# NM_000095.3(COMP):c.1488C>A (p.Asp496Glu)

https://sugi.bio/variant/comp-p-asp496glu

## Summary

**COMP p.Asp496Glu (c.1488C>A)** is classified **Conflicting classifications of pathogenicity** in COMP (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-02). AlphaMissense: likely pathogenic (0.6863); Rare (popmax 0.273%, afr).

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs143714206 · 4 submitters · AlphaMissense likely pathogenic · rare (popmax 0.273%, afr)

## For patients & families {#patients}

This is a change in the COMP gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters.

*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.Asp496Glu |
| Coding change (HGVS c.) | c.1488C>A |
| MANE Select transcript | [NM_000095](https://www.ncbi.nlm.nih.gov/nuccore/NM_000095) |
| dbSNP | [rs143714206](https://www.ncbi.nlm.nih.gov/snp/rs143714206/) |
| Variant type | single nucleotide variant |
| Location | chr19:18785966-18785966 (GRCh38) |
| ClinVar | [VCV597740](https://www.ncbi.nlm.nih.gov/clinvar/variation/597740/) |

**All HGVS expressions:** `NC_000019.10:g.18785966G>T`, `NC_000019.9:g.18896776G>T`, `NG_007070.1:g.10339C>A`, `NM_000095.3:c.1488C>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6863)
- REVEL 0.427 (indeterminate)
- SaProt LLR -8.965 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- SpliceAI predicts **donor loss** (Δ 0.21) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.772, GERP -4.04, phastCons 0.097 — weakly conserved position
- CADD: **PHRED 17.64**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.21**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.21**, acceptor gain **0.00**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.273%** (afr) · FAF95 0.243% · FAF99 0.231% · 204/74,640 in the highest group · 241/1,606,838 alleles overall — rare (popmax 0.273%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.273% | 366 |
| Middle Eastern | 0.0337% | 2,971 |
| Remaining individuals (not grpmax-eligible) | 0.0257% | 3,890 |
| Admixed American | 0.0168% | 5,949 |
| South Asian | 0.00555% | 18,027 |
| European (non-Finnish) | 0.00034% | 294,544 |

*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 **496** lies in the 'disordered' 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.Asp496Glu 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-02.

**Submitter consensus:** conflicting (2 Likely benign, 1 Benign, 1 Uncertain significance).

**Submission history:** 4 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2020-05-14 |
| Eurofins Ntd Llc (ga) | Likely benign | criteria provided, single submitter | clinical testing | 2018-07-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-02 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-02-02 |

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

## Similar variants {#similar}

Related COMP variant pages (same residue, condition, or type): [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), [COMP p.Asp349His](/variant/comp-p-asp349his).

### 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 597740). 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.*