# NM_000095.3(COMP):c.1114GAC[2] (p.Asp374del)

https://sugi.bio/variant/comp-p-asp374del

## Summary

**COMP p.Asp374del (c.1114GAC[2])** is classified **Pathogenic/Likely pathogenic** in COMP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2021-11-22). No gnomAD frequency available for this variant; Associated with pseudoachondroplasia.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1198060288 · 4 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the COMP gene that is considered likely disease-causing, submitted by 4 submitters, and is linked to pseudoachondroplasia.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Worldwide) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | COMP is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Pseudoachondroplasia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Joint hypermobility — Very frequent (99-80%)
- Disproportionate short-limb short stature — Very frequent (99-80%)
- Platyspondyly — Frequent (79-30%)
- Brachydactyly — Frequent (79-30%)
- Waddling gait — Frequent (79-30%)
- Delayed epiphyseal ossification — Frequent (79-30%)
- Osteoarthritis — Frequent (79-30%)
- Generalized joint laxity — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0004540/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COMP](https://sugi.bio/atlas/gene/COMP/) |
| Protein change (HGVS p.) | p.Asp374del |
| Coding change (HGVS c.) | c.1114GAC[2] |
| MANE Select transcript | [NM_000095](https://www.ncbi.nlm.nih.gov/nuccore/NM_000095) |
| dbSNP | [rs1198060288](https://www.ncbi.nlm.nih.gov/snp/rs1198060288/) |
| Variant type | Microsatellite |
| Location | chr19:18787504-18787506 (GRCh38) |
| ClinVar | [VCV1404680](https://www.ncbi.nlm.nih.gov/clinvar/variation/1404680/) |

**All HGVS expressions:** `NC_000019.10:g.18787505TCG[2]`, `NC_000019.9:g.18898314TCG[2]`, `NG_007070.1:g.8794GAC[2]`, `NM_000095.3:c.1114GAC[2]`, `NM_000095.3:c.1120_1122del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 0.275, GERP -2.07, phastCons 0.993 — weakly conserved position
- Molecular consequence: **in-frame indel**.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**COMP** population constraint: LOEUF 1.073, pLI 1.6355e-24, missense-Z 1.5119; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **COMP-related skeletal dysplasia** — Definitive (AD)

## Protein context {#protein}

Residue **374** lies in the 'disordered' region; a UniProt-annotated variant site (in edm1); a UniProt-annotated variant site (in psach; mild form).

AlphaFold model confidence (whole protein): pLDDT 88.60, 67% of residues very-high.

**1 experimental structure(s)** (PDB): [3FBY](https://www.rcsb.org/structure/3FBY).

## What this gene does {#gene-function}

*Describes the biological roles of COMP (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** COMP's established molecular role includes protease binding. p.Asp374del falls in the disordered region.


### Pathways affected {#pathways}

COMP participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [ECM proteoglycans](https://reactome.org/content/detail/R-HSA-3000178) | curated |
| [Integrin cell surface interactions](https://reactome.org/content/detail/R-HSA-216083) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protease binding, calcium ion binding, collagen binding, heparin binding, proteoglycan binding, heparan sulfate proteoglycan binding.

**Biological process:** negative regulation of apoptotic process, protein homooligomerization, limb development, cartilage homeostasis.

## Clinical significance {#significance}

**Pathogenic/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2021-11-22.

**Submitter consensus:** conflicting (3 Pathogenic, 1 Likely pathogenic).

**Submission history:** 4 submissions (2002–2021); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2002-05-01 |
| MGZ Medical Genetics Center | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-11-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2021-11-18 |
| Clinical Biomedical Laboratory, Shriners Hospital For Children - Canada | Pathogenic | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[pseudoachondroplasia](https://sugi.bio/atlas/disease/pseudoachondroplasia/), [multiple epiphyseal dysplasia type 1](https://sugi.bio/atlas/disease/multiple-epiphyseal-dysplasia-type-1/).

**Reported phenotype names (ClinVar):** Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome, not provided, Multiple epiphyseal dysplasia type 1, none provided, PSEUDOACHONDROPLASTIC DYSPLASIA, Pseudoachondroplasia, COMP-Related Pseudoachondroplasia, COMP-Related Multiple Epiphyseal Dysplasia.

## Similar variants {#similar}

Related COMP variant pages (same residue, condition, or type): [COMP p.Asp374_Ile375insAsp](/variant/comp-p-asp374-ile375insasp), [COMP p.Asp473del](/variant/comp-p-asp473del), [COMP p.Asp473dup](/variant/comp-p-asp473dup), [COMP p.Glu457del](/variant/comp-p-glu457del), [COMP p.Gly320_Val321insAspGly](/variant/comp-p-gly320-val321insaspgly), [COMP p.Asp471_Asp473del](/variant/comp-p-asp471-asp473del), [COMP p.Asp472_Asp473dup](/variant/comp-p-asp472-asp473dup), [COMP p.Arg718Trp](/variant/comp-p-arg718trp).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 1404680). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*