	59349113	59349236
ENSE00003645042	59355313	59355420
ENSE00003686404	59347513	59347571

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 99.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 80.5409 / max 667.7673, expressed in 1820 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
172197	80.0151	1820
172198	0.5258	276

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
germinal epithelium of ovary	UBERON:0001304	99.03	gold quality
jejunal mucosa	UBERON:0000399	98.92	gold quality
gingival epithelium	UBERON:0001949	98.87	gold quality
corpus epididymis	UBERON:0004359	98.86	gold quality
caput epididymis	UBERON:0004358	98.78	gold quality
epithelium of nasopharynx	UBERON:0001951	98.64	gold quality
nasopharynx	UBERON:0001728	98.62	gold quality
adrenal tissue	UBERON:0018303	98.60	gold quality
secondary oocyte	CL:0000655	98.49	gold quality
tibia	UBERON:0000979	98.48	gold quality
gingiva	UBERON:0001828	98.48	gold quality
cardia of stomach	UBERON:0001162	98.45	gold quality
seminal vesicle	UBERON:0000998	98.40	gold quality
mucosa of paranasal sinus	UBERON:0005030	98.16	gold quality
pylorus	UBERON:0001166	98.15	gold quality
pericardium	UBERON:0002407	98.03	gold quality
renal medulla	UBERON:0000362	98.01	gold quality
jejunum	UBERON:0002115	98.00	gold quality
cauda epididymis	UBERON:0004360	97.96	gold quality
lower lobe of lung	UBERON:0008949	97.93	silver quality
endometrium	UBERON:0001295	97.83	gold quality
superficial temporal artery	UBERON:0001614	97.81	gold quality
parietal pleura	UBERON:0002400	97.74	gold quality
vena cava	UBERON:0004087	97.59	gold quality
calcaneal tendon	UBERON:0003701	97.42	gold quality
esophagus squamous epithelium	UBERON:0006920	97.41	gold quality
body of pancreas	UBERON:0001150	97.38	gold quality
heart right ventricle	UBERON:0002080	97.31	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.31	gold quality
superior surface of tongue	UBERON:0007371	97.29	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 12.

Experiment	Marker?	Max mean expression
E-MTAB-9467	yes	560.30
E-CURD-88	yes	90.00
E-HCAD-1	yes	56.06
E-CURD-122	yes	53.92
E-HCAD-4	yes	46.47
E-CURD-46	yes	43.11
E-MTAB-8410	yes	26.51
E-HCAD-13	yes	25.76
E-HCAD-9	yes	14.61
E-MTAB-10553	yes	11.19
E-CURD-112	yes	5.73
E-HCAD-32	no	731.58
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

153 targeting LMAN1, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-551B-5P	99.96	71.28	3493

