MANBA

Summary

MANBA (mannosidase beta, HGNC:6831) is a protein-coding gene on chromosome 4q24, encoding Beta-mannosidase (O00462). Exoglycosidase that cleaves the single beta-linked mannose residue from the non-reducing end of all N-linked glycoprotein oligosaccharides.

This gene encodes a member of the glycosyl hydrolase 2 family. The encoded protein localizes to the lysosome where it is the final exoglycosidase in the pathway for N-linked glycoprotein oligosaccharide catabolism. Mutations in this gene are associated with beta-mannosidosis, a lysosomal storage disease that has a wide spectrum of neurological involvement.

Source: NCBI Gene 4126 — RefSeq curated summary.

At a glance

• Gene–disease (curated): beta-mannosidosis (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 17
• Clinical variants (ClinVar): 844 total — 64 pathogenic, 35 likely-pathogenic
• Phenotypes (HPO): 20
• Druggable target: yes
• MANE Select transcript: NM_005908

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6831
Approved symbol	MANBA
Name	mannosidase beta
Location	4q24
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000109323
Ensembl biotype	protein_coding
OMIM	609489
Entrez	4126

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 19 protein_coding, 8 nonsense_mediated_decay, 4 retained_intron

ENST00000505239, ENST00000506478, ENST00000507358, ENST00000508141, ENST00000511813, ENST00000514430, ENST00000642252, ENST00000644159, ENST00000644545, ENST00000644965, ENST00000645348, ENST00000645558, ENST00000646311, ENST00000646451, ENST00000646727, ENST00000647097, ENST00000647129, ENST00000910542, ENST00000910543, ENST00000921426, ENST00000921427, ENST00000921428, ENST00000921429, ENST00000921430, ENST00000921431, ENST00000954425, ENST00000954426, ENST00000954427, ENST00000954428, ENST00000954429, ENST00000954430

RefSeq mRNA: 1 — MANE Select: NM_005908 NM_005908

CCDS: CCDS3658

Canonical transcript exons

ENST00000647097 — 17 exons

Exon	Start	End
ENSE00000735314	102664685	102664852
ENSE00000735318	102668963	102669049
ENSE00003482676	102689574	102689684
ENSE00003506334	102714438	102714561
ENSE00003539181	102634788	102635045
ENSE00003572645	102671281	102671398
ENSE00003595187	102723862	102723967
ENSE00003622752	102673919	102674070
ENSE00003625909	102635865	102636007
ENSE00003641724	102650537	102650701
ENSE00003652457	102722871	102723041
ENSE00003661994	102639713	102639857
ENSE00003663669	102690596	102690771
ENSE00003678673	102726589	102726683
ENSE00003692303	102657682	102657900
ENSE00003820380	102630770	102632281
ENSE00003820998	102760718	102760968

Expression profiles

Bgee: expression breadth ubiquitous, 246 present calls, max score 95.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.0121 / max 475.2758, expressed in 1815 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53397	27.4774	1814
53399	1.9491	1083
53398	1.3381	785
53395	0.2294	89
53396	0.0181	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	95.87	gold quality
mononuclear cell	CL:0000842	95.47	gold quality
leukocyte	CL:0000738	95.32	gold quality
stromal cell of endometrium	CL:0002255	94.10	gold quality
granulocyte	CL:0000094	94.03	gold quality
parotid gland	UBERON:0001831	92.40	gold quality
right adrenal gland cortex	UBERON:0035827	90.91	gold quality
tendon of biceps brachii	UBERON:0008188	90.74	gold quality
blood	UBERON:0000178	90.23	gold quality
calcaneal tendon	UBERON:0003701	90.11	gold quality
left adrenal gland	UBERON:0001234	90.05	gold quality
right lung	UBERON:0002167	90.03	gold quality
left adrenal gland cortex	UBERON:0035825	89.72	gold quality
right adrenal gland	UBERON:0001233	89.52	gold quality
bone marrow cell	CL:0002092	89.34	gold quality
adrenal cortex	UBERON:0001235	89.21	gold quality
adrenal tissue	UBERON:0018303	89.04	gold quality
gall bladder	UBERON:0002110	88.92	gold quality
spleen	UBERON:0002106	88.87	gold quality
adrenal gland	UBERON:0002369	88.85	gold quality
tendon	UBERON:0000043	88.80	gold quality
bone marrow	UBERON:0002371	88.70	gold quality
descending thoracic aorta	UBERON:0002345	88.67	gold quality
islet of Langerhans	UBERON:0000006	87.80	gold quality
mucosa of stomach	UBERON:0001199	87.43	gold quality
upper lobe of left lung	UBERON:0008952	87.36	gold quality
thoracic aorta	UBERON:0001515	87.01	gold quality
ascending aorta	UBERON:0001496	86.92	gold quality
endometrium epithelium	UBERON:0004811	86.87	gold quality
trabecular bone tissue	UBERON:0002483	86.70	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.99

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

32 targeting MANBA, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5680	99.91	69.83	3421
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-1224-5P	99.48	65.59	803
HSA-MIR-6083	99.47	68.73	2393
HSA-MIR-410-3P	99.27	69.98	2457
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-181A-2-3P	98.91	67.60	1168
HSA-MIR-6895-3P	98.79	65.69	996
HSA-MIR-3938	98.72	66.07	834
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-496	98.66	69.80	931
HSA-MIR-218-1-3P	98.63	67.97	832
HSA-MIR-6755-3P	98.61	66.90	834
HSA-MIR-6818-3P	98.56	68.23	1307
HSA-MIR-6810-3P	97.96	64.57	1023
HSA-MIR-6747-3P	97.73	64.84	1596
HSA-MIR-582-3P	96.69	67.38	1019
HSA-MIR-2276-5P	96.27	65.85	937

Literature-anchored findings (GeneRIF, showing 6)

• The MANBA genotypes for a polymorphic CA repeat were related to colorectal cancer risk in a Swedish population but not a Chinese one. In the Swedish population, individuals with < 22 CAs/< 22 CAs had a significantly increased risk for CRC. (PMID:17899454)
• The present analysis of the c.1922G>A MANBA mutation underlines the lack of genotype-phenotype correlation in beta-mannosidosis (PMID:19728872)
• independent putative primary functional variants in NFKB1/MANBA and showed the distinct molecular mechanism by which each putative primary functional variant conferred susceptibility to Primary biliary cholangitis, were identified. (PMID:30528300)
• Kidney disease genetic risk variants alter lysosomal beta-mannosidase (MANBA) expression and disease severity. (PMID:33441424)
• A novel genetic variant potentially altering the expression of MANBA in the cerebellum associated with attention deficit hyperactivity disorder in Han Chinese children. (PMID:34870556)
• Impact of Multiple Sclerosis Risk Polymorphism rs7665090 on MANBA Activity, Lysosomal Endocytosis, and Lymphocyte Activation. (PMID:35897697)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	manba	ENSDARG00000008238
mus_musculus	Manba	ENSMUSG00000028164
rattus_norvegicus	Manba	ENSRNOG00000052247
drosophila_melanogaster	beta-Man	FBGN0037215
caenorhabditis_elegans		WBGENE00007904

Paralogs (1): GUSB (ENSG00000169919)

Protein

Protein identifiers

Beta-mannosidase — O00462 (reviewed: O00462)

Alternative names: Lysosomal beta A mannosidase, Mannanase

All UniProt accessions (13): O00462, A0A2R8Y211, A0A2R8Y4U7, A0A2R8Y524, A0A2R8Y7A0, A0A2R8Y7A7, A0A2R8Y7N1, A0A2R8YCE9, A0A2R8YE79, A0A2R8YEC9, A0A2R8YG98, D6RA01, E9PFW2

UniProt curated annotations — full annotation on UniProt →

Function. Exoglycosidase that cleaves the single beta-linked mannose residue from the non-reducing end of all N-linked glycoprotein oligosaccharides.

Subunit / interactions. Monomer.

Subcellular location. Lysosome.

Tissue specificity. Ubiquitous. Detected in pancreas, kidney and placenta, ands at lower levels in liver, lung, brain, heart and muscle.

Disease relevance. Mannosidosis, beta A, lysosomal (MANSB) [MIM:248510] An autosomal recessive lysosomal storage disease of glycoprotein catabolism. Clinical features are heterogeneous with a wide range of symptoms and age of onset. The disease is associated with a range of neurological involvement, including various degrees of intellectual disability in most of the cases, hearing loss and speech impairment, hypotonia, epilepsy and peripheral neuropathy. Affected individuals have a profound reduction in beta A mannosidase activity in plasma, fibroblasts and leukocytes. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Glycan metabolism; N-glycan degradation.

