MAN2B1

Summary

MAN2B1 (mannosidase alpha class 2B member 1, HGNC:6826) is a protein-coding gene on chromosome 19p13.13, encoding Lysosomal alpha-mannosidase (O00754). Can hydrolyze a variety of glycan substrates containing terminal alpha-mannosidic linkages.

This gene encodes an enzyme that hydrolyzes terminal, non-reducing alpha-D-mannose residues in alpha-D-mannosides. Its activity is necessary for the catabolism of N-linked carbohydrates released during glycoprotein turnover and it is member of family 38 of glycosyl hydrolases. The full length protein is processed in two steps. First, a 49 aa leader sequence is cleaved off and the remainder of the protein is processed into 3 peptides of 70 kDa, 42 kDa (D) and 13/15 kDa (E). Next, the 70 kDa peptide is further processed into three peptides (A, B and C). The A, B and C peptides are disulfide-linked. Defects in this gene have been associated with lysosomal alpha-mannosidosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 4125 — RefSeq curated summary.

At a glance

• Gene–disease (curated): alpha-mannosidosis (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 1,788 total — 111 pathogenic, 172 likely-pathogenic
• Phenotypes (HPO): 131
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000528

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6826
Approved symbol	MAN2B1
Name	mannosidase alpha class 2B member 1
Location	19p13.13
Locus type	gene with protein product
Status	Approved
Aliases	LAMAN
Ensembl gene	ENSG00000104774
Ensembl biotype	protein_coding
OMIM	609458
Entrez	4125

Gene structure

Transcript identifiers

Ensembl transcripts: 37 — 24 protein_coding, 6 retained_intron, 5 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000221363, ENST00000433513, ENST00000456935, ENST00000462144, ENST00000465830, ENST00000466794, ENST00000469423, ENST00000480851, ENST00000486847, ENST00000493218, ENST00000495617, ENST00000593686, ENST00000595880, ENST00000596512, ENST00000596591, ENST00000598876, ENST00000600281, ENST00000858849, ENST00000858850, ENST00000858851, ENST00000858852, ENST00000858853, ENST00000858854, ENST00000858855, ENST00000858856, ENST00000858857, ENST00000935808, ENST00000935809, ENST00000935810, ENST00000935811, ENST00000963997, ENST00000963998, ENST00000963999, ENST00000964000, ENST00000964001, ENST00000964002, ENST00000964003

RefSeq mRNA: 2 — MANE Select: NM_000528 NM_000528, NM_001173498

CCDS: CCDS32919, CCDS54224

Canonical transcript exons

ENST00000456935 — 24 exons

Exon	Start	End
ENSE00000682085	12658428	12658510
ENSE00003469336	12663317	12663462
ENSE00003476699	12658063	12658141
ENSE00003493345	12647443	12647598
ENSE00003499269	12661260	12661376
ENSE00003501860	12649136	12649216
ENSE00003502254	12666543	12666742
ENSE00003527922	12649913	12650014
ENSE00003528450	12647233	12647335
ENSE00003539417	12656949	12657056
ENSE00003539692	12665703	12665805
ENSE00003545789	12665352	12665525
ENSE00003563379	12652363	12652460
ENSE00003570878	12663703	12663835
ENSE00003580801	12656571	12656687
ENSE00003590080	12658224	12658344
ENSE00003602860	12648175	12648402
ENSE00003604138	12657446	12657555
ENSE00003605504	12650104	12650222
ENSE00003608864	12652153	12652270
ENSE00003635960	12664792	12664985
ENSE00003659763	12655694	12655879
ENSE00003660093	12649341	12649428
ENSE00003666540	12646512	12646732

Expression profiles

Bgee: expression breadth ubiquitous, 138 present calls, max score 98.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 50.0317 / max 500.8828, expressed in 1819 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
179323	49.8624	1819
179321	0.1694	58

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
bone marrow cell	CL:0002092	98.89	gold quality
granulocyte	CL:0000094	98.37	gold quality
monocyte	CL:0000576	98.22	gold quality
leukocyte	CL:0000738	98.19	gold quality
bone element	UBERON:0001474	97.81	gold quality
bone marrow	UBERON:0002371	97.81	gold quality
spleen	UBERON:0002106	97.46	gold quality
blood	UBERON:0000178	97.00	gold quality
lymph node	UBERON:0000029	96.98	gold quality
vermiform appendix	UBERON:0001154	96.96	gold quality
tonsil	UBERON:0002372	95.92	gold quality
right lung	UBERON:0002167	94.82	gold quality
stromal cell of endometrium	CL:0002255	94.68	gold quality
gall bladder	UBERON:0002110	94.62	gold quality
upper lobe of left lung	UBERON:0008952	94.52	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.47	gold quality
subcutaneous adipose tissue	UBERON:0002190	94.38	gold quality
apex of heart	UBERON:0002098	94.31	gold quality
small intestine	UBERON:0002108	94.24	gold quality
saliva-secreting gland	UBERON:0001044	94.01	gold quality
body of stomach	UBERON:0001161	94.01	gold quality
minor salivary gland	UBERON:0001830	94.01	gold quality
descending thoracic aorta	UBERON:0002345	93.92	gold quality
adipose tissue	UBERON:0001013	93.88	gold quality
urinary bladder	UBERON:0001255	93.71	gold quality
fundus of stomach	UBERON:0001160	93.65	gold quality
mucosa of stomach	UBERON:0001199	93.61	gold quality
right coronary artery	UBERON:0001625	93.59	gold quality
omental fat pad	UBERON:0010414	93.35	gold quality
skin of leg	UBERON:0001511	93.24	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	38.29
E-CURD-122	yes	13.54
E-MTAB-8410	yes	12.97
E-ANND-3	yes	9.52

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

3 targeting MAN2B1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-924	97.78	66.21	681
HSA-MIR-5699-5P	97.36	67.03	1014
HSA-MIR-6774-5P	95.94	65.18	722

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 8)

• 5 new mutations were found in the MAN2B1 gene: c.157G>T, c.562C>T, c.599A>T, c.293dupA, c.2402G>A (p.E53X, p.R188X, p.H200L, p.Y99VfsX61, p.G801D). p.H200L could involve the catalytic mechanism. p.G801D would affect correct folding. (PMID:15712269)
• Expressed MAN2B1 and MAN2B2 in Drosophila S2 cells and functionally characterized them. MAN2B1 and MAN2B2 were significantly inhibited by the class II alpha-mannosidase inhibitors, swainsonine and mannostatin A. (PMID:19722277)
• MAN2B1 is targeted to the vacuole without passing through the Golgi complex. (PMID:23449646)
• A single nucleotide polymorphism in MAN2B, rs228614, is associated with risk for multiple sclerosis. (PMID:23739915)
• The results showed that the alpha-mannosidosis patient has compound heterozygous mutations in the MAN2B1 gene (PMID:24353136)
• A novel heterozygous mutation (c.2013G>A; p.R638H) of MANBA was identified in patients with autosomal-dominant nystagmus. An additional mutation (c.2346T>A; p.L749H) in MANBA was found by screening patients with sporadic nystagmus. (PMID:25741867)
• Our results indicate a correlation between the MAN2B1 genotypes and the cognitive function, upper limb coordination, balance, FVC% and the storage of oligosaccharides in CSF. (PMID:26048034)
• A diagnosis can be established by measuring the activity of lysosomal alpha-mannosidase in leucocytes and screening for abnormal urinary excretion of mannose-rich oligosaccharides. Genetic confirmation is obtained with the identification of MAN2B1 mutations. (PMID:31241255)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	man2b1	ENSDARG00000001897
mus_musculus	Man2b1	ENSMUSG00000005142
rattus_norvegicus	Man2b1	ENSRNOG00000023910
drosophila_melanogaster	LManII	FBGN0027611
drosophila_melanogaster	LManIII	FBGN0032066
drosophila_melanogaster	LManIV	FBGN0032067
drosophila_melanogaster	LManV	FBGN0032068
drosophila_melanogaster	LManVI	FBGN0032069
drosophila_melanogaster	LManI	FBGN0032253
caenorhabditis_elegans		WBGENE00018877

Paralogs (4): MAN2B2 (ENSG00000013288), MAN2A1 (ENSG00000112893), MAN2C1 (ENSG00000140400), MAN2A2 (ENSG00000196547)

Protein

Protein identifiers

Lysosomal alpha-mannosidase — O00754 (reviewed: O00754)

Alternative names: Lysosomal acid alpha-mannosidase, Mannosidase alpha class 2B member 1, Mannosidase alpha-B

All UniProt accessions (5): O00754, M0QXY0, M0QYZ1, M0QZG6, M0R174

UniProt curated annotations — full annotation on UniProt →

Function. Can hydrolyze a variety of glycan substrates containing terminal alpha-mannosidic linkages. Cleaves alpha 1,2-, alpha 1,3-, and alpha 1,6-linked mannose residues on oligosaccharides generated by N-glycoprotein degradation pathways.

Subunit / interactions. Homodimer.

Subcellular location. Lysosome lumen. Secreted.

Post-translational modifications. First processed into 3 peptides of 70 kDa, 42 kDa (D) and 13/15 kDa (E). The 70 kDa peptide is further processed into three peptides (A, B and C). The A, B and C peptides are disulfide-linked. Heavily glycosylated.

Disease relevance. Mannosidosis, alpha B, lysosomal (MANSA) [MIM:248500] A lysosomal storage disease characterized by accumulation of unbranched oligosaccharide chains. This accumulation is expressed histologically as cytoplasmic vacuolation predominantly in the CNS and parenchymatous organs. Depending on the clinical findings at the age of onset, a severe infantile (type I) and a mild juvenile (type II) form of alpha-mannosidosis are recognized. There is considerable variation in the clinical expression with intellectual disability, recurrent infections, impaired hearing and Hurler-like skeletal changes being the most consistent abnormalities. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by mannostatin A, swainsonine and swainsonine derivates.

Cofactor. Binds 1 zinc ion per subunit.

Similarity. Belongs to the glycosyl hydrolase 38 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O00754-1	1	yes
O00754-2	2

RefSeq proteins (2): NP_000519, NP_001166969 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000602	Glyco_hydro_38_N	Domain
IPR011013	Gal_mutarotase_sf_dom	Homologous_superfamily
IPR011330	Glyco_hydro/deAcase_b/a-brl	Homologous_superfamily
IPR011682	Glyco_hydro_38_C	Domain
IPR013780	Glyco_hydro_b	Homologous_superfamily
IPR015341	Glyco_hydro_38_cen	Domain
IPR027291	Glyco_hydro_38_N_sf	Homologous_superfamily
IPR028995	Glyco_hydro_57/38_cen_sf	Homologous_superfamily
IPR037094	Glyco_hydro_38_cen_sf	Homologous_superfamily
IPR041147	GH38_C	Domain
IPR048534	Man2a1-like_dom	Domain
IPR050843	Glycosyl_Hydrlase_38	Family

Pfam: PF01074, PF07748, PF09261, PF17677, PF21260

Enzyme classification (BRENDA):

• EC 3.2.1.24 — alpha-mannosidase (BRENDA: 56 organisms, 210 substrates, 327 inhibitors, 108 Km, 36 kcat entries)

Substrate kinetics (BRENDA)

33 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
P-NITROPHENYL-ALPHA-D-MANNOPYRANOSIDE	0.048–30	33
4-NITROPHENYL ALPHA-D-MANNOSIDE	0.11–2.9	22
4-METHYLUMBELLIFERYL-ALPHA-D-MANNOPYRANOSIDE	0.0073–5.2	9
4-METHYLUMBELLIFERYL ALPHA-D-MANNOPYRANOSIDE	0.0073–3.6	3
4-NITROPHENYL-ALPHA-D-MANNOPYRANOSIDE	0.0826–1.8	3
MAN9GLCNAC	0.037–0.46	3
2-O-ALPHA-D-MANNOPYRANOSYL-D-MANNOPYRANOSE	0.57–2	2
4-NITROPHENYL ALPHA-D-MANNOPYRANOSIDE	1.48–3.8	2
ALPHA-D-MAN-(1->2)-D-MAN	0.85–2.3	2
ALPHA-D-MAN-(1->4)-D-MAN	2–2.5	2
MAN-ALPHA(1-6)MAN	1.455	2
2,4-DINITROPHENYL ALPHA-D-MANNOSIDE	5	1
2,4-DINITROPHENYL-ALPHA-D-MANNOPYRANOSIDE	25	1
2-O-ALPHA-D-MANNOPYRANOSYL-D-MANNOSE	0.57	1
3-O-ALPHA-D-MANNOPYRANOSYL-ALPHA-D-MANNOPYRANOSE	27	1

Catalyzed reactions (Rhea), 2 shown:

• alpha-D-Man-(1->3)-[alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-D-GlcNAc + H2O = alpha-D-Man-(1->6)-beta-D-Man-(1->4)-D-GlcNAc + D-mannose (RHEA:84975)
• alpha-D-Man-(1->3)-[alpha-D-Man-(1->6)]-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-D-GlcNAc + H2O = alpha-D-Man-(1->6)-beta-D-Man-(1->4)-beta-D-GlcNAc-(1->4)-D-GlcNAc + D-mannose (RHEA:84979)

UniProt features (103 total): sequence variant 70, glycosylation site 11, chain 6, disulfide bond 6, binding site 4, sequence conflict 3, signal peptide 1, splice variant 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00754-F1	91.78	0.86

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): 196 (nucleophile)

Ligand- & substrate-binding residues (4): 196; 446; 72; 74

Disulfide bonds (6): 55, 268–273, 358, 412, 472, 493–501

Glycosylation sites (11): 133, 310, 367, 497, 645, 651, 692, 766, 832, 930, 989

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-8853383	Lysosomal oligosaccharide catabolism
R-HSA-1430728	Metabolism
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-71387	Metabolism of carbohydrates and carbohydrate derivatives

MSigDB gene sets: 471 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, REACTOME_INNATE_IMMUNE_SYSTEM, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GOBP_COGNITION, GOBP_BEHAVIOR, MCLACHLAN_DENTAL_CARIES_UP, GOCC_SECRETORY_GRANULE, MODULE_45, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, KEGG_LYSOSOME, MODULE_16

GO Biological Process (6): mannose metabolic process (GO:0006013), glycoprotein catabolic process (GO:0006516), learning or memory (GO:0007611), carbohydrate metabolic process (GO:0005975), protein deglycosylation (GO:0006517), protein modification process (GO:0036211)

GO Molecular Function (6): alpha-mannosidase activity (GO:0004559), carbohydrate binding (GO:0030246), metal ion binding (GO:0046872), catalytic activity (GO:0003824), hydrolase activity (GO:0016787), hydrolase activity, acting on glycosyl bonds (GO:0016798)

GO Cellular Component (7): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), nucleoplasm (GO:0005654), lysosome (GO:0005764), azurophil granule lumen (GO:0035578), lysosomal lumen (GO:0043202), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Innate Immune System	1
Metabolism of carbohydrates and carbohydrate derivatives	1
Immune System	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
glycoprotein metabolic process	2
cellular anatomical structure	2
vacuolar lumen	2
hexose metabolic process	1
protein catabolic process	1
carbohydrate derivative catabolic process	1
behavior	1
cognition	1
primary metabolic process	1
protein modification process	1
protein metabolic process	1
macromolecule modification	1
mannosidase activity	1
binding	1
cation binding	1
molecular_function	1
catalytic activity	1
hydrolase activity	1
nuclear lumen	1
lytic vacuole	1
secretory granule lumen	1
azurophil granule	1
lysosome	1
extracellular vesicle	1

Protein interactions and networks

STRING

962 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAN2B1	MANBA	O00462	969
MAN2B1	MAN2C1	Q9NTJ4	942
MAN2B1	CD1E	P15812	714
MAN2B1	CD1B	P29016	620
MAN2B1	NAGLU	P54802	585
MAN2B1	FUCA1	P04066	569
MAN2B1	GM2A	P17900	553
MAN2B1	HP	P00737	548
MAN2B1	MAN1A1	P33908	526
MAN2B1	NAGA	P17050	526
MAN2B1	FABP2	P12104	505
MAN2B1	CTBS	Q01459	504
MAN2B1	GUSB	P08236	501
MAN2B1	GNPTG	Q9UJJ9	488
MAN2B1	GMDS	O60547	466

IntAct

45 interactions, top by confidence:

A	B	Type	Score
C1QTNF9	C1QTNF9B	psi-mi:“MI:0914”(association)	0.780
FBXO6	MAN2B1	psi-mi:“MI:0914”(association)	0.640
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
MAN2B1	L2	psi-mi:“MI:0407”(direct interaction)	0.530
L2	MAN2B1	psi-mi:“MI:0915”(physical association)	0.530
FCN1	MAN2B1	psi-mi:“MI:0915”(physical association)	0.370
L2	MAN2B1	psi-mi:“MI:0915”(physical association)	0.370
NS1		psi-mi:“MI:0914”(association)	0.350
LGALS9	PODXL	psi-mi:“MI:0914”(association)	0.350
	VPS37C	psi-mi:“MI:0914”(association)	0.350
LLCFC1	POTEF	psi-mi:“MI:0914”(association)	0.350
CEACAM8	PRRT4	psi-mi:“MI:0914”(association)	0.350
MANEA	AGRN	psi-mi:“MI:0914”(association)	0.350
CD14	MAN2B1	psi-mi:“MI:0914”(association)	0.350
MAN2B1	IGF2R	psi-mi:“MI:0914”(association)	0.350
IL5RA	POTEF	psi-mi:“MI:0914”(association)	0.350
NCR3	POTEF	psi-mi:“MI:0914”(association)	0.350
LYPD4	POTEF	psi-mi:“MI:0914”(association)	0.350
DNAJB9	POTEF	psi-mi:“MI:0914”(association)	0.350
PI15		psi-mi:“MI:0914”(association)	0.350
ELSPBP1	QSOX1	psi-mi:“MI:0914”(association)	0.350
PRG2	QSOX1	psi-mi:“MI:0914”(association)	0.350
SDF2L1	MANBA	psi-mi:“MI:0914”(association)	0.350
C1QB	MANBA	psi-mi:“MI:0914”(association)	0.350

BioGRID (70): MAN2B1 (Affinity Capture-RNA), MAN2B1 (Affinity Capture-RNA), MAN2B1 (Affinity Capture-MS), MAN2B1 (Affinity Capture-MS), AGL (Co-fractionation), DTD1 (Co-fractionation), LRRC47 (Co-fractionation), MAN2B1 (Co-fractionation), MAN2B1 (Co-fractionation), NAGA (Co-fractionation), SNX2 (Co-fractionation), MAN2B1 (Affinity Capture-MS), MAN2B1 (Affinity Capture-MS), MGARP (Co-fractionation), MAN2B1 (Proximity Label-MS)

ESM2 similar proteins: A0JPH3, A3KGW5, A5PMF6, A7MB73, O00754, O09008, O18835, O46432, O77588, P24802, P26572, P27115, P27808, P56434, Q00973, Q02809, Q04519, Q09200, Q09325, Q0VD19, Q12891, Q32NJ7, Q5IGR6, Q5R9N3, Q5T4B2, Q5U309, Q5U367, Q5U483, Q5VSG8, Q5XPT3, Q60HE9, Q63321, Q66PG4, Q6NVG7, Q6P1J0, Q6P7A1, Q6P9A2, Q6PA90, Q8IYK4, Q8K1B9

Diamond homologs: C0HJB3, O00754, O09159, O46432, P34098, P94078, Q29451, Q60HE9, Q8LPJ3, Q8VHC8, Q9FKW9, C0HJW7, Q54KN4, Q55ER0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 45 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
Neutrophil degranulation	11	9.4×	1e-06
Innate Immune System	8	7.5×	7e-04

GO biological processes:

GO term	Partners	Fold	FDR
ERAD pathway	5	26.6×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

1788 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	111
Likely pathogenic	172
Uncertain significance	440
Likely benign	848
Benign	52

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1028817	NM_000528.4(MAN2B1):c.1228C>T (p.Gln410Ter)	Pathogenic
1065630	NM_000528.4(MAN2B1):c.215_216del (p.His72fs)	Pathogenic
1069975	NM_000528.4(MAN2B1):c.323_324delinsAA (p.Leu108Ter)	Pathogenic
1070095	NM_000528.4(MAN2B1):c.2534_2558del (p.Leu845fs)	Pathogenic
1070420	NM_000528.4(MAN2B1):c.293dup (p.Tyr99fs)	Pathogenic
1073941	NM_000528.4(MAN2B1):c.2748_2751del (p.Leu917fs)	Pathogenic
1074138	NM_000528.4(MAN2B1):c.484_487dup (p.Thr163fs)	Pathogenic
1075883	NM_000528.4(MAN2B1):c.1081del (p.Trp361fs)	Pathogenic
1323268	NM_000528.4(MAN2B1):c.262+1G>C	Pathogenic
1350785	NM_000528.4(MAN2B1):c.237_238del (p.Lys79fs)	Pathogenic
1366519	NM_000528.4(MAN2B1):c.1468_1469del (p.Phe490fs)	Pathogenic
1373944	NM_000528.4(MAN2B1):c.979_980del (p.Met327fs)	Pathogenic
1377818	NM_000528.4(MAN2B1):c.1140C>A (p.Tyr380Ter)	Pathogenic
1399644	NM_000528.4(MAN2B1):c.2647del (p.Ala883fs)	Pathogenic
1403859	NM_000528.4(MAN2B1):c.212_215del (p.Thr71fs)	Pathogenic
1404053	NM_000528.4(MAN2B1):c.965_966del (p.Gln321_Tyr322insTer)	Pathogenic
1414117	NM_000528.4(MAN2B1):c.1801del (p.Trp601fs)	Pathogenic
1414424	NM_000528.4(MAN2B1):c.1527+2T>G	Pathogenic
1416748	NM_000528.4(MAN2B1):c.256dup (p.Tyr86fs)	Pathogenic
1418789	NM_000528.4(MAN2B1):c.2512_2513insGGCGCGGG (p.Val838fs)	Pathogenic
1420628	NM_000528.4(MAN2B1):c.166_175del (p.Pro56fs)	Pathogenic
1442745	NM_000528.4(MAN2B1):c.1802G>A (p.Trp601Ter)	Pathogenic
1443259	NM_000528.4(MAN2B1):c.2469_2478del (p.Gly824fs)	Pathogenic
1454963	NM_000528.4(MAN2B1):c.561del (p.Arg188fs)	Pathogenic
1457345	NM_000528.4(MAN2B1):c.627_630+1dup	Pathogenic
1457596	NC_000019.9:g.(?12768867)(12769334_?)del	Pathogenic
1685	NM_000528.4(MAN2B1):c.2278C>T (p.Arg760Ter)	Pathogenic
1705127	NM_000528.4(MAN2B1):c.2088G>A (p.Trp696Ter)	Pathogenic
1709479	NM_000528.4(MAN2B1):c.624dup (p.Ala209fs)	Pathogenic
1964157	NM_000528.4(MAN2B1):c.1204G>T (p.Glu402Ter)	Pathogenic

SpliceAI

4008 predictions. Top by Δscore:

Variant	Effect	Δscore
19:12646633:T:TA	donor_gain	1.0000
19:12646637:T:TA	donor_gain	1.0000
19:12647229:CCACC:C	donor_loss	1.0000
19:12647230:CA:C	donor_loss	1.0000
19:12647232:C:A	donor_loss	1.0000
19:12647232:C:G	donor_loss	1.0000
19:12647331:AGGTC:A	acceptor_gain	1.0000
19:12647332:GGTC:G	acceptor_gain	1.0000
19:12647333:GTC:G	acceptor_gain	1.0000
19:12647333:GTCC:G	acceptor_loss	1.0000
19:12647334:TC:T	acceptor_gain	1.0000
19:12647335:CC:C	acceptor_gain	1.0000
19:12647335:CCTG:C	acceptor_loss	1.0000
19:12647336:C:CC	acceptor_gain	1.0000
19:12647336:CTG:C	acceptor_loss	1.0000
19:12647337:T:C	acceptor_loss	1.0000
19:12647441:AC:A	donor_gain	1.0000
19:12647442:CC:C	donor_gain	1.0000
19:12647442:CCCT:C	donor_gain	1.0000
19:12647479:T:TA	donor_gain	1.0000
19:12647599:C:CC	acceptor_gain	1.0000
19:12648172:CACCT:C	donor_loss	1.0000
19:12648173:A:C	donor_loss	1.0000
19:12648174:C:T	donor_loss	1.0000
19:12648251:T:TA	donor_gain	1.0000
19:12648399:GCAC:G	acceptor_gain	1.0000
19:12648400:CAC:C	acceptor_gain	1.0000
19:12648400:CACC:C	acceptor_gain	1.0000
19:12648401:AC:A	acceptor_gain	1.0000
19:12648402:CC:C	acceptor_gain	1.0000

AlphaMissense

6572 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:12661330:T:A	D319V	0.998
19:12665736:A:G	W77R	0.998
19:12665736:A:T	W77R	0.998
19:12657525:T:A	D447V	0.997
19:12658257:T:A	K399N	0.997
19:12658257:T:G	K399N	0.997
19:12661329:G:C	D319E	0.997
19:12661329:G:T	D319E	0.997
19:12661330:T:G	D319A	0.997
19:12664828:G:C	F198L	0.997
19:12664828:G:T	F198L	0.997
19:12664830:A:G	F198L	0.997
19:12664845:A:G	W193R	0.997
19:12664845:A:T	W193R	0.997
19:12665734:C:A	W77C	0.997
19:12665734:C:G	W77C	0.997
19:12657529:G:C	H446D	0.996
19:12661326:G:C	F320L	0.996
19:12661326:G:T	F320L	0.996
19:12661328:A:G	F320L	0.996
19:12661330:T:C	D319G	0.996
19:12661331:C:G	D319H	0.996
19:12663751:A:G	W239R	0.996
19:12663751:A:T	W239R	0.996
19:12665743:G:C	D74E	0.996
19:12665743:G:T	D74E	0.996
19:12665744:T:A	D74V	0.996
19:12648395:C:G	R815P	0.995
19:12657524:G:C	D447E	0.995
19:12657524:G:T	D447E	0.995

dbSNP variants (sampled 300 via entrez): RS1000012579 (19:12664062 C>CA), RS1000126322 (19:12662684 A>G), RS1000267915 (19:12657401 C>A), RS1000443506 (19:12650858 C>T), RS1000868549 (19:12655738 T>C), RS1000874839 (19:12656841 C>T), RS1000899152 (19:12650807 T>A,C), RS1000931293 (19:12650552 G>C), RS1001045445 (19:12662504 C>G), RS1001135098 (19:12661436 G>A), RS1001364880 (19:12656186 T>A), RS1001476105 (19:12667159 T>C), RS1001534259 (19:12658579 A>C), RS1001566494 (19:12664256 A>C), RS1001780999 (19:12652024 G>A,T)

Disease associations

OMIM: gene MIM:609458 | disease phenotypes: MIM:248500, MIM:123100, MIM:251000

GenCC curated gene-disease

Disease	Classification	Inheritance
alpha-mannosidosis	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
alpha-mannosidosis	Definitive	AR

Mondo (5): alpha-mannosidosis (MONDO:0009561), intellectual disability (MONDO:0001071), craniosynostosis (MONDO:0015469), myoepithelial tumor (MONDO:0002380), methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency (MONDO:0009612)

Orphanet (4): Alpha-mannosidosis (Orphanet:61), Craniosynostosis (Orphanet:1531), Vitamin B12-unresponsive methylmalonic acidemia (Orphanet:27), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

131 total (30 of 131 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000023	Inguinal hernia
HP:0000158	Macroglossia
HP:0000212	Gingival overgrowth
HP:0000248	Brachycephaly
HP:0000256	Macrocephaly
HP:0000272	Malar flattening
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000294	Low anterior hairline
HP:0000297	Facial hypotonia
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000337	Broad forehead
HP:0000388	Otitis media
HP:0000400	Macrotia
HP:0000407	Sensorineural hearing impairment
HP:0000410	Mixed hearing impairment
HP:0000457	Depressed nasal ridge
HP:0000470	Short neck
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000518	Cataract
HP:0000520	Proptosis
HP:0000540	Hypermetropia
HP:0000543	Optic disc pallor
HP:0000545	Myopia
HP:0000546	Retinal degeneration
HP:0000574	Thick eyebrow

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002326_1	Pulmonary emphysema	1.000000e-09

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D003398	Craniosynostoses	C05.116.099.370.894.232; C05.660.207.240; C05.660.906.364; C16.131.621.207.240; C16.131.621.906.364
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009208	Myoepithelioma	C04.557.435.585
D008363	alpha-Mannosidosis	C16.320.565.202.607.500; C16.320.565.595.577.500; C18.452.648.202.607.500; C18.452.648.595.577.500
C565390	Methylmalonic Aciduria due to Methylmalonyl-CoA Mutase Deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4059 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 191 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL371197	TRIDOLGOSIR	2	191

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

ChEMBL bioactivities

12 potent at pChembl≥5 of 32 total, top 11 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.00	IC50	10	nM	TRIDOLGOSIR
7.30	IC50	50	nM	TRIDOLGOSIR
6.36	IC50	440	nM	CHEMBL4465842
6.30	IC50	500	nM	CHEMBL476926
6.26	Ki	550	nM	CHEMBL476926
6.17	Ki	670	nM	CHEMBL476926
6.12	IC50	750	nM	CHEMBL476343
5.70	IC50	2000	nM	CHEMBL476926
5.66	IC50	2200	nM	CHEMBL4462117
5.50	Ki	3200	nM	CHEMBL476926
5.12	IC50	7500	nM	CHEMBL476343

PubChem BioAssay actives

12 with measured affinity, of 174 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
(1S,2R,8R,8aR)-1,2,3,5,6,7,8,8a-octahydroindolizine-1,2,8-triol	341039: Inhibition of alpha-mannosidase in human HCEC	ic50	0.0100	uM
(5S,6R,7S,8R,8aR)-5-[6-[4-[[(1R,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R,36S,37R,38S,39R,40S,41R,42S,43R,44S,45R,46S,47R,48S,49R)-10,15,20,25,30,35-hexakis[[1-[6-[[(5S,6R,7S,8R,8aR)-6,7,8-trihydroxy-3-oxo-1,5,6,7,8,8a-hexahydro-[1,3]oxazolo[3,4-a]pyridin-5-yl]amino]hexyl]triazol-4-yl]methoxymethyl]-36,37,38,39,40,41,42,43,44,45,46,47,48,49-tetradecamethoxy-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan-5-yl]methoxymethyl]triazol-1-yl]hexylamino]-6,7,8-trihydroxy-1,5,6,7,8,8a-hexahydro-[1,3]oxazolo[3,4-a]pyridin-3-one	1598302: Inhibition of Lysosomal alpha-mannosidase in wild-type human fibroblast cell lysates using 4-methylumbelliferone alpha-D-mannopyranoside as a reporter substrate incubated for 60 mins by fluorescence method	ic50	0.4400	uM
(3R,4R,5R)-3,4-dihydroxy-5-[[[(1R)-2-hydroxy-1-phenylethyl]amino]methyl]-1-methylpyrrolidin-2-one	341037: Inhibition of alpha-mannosidase in human LNZ308 cells	ic50	0.5000	uM
[(2R)-2-[[(2R,3R,4R)-3,4-dihydroxy-1-methyl-5-oxopyrrolidin-2-yl]methylamino]-2-phenylethyl] 4-bromobenzoate	341039: Inhibition of alpha-mannosidase in human HCEC	ic50	0.7500	uM
(5S,6R,7S,8R,8aR)-6,7,8-trihydroxy-5-[6-[4-[[(1R,3R,5R,6R,8R,10R,11R,13R,15R,16R,18R,20R,21R,23R,25R,26R,28R,30R,31R,33R,35R,36S,37R,38S,39R,40S,41R,42S,43R,44S,45R,46S,47R,48S,49R)-36,37,38,39,40,41,42,43,44,45,46,47,48,49-tetradecamethoxy-5,15,20,25,30,35-hexakis(methoxymethyl)-2,4,7,9,12,14,17,19,22,24,27,29,32,34-tetradecaoxaoctacyclo[31.2.2.23,6.28,11.213,16.218,21.223,26.228,31]nonatetracontan-10-yl]methoxymethyl]triazol-1-yl]hexylamino]-1,5,6,7,8,8a-hexahydro-[1,3]oxazolo[3,4-a]pyridin-3-one	1598302: Inhibition of Lysosomal alpha-mannosidase in wild-type human fibroblast cell lysates using 4-methylumbelliferone alpha-D-mannopyranoside as a reporter substrate incubated for 60 mins by fluorescence method	ic50	2.2000	uM

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, affects expression, increases abundance	4
bisphenol A	increases expression, decreases methylation	2
Smoke	decreases expression	2
Valproic Acid	increases expression, increases methylation	2
triphenyl phosphate	affects expression	1
cobaltous chloride	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
jinfukang	affects cotreatment, increases expression	1
LDN 193189	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Arsenic	increases expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Carcinogens	decreases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Doxorubicin	decreases expression	1
Hydrogen Peroxide	affects expression	1
Ivermectin	decreases expression	1
Mutagens	decreases expression	1
Selenium	increases expression	1
Tobacco Smoke Pollution	affects expression	1
Antirheumatic Agents	decreases expression	1

ChEMBL screening assays

53 unique, capped per target: 52 binding, 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3385734	Binding	Inhibition of alpha-mannosidase (unknown origin) using p-nitrophenyl-alpha-D-mannopyranoside substrate incubated for 10 mins by UV spectrophotometry	γ-Hydroxyethyl piperidine iminosugar and N-alkylated derivatives: a study of their activity as glycosidase inhibitors and as immunosuppressive agents. — Bioorg Med Chem
CHEMBL4397329	ADMET	Chaperone activity at Lysosomal alpha-mannosidase in human fibroblasts assessed as reduction in cholesterol accumulation at 0.2 uM incubated for 96 hrs by Amplex red cholesterol assay	Pharmacological Chaperones for the Treatment of α-Mannosidosis. — J Med Chem

Cellosaurus cell lines

7 cell lines: 6 finite cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_AB43	GM00654	Finite cell line	Male
CVCL_AB44	GM02049	Finite cell line	Male
CVCL_AB45	GM02817	Finite cell line	Female
CVCL_AB46	GM04518	Finite cell line	Female
CVCL_D5F0	HeLa::TMEM192-3xHA MAN2B1 KO	Cancer cell line	Female
CVCL_M993	GM02051	Finite cell line	Female
CVCL_W641	GM02050	Finite cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00722436	PHASE4	TERMINATED	Tranexamic Acid for Craniofacial Surgery
NCT02188576	PHASE4	COMPLETED	The Efficacy and Population Pharmacokinetics of Tranexamic Acid for Craniosynostosis Surgery
NCT01681953	PHASE3	COMPLETED	A Placebo-Controlled Phase 3 Trial of Repeated Lamazym Treatment of Subjects With Alpha-Mannosidosis
NCT01908712	PHASE3	COMPLETED	Lamazym Aftercare Study FR Designed to Provide Treatment for French Patients
NCT01908725	PHASE3	COMPLETED	Lamazym Aftercare Study
NCT02478840	PHASE3	COMPLETED	Evaluation of Long-term Efficacy of Treatment With Lamazym
NCT04031066	PHASE3	WITHDRAWN	Interventional Study to Assess Efficacy and Safety of Velmanase Alfa in Patients With Alpha Mannosidosis
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00668564	PHASE2	TERMINATED	Hematopoietic Stem Cell Transplantation (HCT) for Inborn Errors of Metabolism
NCT01043640	PHASE2	COMPLETED	Allogeneic Bone Marrow Transplant for Inherited Metabolic Disorders
NCT01285700	PHASE2	UNKNOWN	Dose Finding Study of Recombinant Human Alpha-mannosidase for the Treatment of Patients With Alpha-mannosidosis
NCT01681940	PHASE2	COMPLETED	Long-term Efficacy and Safety of Lamazym for the Treatment of Patients With Alpha-Mannosidosis
NCT02171104	PHASE2	ACTIVE_NOT_RECRUITING	MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis
NCT02998879	PHASE2	COMPLETED	Trial on Safety and Efficacy of Velmanase Alfa Treatment in Pediatric Patients With Alpha-Mannosidosis
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT02229968	PHASE2	ACTIVE_NOT_RECRUITING	Efficacy of Amicar for Children Having Craniofacial Surgery
NCT01268358	PHASE1	COMPLETED	Safety Study of Recombinant Human Alpha-mannosidase for the Treatment of Patients With Alpha-mannosidosis
NCT02254863	PHASE1	RECRUITING	UCB Transplant of Inherited Metabolic Diseases With Administration of Intrathecal UCB Derived Oligodendrocyte-Like Cells
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00912119	PHASE1	COMPLETED	Amicar Pharmacokinetics of Children Having Craniofacial Surgery
NCT03600649	PHASE1	UNKNOWN	Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing or Ewing-related Sarcomas
NCT01372228	PHASE1/PHASE2	TERMINATED	Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders
NCT00498420	Not specified	COMPLETED	The Natural History of Alpha-Mannosidosis
NCT01891422	Not specified	COMPLETED	Longitudinal Studies of the Glycoproteinoses
NCT02141503	Not specified	COMPLETED	Clinical Biomarkers in Alpha-mannosidosis
NCT03264040	Not specified	WITHDRAWN	Biomarker for Mannosidosis Disease (BioMannosidosis)
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT04959240	Not specified	AVAILABLE	Expanded Access to Velmanase Alfa
NCT06184503	Not specified	RECRUITING	Analysis of Velmanase Alfa (Lamzede®)’s Effects in the Body of Children With Alpha-Mannosidosis Under the Age 3