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• Among Papua New Guinea malaria patients, 2 new mannose-binding lectin polymorphic promoter sites were found: one in the untranslated region at position +1 (G–>A, termed R/S), and the 2nd upstream of the gene at position -4 (G–>A, termed T/U). (PMID:12175909)
• MBL deficiency is not a risk factor for SLE in women from the Canary Islands, but it is associated with lower prevalence of autoantibodies and with later age at disease onset and at SLE diagnosis. (PMID:12672193)
• inactivating mutations in MCFD2 cause combined deficiency of factor V and factor VIII with a phenotype indistinguishable from that caused by mutations in LMAN1 (PMID:12717434)
• Data show that the mRNA of lectin ERGIC-53 and its related protein VIP36 is induced by the known inducers of endoplasmic reticulum stress, tunicamycin and thapsigargin. (PMID:12727195)
• an interaction between LMAN1 and FVIII in vivo was mediated via high mannose-containing asparagine-linked oligosaccharides that are densely situated within the B domain of FVIII, as well as protein-protein interactions (PMID:14629470)
• Results describe the x-ray structure of human mannan-binding lectin-associated protein 19 (MAp19), and identify the residues involved in the interaction of MAp19 with mannan-binding lectin and L-ficolin. (PMID:15117939)
• surfactant proteins A and D and mannose-binding lectin play roles in inflammation caused by DNA in lungs and other tissues (PMID:15145932)
• ERGIC-53 and MCFD2 have important functions during cellular response to stress conditions (PMID:15292203)
• The ERGIC-53 is stationary and not simply a collection of mobile carriers that mediate protein traffic from endoplasmic reticulum to Golgi. (PMID:15632110)
• MBL gene polymorphism at codon 54 is not associated with the clearance of hepatitis B virus infection nor progression of disease in chronic hepatitis B virus infection (PMID:15716605)
• MBL1 contains 9 disulfide-linked chains and is therefore trimeric in structure; the oligomerization state of MBL has a direct effect on its carbohydrate-binding properties, but no influence on the interaction with MBL-associated serine proteases (MASPs). (PMID:15728497)
• LMAN1 and MCFD2 form a cargo receptor complex and the primary sorting signals residing in the B domain direct the binding of factor VIII (PMID:15886209)
• Mutations in (LMAN1) and (MCFD2), have been found to be responsible for the dual deficiency of FV and FVIII. (PMID:16044454)
• ERGIC-53 accumulated at the perinuclear region, and remained there even after cells were treated with agents that induce redistribution of Golgi proteins to the ER, indicating an inhibition of Golgi-to-ER transport of ERGIC-53. (PMID:16054885)
• role in Aspergillus mediated allergies and infections (PMID:16114131)
• ERGIC-53 is present exclusively as a hexameric complex in cells (PMID:16257008)
• Mannan-binding lectin activates C3 and the alternative complement pathway without involvement of C2 (PMID:16670774)
• Our findings identify a novel ERGIC-53 substrate, and indicate that interactions with light chains or ERGIC-53 seed muDeltaCH1 condensation in different stations of the early secretory pathway. (PMID:16735443)
• Here, we have observed that NCT N-linked oligosaccharides mediated specific interactions with the secretory pathway lectins calnexin and ERGIC-53 (PMID:16938437)
• Results indicate that ERGIC-53 can bind cargo glycoproteins in an MCFD2-independent fashion and suggest that MCFD2 is a recruitment factor for blood coagulation factors V and VIII. (PMID:17010120)
• a mannose-binding lectin codon 54 gene polymorphism has a role in protection against Chlamydia trachomatis infection and Fallopian tube damage (PMID:17496053)
• ERGIC-53 gene transcription is regulated in response to endoplasmic reticulum stress (PMID:17535801)
• ERGIC-53 bound high-mannose-type oligosaccharides with low affinity and broad specificity, not discriminating between monoglucosylated and deglucosylated high-mannosetype oligosaccharides. (PMID:18025080)
• Silencing Surf4 together with ERGIC-53 or silencing the p24 family member p25 induced an identical phenotype characterized by a reduced number of ERGIC clusters and fragmentation of the Golgi apparatus without effect on anterograde transport. (PMID:18287528)
• MCFD2 may play a primary role in the export of FV and FVIII from the ER, with the impact of LMAN1 mediated indirectly through its interaction with MCFD2 (PMID:18391077)
• Study shows that SUMF1 interacts with protein disulfide isomerase (PDI) and ERp44, two thioredoxin family members residing in the early secretory pathway, and with ERGIC-53, a lectin that shuttles between the ER and the Golgi. (PMID:18508857)
• Data suggest that transient dimerization is an obligatory step in FGFR3 biosynthesis and that TDII/ERGIC-53 complex formation may function as a checkpoint for FGFR3 sorting downstream the endoplasmic reticulum. (PMID:18577465)
• LMAN1 mutational inactivation is a frequent and early event potentially contributing to colorectal tumorigenesis. (PMID:19118014)
• MBL deposition and gene expression in advanced human atherosclerotic lesions revealed the presence of MBL protein in ruptured but not stable atherosclerotic lesions (PMID:19380618)
• Data show that mutations in MCFD2 that disrupt the tertiary structure and abolish LMAN1 binding still retain the FV/FVIII binding activities, suggesting that this interaction is independent of Ca(2+)-induced folding of the protein. (PMID:20007547)
• Data present the crystal structure of the LMAN1/MCFD2 complex and relate it to patient mutations. Circular dichroism data show that the majority of the substitution mutations give rise to a disordered or severely destabilized MCFD2 protein. (PMID:20138881)
• Two new mutations at ERGIC-53 gene in a Turkish family. (PMID:20460353)
• UBXD1 modulates the trafficking of ERGIC-53-containing vesicles by controlling the interaction of transport factors with the cytoplasmic tail of ERGIC-53. (PMID:22337587)
• Mutations in LMAN1 lead to F5F8D (combined deficiency of factor V And factor VIII) due to alterations in LMAN1-MCFD2 complex of coat protein (COP)II complex trafficking machinery; 70% of F5F8D patients have mutations in LMAN1. [REVIEW] (PMID:22764119)
• Data indicate that together with its soluble coreceptor MCFD2, LMAN1 transports coagulation factors V (FV) and VIII (FVIII). (PMID:23709226)
• Studies indicate that the LMAN1-CRD contains distinct, separable binding sites for both its partner protein MCFD2 and the cargo proteins FV/FVIII. (PMID:23852824)
• Authors identified a class of pathogen-derived ERGIC-53 ligands, a lectin-independent basis for their association with ERGIC-53, and a role for ERGIC-53 in the propagation of several highly pathogenic RNA virus families. (PMID:24237698)
• Mannan-binding lectin reduces CpG DNA-induced inflammatory cytokine production in monocytes. (PMID:25664598)
• MMP-9 secretion was reduced in the LMAN1 knockout cell line compared to control cells confirming the functional role of LMAN1. (PMID:26150355)
• Genetic variants in the exon1 of MBL gene per se are not risk factors for Systemic lupus erythematosus (SLE) in South Indian Tamils. However, the association of codon 54 (rs1800450) with medium vessel vasculitis suggests that it may be a genetic modifier of clinical phenotype in SLE. (PMID:28097447)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	lman1	ENSDARG00000069980
mus_musculus	Lman1	ENSMUSG00000041891
rattus_norvegicus	Lman1	ENSRNOG00000024470
drosophila_melanogaster	CG5510	FBGN0039160
caenorhabditis_elegans		WBGENE00002071

Paralogs (3): LMAN2L (ENSG00000114988), LMAN1L (ENSG00000140506), LMAN2 (ENSG00000169223)

Protein

Protein identifiers

Protein ERGIC-53 — P49257 (reviewed: P49257)

Alternative names: ER-Golgi intermediate compartment 53 kDa protein, Gp58, Intracellular mannose-specific lectin MR60, Lectin mannose-binding 1

All UniProt accessions (1): P49257

UniProt curated annotations — full annotation on UniProt →

Function. Mannose-specific lectin. May recognize sugar residues of glycoproteins, glycolipids, or glycosylphosphatidyl inositol anchors and may be involved in the sorting or recycling of proteins, lipids, or both. The LMAN1-MCFD2 complex forms a specific cargo receptor for the ER-to-Golgi transport of selected proteins.

Subunit / interactions. Exists both as a covalent disulfide-linked homohexamer, and a complex of three disulfide-linked dimers non-covalently kept together. Interacts with MCFD2. May interact with TMEM115. Interacts with RAB3GAP1 and RAB3GAP2. Interacts with UBXN6. Interacts with SERPINA1/alpha1-antitrypsin. Interacts with BET1.

Subcellular location. Endoplasmic reticulum-Golgi intermediate compartment membrane. Golgi apparatus membrane. Endoplasmic reticulum membrane.

Tissue specificity. Ubiquitous.

Post-translational modifications. The N-terminal may be partly blocked.

Disease relevance. Factor V and factor VIII combined deficiency 1 (F5F8D1) [MIM:227300] A blood coagulation disorder characterized by bleeding symptoms similar to those in hemophilia or parahemophilia, that are caused by single deficiency of FV or FVIII, respectively. The most common symptoms are epistaxis, menorrhagia, and excessive bleeding during or after trauma. Plasma levels of coagulation factors V and VIII are in the range of 5 to 30% of normal. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The FF ER export motif at the C-terminus is not sufficient to support endoplasmic reticulum exit, and needs assistance of Gln-501 for proper recognition of COPII coat components.

RefSeq proteins (1): NP_005561* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005052	Lectin_leg	Domain
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR051136	Intracellular_Lectin-GPT	Family

Pfam: PF03388

UniProt features (58 total): strand 22, binding site 9, helix 6, sequence variant 5, disulfide bond 3, topological domain 2, turn 2, signal peptide 1, chain 1, site 1, modified residue 1, sequence conflict 1, transmembrane region 1, domain 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

18 structures.

PDB	Method	Resolution (Å)
4YGB	X-RAY DIFFRACTION	1.6
3WHT	X-RAY DIFFRACTION	1.8
3A4U	X-RAY DIFFRACTION	1.84
4YGC	X-RAY DIFFRACTION	2.4
4GKY	X-RAY DIFFRACTION	2.42
3LCP	X-RAY DIFFRACTION	2.45
4YGD	X-RAY DIFFRACTION	2.51
8JP4	ELECTRON MICROSCOPY	2.53
8JP5	ELECTRON MICROSCOPY	2.59
3WHU	X-RAY DIFFRACTION	2.6
4GKX	X-RAY DIFFRACTION	2.7
3WNX	X-RAY DIFFRACTION	2.75
4YGE	X-RAY DIFFRACTION	3.05
8JP6	ELECTRON MICROSCOPY	3.29
8JP9	ELECTRON MICROSCOPY	3.37
8JP8	ELECTRON MICROSCOPY	3.39
8JP7	ELECTRON MICROSCOPY	3.51
8JPG	ELECTRON MICROSCOPY	6.76

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49257-F1	79.71	0.46

Functional residue map

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

Catalytic / active sites (1): 501 (required for er export)

Ligand- & substrate-binding residues (9): 152; 154; 156; 156; 178; 181; 251–253; 88; 121

Post-translational modifications (1): 425

Disulfide bonds (3): 190–230, 466, 475

Function

Pathways and Gene Ontology

Reactome pathways

19 pathways

ID	Pathway
R-HSA-204005	COPII-mediated vesicle transport
R-HSA-5694530	Cargo concentration in the ER
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013106	RHOC GTPase cycle
R-HSA-9013404	RAC2 GTPase cycle
R-HSA-9013405	RHOD GTPase cycle
R-HSA-9013408	RHOG GTPase cycle
R-HSA-9013423	RAC3 GTPase cycle
R-HSA-948021	Transport to the Golgi and subsequent modification
R-HSA-162582	Signal Transduction
R-HSA-194315	Signaling by Rho GTPases
R-HSA-199977	ER to Golgi Anterograde Transport
R-HSA-199991	Membrane Trafficking
R-HSA-392499	Metabolism of proteins
R-HSA-446203	Asparagine N-linked glycosylation
R-HSA-5653656	Vesicle-mediated transport
R-HSA-597592	Post-translational protein modification
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 312 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, WANG_CLIM2_TARGETS_UP, GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_PROTEIN_TARGETING, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_WOUND_HEALING, MARTINEZ_RB1_TARGETS_UP, GOBP_PROTEIN_MATURATION, GOBP_ENDOPLASMIC_RETICULUM_TO_GOLGI_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (11): in utero embryonic development (GO:0001701), protein folding (GO:0006457), endoplasmic reticulum to Golgi vesicle-mediated transport (GO:0006888), endoplasmic reticulum organization (GO:0007029), Golgi organization (GO:0007030), blood coagulation (GO:0007596), positive regulation of organelle organization (GO:0010638), protein transport (GO:0015031), obsolete negative regulation of protein targeting to mitochondrion (GO:1903215), gene expression (GO:0010467), vesicle-mediated transport (GO:0016192)

GO Molecular Function (5): D-mannose binding (GO:0005537), metal ion binding (GO:0046872), obsolete unfolded protein binding (GO:0051082), protein binding (GO:0005515), carbohydrate binding (GO:0030246)

GO Cellular Component (13): Golgi membrane (GO:0000139), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), endoplasmic reticulum-Golgi intermediate compartment (GO:0005793), ER to Golgi transport vesicle membrane (GO:0012507), membrane (GO:0016020), sarcomere (GO:0030017), COPII-coated ER to Golgi transport vesicle (GO:0030134), extracellular matrix (GO:0031012), endoplasmic reticulum-Golgi intermediate compartment membrane (GO:0033116), extracellular exosome (GO:0070062), Golgi apparatus (GO:0005794), endomembrane system (GO:0012505)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
RHO GTPase cycle	6
ER to Golgi Anterograde Transport	2
Asparagine N-linked glycosylation	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Membrane Trafficking	1
Transport to the Golgi and subsequent modification	1
Vesicle-mediated transport	1
Post-translational protein modification	1
Metabolism of proteins	1
Signaling by Rho GTPases	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	4
organelle organization	3
intracellular membrane-bounded organelle	3
cellular anatomical structure	3
cellular process	2
endomembrane system organization	2
transport	2
binding	2
bounding membrane of organelle	2
endomembrane system	2
chordate embryonic development	1
protein maturation	1
intercellular transport	1
intracellular transport	1
Golgi vesicle transport	1
hemostasis	1
wound healing	1
coagulation	1
regulation of organelle organization	1
positive regulation of cellular component organization	1
intracellular protein localization	1
establishment of protein localization	1
macromolecule biosynthetic process	1
monosaccharide binding	1
cation binding	1
Golgi apparatus	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
COPII-coated ER to Golgi transport vesicle	1
transport vesicle membrane	1
coated vesicle membrane	1
myofibril	1
coated vesicle	1
external encapsulating structure	1
endoplasmic reticulum-Golgi intermediate compartment	1
extracellular vesicle	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

1778 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LMAN1	MCFD2	Q8NI22	999
LMAN1	SURF4	O15260	917
LMAN1	SEC31A	O94979	893
LMAN1	COPB1	P53618	889
LMAN1	SEC16A	O15027	879
LMAN1	ERGIC1	Q969X5	857
LMAN1	RAB1B	Q9H0U4	851
LMAN1	ERP44	Q9BS26	847
LMAN1	F8	P00451	842
LMAN1	SEC24C	P53992	830
LMAN1	GOLGA2	Q08379	828
LMAN1	CANX	P27824	805
LMAN1	SEC23A	Q15436	789
LMAN1	MBL2	P11226	770
LMAN1	CALR	P27797	769

IntAct

123 interactions, top by confidence:

A	B	Type	Score
LMAN1	MCFD2	psi-mi:“MI:0407”(direct interaction)	0.960
LMAN1	MCFD2	psi-mi:“MI:0915”(physical association)	0.960
MCFD2	LMAN1	psi-mi:“MI:0915”(physical association)	0.960
MCFD2	LMAN1	psi-mi:“MI:0407”(direct interaction)	0.960
TCTN2	CLGN	psi-mi:“MI:0914”(association)	0.780
EXOC1	EXOC5	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
	XPO1	psi-mi:“MI:0914”(association)	0.530
CLCC1	PLSCR1	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
SURF4	LMAN1	psi-mi:“MI:0403”(colocalization)	0.460
SURF4	LMAN1	psi-mi:“MI:0915”(physical association)	0.460
env	FLOT1	psi-mi:“MI:0914”(association)	0.460
env	PGRMC1	psi-mi:“MI:0914”(association)	0.460
ERP44	LMAN1	psi-mi:“MI:0915”(physical association)	0.460

BioGRID (573): ALDOA (Co-fractionation), ALDOC (Co-fractionation), ATP1A1 (Co-fractionation), ATP1B1 (Co-fractionation), ATP2A2 (Co-fractionation), ATP5A1 (Co-fractionation), ATP5C1 (Co-fractionation), CANX (Co-fractionation), CYC1 (Co-fractionation), EIF3I (Co-fractionation), LGALS1 (Co-fractionation), LMAN1 (Co-fractionation), LMAN1 (Co-fractionation), LMAN1 (Co-fractionation), LMAN1 (Co-fractionation)

ESM2 similar proteins: A0A6I8RMG7, A0AVX7, A2VEI2, A4IG32, A5D7A0, B5X186, B5X4E0, I6L9G5, J3S9D9, O35783, O35887, O93390, O93434, P07214, P09486, P13213, P16975, P20112, P22676, P36377, P36378, P41044, P49257, P61022, P61023, P79881, Q05186, Q14257, Q15293, Q28BT4, Q2KJ39, Q3T0K1, Q4U471, Q5R767, Q5R7F0, Q5ZM44, Q62703, Q62902, Q6IP82, Q6IQP3

Diamond homologs: P49256, P49257, P59481, Q12907, Q2HJD1, Q5FB95, Q5RCF0, Q62902, Q8VCD3, Q9D0F3, Q9DBH5, Q9H0V9, Q9HAT1, Q9TU32, O94401

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 121 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Maturation of DENV proteins	5	12.6×	1e-03
Translocation of SLC2A4 (GLUT4) to the plasma membrane	6	11.0×	7e-04
COPII-mediated vesicle transport	5	9.7×	2e-03
Membrane Trafficking	13	5.7×	5e-05
Vesicle-mediated transport	13	5.4×	7e-05

GO biological processes:

GO term	Partners	Fold	FDR
mitotic cytokinesis	5	12.6×	9e-03
transmembrane transport	6	9.8×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	5
Uncertain significance	145
Likely benign	14
Benign	44

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1802256	NM_005570.4(LMAN1):c.349C>T (p.Arg117Ter)	Pathogenic
3383188	NM_005570.4(LMAN1):c.1366C>T (p.Arg456Ter)	Pathogenic
4278403	NM_005570.4(LMAN1):c.604C>T (p.Arg202Ter)	Pathogenic
4751314	NM_005570.4(LMAN1):c.539del (p.Asn180fs)	Pathogenic
8062	NM_005570.4(LMAN1):c.89dup (p.Asp31fs)	Pathogenic
8063	NM_005570.4(LMAN1):c.1149+2T>C	Pathogenic
8064	NM_005570.4(LMAN1):c.796del (p.Gln266fs)	Pathogenic
8065	NM_005570.4(LMAN1):c.1356del (p.Asn452_Leu453insTer)	Pathogenic
8066	NM_005570.4(LMAN1):c.2T>C (p.Met1Thr)	Pathogenic
2200621	NM_005570.4(LMAN1):c.535_539+2del	Likely pathogenic
3583381	NM_005570.4(LMAN1):c.822G>A (p.Pro274=)	Likely pathogenic
3583382	NM_005570.4(LMAN1):c.49_86dup (p.Gly30fs)	Likely pathogenic
3583383	NM_005570.4(LMAN1):c.15del (p.Arg5fs)	Likely pathogenic
4849411	NM_005570.4(LMAN1):c.478-11_483delinsATTTTTTTAGGAAAAA	Likely pathogenic

SpliceAI

1956 predictions. Top by Δscore:

Variant	Effect	Δscore
18:59333088:TAC:T	donor_loss	1.0000
18:59333120:C:A	donor_gain	1.0000
18:59333242:TTT:T	acceptor_gain	1.0000
18:59333244:TCT:T	acceptor_loss	1.0000
18:59333245:C:A	acceptor_loss	1.0000
18:59333246:T:G	acceptor_loss	1.0000
18:59338551:ACTT:A	donor_loss	1.0000
18:59338553:TTACT:T	donor_loss	1.0000
18:59338554:TA:T	donor_loss	1.0000
18:59338555:A:AC	donor_gain	1.0000
18:59338555:AC:A	donor_loss	1.0000
18:59338555:ACTT:A	donor_gain	1.0000
18:59338556:C:CT	donor_gain	1.0000
18:59338556:CT:C	donor_gain	1.0000
18:59338556:CTT:C	donor_gain	1.0000
18:59338556:CTTC:C	donor_gain	1.0000
18:59338556:CTTCA:C	donor_gain	1.0000
18:59338558:T:TA	donor_gain	1.0000
18:59338709:C:A	donor_gain	1.0000
18:59338781:T:TA	donor_gain	1.0000
18:59338826:T:C	donor_gain	1.0000
18:59338954:C:CC	acceptor_gain	1.0000
18:59346059:T:TC	acceptor_gain	1.0000
18:59346067:T:C	acceptor_gain	1.0000
18:59346067:T:TC	acceptor_gain	1.0000
18:59346072:A:AC	acceptor_gain	1.0000
18:59346078:C:CT	acceptor_gain	1.0000
18:59346079:A:C	acceptor_gain	1.0000
18:59346079:A:T	acceptor_gain	1.0000
18:59346080:T:C	acceptor_gain	1.0000

AlphaMissense

3372 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:59349113:C:G	D255H	1.000
18:59349134:C:G	A248P	1.000
18:59353257:C:G	R195P	1.000
18:59353258:G:C	R195G	1.000
18:59353258:G:T	R195S	1.000
18:59355332:G:A	S153F	1.000
18:59338866:A:G	L348P	0.999
18:59347559:A:T	V259D	0.999
18:59347562:T:C	D258G	0.999
18:59347563:C:G	D258H	0.999
18:59347566:G:C	H257D	0.999
18:59347568:T:A	D256V	0.999
18:59347569:C:G	D256H	0.999
18:59347571:T:A	D255V	0.999
18:59349113:C:A	D255Y	0.999
18:59349124:C:T	G251E	0.999
18:59349127:G:A	T250I	0.999
18:59349131:C:G	A249P	0.999
18:59349133:G:T	A248D	0.999
18:59349136:G:A	S247F	0.999
18:59349136:G:T	S247Y	0.999
18:59349137:A:G	S247P	0.999
18:59349139:A:T	I246K	0.999
18:59349142:C:T	G245E	0.999
18:59349186:A:C	C230W	0.999
18:59349187:C:G	C230S	0.999
18:59349187:C:T	C230Y	0.999
18:59349188:A:G	C230R	0.999
18:59349188:A:T	C230S	0.999
18:59349220:C:T	G219D	0.999

dbSNP variants (sampled 300 via entrez): RS1000055889 (18:59333753 G>A,C), RS1000070794 (18:59340494 A>C), RS1000073080 (18:59350640 T>C), RS1000158468 (18:59358821 TGAGG>T), RS1000161220 (18:59334358 T>A), RS1000234228 (18:59359381 C>A,T), RS1000422602 (18:59359251 T>A), RS1000680151 (18:59334102 T>A), RS1000682834 (18:59335884 A>T), RS1000691099 (18:59351515 A>G), RS1000752346 (18:59329164 T>C), RS1000853908 (18:59345699 C>CT), RS1000910261 (18:59351802 G>A), RS1000940092 (18:59357143 T>C), RS1000967428 (18:59339116 GATTAA>G)

Disease associations

OMIM: gene MIM:601567 | disease phenotypes: MIM:227300, MIM:608133, MIM:134500, MIM:306700

GenCC curated gene-disease

Disease	Classification	Inheritance
factor V and factor VIII, combined deficiency of, type 1	Definitive	Autosomal recessive
combined deficiency of factor V and factor VIII	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
factor V and factor VIII, combined deficiency of, type 1	Definitive	AR

Mondo (5): factor V and factor VIII, combined deficiency of, type 1 (MONDO:0009206), retinitis pigmentosa 7 (MONDO:0011974), hemophilia A (MONDO:0010602), factor V deficiency (MONDO:0020586), combined deficiency of factor V and factor VIII (MONDO:0018175)

Orphanet (4): Combined deficiency of factor V and factor VIII (Orphanet:35909), Retinitis pigmentosa (Orphanet:791), Congenital factor V deficiency (Orphanet:326), Hemophilia A (Orphanet:98878)

HPO phenotypes

20 total (20 of 20 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000132	Menorrhagia
HP:0000225	Gingival bleeding
HP:0000421	Epistaxis
HP:0000790	Hematuria
HP:0000978	Bruising susceptibility
HP:0001892	Abnormal bleeding
HP:0002149	Hyperuricemia
HP:0002170	Intracranial hemorrhage
HP:0002239	Gastrointestinal hemorrhage
HP:0003077	Hyperlipidemia
HP:0003125	Reduced factor VIII activity
HP:0003225	Reduced coagulation factor V activity
HP:0003645	Prolonged partial thromboplastin time
HP:0004846	Prolonged bleeding after surgery
HP:0005261	Joint hemorrhage
HP:0006298	Prolonged bleeding after dental extraction
HP:0008151	Prolonged prothrombin time
HP:0011889	Bleeding with minor or no trauma
HP:0030137	Prolonged bleeding following circumcision

