GeneBe

ACAN

protein-coding

aggrecan, the group of V-set domain containing|Sushi domain containing|Hyalectan proteoglycans|C-type lectin domain containing

Gene summary

This gene is a member of the aggrecan/versican proteoglycan family. The encoded protein is an integral part of the extracellular matrix in cartilagenous tissue and it withstands compression in cartilage. Mutations in this gene may be involved in skeletal dysplasia and spinal degeneration. Multiple alternatively spliced transcript variants that encode different protein isoforms have been observed in this gene. [provided by RefSeq, Jul 2008]

Previous symbols:
  • MSK16
  • CSPG1
  • AGC1

MANE transcript

NM_001369268.1

Inheritance

AR, AD

ClinVar variants

P:238U:935B:399

Top phenotype

Spondyloepimetaphyseal dysplasia, aggrecan type; Spondyloepiphyseal dysplasia, Kimberley type; Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans

gnomAD constraint

pLI —, LoF o/e 0.1

Max pathogenic AF

—

Genomic locus

chr15:88,803,436-88,875,353

External References & Databases

Ensembl (ENSG00000157766)NCBI Gene (176)OMIM (155760)HGNC:319GenCCUniProt (P16112)AlphaFoldClinVar (ACAN)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~71.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spondyloepimetaphyseal dysplasia, aggrecan typeLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013014

Submitter: Ambry Genetics

spondyloepimetaphyseal dysplasia, aggrecan typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013014

Submitter: Labcorp Genetics (formerly Invitae)

spondyloepiphyseal dysplasia, Kimberley typeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012019

Submitter: G2P

osteochondritis dissecansDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017178

Submitter: Illumina

spondyloepimetaphyseal dysplasia, aggrecan typeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013014

Submitter: G2P

short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecansDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100462

Submitter: Ambry Genetics

spondyloepiphyseal dysplasia, Kimberley typeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0012019

Submitter: Ambry Genetics

ACAN-related short stature spectrumDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:1060149

Submitter: ClinGen

*ACAN* was first reported in relation to autosomal semidominant *ACAN*-related short stature spectrum in 2005 (Gleghorn et al., PMID: 16080123). *ACAN*-related short stature spectrum is characterized by short stature with or without advanced bone age, and osteochondritis dissecans. Spondyloepiphyseal dysplasia, Kimberley type (SEDK) may be present in the case of heterozygous alleles. In the case of compound heterozygous or homozygous alleles, spondyloepimetaphyseal dysplasia, aggrecan type will be present. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism. Therefore, the following disease entities have been lumped into one disease entity, SEDK (OMIM:608361), short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans (OMIM:165800), and spondyloepimetaphyseal dysplasia, aggrecan type (OMIM:612813). Twelve variants (missense, nonsense, and frameshift) that have been reported in eleven probands in seven publications (PMIDs: 16080123, 19110214, 24762113, 25741789, 29464738, 30124491, 35620465) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by expression studies, biochemical function, and animal models (PMIDs: 7524681, 23019016, 9192671). *ACAN* is expressed in chondrocytes and critical to the developing skeleton and cartilage function (PMIDs: 7524681, 23019016). Additionally, heterozygous and homozygous *ACAN* defective mice were observed to have severe short stature in addition to other radiographic abnormalities. Similarly, a chicken with nanomelia has been described with homozygous nonsense variants in aggrecan (PMID:7827752). In summary, there is definitive evidence supporting the relationship between *ACAN* and autosomal semidominant *ACAN*-related short stature spectrum. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date May 7, 2025 (SOP Version 11).

spondyloepimetaphyseal dysplasia, aggrecan typeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013014

Submitter: PanelApp Australia

short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecansSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100462

Submitter: PanelApp Australia

spondyloepiphyseal dysplasia, Kimberley typeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0012019

Submitter: Orphanet

spondyloepimetaphyseal dysplasia, aggrecan typeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013014

Submitter: Orphanet

spondyloepiphyseal dysplasia, Kimberley typeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0012019

Submitter: Labcorp Genetics (formerly Invitae)

short stature-advanced bone age-early-onset osteoarthritis syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018566

Submitter: Orphanet

osteochondritis dissecansSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0017178

Submitter: Orphanet

Clinical Genomic Database (CGD)

Spondyloepimetaphyseal dysplasia, aggrecan type; Spondyloepiphyseal dysplasia, Kimberley type; Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecansAD

Manifestation: Craniofacial; Endocrine; Musculoskeletal

Intervention: Endocrine

Rationale: Individuals have been described as benefiting from growth hormone treatment

Refs: 14353963; 14216462; 7331787; 3968094; 1978986; 16080123; 18226555; 19110214; 20137779; 27710243; 28331218; 30124491Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ACAN variants in ClinVar

21 Conditions Cataloged
not providedTotal: 1212
Inborn genetic diseasesTotal: 446
not specifiedTotal: 242
Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecansTotal: 113
ACAN-related disorderTotal: 87
Spondyloepimetaphyseal dysplasia, aggrecan typeTotal: 58
Spondyloepiphyseal dysplasia, Kimberley typeTotal: 50
Osteochondritis dissecansTotal: 38

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001369268.1. 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.

