GMPPB

Summary

GMPPB (GDP-mannose pyrophosphorylase B, HGNC:22932) is a protein-coding gene on chromosome 3p21.31, encoding Mannose-1-phosphate guanylyltransferase catalytic subunit beta (Q9Y5P6). Catalytic subunit of the GMPPA-GMPPB mannose-1-phosphate guanylyltransferase complex. It is a selective cancer dependency (DepMap: 82.2% of cell lines).

This gene is thought to encode a GDP-mannose pyrophosphorylase. The encoded protein catalyzes the conversion of mannose-1-phosphate and GTP to GDP-mannose, a reaction involved in the production of N-linked oligosaccharides. Alternatively spliced transcript variants encoding distinct isoforms have been described.

Source: NCBI Gene 29925 — RefSeq curated summary.

At a glance

• Gene–disease (curated): myopathy caused by variation in GMPPB (Definitive, ClinGen) — +7 more curated relationships
• GWAS associations: 12
• Clinical variants (ClinVar): 473 total — 23 pathogenic, 26 likely-pathogenic
• Phenotypes (HPO): 150
• Cancer dependency (DepMap): dependent in 82.2% of screened cell lines
• MANE Select transcript: NM_021971

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:22932
Approved symbol	GMPPB
Name	GDP-mannose pyrophosphorylase B
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1851
Ensembl gene	ENSG00000173540
Ensembl biotype	protein_coding
OMIM	615320
Entrez	29925

Gene structure

Transcript identifiers

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

ENST00000308375, ENST00000308388, ENST00000480687, ENST00000481959, ENST00000495627, ENST00000677393, ENST00000678010, ENST00000678208, ENST00000678853, ENST00000859688, ENST00000859689, ENST00000859690, ENST00000931336, ENST00000931337, ENST00000931338, ENST00000955679, ENST00000955680, ENST00000955681, ENST00000955682

RefSeq mRNA: 2 — MANE Select: NM_021971 NM_013334, NM_021971

CCDS: CCDS2802, CCDS2803

Canonical transcript exons

ENST00000308388 — 9 exons

Exon	Start	End
ENSE00001208277	49723598	49723951
ENSE00001242547	49719916	49721883
ENSE00003460021	49722972	49723114
ENSE00003512426	49721965	49722147
ENSE00003535881	49722231	49722358
ENSE00003551476	49723392	49723472
ENSE00003576200	49722596	49722754
ENSE00003626554	49723254	49723302
ENSE00003657344	49722432	49722510

Expression profiles

Bgee: expression breadth ubiquitous, 172 present calls, max score 92.06.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.2571 / max 491.4781, expressed in 1812 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42271	18.2571	1812

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	92.06	gold quality
adenohypophysis	UBERON:0002196	91.26	gold quality
mucosa of transverse colon	UBERON:0004991	90.99	gold quality
pituitary gland	UBERON:0000007	89.85	gold quality
bone marrow cell	CL:0002092	89.42	gold quality
right lobe of thyroid gland	UBERON:0001119	88.79	gold quality
minor salivary gland	UBERON:0001830	88.40	gold quality
pancreas	UBERON:0001264	88.06	gold quality
right lobe of liver	UBERON:0001114	87.95	gold quality
left lobe of thyroid gland	UBERON:0001120	87.86	gold quality
right adrenal gland	UBERON:0001233	87.81	gold quality
left adrenal gland	UBERON:0001234	87.75	gold quality
body of stomach	UBERON:0001161	87.73	gold quality
left adrenal gland cortex	UBERON:0035825	87.32	gold quality
right adrenal gland cortex	UBERON:0035827	86.63	gold quality
transverse colon	UBERON:0001157	86.58	gold quality
saliva-secreting gland	UBERON:0001044	86.45	gold quality
vermiform appendix	UBERON:0001154	86.42	gold quality
upper lobe of left lung	UBERON:0008952	86.35	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	86.33	gold quality
thyroid gland	UBERON:0002046	86.23	gold quality
stromal cell of endometrium	CL:0002255	86.20	gold quality
left uterine tube	UBERON:0001303	86.08	gold quality
esophagus mucosa	UBERON:0002469	85.62	gold quality
adrenal cortex	UBERON:0001235	85.55	gold quality
lower esophagus mucosa	UBERON:0035834	85.47	gold quality
adrenal gland	UBERON:0002369	85.42	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.37	gold quality
stomach	UBERON:0000945	85.05	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.01	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-CURD-88	yes	77.95
E-HCAD-1	yes	41.59
E-CURD-122	yes	38.16
E-MTAB-9467	yes	30.61
E-MTAB-8410	yes	23.57
E-ANND-3	yes	22.58
E-MTAB-10553	yes	10.04
E-CURD-112	no	3.60

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

27 targeting GMPPB, 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-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-4722-3P	99.35	65.22	1099
HSA-MIR-6770-5P	98.97	66.76	1853
HSA-MIR-4736	97.96	65.89	1287
HSA-MIR-219B-5P	97.91	65.80	531
HSA-MIR-193B-5P	97.91	65.88	837
HSA-MIR-526B-5P	97.41	67.99	1074
HSA-MIR-6886-3P	96.96	66.36	844
HSA-MIR-3126-5P	96.87	65.83	912
HSA-MIR-6875-5P	96.87	65.49	958
HSA-MIR-3194-5P	96.80	64.90	1027
HSA-MIR-6856-3P	96.47	66.27	781
HSA-MIR-6742-5P	96.32	64.01	869
HSA-MIR-6834-5P	96.25	64.88	823
HSA-MIR-3918	96.13	64.65	1300
HSA-MIR-6851-3P	95.73	65.11	688

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 82.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 13)

• Individuals with GMPPB mutations have hypoglycosylated alpha-dystroglycan in muscle. These mutations cause congenital and limb-girdle muscular dystrophies. (PMID:23768512)
• Work confirms a role for GMPPB defects in alpha-dystroglycanopathy, and suggests that glycosylation may play a role in the neuronal membrane channels or networks involved in the physiology of generalized epilepsy syndromes. (PMID:24780531)
• The phenotypic spectrum of GMPPB mutations was expanded to include limb-girdle muscular dystrophies. (PMID:25681410)
• This study found mutations in GMPPB can lead to a wide spectrum of clinical features where deficit in neuromuscular transmission is the major component in a subset of cases. (PMID:26133662)
• We observe that c.79G>C (p.D27H) is associated with a mild limb-girdle muscular dystrophy phenotype, whereas c.860G>A (p.R287Q) is associated with a relatively severe congenital muscular dystrophy typically involving brain development. (PMID:26310427)
• Patients with GMPPB-CMS have phenotypic features aligned with CMS subtypes harbouring mutations within the early stages of the glycosylation pathway. Additional features shared with the dystroglycanopathies include myopathic features, raised Creatine Kinase levels and variable mild cognitive delay. (PMID:27147698)
• Study finds that the GMPPB mutation spectrum in Chinese patients may differ from that of European populations, with the mutation p.(Arg357His) most frequently found. These mutations may lead to abnormal folding of GMPPB leading to protein aggregates in the cytoplasm rather than an overall loss in protein expression. (PMID:28433477)
• Late-onset limb-girdle muscular dystrophy caused by GMPPB mutations. (PMID:28478914)
• Data demonstrates that a change in beta-dystroglycan electrophoretic mobility in patients with muscular dystrophy is a distinctive marker of the molecular defect in GMPPB. (PMID:29437916)
• Limb-girdle muscular dystrophy due to GMPPB mutations: A case report and comprehensive literature review. (PMID:30684953)
• A founder mutation in the GMPPB gene [c.1000G > A (p.Asp334Asn)] causes a mild form of limb-girdle muscular dystrophy/congenital myasthenic syndrome (LGMD/CMS) in South Indian patients. (PMID:34333724)
• Distinct and Recognisable Muscle MRI Pattern in a Series of Adults Harbouring an Identical GMPPB Gene Mutation. (PMID:34633329)
• Silencing GMPPB Inhibits the Proliferation and Invasion of GBM via Hippo/MMP3 Pathways. (PMID:37834154)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	gmppb	ENSDARG00000017658
mus_musculus	Gmppb	ENSMUSG00000070284
drosophila_melanogaster	Gmppb	FBGN0037279
caenorhabditis_elegans		WBGENE00016583

Paralogs (3): EIF2B3 (ENSG00000070785), GMPPA (ENSG00000144591), EIF2B5 (ENSG00000145191)

Protein

Protein identifiers

Mannose-1-phosphate guanylyltransferase catalytic subunit beta — Q9Y5P6 (reviewed: Q9Y5P6)

Alternative names: GDP-mannose pyrophosphorylase B, GTP-mannose-1-phosphate guanylyltransferase beta

All UniProt accessions (5): Q9Y5P6, A0A7I2V2Y5, A0A7I2V4B5, A0A7I2V691, A0A7I2YQI5

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of the GMPPA-GMPPB mannose-1-phosphate guanylyltransferase complex. Catalyzes the formation of GDP-mannose, an essential precursor of glycan moieties of glycoproteins and glycolipids. Can catalyze the reverse reaction in vitro. Together with GMPPA regulates GDP-alpha-D-mannose levels.

Subunit / interactions. Component of the GMPPA-GMPPB mannose-1-phosphate guanylyltransferase complex composed of 4 GMPPA subunits and 8 GMPPB subunits; the complex is organized into three layers, a central layer made up of 2 GMPPA dimers sandwiched between two layers each made up of 2 GMPPB dimers. GMPPB catalytic activity is reduced when part of the complex and binding of GDP-alpha-D-Mannose by GMPPA induces allosteric feedback inhibition of GMPPB.

Subcellular location. Cytoplasm.

Tissue specificity. Ubiquitously expressed, including in brain and skeletal muscle. Weakly expressed with highest expression in skeletal muscle, brain and gonads.

