# NM_000393.5(COL5A2):c.1524C>T (p.Asp508=)

https://sugi.bio/variant/col5a2-p-asp508

## Summary

**COL5A2 p.Asp508= (c.1524C>T)** is classified **Benign** in COL5A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-03). Very rare (popmax 0.00667%, afr); Associated with Ehlers-Danlos syndrome, classic type, 1.

**At a glance:** Benign · review: Single submitter · rsID rs530691194 · 1 submitter · 1 linked condition · very rare (popmax 0.00667%, afr)

## For patients & families {#patients}

This is a change in the COL5A2 gene that is classified as benign — not considered disease-causing, submitted by 1 submitter, and is linked to Ehlers-Danlos syndrome, classic 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, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Worldwide) |
| Diagnostic panels | COL5A2 is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Classical Ehlers-Danlos syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Hyperextensible skin — Very frequent (99-80%)
- Soft, doughy skin — Very frequent (99-80%)
- Fragile skin — Very frequent (99-80%)
- Striae distensae — Very frequent (99-80%)
- Cigarette-paper scars — Very frequent (99-80%)
- Atrophic scars — Very frequent (99-80%)
- Generalized joint laxity — Very frequent (99-80%)
- Osteopenia — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025140/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COL5A2](https://sugi.bio/atlas/gene/COL5A2/) |
| Protein change (HGVS p.) | p.Asp508= |
| Coding change (HGVS c.) | c.1524C>T |
| MANE Select transcript | [NM_000393](https://www.ncbi.nlm.nih.gov/nuccore/NM_000393) |
| dbSNP | [rs530691194](https://www.ncbi.nlm.nih.gov/snp/rs530691194/) |
| Variant type | single nucleotide variant |
| Location | chr2:189066429-189066429 (GRCh38) |
| ClinVar | [VCV1930016](https://www.ncbi.nlm.nih.gov/clinvar/variation/1930016/) |

**All HGVS expressions:** `LRG_738:g.163873C>T`, `LRG_738t1:c.1524C>T`, `NC_000002.11:g.189931155G>A`, `NC_000002.12:g.189066429G>A`, `NG_011799.3:g.163873C>T`, `NM_000393.5:c.1524C>T`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -0.258, GERP -5.04, phastCons 0.002 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 4.099**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>C, Δ0.85 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 **0.00667%** (afr) · FAF95 0.00255% · FAF99 0.00161% · 5/75,016 in the highest group · 5/1,614,084 alleles overall — very rare (popmax 0.00667%, 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}

**COL5A2** population constraint: LOEUF 0.106, pLI 1, missense-Z 3.3665; 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):

- **Ehlers-Danlos syndrome, classic type** — Definitive (AD)

## Protein context {#protein}

Residue **508** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 53.15, 16% of residues very-high.

## What this gene does {#gene-function}

*Describes the biological roles of COL5A2 (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:** COL5A2's established molecular role includes extracellular matrix structural constituent conferring tensile strength. p.Asp508= falls in the disordered region. In Reactome, COL5A2 is annotated in disease pathway(s) including **Attachment of bacteria to epithelial cells**.

**Disease mechanism (Reactome):** COL5A2 loss or alteration is curated in [Attachment of bacteria to epithelial cells](https://reactome.org/content/detail/R-HSA-9638630).

### Pathways affected {#pathways}

COL5A2 participates in **15 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Attachment of bacteria to epithelial cells](https://reactome.org/content/detail/R-HSA-9638630) | curated |
| [Assembly of collagen fibrils and other multimeric structures](https://reactome.org/content/detail/R-HSA-2022090) | curated |
| [Collagen biosynthesis and modifying enzymes](https://reactome.org/content/detail/R-HSA-1650814) | curated |
| [Collagen chain trimerization](https://reactome.org/content/detail/R-HSA-8948216) | curated |
| [Collagen degradation](https://reactome.org/content/detail/R-HSA-1442490) | curated |
| [Developmental Lineage of Pancreatic Ductal Cells](https://reactome.org/content/detail/R-HSA-9925563) | curated |
| [Developmental Lineage of Pancreatic Endocrine Mid Progenitor Cells](https://reactome.org/content/detail/R-HSA-9981148) | curated |
| [ECM proteoglycans](https://reactome.org/content/detail/R-HSA-3000178) | curated |
| [Fibronectin matrix formation](https://reactome.org/content/detail/R-HSA-1566977) | curated |
| [Integrin cell surface interactions](https://reactome.org/content/detail/R-HSA-216083) | curated |
| [MET activates PTK2 signaling](https://reactome.org/content/detail/R-HSA-8874081) | curated |
| [NCAM1 interactions](https://reactome.org/content/detail/R-HSA-419037) | curated |
| [Non-integrin membrane-ECM interactions](https://reactome.org/content/detail/R-HSA-3000171) | curated |
| [Signaling by PDGF](https://reactome.org/content/detail/R-HSA-186797) | curated |
| [Syndecan interactions](https://reactome.org/content/detail/R-HSA-3000170) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** extracellular matrix structural constituent conferring tensile strength.

**Biological process:** collagen fibril organization, skin development, eye morphogenesis, negative regulation of endodermal cell differentiation.

## Clinical significance {#significance}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-06-03.

**Submitter consensus:** unanimous (1/1 Benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2022-06-03 |

## Associated conditions {#conditions}

[Ehlers-Danlos syndrome, classic type, 1](https://sugi.bio/atlas/disease/ehlers-danlos-syndrome-classic-type-1/).

**Reported phenotype names (ClinVar):** Ehlers-Danlos syndrome, classic type, 1, Ehlers-Danlos syndrome, type 1, Ehlers-Danlos Syndrome, Classic Type, COL5A1-Related, EDS I, EHLERS-DANLOS SYNDROME, GRAVIS TYPE, EHLERS-DANLOS SYNDROME, SEVERE CLASSIC TYPE.

## Similar variants {#similar}

Related COL5A2 variant pages (same residue, condition, or type): [COL5A2 c.1159-1G>A](/variant/col5a2-c-1159-minus-1g-a), [COL5A2 c.369+1G>T](/variant/col5a2-c-369-plus-1g-t), [COL5A2 p.Gly252Cys](/variant/col5a2-p-gly252cys), [COL5A2 p.Pro659=](/variant/col5a2-p-pro659), [COL5A2 c.1005+4T>C](/variant/col5a2-c-1005-plus-4t-c), [COL5A2 c.1618-7G>A](/variant/col5a2-c-1618-minus-7g-a), [COL5A2 c.1716+5G>A](/variant/col5a2-c-1716-plus-5g-a), [COL5A2 c.1717-3C>T](/variant/col5a2-c-1717-minus-3c-t).

### 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 1930016). 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.*