ACAN

Chr 15ADAR

aggrecan

Also known as: AGC1, AGCAN, CSPG1, CSPGCP, MSK16, SEDK, SSOAOD

NCBI Gene: 176ENSG00000157766UniProt: P16112

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]

Primary Disease Associations & Inheritance

?Spondyloepiphyseal dysplasia, Kimberley typeMIM #608361
AD
Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecansMIM #165800
AD
Spondyloepimetaphyseal dysplasia, aggrecan typeMIM #612813
AR
1724
ClinVar variants
47
Pathogenic / LP
1.00
pLI score· haploinsufficient
3
Active trials
Clinical Summary— ACAN
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
47 Pathogenic / Likely Pathogenic· 251 VUS of 1724 total submissions
💊
Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.18LOEUF
pLI 1.000
Z-score 7.08
OE 0.10 (0.05–0.18)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.21Z-score
OE missense 0.98 (0.94–1.03)
1197 obs / 1217.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.10 (0.05–0.18)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.98 (0.94–1.03)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.98
0≤1.21.6
LoF obs/exp: 7 / 71.7Missense obs/exp: 1197 / 1217.3Syn Z: 0.29

ClinVar Variant Classifications

1724 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic35
Likely Pathogenic12
VUS251
Likely Benign84
Benign2
35
Pathogenic
12
Likely Pathogenic
251
VUS
84
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
25
0
10
0
35
Likely Pathogenic
9
0
3
0
12
VUS
1
233
15
2
251
Likely Benign
0
4
25
55
84
Benign
0
0
1
1
2
Total352375458384

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ACAN · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

ACAN-related spondyloepimetaphyseal dysplasia, aggrecan type

definitive
ARUndeterminedAltered Gene Product Structure
Dev. DisordersSkeletal
G2P ↗
missense variantinframe deletioninframe insertion

ACAN-related spondyloepiphyseal dysplasia

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersSkeletal
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
AGGRECAN; ACAN
MIM #155760 · *

?Spondyloepiphyseal dysplasia, Kimberley type

MIM #608361

Molecular basis of disorder known

Autosomal dominant

Short stature and advanced bone age, with or without early-onset osteoarthritis and/or osteochondritis dissecans

MIM #165800

Molecular basis of disorder known

Autosomal dominant

Spondyloepimetaphyseal dysplasia, aggrecan type

MIM #612813

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The physiological metabolite α-ketoglutarate ameliorates osteoarthritis by regulating mitophagy and oxidative stress.
Liu L et al.·Redox Biol
2023
Genetics of short stature.
Nicolae R et al.·Curr Opin Pediatr
2025Review
Bioenergetic-active exosomes for cartilage regeneration and homeostasis maintenance.
Liu X et al.·Sci Adv
2024
Inflammatory and Metabolic Signaling Interfaces of the Hypertrophic and Senescent Chondrocyte Phenotypes Associated with Osteoarthritis.
Horváth E et al.·Int J Mol Sci
2023Review
Clinical Characteristics of Short-Stature Patients With Collagen Gene Mutation and the Therapeutic Response to rhGH.
Chen M et al.·Front Endocrinol (Lausanne)
2022Cohort
Genotype and phenotype in patients with ACAN gene variants: Three cases and literature review.
Tang W et al.·Mol Genet Genomic Med
2024Review
Description of the molecular and phenotypic spectrum in Chinese patients with aggrecan deficiency: Novel ACAN heterozygous variants in eight Chinese children and a review of the literature.
Deng S et al.·Front Endocrinol (Lausanne)
2022Review
Dysfunctional autophagy triggers STING1 activation to exacerbate cartilage degeneration in obesity-associated osteoarthritis.
Kang X et al.·Autophagy
2025Functional
Clinical Characteristics of Pathogenic ACAN Variants and 3-Year Response to Growth Hormone Treatment: Real-World Data.
Renes JS et al.·Horm Res Paediatr
2024
Growth-Promoting Therapies May Be Useful In Short Stature Patients With Nonspecific Skeletal Abnormalities Caused By Acan Heterozygous Mutations: Six Chinese Cases And Literature Review.
Liang H et al.·Endocr Pract
2020Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Knee Osteoarthritis

Dietary Supplementation With Blueberry in OA

ACTIVE NOT RECRUITING
NCT05784545Phase NAUniversity of ExeterStarted 2023-05-22
Blueberry powder supplementMaltodextrin supplementation
Adolescent Idiopathic Scoliosis

Identification of Circulating microRNAs in Adolescent Idiopathic Scoliosis

RECRUITING
NCT04746586Istituto Ortopedico RizzoliStarted 2020-07-22
Circulating MiRNA indentification
Hand OsteoarthritisErosive Osteoarthritis

Methotrexate in Erosive Inflammatory Hand Osteoarthritis

ACTIVE NOT RECRUITING
NCT04579848Phase PHASE4Diakonhjemmet HospitalStarted 2021-08-12
Methotrexate TabletsPlaceboFolic Acid 1 MG

External Resources

Links to major genomics databases and tools