Disease relevance. Muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies A14 (MDDGA14) [MIM:615350] An autosomal recessive disorder characterized by congenital muscular dystrophy associated with brain anomalies, eye malformations, and profound intellectual disability. The disorder includes a severe form designated as Walker-Warburg syndrome and a less severe phenotype known as muscle-eye-brain disease. MDDGA14 features include increased muscle tone, microcephaly, cleft palate, feeding difficulties, severe muscle weakness, sensorineural hearing loss, cerebellar hypoplasia, ataxia, and retinal dysfunction. The disease is caused by variants affecting the gene represented in this entry. Muscular dystrophy-dystroglycanopathy congenital with impaired intellectual development B14 (MDDGB14) [MIM:615351] A congenital muscular dystrophy characterized by severe muscle weakness apparent in infancy and intellectual disability. Some patients may have additional features, such as microcephaly, cardiac dysfunction, seizures, or cerebellar hypoplasia. The disease is caused by variants affecting the gene represented in this entry. Muscular dystrophy-dystroglycanopathy limb-girdle C14 (MDDGC14) [MIM:615352] An autosomal recessive form of muscular dystrophy characterized by mild proximal muscle weakness with onset in early childhood. Some patients may have additional features, such as mild intellectual disability or seizures. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Enzyme activity is reduced by incorporation into the GMPPA-GMPPB mannose-1-phosphate guanylyltransferase complex. Allosterically inhibited, when part of the GMPPA-GMPPB complex, by GDP-alpha-D-mannose binding to GMPPA.

Cofactor. Coordinates binding with substrate and required for enzymatic activity.

Domain organisation. The N-terminal substrate-binding domain adopts a Rossman-like fold and has a binding pocket for GTP or GDP-alpha-D-mannose. Substrate binding is coordinated by an Mg(2+) ion. The C-terminal domain consists of a series of tandem hexapeptide repeats that adopt a beta-helix conformation. The beta-helix forms several protein interaction surfaces involved in assembly of the GMPPA-GMPPB mannose-1-phosphate guanylyltransferase complex.

Pathway. Nucleotide-sugar biosynthesis; GDP-alpha-D-mannose biosynthesis; GDP-alpha-D-mannose from alpha-D-mannose 1-phosphate (GTP route): step 1/1.

Similarity. Belongs to the transferase hexapeptide repeat family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y5P6-1	1	yes
Q9Y5P6-2	2

RefSeq proteins (2): NP_037466, NP_068806* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005835	NTP_transferase_dom	Domain
IPR018357	Hexapep_transf_CS	Conserved_site
IPR029044	Nucleotide-diphossugar_trans	Homologous_superfamily
IPR045233	GMPPB_N	Domain
IPR050486	Mannose-1P_guanyltransferase	Family
IPR056729	GMPPB_C	Domain

Pfam: PF00483, PF25087

Enzyme classification (BRENDA):

• EC 2.7.7.13 — mannose-1-phosphate guanylyltransferase (BRENDA: 33 organisms, 98 substrates, 55 inhibitors, 69 Km, 3 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
ALPHA-D-MANNOSE 1-PHOSPHATE	0.0082–0.19	18
GTP	0.0026–1	16
GDPMANNOSE	—	6
DIPHOSPHATE	0.089–0.5	5
GDP-MANNOSE	0.024–2.9	4
MG2+	0.002–1.9	4
MANNOSE 1-PHOSPHATE	0.0004–0.2	3
GDP-ALPHA-D-MANNOSE	0.001–2.9	2
2-DEOXY-D-GLUCOSE 1-PHOSPHATE	41.1	1
3-DEOXY-D-ARABINO-HEXOSE 1-PHOSPHATE	15.2	1
4-DEOXY-ALPHA-D-LYXO-HEXOSE 1-PHOSPHATE	0.94	1
ALPHA-D-GLUCOSE 1-PHOSPHATE	0.094	1
ALPHA-D-LYXOSE-1-PHOSPHATE	13.8	1
ATP	0.29	1
D-MANNOSE 1-PHOSPHATE	0.012	1

Catalyzed reactions (Rhea), 1 shown:

• alpha-D-mannose 1-phosphate + GTP + H(+) = GDP-alpha-D-mannose + diphosphate (RHEA:15229)

UniProt features (75 total): strand 21, sequence variant 20, helix 10, mutagenesis site 9, turn 6, binding site 4, region of interest 2, chain 1, active site 1, splice variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
7D73	ELECTRON MICROSCOPY	3
7D74	ELECTRON MICROSCOPY	3.1
7D72	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5P6-F1	96.33	0.95

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): 162

Ligand- & substrate-binding residues (4): 110; 110; 218; 218

Mutagenesis-validated functional residues (9):

Position	Phenotype
193	reduces enzymatic activity.
218	reduces gdp-alpha-d-mannose binding affinity and inhibits catalytic activity but does not affect assembly of gmppa-gmppb
218	abrogates enzyme activity.
266	reduces interaction with gmppb but not with gmppa.
287	disrupts interaction with other gmppb molecules but not with gmppa.
303	reduces interaction with gmppb but not with gmppa.
335	disrupted interaction with gmppa and other gmppb molecules.
344–347	does not disrupt the interaction with gmppa or other gmppb molecules.
358–360	reduced efficiency of allosteric inhibition by gmppa but interaction with gmppa or other gmppb molecules is not disrupte

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-446205	Synthesis of GDP-mannose

MSigDB gene sets: 437 (showing top): TAATAAT_MIR126, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOSIDE_PHOSPHATE_BIOSYNTHETIC_PROCESS, GGGTGGRR_PAX4_03, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, COUP_01, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, KOYAMA_SEMA3B_TARGETS_UP, GOBP_CARBOHYDRATE_DERIVATIVE_BIOSYNTHETIC_PROCESS, HNF4_01, AACTTT_UNKNOWN, KEGG_FRUCTOSE_AND_MANNOSE_METABOLISM, CTCAAGA_MIR526B, MULLIGAN_NTF3_SIGNALING_VIA_INSR_AND_IGF1R_UP

GO Biological Process (5): GDP-mannose biosynthetic process (GO:0009298), GDP-mannose metabolic process (GO:0019673), obsolete GDP-mannose biosynthetic process from mannose (GO:0061728), obsolete protein glycosylation (GO:0006486), biosynthetic process (GO:0009058)

GO Molecular Function (7): mannose-1-phosphate guanylyltransferase (GTP) activity (GO:0004475), GTP binding (GO:0005525), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), protein binding (GO:0005515), transferase activity (GO:0016740), nucleotidyltransferase activity (GO:0016779)

GO Cellular Component (3): cytoplasm (GO:0005737), cytosol (GO:0005829), GDP-mannose pyrophosphorylase complex (GO:0120508)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Synthesis of substrates in N-glycan biosythesis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
phosphomannomutase activity	1
nucleotide-sugar biosynthetic process	1
GDP-mannose metabolic process	1
nucleotide-sugar metabolic process	1
metabolic process	1
guanylyltransferase activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
transferase activity, transferring phosphorus-containing groups	1
intracellular anatomical structure	1
cytoplasm	1
transferase complex, transferring phosphorus-containing groups	1

Protein interactions and networks

STRING

2413 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GMPPB	POMT2	Q9UKY4	826
GMPPB	POMGNT2	Q8NAT1	819
GMPPB	FKRP	Q9H9S5	817
GMPPB	RXYLT1	Q9Y2B1	813
GMPPB	POMT1	Q9Y6A1	796
GMPPB	FKTN	O75072	795
GMPPB	B3GALNT2	Q8NCR0	792
GMPPB	POMK	Q9H5K3	789
GMPPB	POMGNT1	Q8WZA1	782
GMPPB	DOLK	Q9UPQ8	773
GMPPB	DPM3	Q9P2X0	771
GMPPB	DPM1	O60762	762
GMPPB	DPM2	O94777	753
GMPPB	DPAGT1	Q9H3H5	714
GMPPB	DAG1	Q14118	705

IntAct

50 interactions, top by confidence:

A	B	Type	Score
GMPPA	GMPPB	psi-mi:“MI:0915”(physical association)	0.870
GMPPB	GMPPA	psi-mi:“MI:0915”(physical association)	0.870
GOLPH3	RCC1L	psi-mi:“MI:0914”(association)	0.640
TXNDC5	GMPPB	psi-mi:“MI:0915”(physical association)	0.560
GMPPB	TXNDC5	psi-mi:“MI:0915”(physical association)	0.560
POLR1C	GMPPB	psi-mi:“MI:0915”(physical association)	0.560
DPPA4	GMPPB	psi-mi:“MI:0915”(physical association)	0.560
GLYCTK	GMPPB	psi-mi:“MI:0915”(physical association)	0.560
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
TXNDC5	GMPPB	psi-mi:“MI:0915”(physical association)	0.370
Sesn2	CASTOR2	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
BRICD5	POTEF	psi-mi:“MI:0914”(association)	0.350
GMPPB	PRMT3	psi-mi:“MI:0914”(association)	0.350
KRTAP19-6	PREP	psi-mi:“MI:0914”(association)	0.350
EPB41L5	LIN7A	psi-mi:“MI:0914”(association)	0.350
EIF2B5	KCNN4	psi-mi:“MI:0914”(association)	0.350
GMPPB	MNAT1	psi-mi:“MI:0914”(association)	0.350
GOLPH3	MDC1	psi-mi:“MI:0914”(association)	0.350
AZU1	UBA6	psi-mi:“MI:0914”(association)	0.350
DDX28	UBA6	psi-mi:“MI:0914”(association)	0.350
ERF	DVL2	psi-mi:“MI:0914”(association)	0.350
GAB2	UBA6	psi-mi:“MI:0914”(association)	0.350
GOLPH3	FAM20B	psi-mi:“MI:0914”(association)	0.350

BioGRID (96): GMPPA (Two-hybrid), TXNDC5 (Two-hybrid), GMPPA (Affinity Capture-MS), CCNB2 (Affinity Capture-MS), PRMT3 (Affinity Capture-MS), EIF2D (Affinity Capture-MS), HACL1 (Affinity Capture-MS), PI4K2B (Affinity Capture-MS), PRUNE (Affinity Capture-MS), DHODH (Affinity Capture-MS), PUSL1 (Affinity Capture-MS), GMPPB (Affinity Capture-MS), GMPPA (Two-hybrid), CCS (Co-fractionation), FKBP1B (Co-fractionation)