Similarity. Belongs to the glycosyl hydrolase 2 family.

RefSeq proteins (1): NP_005899* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006103	Glyco_hydro_2_cat	Domain
IPR008979	Galactose-bd-like_sf	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR017853	GH_hydrolase_sf	Homologous_superfamily
IPR036156	Beta-gal/glucu_dom_sf	Homologous_superfamily
IPR041447	Mannosidase_ig	Domain
IPR041625	Beta-mannosidase_Ig	Domain
IPR050887	Beta-mannosidase_GH2	Family
IPR054593	Beta-mannosidase-like_N2	Domain

Pfam: PF02836, PF17753, PF17786, PF22666

UniProt features (29 total): glycosylation site 8, sequence variant 7, disulfide bond 4, mutagenesis site 3, active site 2, binding site 2, signal peptide 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00462-F1	96.05	0.96

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 (2): 457 (proton donor); 554 (nucleophile)

Ligand- & substrate-binding residues (2): 190–192; 456

Disulfide bonds (4): 167–176, 540–629, 732–761, 764–769

Glycosylation sites (8): 284, 297, 302, 763, 28, 35, 77, 280

Mutagenesis-validated functional residues (3):

Position	Phenotype
638	no effect on enzyme activity (in vitro).
641	no effect on enzyme activity (in vitro). decreased protein stability.
749	no effect on enzyme activity (in vitro). no effect on protein stability.

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: 197 (showing top): GOBP_OLIGOSACCHARIDE_METABOLIC_PROCESS, REACTOME_INNATE_IMMUNE_SYSTEM, chr4q24, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_OLIGOSACCHARIDE_CATABOLIC_PROCESS, KEGG_LYSOSOME, CAGCTG_AP4_Q5, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, BROWNE_HCMV_INFECTION_48HR_DN, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, GOBP_CARBOHYDRATE_METABOLIC_PROCESS

GO Biological Process (4): glycoprotein catabolic process (GO:0006516), oligosaccharide catabolic process (GO:0009313), protein modification process (GO:0036211), carbohydrate metabolic process (GO:0005975)

GO Molecular Function (4): beta-mannosidase activity (GO:0004567), hydrolase activity, hydrolyzing O-glycosyl compounds (GO:0004553), hydrolase activity (GO:0016787), hydrolase activity, acting on glycosyl bonds (GO:0016798)

GO Cellular Component (4): plasma membrane (GO:0005886), azurophil granule membrane (GO:0035577), lysosomal lumen (GO:0043202), lysosome (GO:0005764)

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	1
protein catabolic process	1
carbohydrate derivative catabolic process	1
oligosaccharide metabolic process	1
carbohydrate catabolic process	1
protein metabolic process	1
macromolecule modification	1
primary metabolic process	1
mannosidase activity	1
hydrolase activity, acting on glycosyl bonds	1
catalytic activity	1
hydrolase activity	1
membrane	1
cell periphery	1
lysosomal membrane	1
secretory granule membrane	1
azurophil granule	1
lysosome	1
vacuolar lumen	1
lytic vacuole	1

Protein interactions and networks

STRING

1836 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MANBA	MAN2B1	O00754	969
MANBA	SGSH	P51688	880
MANBA	MAN2C1	Q9NTJ4	774
MANBA	FABP2	P12104	761
MANBA	GLA	P06280	699
MANBA	AMY1B	P04745	686
MANBA	AMY2B	P19961	686
MANBA	AMY2A	P04746	684
MANBA	ADH5	P11766	648
MANBA	FUCA1	P04066	590
MANBA	GUSB	P08236	574
MANBA	ADH1C	P00326	549
MANBA	FUCA2	Q9BTY2	528
MANBA	NAGA	P17050	516
MANBA	GNPTAB	Q3T906	494

IntAct

77 interactions, top by confidence:

