# NM_000095.3(COMP):c.1993C>A (p.Arg665=)

https://sugi.bio/variant/comp-p-arg665

## Summary

**COMP p.Arg665= (c.1993C>A)** is classified **Uncertain significance** in COMP (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-12). Absent from gnomAD v4.1; Associated with multiple epiphyseal dysplasia type 1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs370202476 · 1 submitter · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the COMP gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to multiple epiphyseal dysplasia type 1.

*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) | Childhood |
| Diagnostic panels | COMP is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Multiple epiphyseal dysplasia type 1** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Gait disturbance — Frequent (79-30%)
- Hip dysplasia — Frequent (79-30%)
- Short long bone — Frequent (79-30%)
- Arthralgia of the hip — Frequent (79-30%)
- Knee pain — Frequent (79-30%)
- Postexertional malaise — Frequent (79-30%)
- Limitation of joint mobility — Occasional (29-5%)
- Joint stiffness — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002180/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.Arg665= |
| Coding change (HGVS c.) | c.1993C>A |
| MANE Select transcript | [NM_000095](https://www.ncbi.nlm.nih.gov/nuccore/NM_000095) |
| dbSNP | [rs370202476](https://www.ncbi.nlm.nih.gov/snp/rs370202476/) |
| Variant type | single nucleotide variant |
| Location | chr19:18784285-18784285 (GRCh38) |
| ClinVar | [VCV328610](https://www.ncbi.nlm.nih.gov/clinvar/variation/328610/) |

**All HGVS expressions:** `NC_000019.10:g.18784285G>T`, `NC_000019.9:g.18895095G>T`, `NG_007070.1:g.12020C>A`, `NM_000095.3:c.1993C>A`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.60) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.705, GERP 0.832, phastCons 0.999 — highly conserved position (PP3-type support)
- CADD: **PHRED 18.9**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.60**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.60**.
- Pangolin: Δ**0.40** (gain), gain 0.40 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **665** lies in the tsp c-terminal domain; the 'mediates cell survival and induction of the iap family of survival proteins' region; a β-strand; a disulfide bond.

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.Arg665= falls in the tsp c-terminal domain.


### 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-01-12.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2018); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Multiple epiphyseal dysplasia type 1, Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome, COMP-Related Multiple Epiphyseal Dysplasia, COMP-Related Pseudoachondroplasia, PSEUDOACHONDROPLASTIC DYSPLASIA, Pseudoachondroplasia.

## Similar variants {#similar}

Related COMP variant pages (same residue, condition, or type): [COMP p.Arg665Trp](/variant/comp-p-arg665trp), [COMP p.Arg718Trp](/variant/comp-p-arg718trp), [COMP p.Asn489Lys](/variant/comp-p-asn489lys), [COMP p.Asn523Lys](/variant/comp-p-asn523lys), [COMP p.Asn555Lys](/variant/comp-p-asn555lys), [COMP p.Asp269Gly](/variant/comp-p-asp269gly), [COMP p.Asp273Val](/variant/comp-p-asp273val), [COMP p.Asp326Asn](/variant/comp-p-asp326asn).

### 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 328610). 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.*