ESM2 similar proteins: A2VD83, A3QMC8, B5EUW3, B8G1G5, O22287, O74484, O74624, O93827, P0C5I2, P0CO20, P0CO21, P41940, P43796, Q24VW5, Q295Y7, Q2UJU5, Q2YDJ9, Q4I1Y5, Q4QK69, Q4U3E8, Q54K39, Q5B1J4, Q5DZC0, Q61S97, Q65FS5, Q68EQ1, Q68EY9, Q6BN12, Q6CCU3, Q6DBU5, Q6FRY2, Q6LKA2, Q6Z9A3, Q70SJ2, Q752H4, Q7JZB4, Q7MEE9, Q7MJ49, Q7RVR8, Q84JH5

Diamond homologs: A2VD83, A3QMC8, B0CM52, B1L9R3, B9CM12, B9K6N9, I3LUP1, L7N6A5, O22287, O74484, O74624, O93827, P0C5I2, P0CO20, P0CO21, P26396, P37820, P41940, P74285, Q0P8J1, Q0P8J8, Q0VFM6, Q295Y7, Q2UJU5, Q2YDJ9, Q4I1Y5, Q4U3E8, Q54K39, Q58730, Q5B1J4, Q5XIC1, Q61S97, Q66KG5, Q68EQ1, Q68EY9, Q6BN12, Q6CCU3, Q6DBU5, Q6DKE9, Q6FRY2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	23
Likely pathogenic	26
Uncertain significance	212
Likely benign	158
Benign	10

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1072060	NM_021971.4(GMPPB):c.294dup (p.Glu99Ter)	Pathogenic
1508556	NM_021971.4(GMPPB):c.1039_1042dup (p.Ser348Ter)	Pathogenic
1948644	NM_021971.4(GMPPB):c.1051_1054dup (p.Ser352Ter)	Pathogenic
2001208	NM_021971.4(GMPPB):c.225del (p.Ser76fs)	Pathogenic
2070938	NM_021971.4(GMPPB):c.972dup (p.Val325fs)	Pathogenic
2125713	NM_021971.4(GMPPB):c.951G>A (p.Trp317Ter)	Pathogenic
2151975	NM_021971.4(GMPPB):c.854_855del (p.Cys285fs)	Pathogenic
225925	NM_021971.4(GMPPB):c.859C>T (p.Arg287Trp)	Pathogenic
265184	NM_021971.4(GMPPB):c.260-1G>A	Pathogenic
2936436	NM_021971.4(GMPPB):c.132_141del (p.Gly45fs)	Pathogenic
2953265	NM_021971.4(GMPPB):c.618dup (p.Leu207fs)	Pathogenic
3750006	NM_021971.4(GMPPB):c.444del (p.Cys149fs)	Pathogenic
3764631	NM_021971.4(GMPPB):c.1013_1017dup (p.Gly340fs)	Pathogenic
474016	NM_021971.4(GMPPB):c.365_366dup (p.Phe123fs)	Pathogenic
4783624	NM_021971.4(GMPPB):c.797G>A (p.Cys266Tyr)	Pathogenic
560362	NM_021971.4(GMPPB):c.358A>G (p.Met120Val)	Pathogenic
571713	NM_021971.4(GMPPB):c.790C>T (p.Gln264Ter)	Pathogenic
60541	NM_021971.4(GMPPB):c.220C>T (p.Arg74Ter)	Pathogenic
60542	NM_021971.4(GMPPB):c.64C>T (p.Pro22Ser)	Pathogenic
60544	NM_021971.4(GMPPB):c.95C>T (p.Pro32Leu)	Pathogenic
620253	NM_021971.4(GMPPB):c.490C>T (p.Gln164Ter)	Pathogenic
647358	NM_021971.4(GMPPB):c.109C>T (p.Gln37Ter)	Pathogenic
663873	NM_021971.4(GMPPB):c.271_283del (p.Ala91fs)	Pathogenic
1066587	NM_021971.4(GMPPB):c.769-2A>G	Likely pathogenic
1180706	NM_021971.4(GMPPB):c.655A>T (p.Ile219Phe)	Likely pathogenic
1299526	NM_021971.4(GMPPB):c.827C>T (p.Pro276Leu)	Likely pathogenic
1324486	NM_021971.4(GMPPB):c.633_636dup (p.Gln213fs)	Likely pathogenic
1324488	NM_021971.4(GMPPB):c.1008_1009del (p.Tyr337fs)	Likely pathogenic
1324489	NM_021971.4(GMPPB):c.129+1G>T	Likely pathogenic
1324490	NM_021971.4(GMPPB):c.824dup (p.Pro276fs)	Likely pathogenic

SpliceAI

2055 predictions. Top by Δscore:

Variant	Effect	Δscore
3:49720631:G:GT	donor_gain	1.0000
3:49720649:GAGCT:G	donor_gain	1.0000
3:49720651:GCT:G	donor_gain	1.0000
3:49720654:G:GG	donor_gain	1.0000
3:49720798:A:AG	acceptor_gain	1.0000
3:49720799:G:GG	acceptor_gain	1.0000
3:49720892:CTGG:C	donor_loss	1.0000
3:49720893:TGGT:T	donor_loss	1.0000
3:49720896:T:G	donor_loss	1.0000
3:49721018:A:AG	acceptor_gain	1.0000
3:49721019:G:GG	acceptor_gain	1.0000
3:49721102:GCAA:G	donor_gain	1.0000
3:49721103:CAAG:C	donor_loss	1.0000
3:49721104:AAGT:A	donor_loss	1.0000
3:49721105:AGT:A	donor_loss	1.0000
3:49721106:G:GG	donor_gain	1.0000
3:49721106:G:T	donor_loss	1.0000
3:49721107:T:A	donor_loss	1.0000
3:49721964:CCCA:C	donor_gain	1.0000
3:49721967:A:AC	donor_gain	1.0000
3:49721968:C:CC	donor_gain	1.0000
3:49722007:AAG:A	donor_gain	1.0000
3:49722430:AC:A	donor_gain	1.0000
3:49722431:CC:C	donor_gain	1.0000
3:49722441:C:CA	donor_gain	1.0000
3:49722511:C:CC	acceptor_gain	1.0000
3:49722591:CACA:C	donor_gain	1.0000
3:49722595:CCTGG:C	donor_loss	1.0000
3:49722965:GCCTT:G	donor_loss	1.0000
3:49722966:CCTTA:C	donor_loss	1.0000

AlphaMissense

2342 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:49723045:T:A	D110V	1.000
3:49723045:T:C	D110G	1.000
3:49723045:T:G	D110A	1.000
3:49722316:C:T	G228D	0.999
3:49722340:C:T	G220E	0.999
3:49722341:C:A	G220W	0.999
3:49722345:G:C	D218E	0.999
3:49722345:G:T	D218E	0.999
3:49722346:T:A	D218V	0.999
3:49722346:T:C	D218G	0.999
3:49722346:T:G	D218A	0.999
3:49722347:C:G	D218H	0.999
3:49722353:A:G	W216R	0.999
3:49722353:A:T	W216R	0.999
3:49722490:C:A	E194D	0.999
3:49722490:C:G	E194D	0.999
3:49722491:T:A	E194V	0.999
3:49722636:C:T	G174D	0.999
3:49722641:G:C	N172K	0.999
3:49722641:G:T	N172K	0.999
3:49722675:T:A	E161V	0.999
3:49722680:G:C	F159L	0.999
3:49722680:G:T	F159L	0.999
3:49722681:A:G	F159S	0.999
3:49722682:A:G	F159L	0.999
3:49722723:C:T	G145D	0.999
3:49722724:C:A	G145C	0.999
3:49722724:C:G	G145R	0.999
3:49723044:G:C	D110E	0.999
3:49723044:G:T	D110E	0.999

dbSNP variants (sampled 300 via entrez): RS1000673129 (3:49725816 C>T), RS1000783242 (3:49720182 G>A,C), RS1000848134 (3:49721336 C>T), RS1001399602 (3:49721226 T>G), RS1001524150 (3:49723986 C>T), RS1001931573 (3:49722201 G>A), RS1002002841 (3:49723840 C>T), RS1002239690 (3:49719828 A>G), RS1002590491 (3:49725467 G>A), RS1002600850 (3:49724893 T>G), RS1005096711 (3:49720342 G>A,T), RS1005592521 (3:49725100 C>T), RS1006738941 (3:49724469 A>C,G), RS1007150882 (3:49724690 C>T), RS1008153286 (3:49723792 C>T)

Disease associations

OMIM: gene MIM:615320 | disease phenotypes: MIM:615350, MIM:615351, MIM:615352

GenCC curated gene-disease

Disease	Classification	Inheritance
muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14	Definitive	Autosomal recessive
autosomal recessive limb-girdle muscular dystrophy type 2T	Strong	Autosomal recessive
congenital myasthenic syndrome	Strong	Autosomal recessive
myopathy caused by variation in GMPPB	Strong	Autosomal recessive
congenital myasthenic syndromes with glycosylation defect	Supportive	Autosomal recessive
congenital muscular dystrophy with cerebellar involvement	Supportive	Autosomal recessive
congenital muscular dystrophy with intellectual disability	Supportive	Autosomal recessive
muscle-eye-brain disease	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
myopathy caused by variation in GMPPB	Definitive	AR

Mondo (12): muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A14 (MONDO:0014140), muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B14 (MONDO:0014141), autosomal recessive limb-girdle muscular dystrophy type 2T (MONDO:0014142), muscular dystrophy (MONDO:0020121), myopathy caused by variation in GMPPB (MONDO:0700084), limb-girdle muscular dystrophy (MONDO:0016971), muscular dystrophy-dystroglycanopathy (MONDO:0018276), congenital myasthenic syndrome (MONDO:0018940), (MONDO:0018144), (MONDO:0018277), congenital muscular dystrophy with intellectual disability (MONDO:0018278), muscle-eye-brain disease (MONDO:0018939)

Orphanet (5): GMPPB-related limb-girdle muscular dystrophy R19 (Orphanet:363623), Muscle-eye-brain disease (Orphanet:588), Muscular dystrophy (Orphanet:98473), Limb-girdle muscular dystrophy (Orphanet:263), Congenital muscular dystrophy due to dystroglycanopathy (Orphanet:370953)

HPO phenotypes

150 total (30 of 150 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000054	Micropenis
HP:0000158	Macroglossia
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000407	Sensorineural hearing impairment
HP:0000467	Neck muscle weakness
HP:0000478	Abnormality of the eye
HP:0000485	Megalocornea
HP:0000486	Strabismus
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000508	Ptosis
HP:0000518	Cataract
HP:0000525	Abnormality iris morphology
HP:0000541	Retinal detachment
HP:0000545	Myopia
HP:0000568	Microphthalmia
HP:0000580	Pigmentary retinopathy
HP:0000589	Coloboma
HP:0000609	Optic nerve hypoplasia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000707	Abnormality of the nervous system
HP:0001249	Intellectual disability
HP:0001250	Seizure

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST000964_6	Ulcerative colitis	2.000000e-17
GCST003818_48	Resting heart rate	3.000000e-13
GCST006920_7	Regular attendance at a gym or sports club	6.000000e-10
GCST006922_9	Regular attendance at a religious group	3.000000e-08
GCST007044_11	Extremely high intelligence	4.000000e-08
GCST007559_24	Sleep duration (short sleep)	3.000000e-08
GCST008512_6	Multisite chronic pain	8.000000e-10
GCST010698_80	Subcortical volume (min-P)	3.000000e-24
GCST010699_110	Brain morphology (min-P)	4.000000e-08
GCST010701_52	Cortical surface area (MOSTest)	1.000000e-16
GCST010702_36	Subcortical volume (MOSTest)	1.000000e-10
GCST010703_262	Brain morphology (MOSTest)	2.000000e-13

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0009592	social interaction measurement
EFO:0004337	intelligence
EFO:0010100	multisite chronic pain
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D009136	Muscular Dystrophies	C05.651.534.500; C10.668.491.175.500; C16.320.577
D049288	Muscular Dystrophies, Limb-Girdle	C05.651.534.500.280; C10.668.491.175.500.149; C16.320.577.280
D020294	Myasthenic Syndromes, Congenital	C10.668.758.800; C16.320.590

