Sarcoglycanopathy

Summary

Sarcoglycanopathy (MONDO:0016140) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 81

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	sarcoglycanopathy
Mondo ID	MONDO:0016140
MeSH	D058088
Orphanet	207052
UMLS	C2936331
MedGen	424705
GARD	0020389
Is cancer (heuristic)	no

Also known as: qualitative or quantitative defects of sarcoglycan

Data availability: 81 ClinVar variants.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › qualitative or quantitative protein defects in neuromuscular diseases › sarcoglycanopathy

Related subtypes (18): neuromuscular disease caused by qualitative or quantitative defects of dysferlin, caveolinopathy, neuromuscular disease caused by qualitative or quantitative defects of dystrophin, neuromuscular disease caused by qualitative or quantitative defects of perlecan, neuromuscular disease caused by qualitative or quantitative defects of TRIM32, neuromuscular disease caused by qualitative or quantitative defects of myofibrillar proteins, neuromuscular disease caused by qualitative or quantitative defects of titin, neuromuscular disease caused by qualitative or quantitative defects of telethonin, neuromuscular disease caused by qualitative or quantitative defects of alpha-actin, neuromuscular disease caused by qualitative or quantitative defects of nebulin, neuromuscular disease caused by qualitative or quantitative defects of beta-myosin heavy chain (MYH7), neuromuscular disease caused by qualitative or quantitative defects of selenoprotein N1, neuromuscular disease caused by qualitative or quantitative defects of plectin, neuromuscular disease caused by qualitative or quantitative defects of protein SERCA1, neuromuscular disease caused by qualitative or quantitative defects of tropomyosin, neuromuscular disease caused by qualitative or quantitative defects of alpha-dystroglycan, alpha-actinopathy, collagen 6-related myopathy

Subtypes (4): qualitative or quantitative defects of alpha-sarcoglycan, qualitative or quantitative defects of beta-sarcoglycan, qualitative or quantitative defects of gamma-sarcoglycan, qualitative or quantitative defects of delta-sarcoglycan

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

81 retrieved; paginated sample, class counts are floors:

27 uncertain significance, 22 conflicting classifications of pathogenicity, 16 benign, 9 benign/likely benign, 4 likely benign, 2 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
167677	NM_000023.4(SGCA):c.739G>A (p.Val247Met)	SGCA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9437	NM_000023.4(SGCA):c.229C>T (p.Arg77Cys)	SGCA	Pathogenic	reviewed by expert panel
9439	NM_000023.4(SGCA):c.850C>T (p.Arg284Cys)	SGCA	Pathogenic	reviewed by expert panel
197618	NM_000023.4(SGCA):c.421C>A (p.Arg141Ser)	SGCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
198032	NM_000023.4(SGCA):c.690G>C (p.Leu230=)	SGCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
198033	NM_000023.4(SGCA):c.680C>G (p.Pro227Arg)	SGCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
254721	NM_000023.4(SGCA):c.662G>A (p.Arg221His)	SGCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
283448	NM_000023.4(SGCA):c.80C>T (p.Thr27Met)	SGCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
284685	NM_000023.4(SGCA):c.307A>G (p.Ile103Val)	SGCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285931	NM_000023.4(SGCA):c.764C>T (p.Pro255Leu)	SGCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
289773	NM_000023.4(SGCA):c.555C>A (p.Val185=)	SGCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
290709	NM_000023.4(SGCA):c.657C>T (p.His219=)	SGCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
324037	NM_000023.4(SGCA):c.-31T>C	SGCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
324041	NM_000023.4(SGCA):c.158-11G>A	SGCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
324042	NM_000023.4(SGCA):c.158-10C>G	SGCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
324043	NM_000023.4(SGCA):c.648C>T (p.Pro216=)	SGCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
324044	NM_000023.4(SGCA):c.690G>A (p.Leu230=)	SGCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
747657	NM_000023.4(SGCA):c.956+7G>A	SGCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
891266	NM_000023.4(SGCA):c.958C>T (p.Leu320=)	SGCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
92303	NM_000023.4(SGCA):c.328C>T (p.Arg110Trp)	SGCA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
285833	NM_000231.3(SGCG):c.832G>A (p.Gly278Ser)	SGCG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
510270	NM_000231.3(SGCG):c.505+15G>A	SGCG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
691731	NM_000231.3(SGCG):c.371G>T (p.Gly124Val)	SGCG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
706196	NM_000231.3(SGCG):c.615C>A (p.Ala205=)	SGCG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
881418	NM_000231.3(SGCG):c.259T>C (p.Leu87=)	SGCG	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
282511	NM_000023.4(SGCA):c.929A>G (p.Tyr310Cys)	SGCA	Uncertain significance	criteria provided, multiple submitters, no conflicts
324038	NM_000023.4(SGCA):c.-28C>T	SGCA	Uncertain significance	criteria provided, single submitter
324039	NM_000023.4(SGCA):c.-18G>A	SGCA	Uncertain significance	criteria provided, multiple submitters, no conflicts
324040	NM_000023.4(SGCA):c.-5C>G	SGCA	Uncertain significance	criteria provided, multiple submitters, no conflicts
324045	NM_000023.4(SGCA):c.1063C>T (p.Arg355Trp)	SGCA	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SACS	Orphanet:98	Autosomal recessive spastic ataxia of Charlevoix-Saguenay
SGCA	Orphanet:62	Alpha-sarcoglycan-related limb-girdle muscular dystrophy R3
SGCG	Orphanet:353	Gamma-sarcoglycan-related limb-girdle muscular dystrophy R5

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SACS	HGNC:10519	ENSG00000151835	Q9NZJ4	Sacsin	clinvar
SGCA	HGNC:10805	ENSG00000108823	Q16586	Alpha-sarcoglycan	clinvar
SGCG	HGNC:10809	ENSG00000102683	Q13326	Gamma-sarcoglycan	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SACS	Sacsin	Co-chaperone which acts as a regulator of the Hsp70 chaperone machinery and may be involved in the processing of other ataxia-linked proteins.
SGCA	Alpha-sarcoglycan	Component of the sarcoglycan complex, a subcomplex of the dystrophin-glycoprotein complex which forms a link between the F-actin cytoskeleton and the extracellular matrix.
SGCG	Gamma-sarcoglycan	Component of the sarcoglycan complex, a subcomplex of the dystrophin-glycoprotein complex which forms a link between the F-actin cytoskeleton and the extracellular matrix.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SACS	Other/Unknown	no		Ubiquitin-like_dom, DnaJ_domain, HEPN_dom
SGCA	Other/Unknown	no		Cadg, Sarcoglycan_alpha/epsilon, Cadherin-like_sf
SGCG	Other/Unknown	no		Sarcoglycan, Sarcoglycan_gamma/delta/zeta

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
frontal pole	1
middle frontal gyrus	1
apex of heart	1
gastrocnemius	1
hindlimb stylopod muscle	1
gluteal muscle	1
skeletal muscle tissue of rectus abdominis	1
triceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SACS	286	ubiquitous	marker	Brodmann (1909) area 23, middle frontal gyrus, frontal pole
SGCA	190	broad	marker	hindlimb stylopod muscle, gastrocnemius, apex of heart
SGCG	184	broad	marker	skeletal muscle tissue of rectus abdominis, gluteal muscle, triceps brachii

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SACS	1,441
SGCA	1,132
SGCG	923

Intra-cohort edges

A	B	Sources
SACS	SGCG	string_interaction
SGCA	SGCG	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SACS	Q9NZJ4	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SGCG	Q13326	80.24
SGCA	Q16586	80.15

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of the dystrophin-glycoprotein complex (DGC)	2	308.6×	3e-05	SGCA, SGCG
Non-integrin membrane-ECM interactions	2	154.3×	6e-05	SGCA, SGCG
Extracellular matrix organization	2	63.1×	2e-04	SGCA, SGCG

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
muscle organ development	2	111.2×	7e-04	SGCA, SGCG
negative regulation of inclusion body assembly	1	561.7×	0.006	SACS
cardiac muscle tissue development	1	295.6×	0.007	SGCG
heart contraction	1	255.3×	0.007	SGCG
muscle contraction	1	69.3×	0.020	SGCA
protein folding	1	34.5×	0.034	SACS
gene expression	1	26.6×	0.037	SGCG

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SACS	0	0
SGCA	0	0
SGCG	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	SACS, SGCA, SGCG

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)
SACS	0	—
SGCA	0	—
SGCG	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.