ACAN

Chr 15ADAR

aggrecan

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

NCBI Gene: 176 ENSG00000157766 UniProt: P16112 OMIM: 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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

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

217 unique Pathogenic / Likely Pathogenic· 913 VUS of 1732 total submissions

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Clinical Trials

2 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 OE?0.10 (0.05–0.18)

0≤0.351.4

Missense OE?0.98 (0.94–1.03)

0≤0.61.4

Synonymous OE?0.98

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

This gene — mechanism propensity

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 · 90% 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.1

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

References

1.PMID 32575104 ↗

ClinVar Variant Classifications

1732 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic137

Likely Pathogenic80

VUS913

Likely Benign420

Benign122

Conflicting44

137

Pathogenic

Likely Pathogenic

913

VUS

420

Likely Benign

122

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	123	6	8	0	137
Likely Pathogenic	72	8	0	0	80
VUS	7	863	29	14	913
Likely Benign	0	58	111	251	420
Benign	0	17	68	37	122
Conflicting	—				44
Total	202	952	216	302	1,716

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

View in ClinVar →

34 pathogenic / likely-pathogenic (of 39) ClinVar copy-number / structural variants overlap ACAN — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →