# NM_000095.3(COMP):c.1484C>A (p.Ala495Glu)

https://sugi.bio/variant/comp-p-ala495glu

## Summary

**COMP p.Ala495Glu (c.1484C>A)** is classified **Uncertain significance** in COMP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely benign (0.0863); Very rare (popmax 0.00405%, afr); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00405%, afr)

## 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 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.Ala495Glu |
| Coding change (HGVS c.) | c.1484C>A |
| MANE Select transcript | [NM_000095](https://www.ncbi.nlm.nih.gov/nuccore/NM_000095) |
| Variant type | single nucleotide variant |
| Location | chr19:18785970-18785970 (GRCh38) |
| ClinVar | [VCV4232737](https://www.ncbi.nlm.nih.gov/clinvar/variation/4232737/) |

**All HGVS expressions:** `NC_000019.10:g.18785970G>T`, `NC_000019.9:g.18896780G>T`, `NG_007070.1:g.10335C>A`, `NG_007070.2:g.10335C>A`, `NM_000095.3:c.1484C>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0863)
- REVEL 0.46 (indeterminate)
- SaProt LLR -7.67 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP -0.509, GERP -4.04 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 1.125**. 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>C, Δ0.34 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 **0.00405%** (afr) · FAF95 0.00107% · FAF99 0.000498% · 3/74,156 in the highest group · 3/1,601,946 alleles overall — very rare (popmax 0.00405%, afr).

*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 **495** lies in the 'disordered' 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.Ala495Glu 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-04.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-04 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related COMP variant pages (same residue, condition, or type): [COMP p.Ala495Thr](/variant/comp-p-ala495thr), [COMP p.Ala495=](/variant/comp-p-ala495), [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.Arg665Trp](/variant/comp-p-arg665trp), [COMP p.Arg689Trp](/variant/comp-p-arg689trp).

### 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 2026-07-14); 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 4232737). 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.*