CSGALNACT1
protein-codingchondroitin sulfate N-acetylgalactosaminyltransferase 1, the group of Beta 4-glycosyltransferases
Gene summary
This gene encodes an enzyme that transfers N-acetylglucosamine (GalNAc) to the core tetrasaccharide linker and to elongating chondroitin sulfate chains in proteoglycans. Knockout of the orthologous mouse gene indicates that the protein is necessary for normal cartilage development and aggrecan metabolism. Mutations in this gene are associated with multiple sclerosis progression, and with mild skeletal dysplasia and joint laxity. [provided by RefSeq, Aug 2017]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~353.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0030029
Submitter: ClinGen
CSGALNACT1 was first reported in relation to autosomal recessive mild skeletal dysplasia with joint laxity and advanced bone age (SDJLABA) in 2017 (Vodopiutz et al., PMID:27599773). CSGALNACT1 is a highly conserved gene mapped to chromosome 8p21. It encodes chondroitin sulfate N-acetylgalactosaminyltransferase 1 (CSGalNAct-1) and plays a major role in the chondroitin sulfate chain biosynthesis and therefore in the synthesis of glycosaminoglycans. Persons with this condition typically present with mild skeletal dysplasia, advanced bone age, non-proportional short stature, hyperlordosis, pes planus, and joint laxity (PMIDs: 27599773, PMID:31325655, 31705726). Six variants (including missense, frameshift, and intragenic deletions) reported in 4 probands in 3 publications are included in this curation [PMIDs: 27599773, 31325655, 31705726]. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is supported by functional evidence, including significantly reduced CSGalNAct-1 activity in vitro (PMIDs: 27599773, 31705726). Further evidence comes from the observed skeletal dysplasia reminiscent of CSGALNACT1-/- mice (Watanabe et al., PMIDs:20812917, 31705726). The most recent report suggests the term CSGALNACT1-CDG (PMID: 31705726). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on the meeting date June 5, 2025 (SOP Version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0030029
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0030029
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CSGALNACT1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001354483.2. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 85 | 4 | 90 | ||
| missense | 3 | 181 | 15 | 4 | 203 | |
| nonsense | 3 | 2 | 3 | 8 | ||
| start loss | 0 | |||||
| frameshift | 8 | 1 | 1 | 10 | ||
| splice donor/acceptor (+/-2bp) | 1 | 4 | 5 | |||
| Total | 11 | 6 | 190 | 101 | 8 | 316 |
Highest pathogenic variant AF is 0.000091686285
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001341412.1 | 7 | MANE Select | |
| Ensembl | ENSP00000509853.1 | 7 | MANE Select | |
| RefSeq | NP_001123990.1 | 7 | Standard | |
| RefSeq | NP_001341404.1 | 7 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Glycosaminoglycan biosynthesis - chondroitin sulfate / dermatan sulfate - Homo sapiens (human)
- Metabolism of carbohydrates
- Chondroitin sulfate biosynthesis
- Chondroitin sulfate/dermatan sulfate metabolism
- Glycosaminoglycan metabolism
Biological Process
- endochondral ossification
- nervous system development
- cell recognition
- cell population proliferation
- anatomical structure morphogenesis
Molecular Function
- acetylgalactosaminyltransferase activity
- peptidoglycan glycosyltransferase activity
- glucuronosyltransferase activity
- metal ion binding
- glucuronylgalactosylproteoglycan 4-beta-N-acetylgalactosaminyltransferase activity
Cellular Component
- Golgi membrane
- integral component of Golgi membrane
- Golgi cisterna membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000454498
- Coding exons
- 7
- Length
- 353869
- Individuals with no LoFs
- 125687
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 60
- Defined
- 125748
- p
- 0.000243
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -2.63 | 425 | 297 | 1.43 | 0.0000184 | 3527 |
| Missense (PolyPhen) | 180 | 136.35 | 1.3202 | 1632 | ||
| Synonymous | -4.14 | 173 | 116 | 1.49 | 0.00000739 | 1001 |
| Loss of Function | 0.312 | 21 | 22.6 | 0.929 | 0.00000123 | 257 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00018 | 0.00018 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00071 | 0.00071 | rare |
| Finnish | 0.00014 | 0.00014 | rare |
| European (Non-Finnish) | 0.00026 | 0.00025 | rare |
| South Asian | 0.00036 | 0.00033 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transfers 1,4-N-acetylgalactosamine (GalNAc) from UDP- GalNAc to the non-reducing end of glucuronic acid (GlcUA). Required for addition of the first GalNAc to the core tetrasaccharide linker and for elongation of chondroitin chains. Important role in chondroitin chain biosynthesis in cartilage formation and subsequent endochondral ossification (PubMed:11788602, PubMed:12163485, PubMed:12446672, PubMed:17145758). Moreover, is involved in the metabolism of aggrecan (By similarity). {ECO:0000250|UniProtKB:Q8BJQ9, ECO:0000269|PubMed:11788602, ECO:0000269|PubMed:12163485, ECO:0000269|PubMed:12446672, ECO:0000269|PubMed:17145758, ECO:0000269|PubMed:21160489, ECO:0000269|PubMed:27599773}.;
Recessive Scores
- pRec
- 0.115
Intolerance Scores
- LoFtool
- 0.799
- RVIS EVS
- -0.1
- RVIS percentile EVS
- 45.65
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.425
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |