limb-girdle muscular dystrophy due to POMK deficiency

Summary

limb-girdle muscular dystrophy due to POMK deficiency (MONDO:0014489) is a disease with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 4
• ClinVar variants: 244

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	limb-girdle muscular dystrophy due to POMK deficiency
Mondo ID	MONDO:0014489
OMIM	616094
Orphanet	445110
DOID	DOID:0112381
UMLS	C4015184
MedGen	863621
GARD	0017769
Is cancer (heuristic)	no

Also known as: LGMD due to POMK deficiency · MDDGC12 · muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 12

Data availability: 244 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › congenital muscular dystrophy › muscular dystrophy-dystroglycanopathy › muscular dystrophy-dystroglycanopathy, type C › limb-girdle muscular dystrophy due to POMK deficiency

Related subtypes (8): autosomal recessive limb-girdle muscular dystrophy type 2K, autosomal recessive limb-girdle muscular dystrophy type 2M, autosomal recessive limb-girdle muscular dystrophy type 2O, autosomal recessive limb-girdle muscular dystrophy type 2N, autosomal recessive limb-girdle muscular dystrophy type 2P, autosomal recessive limb-girdle muscular dystrophy type 2T, autosomal recessive limb-girdle muscular dystrophy type 2U, muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 8

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

244 retrieved; paginated sample, class counts are floors:

117 uncertain significance, 80 likely benign, 19 pathogenic, 14 conflicting classifications of pathogenicity, 6 benign/likely benign, 5 pathogenic/likely pathogenic, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071646	NM_032237.5(POMK):c.152del (p.Asp51fs)	POMK	Pathogenic	criteria provided, single submitter
1076046	NM_032237.5(POMK):c.43C>T (p.Arg15Ter)	POMK	Pathogenic	criteria provided, multiple submitters, no conflicts
1323591	NM_032237.5(POMK):c.907C>T (p.Arg303Ter)	POMK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
133346	NM_032237.5(POMK):c.325C>T (p.Gln109Ter)	POMK	Pathogenic	criteria provided, single submitter
1339764	NM_032237.5(POMK):c.386_387del (p.Leu129fs)	POMK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451698	NM_032237.5(POMK):c.452_455dup (p.His152fs)	POMK	Pathogenic	criteria provided, single submitter
1911792	NM_032237.5(POMK):c.754dup (p.Asp252fs)	POMK	Pathogenic	criteria provided, single submitter
2002655	NM_032237.5(POMK):c.280A>T (p.Arg94Ter)	POMK	Pathogenic	criteria provided, single submitter
2158045	NM_032237.5(POMK):c.94_98del (p.Thr32fs)	POMK	Pathogenic	criteria provided, single submitter
2165161	NM_032237.5(POMK):c.247C>T (p.Gln83Ter)	POMK	Pathogenic	criteria provided, single submitter
2634888	NM_032237.5(POMK):c.398_399del (p.His133fs)	POMK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2926947	NM_032237.5(POMK):c.459del (p.Pro153_Leu154insTer)	POMK	Pathogenic	criteria provided, single submitter
2932937	NM_032237.5(POMK):c.724dup (p.Val242fs)	POMK	Pathogenic	criteria provided, single submitter
2945834	NM_032237.5(POMK):c.847del (p.Trp283fs)	POMK	Pathogenic	criteria provided, single submitter
2951325	NM_032237.5(POMK):c.645T>G (p.Tyr215Ter)	POMK	Pathogenic	criteria provided, single submitter
3752434	NM_032237.5(POMK):c.61del (p.Val21fs)	POMK	Pathogenic	criteria provided, single submitter
3760619	NM_032237.5(POMK):c.91_98dup (p.Leu34fs)	POMK	Pathogenic	criteria provided, single submitter
4791932	NM_032237.5(POMK):c.43del (p.Arg15fs)	POMK	Pathogenic	criteria provided, single submitter
582702	NM_032237.5(POMK):c.238_239del (p.Glu80fs)	POMK	Pathogenic	criteria provided, single submitter
651249	NC_000008.11:g.(?43103539)(43103840_?)del	POMK	Pathogenic	criteria provided, single submitter
817678	NM_032237.5(POMK):c.43dup (p.Arg15fs)	POMK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
849427	NM_032237.5(POMK):c.10C>T (p.Gln4Ter)	POMK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
949777	NM_032237.5(POMK):c.282+1G>C	POMK	Pathogenic	criteria provided, single submitter
95452	NM_001077365.2(POMT1):c.1087C>T (p.Gln363Ter)	POMT1	Pathogenic	criteria provided, multiple submitters, no conflicts
1312144	NM_032237.5(POMK):c.256C>T (p.Arg86Cys)	POMK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
160349	NM_032237.5(POMK):c.905T>A (p.Val302Asp)	POMK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2683017	NM_032237.5(POMK):c.803del (p.Phe268fs)	POMK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
432418	NM_032237.5(POMK):c.20A>G (p.Asn7Ser)	POMK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
436700	NM_032237.5(POMK):c.565A>G (p.Ile189Val)	POMK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
436703	NM_032237.5(POMK):c.373A>T (p.Met125Leu)	POMK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
POMK	Definitive	Autosomal recessive	muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type a, 12	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
POMK	Orphanet:370959	Congenital muscular dystrophy with cerebellar involvement
POMK	Orphanet:445110	Limb-girdle muscular dystrophy due to POMK deficiency
POMK	Orphanet:899	Walker-Warburg syndrome
HGSNAT	Orphanet:791	Retinitis pigmentosa
HGSNAT	Orphanet:79271	Sanfilippo syndrome type C
POMT1	Orphanet:370959	Congenital muscular dystrophy with cerebellar involvement
POMT1	Orphanet:370968	Congenital muscular dystrophy with intellectual disability
POMT1	Orphanet:370980	Congenital muscular dystrophy without intellectual disability
POMT1	Orphanet:588	Muscle-eye-brain disease
POMT1	Orphanet:86812	POMT1-related limb-girdle muscular dystrophy R11
POMT1	Orphanet:899	Walker-Warburg syndrome

