GeneBe

COMP

protein-coding

cartilage oligomeric matrix protein, the group of Thrombospondin family

Gene summary

The protein encoded by this gene is a noncollagenous extracellular matrix (ECM) protein. It consists of five identical glycoprotein subunits, each with EGF-like and calcium-binding (thrombospondin-like) domains. Oligomerization results from formation of a five-stranded coiled coil and disulfides. Binding to other ECM proteins such as collagen appears to depend on divalent cations. Contraction or expansion of a 5 aa aspartate repeat and other mutations can cause pseudochondroplasia (PSACH) and multiple epiphyseal dysplasia (MED). [provided by RefSeq, Jul 2016]

Previous symbols:
  • PSACH
  • EDM1
  • EPD1

MANE transcript

NM_000095.3

Inheritance

AD

ClinVar variants

P:178U:390B:152

Top phenotype

Carpal tunnel syndrome 2; Epiphyseal dysplasia, multiple, 1; Pseudoachondroplasia

gnomAD constraint

pLI —, LoF o/e 0.53

Max pathogenic AF

—

Genomic locus

chr19:18,782,773-18,791,305

External References & Databases

Ensembl (ENSG00000105664)NCBI Gene (1311)OMIM (600310)HGNC:2227GenCCUniProt (P49747)AlphaFoldClinVar (COMP)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~8.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pseudoachondroplasiaLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0008322

Submitter: Labcorp Genetics (formerly Invitae)

COMP-related skeletal dysplasiaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100593

Submitter: ClinGen

*COMP* has been first reported in association with autosomal dominant *COMP*-related skeletal dysplasia in 1993 (Hecht et al., PMID: 8307577). *COMP* has also been associated with multiple epiphyseal dysplasia and pseudoachondroplasia. There is no clear locus specificity of variation within the gene to determine a clear genotype-phenotype correlation and there is substantial phenotypic overlap between the two disease entities. Therefore, per criteria outlined by the ClinGen Lumping and Splitting guidelines, they have been lumped as one disease entity, *COMP*-related skeletal dysplasia. Evidence supporting this gene-disease relationship includes case-level, segregation, and experimental data. At least 15 unique variants (missense, inframe indels) in *COMP* have been identified in 15 patients with skeletal dysplasia in 10 publications (PMIDs: 8307577, 9388247, 21644213, 21922596, 27330822, 29899997, 26920793, 21965141, 11565064, 15756302). Additionally, variants in *COMP* segregated with disease in 15 additional family members (PMIDs: 8307577, 11565064, 15756302, 26920793). This gene-disease relationship is supported by mouse models, expression studies, and in vitro functional assays (PMIDs: 20578249, 18576344, 11084047, 12801484, 17570134, 22006726, 10753957, 1556121). In summary, *COMP* is definitively associated with autosomal dominant *COMP*-related skeletal dysplasia. 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 Skeletal Disorders Gene Curation Expert Panel on the meeting date February 28th, 2025 (SOP Version 11).

pseudoachondroplasiaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008322

Submitter: Illumina

multiple epiphyseal dysplasia type 1STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007561

Submitter: Labcorp Genetics (formerly Invitae)

pseudoachondroplasiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008322

Submitter: Labcorp Genetics (formerly Invitae)

multiple epiphyseal dysplasia type 1SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007561

Submitter: Orphanet

pseudoachondroplasiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008322

Submitter: Orphanet

COMP-related skeletal dysplasiaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100593

Submitter: G2P

Clinical Genomic Database (CGD)

Carpal tunnel syndrome 2; Epiphyseal dysplasia, multiple, 1; PseudoachondroplasiaAD

Manifestation: Musculoskeletal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 13633894; 3314506; 7907311; 7670471; 7670472; 8725795; 9021009; 9188668; 9887340; 11968079; 14684695; 15266613; 15551305; 17579668; 20301302; 20830670; 21599986; 21644213; 21922596; 21965141; 22006726; 32686688Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to COMP variants in ClinVar

14 Conditions Cataloged
not providedTotal: 689
Pseudoachondroplastic spondyloepiphyseal dysplasia syndromeTotal: 128
Multiple epiphyseal dysplasia type 1Total: 117
Inborn genetic diseasesTotal: 109
not specifiedTotal: 63
COMP-related disorderTotal: 53
Multiple epiphyseal dysplasiaTotal: 14
Carpal tunnel syndrome 2Total: 14

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000095.3. 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
13
clinvar
124
clinvar
5
clinvar
 142
missense
49
clinvar
119
clinvar
338
clinvar
23
clinvar
 529
nonsense
13
clinvar
 13
start loss
1
clinvar
 1
frameshift
2
clinvar
3
clinvar
13
clinvar
 18
splice donor/acceptor (+/-2bp)
1
clinvar
4
clinvar
12
clinvar
 17
Total521263901475720