A	B	Type	Score
SCGB1D1	MANBA	psi-mi:“MI:0914”(association)	0.640
SCGB1D1	FAM234B	psi-mi:“MI:0914”(association)	0.530
ODAPH	TCAF2	psi-mi:“MI:0914”(association)	0.530
DEFA1	MANBA	psi-mi:“MI:0914”(association)	0.530
ADAMTS4	MANBA	psi-mi:“MI:0914”(association)	0.530
PRSS37	MANBA	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
CMA1	MANBA	psi-mi:“MI:0914”(association)	0.530
CTSG	MANBA	psi-mi:“MI:0914”(association)	0.530
TAFA3	FUOM	psi-mi:“MI:0914”(association)	0.350
KLK11	DENND11	psi-mi:“MI:0914”(association)	0.350
PTPRK	MANBA	psi-mi:“MI:0914”(association)	0.350
TAZ	MANBA	psi-mi:“MI:0914”(association)	0.350
LYZL1	MANBA	psi-mi:“MI:0914”(association)	0.350
KIRREL2	MANBA	psi-mi:“MI:0914”(association)	0.350
LYZL2	MANBA	psi-mi:“MI:0914”(association)	0.350
PIP	RBM47	psi-mi:“MI:0914”(association)	0.350
C1QTNF8	VWA8	psi-mi:“MI:0914”(association)	0.350
CEACAM8	PRRT4	psi-mi:“MI:0914”(association)	0.350
GPIHBP1	SAC3D1	psi-mi:“MI:0914”(association)	0.350
IGFL3	CBX4	psi-mi:“MI:0914”(association)	0.350

BioGRID (101): MANBA (Affinity Capture-MS), MANBA (Affinity Capture-MS), MANBA (Affinity Capture-MS), MANBA (Affinity Capture-MS), MANBA (Affinity Capture-MS), MANBA (Affinity Capture-MS), MANBA (Affinity Capture-MS), MANBA (Affinity Capture-MS), MANBA (Affinity Capture-MS), MANBA (Affinity Capture-MS), MANBA (Affinity Capture-MS), MANBA (Affinity Capture-MS), MANBA (Affinity Capture-MS), MANBA (Affinity Capture-MS), MANBA (Affinity Capture-MS)

ESM2 similar proteins: A0A2I4HXH5, A5D6U8, B3A0N5, B6EWW8, E0D877, F8S0Z7, O00462, O35409, P05089, P15693, P19492, P21588, P21589, P29240, P31422, P42263, P49614, P49900, P50635, P52307, P70627, P83456, P83852, Q05927, Q14832, Q1ZZH1, Q29444, Q2KJ64, Q4FZV0, Q561R9, Q5R979, Q5RAL3, Q5RFI5, Q5TVM9, Q5XGR8, Q61503, Q641Z7, Q6AYS4, Q6PCE3, Q8CAA7

Diamond homologs: A1CGA8, A1D911, A2QYN2, B0YBU9, B8NW36, I2C092, O00462, Q0CCA0, Q29444, Q2TXB7, Q4FZV0, Q4WAH4, Q5B7W2, Q8K2I4, Q95327, A1CTM5, A1DMT2, A2QWU9, B0Y7S2, B8NP78, O74168, Q0CI48, Q2UN00, Q4WMS9, Q5BCI8, Q5H7P5, Q75W54, Q9UUZ3, Q93324, T2KM09, A8AKB8, Q48727, A1JTC4, A3FEW8, A4W7D2, A6TI29, A7KGA5, A7LXS9, O52847, P06864

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	64
Likely pathogenic	35
Uncertain significance	239
Likely benign	366
Benign	78

