# NM_000093.5(COL5A1):c.4987T>G (p.Ser1663Ala)

https://sugi.bio/variant/col5a1-p-ser1663ala

## Summary

**COL5A1 p.Ser1663Ala (c.4987T>G)** is classified **Uncertain significance** in COL5A1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-26). AlphaMissense: likely benign (0.0728); Very rare (popmax 0.00017%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1436371955 · 3 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the COL5A1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 3 submitters, and is linked to familial thoracic aortic aneurysm and aortic dissection.

*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) | Adolescent, Adult, Childhood |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | COL5A1 is a diagnostic-grade gene on 5 Genomics England panels |

**Commonly reported features of Familial thoracic aortic aneurysm and aortic dissection** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Cutis marmorata — Very frequent (99-80%)
- Abnormality of connective tissue — Very frequent (99-80%)
- Cystic medial necrosis of the aorta — Very frequent (99-80%)
- Abnormality iris morphology — Frequent (79-30%)
- Hypertension — Frequent (79-30%)
- Cardiomegaly — Frequent (79-30%)
- Aortic regurgitation — Frequent (79-30%)
- Coronaryartery atherosclerosis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002249/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COL5A1](https://sugi.bio/atlas/gene/COL5A1/) |
| Protein change (HGVS p.) | p.Ser1663Ala |
| Coding change (HGVS c.) | c.4987T>G |
| MANE Select transcript | [NM_000093](https://www.ncbi.nlm.nih.gov/nuccore/NM_000093) |
| dbSNP | [rs1436371955](https://www.ncbi.nlm.nih.gov/snp/rs1436371955/) |
| Variant type | single nucleotide variant |
| Location | chr9:134825824-134825824 (GRCh38) |
| ClinVar | [VCV1915990](https://www.ncbi.nlm.nih.gov/clinvar/variation/1915990/) |

**All HGVS expressions:** `LRG_737:g.189019T>G`, `LRG_737t1:c.4987T>G`, `LRG_737t2:c.4987T>G`, `NC_000009.11:g.137717670T>G`, `NC_000009.12:g.134825824T>G`, `NG_008030.1:g.189019T>G`, `NM_000093.3:c.4987T>G`, `NM_000093.5:c.4987T>G`, `NM_001278074.1:c.4987T>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0728)
- REVEL 0.069 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -9.021 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 2.784, GERP 0.843, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.2**. 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 0.93** across the covering region of the MANE Select transcript (134,823,447–134,842,300), spanning 18,853 bp. Chi-square p 0.18. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,310 in the highest group · 2/1,460,724 alleles overall — very rare (popmax 0.00017%, nfe).

*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}

**COL5A1** population constraint: LOEUF 0.089, pLI 1, missense-Z 4.1992; ClinGen dosage — haploinsufficiency 3, 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):

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

## Protein context {#protein}

Residue **1663** lies in a disulfide bond; the fibrillar collagen nc1 domain.

AlphaFold model confidence (whole protein): pLDDT 52.54, 19% of residues very-high.

**1 experimental structure(s)** (PDB): [7Y37](https://www.rcsb.org/structure/7Y37).

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

*Describes the biological roles of COL5A1 (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:** COL5A1's established molecular role includes heparin binding. p.Ser1663Ala falls in the fibrillar collagen nc1 domain. In Reactome, COL5A1 is annotated in disease pathway(s) including **Attachment of bacteria to epithelial cells**.

**Disease mechanism (Reactome):** COL5A1 loss or alteration is curated in [Attachment of bacteria to epithelial cells](https://reactome.org/content/detail/R-HSA-9638630).

### Pathways affected {#pathways}

COL5A1 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:** heparin binding, extracellular matrix structural constituent conferring tensile strength, proteoglycan binding, platelet-derived growth factor binding.

**Biological process:** cell adhesion, cell migration, collagen fibril organization, collagen biosynthetic process, wound healing, spreading of epidermal cells, skin development.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-26.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2024–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-11 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-12 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-02-26 |

## Associated conditions {#conditions}

[familial thoracic aortic aneurysm and aortic dissection](https://sugi.bio/atlas/disease/familial-thoracic-aortic-aneurysm-and-aortic-dissection/), [Ehlers-Danlos syndrome, classic type, 1](https://sugi.bio/atlas/disease/ehlers-danlos-syndrome-classic-type-1/).

**Reported phenotype names (ClinVar):** Familial thoracic aortic aneurysm and aortic dissection, Ehlers-Danlos syndrome, classic type, 1, not specified, Thoracic aortic aneurysms and dissections, 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, AllHighlyPenetrant.

## Similar variants {#similar}

Related COL5A1 variant pages (same residue, condition, or type): [COL5A1 c.1332+1G>T](/variant/col5a1-c-1332-plus-1g-t), [COL5A1 c.1720-11T>A](/variant/col5a1-c-1720-minus-11t-a), [COL5A1 c.2034+1G>A](/variant/col5a1-c-2034-plus-1g-a), [COL5A1 c.2430+1G>A](/variant/col5a1-c-2430-plus-1g-a), [COL5A1 c.2430+1G>C](/variant/col5a1-c-2430-plus-1g-c), [COL5A1 c.2701-25T>G](/variant/col5a1-c-2701-minus-25t-g), [COL5A1 c.4338+1G>A](/variant/col5a1-c-4338-plus-1g-a), [COL5A1 c.5067+1G>A](/variant/col5a1-c-5067-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 1915990). 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.*