EffectPLPVUSLBBSum
synonymous
20
clinvar
283
clinvar
20
clinvar
 323
missense
5
clinvar
13
clinvar
907
clinvar
87
clinvar
9
clinvar
 1021
nonsense
53
clinvar
27
clinvar
2
clinvar
 82
start loss
1
clinvar
1
clinvar
 2
frameshift
69
clinvar
47
clinvar
3
clinvar
 119
splice donor/acceptor (+/-2bp)
4
clinvar
19
clinvar
2
clinvar
 25
Total131107935370291572

Highest pathogenic variant AF is 0.00028159248

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 22 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001369268.1RefSeqNP_001356197.118MANE Select
ENST00000560601.4EnsemblENSP00000453581.218MANE Select
NM_001135.4RefSeqNP_001126.315Standard
NM_001411096.1RefSeqNP_001398025.116Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
acanaDanio rerio

Structure: atrium

Quality: increased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Spinal Cord Injury
  • Endochondral Ossification
  • Metabolism of carbohydrates
  • Keratan sulfate biosynthesis
  • Keratan sulfate/keratin metabolism

Biological Process

  • skeletal system development
  • cartilage condensation
  • chondrocyte development
  • proteolysis
  • cell adhesion

Molecular Function

  • extracellular matrix structural constituent
  • protein binding
  • hyaluronic acid binding
  • extracellular matrix structural constituent conferring compression resistance
  • carbohydrate binding

Cellular Component

  • extracellular region
  • basement membrane
  • Golgi lumen
  • extracellular matrix
  • lysosomal lumen

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000439576
Coding exons
17
Length
71912
Individuals with no LoFs
124951
Homozygous LoFs
0
Heterozygous LoFs
13
Defined
124964
p
0.0000520
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.20711971.22e+30.9830.000071715847
Missense (PolyPhen)323330.930.976054398
Synonymous0.2944985060.9830.00003255615
Loss of Function7.08771.70.09760.00000354981

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000190.00019rare
Latino/Admixed American00.0absent
Ashkenazi Jewish0.0000990.000099rare
East Asian0.000220.00017rare
Finnish00.0absent
European (Non-Finnish)0.0000350.000035rare
South Asian0.0000650.000065rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: This proteoglycan is a major component of extracellular matrix of cartilagenous tissues. A major function of this protein is to resist compression in cartilage. It binds avidly to hyaluronic acid via an N-terminal globular region.;
Disease
DISEASE: Spondyloepiphyseal dysplasia type Kimberley (SEDK) [MIM:608361]: Spondyloepiphyseal dysplasias are a heterogeneous group of congenital chondrodysplasias that specifically affect epiphyses and vertebrae. The autosomal dominant SEDK is associated with premature degenerative arthropathy. {ECO:0000269|PubMed:16080123}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spondyloepimetaphyseal dysplasia, aggrecan type (SEMDAG) [MIM:612813]: A bone disease characterized by severe short stature, macrocephaly, severe midface hypoplasia, short neck, barrel chest and brachydactyly. The radiological findings comprise long bones with generalized irregular epiphyses with widened metaphyses, especially at the knees, platyspondyly, and multiple cervical-vertebral clefts. {ECO:0000269|PubMed:19110214}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans (SSOAOD) [MIM:165800]: An autosomal dominant disease characterized by short stature, advanced bone maturation, early-onset osteoarthritis, and mild dysmorphic features consisting of midface hypoplasia, brachydactyly, broad great toes, and lumbar lordosis. Other features include intervertebral disk disease and osteochondritis dissecans. Osteochondritis dissecans is defined as a separation of cartilage and subchondral bone from the surrounding tissue. {ECO:0000269|PubMed:20137779}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.570

Intolerance Scores

LoFtool
0.0378
RVIS EVS
1.28
RVIS percentile EVS
93.77

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.555

Gene Damage Prediction

AllRecessiveDominant
MendelianHighHighHigh
Primary ImmunodeficiencyHighHighHigh
CancerHighHighHigh
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