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST003837_8	Chronotype	7.000000e-10
GCST003838_8	Morning vs. evening chronotype	1.000000e-06
GCST008309_7	Cardiac troponin-I levels	1.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010071	cardiac troponin I measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D005166	Factor V Deficiency	C15.378.100.100.300; C15.378.100.141.300; C15.378.463.300; C16.320.099.300
D006467	Hemophilia A	C15.378.100.100.500; C15.378.100.141.500; C15.378.463.500; C16.320.099.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066884 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, affects cotreatment, decreases expression	6
sodium arsenite	affects expression, decreases expression, increases abundance, increases expression	4
bisphenol A	decreases expression, increases expression	3
trichostatin A	affects cotreatment, decreases expression	3
mercuric bromide	decreases expression, affects cotreatment	2
perfluorooctane sulfonic acid	increases expression, decreases expression	2
entinostat	decreases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
Panobinostat	decreases expression, affects cotreatment	2
Benzo(a)pyrene	decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
geldanamycin	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
1-nitropyrene	increases expression	1
U 0126	affects reaction, affects expression	1
belinostat	decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects expression	1
LDN 193189	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Sunitinib	increases expression	1
Arsenic	increases abundance, increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651697	Binding	Binding affinity to human LMAN1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3A7	Abcam HEK293T LMAN1 KO	Transformed cell line	Female
CVCL_D7TN	Ubigene A-549 LMAN1 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00002386	PHASE4	COMPLETED	Effect of Indinavir Plus Two Other Anti-HIV Drugs on Blood Clotting in HIV-Positive Males With Hemophilia
NCT00092976	PHASE4	COMPLETED	Study Evaluating ReFacto® in Hemophilia A Undergoing Major Surgery
NCT00151385	PHASE4	WITHDRAWN	Study Evaluating Inhibitor Specificity in Hemophilia A
NCT00168051	PHASE4	WITHDRAWN	Study Comparing Blood Levels of ReFacto and Advante in Hemophilia A
NCT00243386	PHASE4	COMPLETED	Prophylaxis Study of Recombinant Factor VIII Manufactured Protein-Free (rAHF-PFM) in Patients With Hemophilia A
NCT00284193	PHASE4	COMPLETED	Combination Therapy of Low Doses of rFVIIa and FEIBA for Severe Hemophilia A Patients With an Inhibitor to Factor VIII
NCT00289536	PHASE4	COMPLETED	Dose-Response Study of Recombinant Factor VIII Manufactured Protein-Free (rAHF-PFM) in Patients With Hemophilia A
NCT00357656	PHASE4	COMPLETED	Phase 3/4 Study of a Recombinant Protein-Free Factor VIII (rAHF-PFM): Comparison of Continuous Infusion Versus Intermittent Bolus Infusion in Hemophilia A Subjects Undergoing Major Orthopedic Surgery
NCT00586521	PHASE4	COMPLETED	BAY14-2222 Prophylaxis and Joint Function Improvement (Adults)
NCT00621673	PHASE4	TERMINATED	Assessment of the Risk of Inhibitor Formation in Previously Treated Patients With Severe Hemophilia A
NCT00632814	PHASE4	COMPLETED	Russian Kogenate Pediatric Study
NCT00638001	PHASE4	COMPLETED	Impact of Conservative Treatment by Custom-made Orthoses in Patients With Haemophilic Ankle Arthropathy
NCT00666406	PHASE4	COMPLETED	Pharmacokinetic Comparison of Advate rAHF-PFM With Recombinate rAHF in Patients With Severe Hemophilia A
NCT00765726	PHASE4	TERMINATED	Study Evaluating The Safety Of Xyntha In Usual Care Settings
NCT00884390	PHASE4	TERMINATED	Study Evaluating Safety Of Patients Switching To ReFacto AF In Usual Care Settings
NCT00914459	PHASE4	COMPLETED	Study Evaluating Safety And Efficacy Of Moroctocog Alfa (AF-CC) In Previously Treated Hemophilia A Patients
NCT00916032	PHASE4	COMPLETED	Pharmacokinetic Study of ADVATE 3000 IU in Previously Treated Patients With Severe Hemophilia A
NCT00927667	PHASE4	COMPLETED	Joint Status in Subjects With Severe Hemophilia A in Relation to Different Treatment Regimens
NCT00950170	PHASE4	COMPLETED	Study of Safety And Efficacy Of ReFacto AF In Previously Untreated Hemophilia A Patients In The Usual Care Setting
NCT01064284	PHASE4	COMPLETED	Survey of Inhibitors in Plasma-Product Exposed Toddlers
NCT01748201	PHASE4	COMPLETED	Viscosupplementation in Patients With Hemophilic Arthropathy
NCT01810666	PHASE4	COMPLETED	Prophylaxis Versus on Demand Treatment for Children With Hemophilia A
NCT01811875	PHASE4	TERMINATED	Post-Marketing Safety Study Following Long-Term Prophylactic OptivateTreatment in Subjects With Severe Haemophilia A
NCT02170402	PHASE4	COMPLETED	China ADVATE PTP Study
NCT02314325	PHASE4	UNKNOWN	Subclinical Joint Bleeding in Irish Adults With Severe Haemophilia A on Personalised Prophylaxis Regimens
NCT02479087	PHASE4	UNKNOWN	Safety/Efficacy Study to Assess Whether FVIII/VWF Concentrate Can Induce Immune Tolerance in Haemophilia A Patients
NCT02492984	PHASE4	COMPLETED	PF-05208756, Moroctocog Alfa (AF-CC), Xyntha For Hemophilia A
NCT02697370	PHASE4	COMPLETED	Efficacy and Cost Effectiveness of Pharmacokinetic Dosing in Haemophilia A
NCT02727647	PHASE4	COMPLETED	Comparison of Different Prophylaxis Regimens for Moderate to Severe Hemophilia A Pediatric Patients
NCT03103542	PHASE4	COMPLETED	Study of rFVIIIFc for Immune Tolerance Induction (ITI) in Haemophilia A Patients With Inhibitors Who Have Failed Previous ITI Therapies
NCT03204539	PHASE4	TERMINATED	INdividualized ITI Based on Fviii(ATE) Protection by VWF
NCT03361137	PHASE4	TERMINATED	Study of Emicizumab Prophylaxis in Participants With Hemophilia A With or Without Inhibitors Undergoing Minor Surgical Procedures
NCT03379974	PHASE4	COMPLETED	Exercise Versus DDAVP in Patients With Mild Hemophilia A
NCT03449342	PHASE4	COMPLETED	Research Study to Look at Side Effects During Regular Injection With Factor VIII Medicine Named Turoctocog Alfa for a 8 Weeks Period
NCT03915080	PHASE4	COMPLETED	Optimizing the Use of Prophylaxis in Patients With Severe Haemophilia A
NCT03947567	PHASE4	UNKNOWN	Safety and Efficacy of Long-term Treatment With SCT800 in Previously Treated Hemophilia A Patients.
NCT04085458	PHASE4	COMPLETED	Study to Gain More Information on How Safe and Effective Jivi Works in Patients With Severe Hemophilia A (Post-marketing Investigation)
NCT04396639	PHASE4	COMPLETED	Moroctocog Alfa (AF-CC) for Prophylaxis and Treatment of Bleeding Episodes in Previously Treated Hemophilia A Patients
NCT04565236	PHASE4	COMPLETED	A Post Approval Commitment Study to Gain More Information on How Safe and Effective KOVALTRY is in Chinese Children, Adolescents /Adults With Severe Hemophilia A
NCT04621916	PHASE4	UNKNOWN	Preventing Inhibitor Recurrence Indefinitely