ACAN

Chr 15ADAR

aggrecan

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

NCBI Gene: 176ENSG00000157766UniProt: P16112OMIM: 155760

The encoded protein is a major component of cartilage extracellular matrix that resists compression and binds to hyaluronic acid. Mutations cause skeletal dysplasias including spondyloepiphyseal dysplasia, short stature with advanced bone age, and early-onset osteoarthritis, with both autosomal dominant and recessive inheritance patterns. This gene is highly constrained against loss-of-function variants (pLI >0.99), reflecting its essential role in skeletal development and maintenance.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismAD/ARLOEUF 0.183 OMIM phenotypes
Clinical Summary— ACAN
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Gene-Disease Validity (ClinGen)
ACAN-related short stature spectrum · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.
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ClinVar Variants
33 unique Pathogenic / Likely Pathogenic· 184 VUS of 300 total submissions
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Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — ACAN
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
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
0.21Z-score
OE missense 0.98 (0.94–1.03)
1197 obs / 1217.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.10 (0.05–0.18)
0≤0.351.4
Missense OE0.98 (0.94–1.03)
0≤0.61.4
Synonymous OE0.98
0≤1.21.6
LoF obs/exp: 7 / 71.7Missense obs/exp: 1197 / 1217.3Syn Z: 0.29
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveACAN-related spondyloepimetaphyseal dysplasia, aggrecan typeOTHERAR
definitiveACAN-related spondyloepiphyseal dysplasiaLOFAD
DN
0.5181th %ile
GOF
0.5170th %ile
LOF
0.53top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOF1 literature citation · 94% of P/LP variants are LoF · LOEUF 0.18

Literature Evidence

LOFCarriers of ACAN haploinsufficiency have an elevated mean AS/H in childhood and adolescence and a slightly elevated ratio till 50 years.PMID:32575104

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

300 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic28
Likely Pathogenic5
VUS184
Likely Benign79
Benign1
28
Pathogenic
5
Likely Pathogenic
184
VUS
79
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
27
1
0
0
28
Likely Pathogenic
4
1
0
0
5
VUS
3
166
13
2
184
Likely Benign
0
1
31
47
79
Benign
0
0
1
0
1
Total341694549297

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.

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients