# NM_000095.3(COMP):c.1153_1155del (p.Asp385del)

https://sugi.bio/variant/comp-p-asp385del

## Summary

**COMP p.Asp385del (c.1153_1155del)** is classified **Likely pathogenic** in COMP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-26). No gnomAD frequency available for this variant; Associated with COMP-related disorder.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs2145901379 · 2 submitters · 1 linked condition · 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 2 submitters, and is linked to COMP-related disorder.

*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.*

**Support & next steps:** [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.Asp385del |
| Coding change (HGVS c.) | c.1153_1155del |
| MANE Select transcript | [NM_000095](https://www.ncbi.nlm.nih.gov/nuccore/NM_000095) |
| dbSNP | [rs2145901379](https://www.ncbi.nlm.nih.gov/snp/rs2145901379/) |
| Variant type | Deletion |
| Location | chr19:18786631-18786633 (GRCh38) |
| ClinVar | [VCV1510817](https://www.ncbi.nlm.nih.gov/clinvar/variation/1510817/) |

**All HGVS expressions:** `NC_000019.10:g.18786632_18786634del`, `NC_000019.9:g.18897442_18897444del`, `NG_007070.1:g.9672_9674del`, `NM_000095.3:c.1153_1155del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.798, GERP 2.02, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **in-frame indel**.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion 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, triplosensitivity 0 (0–3 scale). *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 **385** lies in the 'disordered' region; a UniProt-annotated variant site (in edm1; atypical form); a UniProt-annotated variant site (in edm1).

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.Asp385del 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}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-04-26.

**Submitter consensus:** unanimous (2/2 Likely pathogenic).

**Submission history:** 2 submissions (2022–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-09-27 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-04-26 |

## Associated conditions {#conditions}

[COMP-related disorder](https://sugi.bio/atlas/disease/comp-related-disorder/).

**Reported phenotype names (ClinVar):** COMP-related disorder, not provided, COMP-related disorders, COMP-related condition, none provided.

## Same-residue context {#hotspot}

Residue **385** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [COMP p.Asp385His](/variant/comp-p-asp385his), [COMP p.Asp385Tyr](/variant/comp-p-asp385tyr), [COMP p.Asp385Asn](/variant/comp-p-asp385asn). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related COMP variant pages (same residue, condition, or type): [COMP p.Asp385Asn](/variant/comp-p-asp385asn), [COMP p.Glu341_Asp342del](/variant/comp-p-glu341-asp342del), [COMP p.Asp385His](/variant/comp-p-asp385his), [COMP p.Asp385Tyr](/variant/comp-p-asp385tyr), [COMP p.Asn489Lys](/variant/comp-p-asn489lys), [COMP p.Asp326Asn](/variant/comp-p-asp326asn), [COMP p.Asp401Asn](/variant/comp-p-asp401asn), [COMP p.Asp458Gly](/variant/comp-p-asp458gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 1510817). 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.*