# NM_000095.3(COMP):c.1993C>T (p.Arg665Trp)

https://sugi.bio/variant/comp-p-arg665trp

## Summary

**COMP p.Arg665Trp (c.1993C>T)** is classified **Uncertain significance** in COMP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-02). AlphaMissense: likely benign (0.1954); Ultra-rare (popmax 0.0329%, mid); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs370202476 · 4 submitters · 1 linked condition · AlphaMissense likely benign · ultra-rare (popmax 0.0329%, mid)

## 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 4 submitters, and is linked to Inborn genetic diseases.

*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.Arg665Trp |
| Coding change (HGVS c.) | c.1993C>T |
| 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 | [VCV1034755](https://www.ncbi.nlm.nih.gov/clinvar/variation/1034755/) |

**All HGVS expressions:** `NC_000019.10:g.18784285G>A`, `NC_000019.9:g.18895095G>A`, `NG_007070.1:g.12020C>T`, `NM_000095.2:c.1993C>T`, `NM_000095.3:c.1993C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1954)
- REVEL 0.632 (indeterminate)
- SaProt LLR -13.19 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL makes no call
- Conservation: phyloP 4.705, GERP 0.832, phastCons 0.999 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 27.5**. 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 (G>T, Δ0.60 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 (gnomAD v4.1): grpmax **0.0329%** (mid) · FAF95 0.00581% · FAF99 0.00321% · 2/6,076 in the highest group · 65/1,613,976 alleles overall — ultra-rare (popmax 0.0329%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0329% | 3,038 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,622 |
| European (non-Finnish) | 0.00458% | 21,853 |
| South Asian | 0.00329% | 30,361 |
| African / African-American | 0.00267% | 37,460 |

*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.

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.Arg665Trp 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-08-02.

**Submitter consensus:** unanimous (4/4 Uncertain significance).

**Submission history:** 4 submissions (2023–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-11-08 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-16 |
| CeGaT Center for Human Genetics Tuebingen | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-04-01 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, none provided.

## Similar variants {#similar}

Related COMP variant pages (same residue, condition, or type): [COMP p.Arg665=](/variant/comp-p-arg665), [COMP p.Arg247Ser](/variant/comp-p-arg247ser), [COMP p.Arg352Trp](/variant/comp-p-arg352trp), [COMP p.Arg379Gln](/variant/comp-p-arg379gln), [COMP p.Arg381Leu](/variant/comp-p-arg381leu), [COMP p.Arg689Trp](/variant/comp-p-arg689trp), [COMP p.Arg721His](/variant/comp-p-arg721his), [COMP p.Asp422Gly](/variant/comp-p-asp422gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 1034755). 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.*