# NM_000095.3(COMP):c.1454G>T (p.Arg485Leu)

https://sugi.bio/variant/comp-p-arg485leu

## Summary

**COMP p.Arg485Leu (c.1454G>T)** is classified **Likely pathogenic** in COMP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-11). AlphaMissense: ambiguous (0.5412); Absent from gnomAD v4.1; Associated with multiple epiphyseal dysplasia type 1.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense ambiguous · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the COMP gene that is considered likely disease-causing, 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.Arg485Leu |
| Coding change (HGVS c.) | c.1454G>T |
| MANE Select transcript | [NM_000095](https://www.ncbi.nlm.nih.gov/nuccore/NM_000095) |
| Variant type | single nucleotide variant |
| Location | chr19:18786000-18786000 (GRCh38) |
| ClinVar | [VCV4072050](https://www.ncbi.nlm.nih.gov/clinvar/variation/4072050/) |

**All HGVS expressions:** `NC_000019.10:g.18786000C>A`, `NC_000019.9:g.18896810C>A`, `NG_007070.1:g.10305G>T`, `NG_007070.2:g.10305G>T`, `NM_000095.3:c.1454G>T`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this damaging; AlphaMissense is indeterminate — descriptive only.

- AlphaMissense **ambiguous** (0.5412) — no call either way
- REVEL 0.849 (moderately pathogenic-leaning)
- SaProt LLR -11.386 (damaging)
- → **In-silico consensus:** REVEL and SaProt both call this damaging; AlphaMissense is indeterminate
- Conservation: phyloP 7.591, GERP 2.02, phastCons 1 — highly conserved
- CADD: **PHRED 30.0**. 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.*
- Regional missense constraint: **o/e 0.84** across the covering region of the MANE Select transcript (18,782,918–18,791,269), spanning 8,351 bp. Chi-square p 2.2e-07. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.21 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code 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 0/3, 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 **485** lies in the 'disordered' region.

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.Arg485Leu 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 Single submitter *(criteria provided, single submitter)*, last evaluated 2023-12-11.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Institute of Human Genetics Munich, TUM University Hospital | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-12-11 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Multiple epiphyseal dysplasia type 1, COMP-Related Multiple Epiphyseal Dysplasia.

## Similar variants {#similar}

Related COMP variant pages (same residue, condition, or type): [COMP p.Arg485His](/variant/comp-p-arg485his), [COMP p.Arg485Gly](/variant/comp-p-arg485gly), [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.Asp326Asn](/variant/comp-p-asp326asn), [COMP p.Asp385Asn](/variant/comp-p-asp385asn).

### 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 4072050). 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.*