Highest pathogenic variant AF is 0.000037644313

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000095.3RefSeqNP_000086.219MANE Select
ENST00000222271.7EnsemblENSP00000222271.219MANE Select
ENST00000425807.1EnsemblENSP00000403792.118Standard
ENST00000425807.2EnsemblENSP00000403792.118Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • PI3K-Akt signaling pathway - Homo sapiens (human)
  • ECM-receptor interaction - Homo sapiens (human)
  • Focal adhesion - Homo sapiens (human)
  • Phagosome - Homo sapiens (human)
  • Malaria - Homo sapiens (human)

Biological Process

  • skeletal system development
  • chondrocyte development
  • apoptotic process
  • response to unfolded protein
  • protein secretion

Molecular Function

  • protease binding
  • integrin binding
  • extracellular matrix structural constituent
  • calcium ion binding
  • protein binding

Cellular Component

  • extracellular region
  • extracellular space
  • extracellular matrix
  • protein-containing complex
  • collagen-containing extracellular matrix

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000222271
Coding exons
19
Length
8541
Individuals with no LoFs
125684
Homozygous LoFs
0
Heterozygous LoFs
64
Defined
125748
p
0.000255
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.783484550.7650.00002704976
Missense (PolyPhen)174242.510.717492696
Synonymous0.5591781880.9480.00001231408
Loss of Function2.732139.50.5310.00000191411

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000440.00037rare
Latino/Admixed American0.000200.00020rare
Ashkenazi Jewish0.000690.00069rare
East Asian0.000230.00022rare
Finnish00.0absent
European (Non-Finnish)0.000240.00024rare
South Asian0.000420.00042rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: May play a role in the structural integrity of cartilage via its interaction with other extracellular matrix proteins such as the collagens and fibronectin. Can mediate the interaction of chondrocytes with the cartilage extracellular matrix through interaction with cell surface integrin receptors. Could play a role in the pathogenesis of osteoarthritis. Potent suppressor of apoptosis in both primary chondrocytes and transformed cells. Suppresses apoptosis by blocking the activation of caspase-3 and by inducing the IAP family of survival proteins (BIRC3, BIRC2, BIRC5 and XIAP). Essential for maintaining a vascular smooth muscle cells (VSMCs) contractile/differentiated phenotype under physiological and pathological stimuli. Maintains this phenotype of VSMCs by interacting with ITGA7 (By similarity). {ECO:0000250, ECO:0000269|PubMed:16051604, ECO:0000269|PubMed:16542502, ECO:0000269|PubMed:17993464}.;
Disease
DISEASE: Multiple epiphyseal dysplasia 1 (EDM1) [MIM:132400]: A generalized skeletal dysplasia associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. Radiological examination of the skeleton shows delayed, irregular mineralization of the epiphyseal ossification centers and of the centers of the carpal and tarsal bones. Multiple epiphyseal dysplasia is broadly categorized into the more severe Fairbank and the milder Ribbing types. The Fairbank type is characterized by shortness of stature, short and stubby fingers, small epiphyses in several joints, including the knee, ankle, hand, and hip. The Ribbing type is confined predominantly to the hip joints and is characterized by hands that are normal and stature that is normal or near-normal. {ECO:0000269|PubMed:11084047, ECO:0000269|PubMed:11565064, ECO:0000269|PubMed:21922596, ECO:0000269|PubMed:7670472, ECO:0000269|PubMed:9021009, ECO:0000269|PubMed:9184241, ECO:0000269|PubMed:9452026, ECO:0000269|PubMed:9463320, ECO:0000269|PubMed:9921895}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Pseudoachondroplasia (PSACH) [MIM:177170]: A skeletal dysplasia usually manifesting in the second year of life and characterized by moderate to severe disproportionate short stature, deformity of the lower limbs, brachydactyly, ligamentous laxity, and degenerative joint disease. {ECO:0000269|PubMed:10852928, ECO:0000269|PubMed:11084047, ECO:0000269|PubMed:11746044, ECO:0000269|PubMed:11746045, ECO:0000269|PubMed:21922596, ECO:0000269|PubMed:7670471, ECO:0000269|PubMed:7670472, ECO:0000269|PubMed:9184241, ECO:0000269|PubMed:9452026, ECO:0000269|PubMed:9452063, ECO:0000269|PubMed:9463320, ECO:0000269|PubMed:9921895}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.722

Intolerance Scores

LoFtool
0.175
RVIS EVS
-0.49
RVIS percentile EVS
22.65

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.380

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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