# NM_000090.4(COL3A1):c.1662C>G (p.Pro554=)

https://sugi.bio/variant/col3a1-p-pro554

## Summary

**COL3A1 p.Pro554= (c.1662C>G)** is classified **Conflicting classifications of pathogenicity** in COL3A1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-02-03). Very rare (popmax 0.0011%, nfe); Associated with Ehlers-Danlos syndrome, vascular type.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs373963384 · 4 submitters · 2 linked conditions · very rare (popmax 0.0011%, nfe)

## For patients & families {#patients}

This is a change in the COL3A1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to Ehlers-Danlos syndrome, vascular type.

*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, Autosomal recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Worldwide) |
| Clinical trials | 14 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | COL3A1 is a diagnostic-grade gene on 11 Genomics England panels |

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

- Bladder diverticulum — Very frequent (99-80%)
- Cryptorchidism — Very frequent (99-80%)
- Abnormal oral frenulum morphology — Very frequent (99-80%)
- Abnormality of the face — Very frequent (99-80%)
- Epicanthus — Very frequent (99-80%)
- Hypertelorism — Very frequent (99-80%)
- Protruding ear — Very frequent (99-80%)
- Abnormal eyelash morphology — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002082/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COL3A1](https://sugi.bio/atlas/gene/COL3A1/) |
| Protein change (HGVS p.) | p.Pro554= |
| Coding change (HGVS c.) | c.1662C>G |
| MANE Select transcript | [NM_000090](https://www.ncbi.nlm.nih.gov/nuccore/NM_000090) |
| dbSNP | [rs373963384](https://www.ncbi.nlm.nih.gov/snp/rs373963384/) |
| Variant type | single nucleotide variant |
| Location | chr2:188996178-188996178 (GRCh38) |
| ClinVar | [VCV1403090](https://www.ncbi.nlm.nih.gov/clinvar/variation/1403090/) |

**All HGVS expressions:** `LRG_3:g.26806C>G`, `LRG_3t1:c.1662C>G`, `NC_000002.11:g.189860904C>G`, `NC_000002.12:g.188996178C>G`, `NG_007404.1:g.26806C>G`, `NM_000090.4:c.1662C>G`

## 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 -20, GERP -3.79 — fast-evolving / accelerated position
- CADD: **PHRED 0.006**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for COL3A1 (1,191 scored positions, the nearest 1 base away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.0011%** (nfe) · FAF95 0.000615% · FAF99 0.000474% · 13/1,179,406 in the highest group · 13/1,612,850 alleles overall — very rare (popmax 0.0011%, 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}

**COL3A1** population constraint: LOEUF 0.291, pLI 1, missense-Z 4.6137; ClinGen dosage — haploinsufficiency 3/3, 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, vascular type** — Definitive (AD)

## Protein context {#protein}

Residue **554** lies in a modified residue (4-hydroxyproline); a UniProt-annotated variant site (in pmgedsv); an α-helix; the 'disordered' region; the 'triple-helical region' region.

AlphaFold model confidence (whole protein): pLDDT 54.98, 19% of residues very-high.

**11 experimental structure(s)** (PDB): [2V53](https://www.rcsb.org/structure/2V53), [3DMW](https://www.rcsb.org/structure/3DMW), [4AE2](https://www.rcsb.org/structure/4AE2), [4AEJ](https://www.rcsb.org/structure/4AEJ), [4AK3](https://www.rcsb.org/structure/4AK3), [4GYX](https://www.rcsb.org/structure/4GYX).

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

*Describes the biological roles of COL3A1 (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:** COL3A1's established molecular role includes protease binding. p.Pro554= falls in the disordered region.


### Pathways affected {#pathways}

COL3A1 participates in **16 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [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 |
| [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 |
| [Fibronectin matrix formation](https://reactome.org/content/detail/R-HSA-1566977) | curated |
| [Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell](https://reactome.org/content/detail/R-HSA-198933) | 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 |
| [Collagen degradation](https://reactome.org/content/detail/R-HSA-1442490) | electronic |
| [ECM proteoglycans](https://reactome.org/content/detail/R-HSA-3000178) | electronic |
| [Scavenging by Class A Receptors](https://reactome.org/content/detail/R-HSA-3000480) | electronic |
| [Syndecan interactions](https://reactome.org/content/detail/R-HSA-3000170) | electronic |

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

**Molecular function:** protease binding, integrin binding, extracellular matrix structural constituent, extracellular matrix structural constituent conferring tensile strength, platelet-derived growth factor binding.

**Biological process:** cell-matrix adhesion, transforming growth factor beta receptor signaling pathway, integrin-mediated signaling pathway, heart development, response to radiation, peptide cross-linking.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-02-03.

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

**Submission history:** 4 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-03 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-09 |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2024-03-14 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2024-02-28 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Ehlers-Danlos syndrome, type 4, Familial thoracic aortic aneurysm and aortic dissection, Ehlers-Danlos syndrome vascular type, Ehlers Danlos syndrome, ecchymotic type, Ehlers Danlos syndrome, arterial type, Ehlers Danlos syndrome, Sack-Barabas type, Ehlers-Danlos Syndrome Type IV, Thoracic aortic aneurysms and dissections.

## Similar variants {#similar}

Related COL3A1 variant pages (same residue, condition, or type): [COL3A1 p.Pro554Leu](/variant/col3a1-p-pro554leu), [COL3A1 p.Pro554Ala](/variant/col3a1-p-pro554ala), [COL3A1 c.1051-1G>C](/variant/col3a1-c-1051-minus-1g-c), [COL3A1 c.1294-1G>A](/variant/col3a1-c-1294-minus-1g-a), [COL3A1 c.1347+1G>A](/variant/col3a1-c-1347-plus-1g-a), [COL3A1 c.1348-2A>G](/variant/col3a1-c-1348-minus-2a-g), [COL3A1 c.1662+1G>A](/variant/col3a1-c-1662-plus-1g-a), [COL3A1 c.1663-1G>A](/variant/col3a1-c-1663-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1403090). 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.*