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1369625	NM_005908.4(MANBA):c.279G>A (p.Trp93Ter)	Pathogenic
1406698	NM_005908.4(MANBA):c.2030G>A (p.Trp677Ter)	Pathogenic
1457048	NM_005908.4(MANBA):c.1628G>A (p.Trp543Ter)	Pathogenic
1677	NM_005908.4(MANBA):c.563_572dup (p.Asp191_Trp192insTer)	Pathogenic
1678	NM_005908.4(MANBA):c.1705-1G>A	Pathogenic
1679	NM_005908.4(MANBA):c.1513T>C (p.Ser505Pro)	Pathogenic
1680	NM_005908.4(MANBA):c.375A>G (p.Arg125=)	Pathogenic
1681	NM_005908.4(MANBA):c.247G>T (p.Glu83Ter)	Pathogenic
1682	NM_005908.4(MANBA):c.1276C>T (p.Gln426Ter)	Pathogenic
1683	NM_005908.4(MANBA):c.1454_1455del (p.Tyr485fs)	Pathogenic
1958813	NM_005908.4(MANBA):c.1153_1162del (p.Asn385fs)	Pathogenic
1978132	NM_005908.4(MANBA):c.1156_1157del (p.Thr386fs)	Pathogenic
2058638	NM_005908.4(MANBA):c.1649del (p.Arg550fs)	Pathogenic
2070212	NM_005908.4(MANBA):c.1534G>T (p.Glu512Ter)	Pathogenic
2095842	NM_005908.4(MANBA):c.2101_2102insTGTGACGGGCGCGGTGGCTCACGCCTGTAATCCCAGCACTGTGGGAGGCCGAGGCGGGCGGATCACGAGGTCAGNNNNNNNNNNAAAAAAAAAAAAAAAAAAAAGAGAATGAAAACA (p.Thr701delinsMetTer)	Pathogenic
2109699	NM_005908.4(MANBA):c.1724G>A (p.Trp575Ter)	Pathogenic
2142091	NM_005908.4(MANBA):c.63_64del (p.Ser22fs)	Pathogenic
2664650	NM_005908.4(MANBA):c.1486-2A>G	Pathogenic
2703999	NM_005908.4(MANBA):c.1836dup (p.Arg613fs)	Pathogenic
2704638	NM_005908.4(MANBA):c.1453dup (p.Tyr485fs)	Pathogenic
2709615	NM_005908.4(MANBA):c.2102_2103insAT (p.Phe702fs)	Pathogenic
2719776	NM_005908.4(MANBA):c.1234dup (p.Trp412fs)	Pathogenic
2727927	NM_005908.4(MANBA):c.1096C>T (p.Arg366Ter)	Pathogenic
2728766	NM_005908.4(MANBA):c.1644del (p.Ala549fs)	Pathogenic
2742785	NM_005908.4(MANBA):c.870G>A (p.Trp290Ter)	Pathogenic
2746804	NM_005908.4(MANBA):c.386del (p.Asp129fs)	Pathogenic
2748201	NM_005908.4(MANBA):c.819del (p.Ile274fs)	Pathogenic
2760943	NM_005908.4(MANBA):c.1101_1111del (p.Thr368fs)	Pathogenic
2787022	NM_005908.4(MANBA):c.2333_2334del (p.Asp778fs)	Pathogenic
2833150	NM_005908.4(MANBA):c.2244C>A (p.Cys748Ter)	Pathogenic

SpliceAI

4812 predictions. Top by Δscore:

Variant	Effect	Δscore
4:102633176:A:AC	donor_gain	1.0000
4:102633215:AGG:A	donor_gain	1.0000
4:102634786:A:AC	donor_gain	1.0000
4:102634787:C:CC	donor_gain	1.0000
4:102650532:CTTA:C	donor_loss	1.0000
4:102650533:TTA:T	donor_loss	1.0000
4:102650534:TA:T	donor_loss	1.0000
4:102650700:ACC:A	acceptor_loss	1.0000
4:102650701:CCTT:C	acceptor_loss	1.0000
4:102650702:C:CC	acceptor_gain	1.0000
4:102650703:T:C	acceptor_gain	1.0000
4:102664679:A:AC	donor_gain	1.0000
4:102664680:C:CC	donor_gain	1.0000
4:102664680:CTTA:C	donor_gain	1.0000
4:102664681:TTA:T	donor_loss	1.0000
4:102664682:TA:T	donor_loss	1.0000
4:102664683:A:AC	donor_gain	1.0000
4:102664683:ACTG:A	donor_gain	1.0000
4:102664683:ACTGC:A	donor_gain	1.0000
4:102664684:C:CA	donor_gain	1.0000
4:102664684:CT:C	donor_gain	1.0000
4:102664684:CTG:C	donor_gain	1.0000
4:102664684:CTGC:C	donor_gain	1.0000
4:102664684:CTGCC:C	donor_gain	1.0000
4:102664729:AGT:A	donor_gain	1.0000
4:102664848:TTGAT:T	acceptor_gain	1.0000
4:102664849:TGAT:T	acceptor_gain	1.0000
4:102664850:GAT:G	acceptor_gain	1.0000
4:102664851:AT:A	acceptor_gain	1.0000
4:102664851:ATCTG:A	acceptor_gain	1.0000