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
Cyclosporine	increases expression	3
2,2’,4,4’-tetrabromodiphenyl ether	increases expression, decreases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
Tunicamycin	increases expression	2
bisphenol F	increases expression	1
2,4,6-tribromophenol	decreases expression	1
bisphenol A	decreases expression	1
tetrahydropalmatine	increases expression	1
cobaltous chloride	decreases expression	1
beta-methylcholine	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
pentabromodiphenyl ether	increases expression	1
2-palmitoylglycerol	increases expression	1
bisphenol S	affects cotreatment, decreases expression	1
jinfukang	increases expression	1
bisphenol AF	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	increases expression	1
Cadmium	increases abundance, increases expression	1
Dexamethasone	decreases expression, affects cotreatment	1
Diazinon	increases methylation	1
Formaldehyde	decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Nickel	increases expression	1
Quercetin	increases expression	1
Dihydrotestosterone	increases expression	1
Vincristine	decreases expression	1
Zinc	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01882400	PHASE4	COMPLETED	Assessment of Response to Treatment of Osteoporosis With Oral Bisphosphonates in Patients With Muscular Dystrophy
NCT01254019	PHASE3	COMPLETED	A Clinical Study to Assess the Efficacy and Safety of GSK2402968 in Subjects With Duchenne Muscular Dystrophy
NCT01480245	PHASE3	TERMINATED	Open Label Study of GSK2402968 in Subjects With Duchenne Muscular Dystrophy
NCT01803412	PHASE3	TERMINATED	A Study of the Safety, Tolerability & Efficacy of Long-term Administration of Drisapersen in US & Canadian Subjects
NCT01826487	PHASE3	COMPLETED	Phase 3 Study of Ataluren in Participants With Nonsense Mutation Duchenne Muscular Dystrophy (nmDMD)
NCT01890798	PHASE3	WITHDRAWN	Drisapersen Duchenne Muscular Dystrophy (DMD) Treatment Protocol
NCT02090959	PHASE3	TERMINATED	An Extension Study of Ataluren (PTC124) in Participants With Nonsense Mutation Dystrophinopathy
NCT02432885	PHASE3	COMPLETED	Myocardial Fibrosis Progression in Duchenne and Becker Muscular Dystrophy - ACE Inhibitor Therapy Trial
NCT03179631	PHASE3	COMPLETED	Long-Term Outcomes of Ataluren in Duchenne Muscular Dystrophy
NCT05126758	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Deramiocel (CAP-1002) in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT07587242	PHASE3	NOT_YET_RECRUITING	A Phase 3 Study to Evaluate the Safety and Efficacy of AOC 1044 (Also Referred to as Delpacibart Zotadirsen) in Participants With DMD With Gene Mutations Amenable to Exon 44 Skipping
NCT07608432	PHASE3	RECRUITING	Efficacy, Safety, and Tolerability of Zeleciment Rostudirsen (DYNE-251) Administered Intravenously Every 4 Weeks in Ambulatory Participants With Duchenne Muscular Dystrophy (FORZETTO)
NCT03783923	PHASE3	TERMINATED	A Study of Deflazacort (Emflaza®) in Participants With Limb-Girdle Muscular Dystrophy 2I (LGMD2I)
NCT06246513	PHASE3	ACTIVE_NOT_RECRUITING	A Trial to Learn More About an Experimental Gene Therapy Called Bidridistrogene Xeboparvovec (SRP-9003) as a Possible Treatment for Limb Girdle Muscular Dystrophy 2E/R4
NCT01153932	PHASE2	COMPLETED	Phase II Doubleblind Exploratory Study of GSK2402968 in Ambulant Subjects With Duchenne Muscular Dystrophy
NCT01462292	PHASE2	COMPLETED	A Clinical Study to Assess Two Doses of GSK2402968 in Subjects With Duchenne Muscular Dystrophy (DMD)
NCT01910649	PHASE2	TERMINATED	A Phase I/II, Open Label, Escalating Dose, Pilot Study to Assess Effect, Safety, Tolerability and PK of Multiple SC Doses of Drisapersen in Patients With Duchenne Muscular Dystrophy and to Assess the Potential for IV Dosing as an Alternative Route of Administration
NCT03406780	PHASE2	COMPLETED	A Study of CAP-1002 in Ambulatory and Non-Ambulatory Patients With Duchenne Muscular Dystrophy
NCT05479981	PHASE2	COMPLETED	Extension of AOC 1001-CS1 (MARINA) Study in Adult Myotonic Dystrophy Type 1 (DM1) Patients
NCT06290713	PHASE2	RECRUITING	Vasodilator and Exercise Study for DMD (VASO-REx)
NCT06547216	PHASE2	ACTIVE_NOT_RECRUITING	Phase 2 Open-label Extension Study of AOC 1020 in Participants With Facioscapulohumeral Muscular Dystrophy (FSHD)
NCT07287189	PHASE2	RECRUITING	Phase 2 Study of SAT-3247 in Pediatric Ambulatory Patients
NCT04054375	PHASE2	COMPLETED	Weekly Steroids in Muscular Dystrophy
NCT01203592	PHASE1	COMPLETED	Efficacy of Albuterol in the Treatment of Congenital Myasthenic Syndromes
NCT06436742	PHASE1	RECRUITING	A Phase 1b Study to Investigate Safety and Tolerability of ARGX-119 in Adult Participants With DOK7-Congenital Myasthenic Syndromes (CMS)
NCT07226726	PHASE1	RECRUITING	Patients With Congenital Myasthenic Syndrome Will be Treated With Mesenchymal Stem Cell Exosome Solution
NCT00494195	PHASE1	COMPLETED	Gene Transfer Therapy for Treating Children and Adults With Limb Girdle Muscular Dystrophy Type 2D (LGMD2D)
NCT00674843	PHASE1	UNKNOWN	The Efficacy of Using Far Infrared Radiation to Manage Muscular Dystrophies
NCT00873782	PHASE1	COMPLETED	Safety Study of Transvenous Limb Perfusion in Human Muscular Dystrophy
NCT01128855	PHASE1	COMPLETED	A Double-blind, Escalating Dose, Randomized, Placebo-controlled Study Assessing PK, Safety, Tolerability in Non-ambulant DMD Subjects
NCT02241928	PHASE1	WITHDRAWN	Stem Cell Therapy in Muscular Dystrophy
NCT03627494	PHASE1	COMPLETED	First Time in Human (FTIH) Study to Evaluate the Safety, Pharmacokinetics, and Pharmacodynamics of Single and Repeat Doses of GSK3439171A in Healthy Subjects and to Assess Food Effect
NCT05492734	PHASE1	COMPLETED	A Study to Assess the Feasibility of Non-invasive Dried Blood Sampling
NCT05730842	PHASE1	COMPLETED	Absorption, Metabolism, Excretion and Absolute Bioavailability of EDG-5506 in Healthy Volunteers
NCT01344798	PHASE1	COMPLETED	Clinical Study of AAV1-gamma-sarcoglycan Gene Therapy for Limb Girdle Muscular Dystrophy Type 2C
NCT02050776	PHASE1	WITHDRAWN	Stem Cell Therapy in Limb Girdle Muscular Dystrophy
NCT02245711	PHASE1	WITHDRAWN	Cell Therapy in Limb Girdle Muscular Dystrophy
NCT05876780	PHASE1	ACTIVE_NOT_RECRUITING	A Gene Transfer Single Dose Study to Evaluate the Safety, Tolerability and Efficacy of SRP-9003 in Non-Ambulatory and Ambulatory Participants With Limb Girdle Muscular Dystrophy, Type 2E/R4 (Beta-Sarcoglycan [β-SG] Deficiency)
NCT05906251	PHASE1	TERMINATED	A Gene Transfer Study to Evaluate the Safety, Tolerability and Efficacy of SRP-6004 in Ambulatory Participants With Limb Girdle Muscular Dystrophy, Type 2B/R2 (LGMD2B/R2, Dysferlin [DYSF] Related)
NCT06747273	PHASE1	TERMINATED	Study to Evaluate the Safety, Tolerability, and Efficacy of SRP-9004 Administered by Systemic Infusion in Limb Girdle Muscular Dystrophy Type 2D/R3 Participants in the United States