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
POMK	HGNC:26267	ENSG00000185900	Q9H5K3	Protein O-mannose kinase	gencc,clinvar
HGSNAT	HGNC:26527	ENSG00000165102	Q68CP4	Heparan-alpha-glucosaminide N-acetyltransferase	clinvar
FNTA	HGNC:3782	ENSG00000168522	P49354	Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha	clinvar
POMT1	HGNC:9202	ENSG00000130714	Q9Y6A1	Protein O-mannosyl-transferase 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
POMK	Protein O-mannose kinase	Protein O-mannose kinase that specifically mediates phosphorylation at the 6-position of an O-mannose of the trisaccharide (N-acetylgalactosamine (GalNAc)-beta-1,3-N-acetylglucosamine (GlcNAc)-beta-1,4-mannose) to generate phosphorylated O…
HGSNAT	Heparan-alpha-glucosaminide N-acetyltransferase	Lysosomal acetyltransferase that acetylates the non-reducing terminal alpha-glucosamine residue of intralysosomal heparin or heparan sulfate, converting it into a substrate for luminal alpha-N-acetyl glucosaminidase.
FNTA	Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha	Essential subunit of both the farnesyltransferase and the geranylgeranyltransferase complex.
POMT1	Protein O-mannosyl-transferase 1	Transfers mannosyl residues to the hydroxyl group of serine or threonine residues.

Protein-family classification

Druggable: 4 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	3	9.0×	0.004
Kinase	1	6.9×	0.137

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
POMK	Kinase	yes	2.7.1.183	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Kinase-like_dom_sf
HGSNAT	Enzyme (other)	yes	2.3.1.78	HGSNAT_cat
FNTA	Enzyme (other)	yes	2.5.1.58	Prenyl_trans_a
POMT1	Enzyme (other)	yes	2.4.1.109	ArnT-like_N, MIR_motif, PMT-like

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 10	1
middle temporal gyrus	1
paraflocculus	1
cervix squamous epithelium	1
mucosa of stomach	1
right uterine tube	1
esophagus squamous epithelium	1
gingival epithelium	1
olfactory bulb	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
POMK	289	ubiquitous	yes	paraflocculus, middle temporal gyrus, Brodmann (1909) area 10
HGSNAT	287	ubiquitous	marker	mucosa of stomach, right uterine tube, cervix squamous epithelium
FNTA	298	ubiquitous	marker	esophagus squamous epithelium, gingival epithelium, olfactory bulb
POMT1	264	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
POMT1	1,475
POMK	1,251
FNTA	1,080
HGSNAT	863

Intra-cohort edges

A	B	Sources
FNTA	HGSNAT	string_interaction
FNTA	POMK	string_interaction
HGSNAT	POMK	string_interaction
POMK	POMT1	biogrid_interaction, string_interaction

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FNTA	P49354	14
HGSNAT	Q68CP4	12

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
POMK	Q9H5K3	91.62
POMT1	Q9Y6A1	88.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 4 evidence-associated genes (4 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
DAG1 core M3 glycosylations	2	951.7×	2e-05	POMK, POMT1
MPS IIIC - Sanfilippo syndrome C	1	2855.0×	0.003	HGSNAT
Defective POMT2 causes MDDGA2, MDDGB2 and MDDGC2	1	951.7×	0.004	POMT1
Defective POMT1 causes MDDGA1, MDDGB1 and MDDGC1	1	951.7×	0.004	POMT1
DAG1 core M1 glycosylations	1	713.8×	0.005	POMT1
DAG1 core M2 glycosylations	1	571.0×	0.005	POMT1
GBP-mediated host defense	1	259.6×	0.009	FNTA
HS-GAG degradation	1	124.1×	0.014	HGSNAT
Apoptotic cleavage of cellular proteins	1	119.0×	0.014	FNTA
RAS processing	1	119.0×	0.014	FNTA
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	1	84.0×	0.018	POMT1
Inactivation, recovery and regulation of the phototransduction cascade	1	79.3×	0.018	FNTA
O-linked glycosylation	1	36.1×	0.036	POMK
Potential therapeutics for SARS	1	28.6×	0.042	FNTA
Neutrophil degranulation	1	5.8×	0.184	HGSNAT
Post-translational protein modification	1	4.8×	0.205	POMK
Metabolism of proteins	1	3.1×	0.286	POMK

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein O-linked glycosylation	2	112.3×	0.002	POMK, POMT1
peptide pheromone maturation	1	4213.0×	0.002	FNTA
protein farnesylation	1	1404.3×	0.005	FNTA
protein geranylgeranylation	1	702.2×	0.005	FNTA
regulation of microtubule-based movement	1	702.2×	0.005	FNTA
carbohydrate phosphorylation	1	526.6×	0.005	POMK
heparan sulfate proteoglycan catabolic process	1	468.1×	0.005	HGSNAT
skeletal muscle acetylcholine-gated channel clustering	1	468.1×	0.005	FNTA
positive regulation of skeletal muscle acetylcholine-gated channel clustering	1	468.1×	0.005	FNTA
protein O-linked glycosylation via mannose	1	234.1×	0.009	POMT1
lysosomal transport	1	175.5×	0.009	HGSNAT
protein complex oligomerization	1	168.5×	0.009	HGSNAT
positive regulation of Rac protein signal transduction	1	162.0×	0.009	FNTA
Rac protein signal transduction	1	140.4×	0.010	FNTA
neuromuscular process	1	131.7×	0.010	POMK
sensory perception of pain	1	93.6×	0.013	POMK
learning or memory	1	60.2×	0.019	POMK
transforming growth factor beta receptor signaling pathway	1	39.8×	0.028	FNTA
extracellular matrix organization	1	30.5×	0.034	POMT1
brain development	1	19.9×	0.049	POMK

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 3

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
FNTA	CORTISONE ACETATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FNTA	6	4
POMK	0	0
HGSNAT	0	0
POMT1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CORTISONE ACETATE	4	FNTA
LONAFARNIB	4	FNTA
TIPIFARNIB	3	FNTA
L-778123 FREE BASE	1	FNTA
GGTI-2418	1	FNTA
BMS-214662	1	FNTA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
FNTA	513	Binding:438, Functional:75

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
POMK	2.7.1.183	glycoprotein-mannosyl O6-kinase
HGSNAT	2.3.1.78	heparan-alpha-glucosaminide N-acetyltransferase
FNTA	2.5.1.58, 2.5.1.59	protein farnesyltransferase, protein geranylgeranyltransferase type I
POMT1	2.4.1.109	dolichyl-phosphate-mannose-protein mannosyltransferase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
FNTA	513

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

6 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
CORTISONE ACETATE	4	FNTA
LONAFARNIB	4	FNTA
TIPIFARNIB	3	FNTA
L-778123 FREE BASE	1	FNTA
GGTI-2418	1	FNTA
BMS-214662	1	FNTA

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	FNTA
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	HGSNAT
D	Druggable family + AlphaFold only, no drug	2	POMK, POMT1
E	Difficult family or no structure, no drug	0

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
POMK	0	—
HGSNAT	0	—
POMT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.