AlphaMissense

5838 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:102639758:A:G	W657R	0.997
4:102639758:A:T	W657R	0.997
4:102671343:A:G	W390R	0.997
4:102671343:A:T	W390R	0.997
4:102657724:T:A	E554D	0.996
4:102657724:T:G	E554D	0.996
4:102639756:C:A	W657C	0.995
4:102639756:C:G	W657C	0.995
4:102650652:C:G	R585P	0.995
4:102635989:T:A	K678I	0.994
4:102657725:T:A	E554V	0.994
4:102657868:A:C	S506R	0.994
4:102657868:A:T	S506R	0.994
4:102657870:T:G	S506R	0.994
4:102671341:C:A	W390C	0.994
4:102671341:C:G	W390C	0.994
4:102639725:A:G	W668R	0.992
4:102639725:A:T	W668R	0.992
4:102639740:A:G	W663R	0.992
4:102639740:A:T	W663R	0.992
4:102664816:A:G	W452R	0.992
4:102664816:A:T	W452R	0.992
4:102714537:A:G	W192R	0.992
4:102714537:A:T	W192R	0.992
4:102714543:A:G	W190R	0.992
4:102714543:A:T	W190R	0.992
4:102714547:A:C	F188L	0.992
4:102714547:A:T	F188L	0.992
4:102714549:A:G	F188L	0.992
4:102664802:A:C	N456K	0.991

dbSNP variants (sampled 300 via entrez): RS1000006390 (4:102752700 A>C,T), RS1000014032 (4:102733152 T>C), RS1000029682 (4:102688760 A>C), RS1000044492 (4:102636999 C>T), RS10000705 (4:102703081 T>G), RS1000107881 (4:102736724 T>A), RS1000123090 (4:102676559 A>G), RS1000128447 (4:102632831 A>G), RS1000175796 (4:102746106 G>A,C), RS1000194281 (4:102642965 T>C), RS1000204837 (4:102653108 A>G), RS1000250058 (4:102632505 A>T), RS1000266544 (4:102739437 C>A,T), RS1000296267 (4:102705861 C>T), RS1000313342 (4:102659901 C>T)

Disease associations

OMIM: gene MIM:609489 | disease phenotypes: MIM:248510, MIM:156000

GenCC curated gene-disease

Disease	Classification	Inheritance
beta-mannosidosis	Definitive	Autosomal recessive
congenital nystagmus	Moderate	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
beta-mannosidosis	Definitive	AR

Mondo (5): beta-mannosidosis (MONDO:0009562), hearing loss disorder (MONDO:0005365), Meniere disease (MONDO:0007972), intellectual disability (MONDO:0001071), congenital nystagmus (MONDO:0005712)

Orphanet (3): Beta-mannosidosis (Orphanet:118), NON RARE IN EUROPE: Menière disease (Orphanet:45360), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

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

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000503	Tortuosity of conjunctival vessels
HP:0000718	Aggressive behavior
HP:0000752	Hyperactivity
HP:0001014	Angiokeratoma
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001290	Generalized hypotonia
HP:0001999	Abnormal facial shape
HP:0002167	Abnormal speech pattern
HP:0002205	Recurrent respiratory infections
HP:0002719	Recurrent infections
HP:0003593	Infantile onset
HP:0005247	Hypoplasia of the abdominal wall musculature
HP:0007108	Demyelinating peripheral neuropathy
HP:0012066	Increased urinary disaccharide excretion
HP:0034367	Decreased circulating beta-mannosidase activity
HP:4000205	Reduced tissue beta-mannosidase activity

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST001198_30	Multiple sclerosis	1.000000e-07
GCST001728_8	Ulcerative colitis	4.000000e-12
GCST003129_19	Primary biliary cholangitis	8.000000e-10
GCST004030_20	Primary sclerosing cholangitis	1.000000e-07
GCST004627_60	Lymphocyte count	1.000000e-31
GCST005038_38	Allergic disease (asthma, hay fever or eczema)	4.000000e-11
GCST005531_114	Multiple sclerosis	1.000000e-08
GCST005538_4	Sarcoidosis	1.000000e-09
GCST005581_2	Primary biliary cirrhosis	8.000000e-14
GCST006409_3	Allergic rhinitis	1.000000e-15
GCST006585_1594	Blood protein levels	3.000000e-69
GCST007036_2	Primary biliary cholangitis	9.000000e-10
GCST007876_43	Estimated glomerular filtration rate	4.000000e-10
GCST008919_4	Asthma and attention deficit hyperactivity disorder	3.000000e-08
GCST90002388_350	Lymphocyte count	3.000000e-57
GCST90011898_161	Alanine aminotransferase levels	6.000000e-09
GCST90011900_87	Serum alkaline phosphatase levels	1.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004587	lymphocyte count
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008575	Meniere Disease	C09.218.568.217.500
D020417	Nystagmus, Congenital	C10.292.562.675.300; C11.590.400.300; C16.614.643
D044905	beta-Mannosidosis	C16.320.565.202.607.750; C16.320.565.595.577.750; C18.452.648.202.607.750; C18.452.648.595.577.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3903 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.60	Ki	25	nM	CHEMBL62552
5.00	Ki	1e+04	nM	CHEMBL62534

PubChem BioAssay actives

2 with measured affinity, of 58 total; 2 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
[[3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-ylidene]amino] N-phenylcarbamate	44231: The compound was tested for its inhibitory activity against beta-mannosidase	ki	0.0250	uM
(2Z)-2-(2,4-dinitrophenoxy)imino-6-(hydroxymethyl)oxane-3,4,5-triol	44231: The compound was tested for its inhibitory activity against beta-mannosidase	ki	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	4
bisphenol A	increases expression, affects cotreatment	2
Acetaminophen	affects expression, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
GSK-J4	increases expression	1
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
benzo(e)pyrene	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
K 7174	increases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
bisphenol S	affects cotreatment, increases expression	1
gardiquimod	decreases expression, decreases reaction	1
bisphenol AF	increases expression	1
Decitabine	affects expression	1
Air Pollutants	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Cisplatin	affects expression	1
Dexamethasone	affects cotreatment, increases expression	1
Dimethyl Sulfoxide	increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	increases expression	1
Lead	affects expression	1
Methapyrilene	increases methylation	1
Methyl Methanesulfonate	increases expression	1
Phthalic Acids	decreases methylation	1
Rotenone	increases expression	1
Tretinoin	increases expression	1
Urethane	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1

ChEMBL screening assays

13 unique, capped per target: 11 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4008569	Binding	Inhibition of human lysosomal beta-mannosidase assessed as formation of 4-methylumbelliferone from 4-methylumbelliferyl alpha-D-glucopyranoside up to 200 uM by luminescence spectrophotometry	Fluorinated Chaperone-β-Cyclodextrin Formulations for β-Glucocerebrosidase Activity Enhancement in Neuronopathic Gaucher Disease. — J Med Chem
CHEMBL823893	Functional	Competitive Inhibition constant on almonds beta Mannosidase; MI=Moderate Inhibition	Synthesis and biological activity of C-6 modified derivatives of the glucosidase inhibitor 1-deoxynojirimycin. — Bioorg Med Chem Lett

Cellosaurus cell lines

6 cell lines: 5 finite cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C0LR	GM28364	Transformed cell line	Female
CVCL_D3AG	GM29051	Finite cell line	Male
CVCL_D3AH	GM29071	Finite cell line	Female
CVCL_D3AK	GM29118	Finite cell line	Male
CVCL_D6WG	GM29052	Finite cell line	Male
CVCL_F0Z0	GM29359	Finite cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00001866	PHASE2	COMPLETED	Eye Muscle Surgery to Treat Congenital Nystagmus
NCT00799942	PHASE2	TERMINATED	Open-lable Extension Study on Safety and Efficacy of Neramexane to Treat Congenital and Acquired Nystagmus
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT01891422	Not specified	COMPLETED	Longitudinal Studies of the Glycoproteinoses
NCT00001861	Not specified	COMPLETED	Screening for Studies on Nystagmus and Strabismus
NCT00702832	Not specified	COMPLETED	Effect of Vestibular Rehabilitation - a Randomized Controlled Trial
NCT00928954	Not specified	COMPLETED	Cross-over Comparison of Gabapentin and Memantine as Treatment for Acquired Nystagmus
NCT03603301	Not specified	UNKNOWN	Vision in Children Born to Opioid-dependent Methadone-maintained Mothers
NCT04770519	Not specified	RECRUITING	Genetic Studies of Strabismus, Nystagmus, and Associated Disorders
NCT07126938	Not specified	COMPLETED	Alcohol Impairment Detection in Healthy Adult Users With the Gaize Device