Spondyloepimetaphyseal dysplasia, aggrecan type

disease

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Also known as SEMD, aggrecan typeSEMDAG

Summary

Spondyloepimetaphyseal dysplasia, aggrecan type (MONDO:0013014) is a disease caused by ACAN (GenCC Definitive), with 1 cohort gene.

At a glance

Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
Causal gene: ACAN (GenCC Definitive)
Cohort genes: 1
ClinVar variants: 82
Phenotypes (HPO): 16

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0000303	Mandibular prognathia	Very frequent (80-99%)
HP:0000358	Posteriorly rotated ears	Very frequent (80-99%)
HP:0000470	Short neck	Very frequent (80-99%)
HP:0001156	Brachydactyly	Very frequent (80-99%)
HP:0001382	Joint hypermobility	Very frequent (80-99%)
HP:0001552	Barrel-shaped chest	Very frequent (80-99%)
HP:0001597	Abnormality of the nail	Very frequent (80-99%)
HP:0002938	Lumbar hyperlordosis	Very frequent (80-99%)
HP:0003027	Mesomelia	Very frequent (80-99%)
HP:0004482	Relative macrocephaly	Very frequent (80-99%)
HP:0005285	Absent nasal bridge	Very frequent (80-99%)
HP:0008905	Rhizomelia	Very frequent (80-99%)
HP:0011304	Broad thumb	Very frequent (80-99%)
HP:0011800	Midface retrusion	Very frequent (80-99%)
HP:0001609	Hoarse voice	Frequent (30-79%)
HP:0002795	Abnormal respiratory system physiology	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	spondyloepimetaphyseal dysplasia, aggrecan type
Mondo ID	MONDO:0013014
MeSH	C567558
OMIM	612813
Orphanet	171866
ICD-11	1133152894
SNOMED CT	719165004
UMLS	C2748544
MedGen	411237
GARD	0010513
Is cancer (heuristic)	no

Also known as: SEMD, aggrecan type · SEMDAG · spondyloepimetaphyseal dysplasia, aggrecan type

Data availability: 82 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder › bone development disease › osteochondrodysplasia › spondyloepimetaphyseal dysplasia › spondyloepimetaphyseal dysplasia, aggrecan type

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

82 retrieved; paginated sample, class counts are floors:

46 benign, 16 uncertain significance, 8 benign/likely benign, 5 likely pathogenic, 4 pathogenic, 1 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069109	NM_001369268.1(ACAN):c.1097dup (p.Gly366_Glu367insTer)	ACAN	Pathogenic	criteria provided, multiple submitters, no conflicts
1189835	NM_001369268.1(ACAN):c.492C>A (p.Tyr164Ter)	ACAN	Pathogenic	criteria provided, multiple submitters, no conflicts
1328253	NM_001369268.1(ACAN):c.2023C>T (p.Arg675Ter)	ACAN	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
618999	NM_001369268.1(ACAN):c.4138G>T (p.Val1380Phe)	ACAN	Pathogenic	no assertion criteria provided
619000	NM_001369268.1(ACAN):c.5061T>A (p.Ser1687Arg)	ACAN	Pathogenic	no assertion criteria provided
14305	NM_001369268.1(ACAN):c.7255G>A (p.Asp2419Asn)	ACAN	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382910	NM_001369268.1(ACAN):c.2858dup (p.Asp953fs)	ACAN	Likely pathogenic	criteria provided, single submitter
3577865	NM_001369268.1(ACAN):c.2534C>A (p.Ser845Ter)	ACAN	Likely pathogenic	criteria provided, single submitter
3577866	NM_001369268.1(ACAN):c.2587del (p.Ala863fs)	ACAN	Likely pathogenic	criteria provided, single submitter
3764676	NM_001369268.1(ACAN):c.247G>T (p.Glu83Ter)	ACAN	Likely pathogenic	criteria provided, single submitter
1027792	NM_001369268.1(ACAN):c.1575C>G (p.Asp525Glu)	ACAN	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1034408	NM_001369268.1(ACAN):c.5434G>A (p.Val1812Ile)	ACAN	Uncertain significance	criteria provided, single submitter
1367420	NM_001369268.1(ACAN):c.6945A>T (p.Ile2315=)	ACAN	Uncertain significance	criteria provided, multiple submitters, no conflicts
1367485	NM_001369268.1(ACAN):c.836G>A (p.Arg279Gln)	ACAN	Uncertain significance	criteria provided, multiple submitters, no conflicts
1679571	NM_001369268.1(ACAN):c.2539C>G (p.Pro847Ala)	ACAN	Uncertain significance	criteria provided, single submitter
1804881	NM_001369268.1(ACAN):c.1817C>G (p.Ala606Gly)	ACAN	Uncertain significance	criteria provided, single submitter
2584787	NM_001369268.1(ACAN):c.188C>A (p.Ala63Asp)	ACAN	Uncertain significance	criteria provided, single submitter
2584788	NM_001369268.1(ACAN):c.7508G>A (p.Arg2503Gln)	ACAN	Uncertain significance	criteria provided, multiple submitters, no conflicts
287741	NM_001369268.1(ACAN):c.6113C>T (p.Thr2038Ile)	ACAN	Uncertain significance	criteria provided, multiple submitters, no conflicts
3367101	NM_001369268.1(ACAN):c.7678C>T (p.Arg2560Trp)	ACAN	Uncertain significance	criteria provided, multiple submitters, no conflicts
3367102	NM_001369268.1(ACAN):c.7250T>G (p.Leu2417Arg)	ACAN	Uncertain significance	criteria provided, single submitter
3376247	NM_001369268.1(ACAN):c.818G>T (p.Cys273Phe)	ACAN	Uncertain significance	criteria provided, single submitter
3577864	NM_001369268.1(ACAN):c.1624C>T (p.Arg542Trp)	ACAN	Uncertain significance	criteria provided, single submitter
546313	NM_001369268.1(ACAN):c.512C>T (p.Ala171Val)	ACAN	Uncertain significance	criteria provided, multiple submitters, no conflicts
800829	NM_001369268.1(ACAN):c.5546G>A (p.Gly1849Asp)	ACAN	Uncertain significance	no assertion criteria provided
828193	NM_001369268.1(ACAN):c.37del (p.Val13fs)	ACAN	Uncertain significance	criteria provided, single submitter
828194	NM_001369268.1(ACAN):c.6697C>T (p.His2233Tyr)	ACAN	Uncertain significance	criteria provided, single submitter
1077086	NM_001369268.1(ACAN):c.3637G>A (p.Ala1213Thr)	ACAN	Benign	criteria provided, multiple submitters, no conflicts
1098867	NM_001369268.1(ACAN):c.7233C>G (p.Asp2411Glu)	ACAN	Benign	criteria provided, multiple submitters, no conflicts
1174760	NM_001369268.1(ACAN):c.2815T>A (p.Ser939Thr)	ACAN	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 15 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ACAN	Definitive	Autosomal dominant	spondyloepiphyseal dysplasia, Kimberley type	15

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACAN	Orphanet:171866	Spondyloepimetaphyseal dysplasia, aggrecan type
ACAN	Orphanet:251262	Familial osteochondritis dissecans
ACAN	Orphanet:435804	Short stature-advanced bone age-early-onset osteoarthritis syndrome
ACAN	Orphanet:93283	Spondyloepiphyseal dysplasia, Kimberley type

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACAN	HGNC:319	ENSG00000157766	P16112	Aggrecan core protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACAN	Aggrecan core protein	This proteoglycan is a major component of extracellular matrix of cartilagenous tissues.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Complement	1	268.0×	0.004

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACAN	Complement	yes		Sushi_SCR_CCP_dom, Link_dom, EGF

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cartilage tissue	1
descending thoracic aorta	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACAN	181	broad	marker	tibia, cartilage tissue, descending thoracic aorta

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACAN	2,200

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACAN	P16112	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective CHST6 causes MCDC1	1	1427.5×	0.002	ACAN
Defective ST3GAL3 causes MCT12 and EIEE15	1	1427.5×	0.002	ACAN
Defective B4GALT1 causes B4GALT1-CDG (CDG-2d)	1	1427.5×	0.002	ACAN
Keratan sulfate degradation	1	713.8×	0.002	ACAN
Keratan sulfate biosynthesis	1	380.7×	0.004	ACAN
ECM proteoglycans	1	150.3×	0.008	ACAN
Degradation of the extracellular matrix	1	117.7×	0.008	ACAN

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
skeletal system development	1	125.8×	0.017	ACAN
central nervous system development	1	115.4×	0.017	ACAN
cell adhesion	1	37.5×	0.029	ACAN
proteolysis	1	34.2×	0.029	ACAN

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACAN	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ACAN
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ACAN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: ACAN