# NM_000089.4(COL1A2):c.1446A>C (p.Pro482=)

https://sugi.bio/variant/col1a2-p-pro482

## Summary

**COL1A2 p.Pro482= (c.1446A>C)** is classified **Benign** in COL1A2 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-04). Common (popmax 36.3%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with osteogenesis imperfecta type 1.

**At a glance:** Benign · review: Multiple submitters · rsID rs412777 · 12 submitters · 7 linked conditions · common (popmax 36.3%, nfe) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the COL1A2 gene that is classified as benign — not considered disease-causing, submitted by 12 submitters, and is linked to osteogenesis imperfecta 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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0008694/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COL1A2](https://sugi.bio/atlas/gene/COL1A2/) |
| Protein change (HGVS p.) | p.Pro482= |
| Coding change (HGVS c.) | c.1446A>C |
| MANE Select transcript | [NM_000089](https://www.ncbi.nlm.nih.gov/nuccore/NM_000089) |
| dbSNP | [rs412777](https://www.ncbi.nlm.nih.gov/snp/rs412777/) |
| Variant type | single nucleotide variant |
| Location | chr7:94412625-94412625 (GRCh38) |
| ClinVar | [VCV254952](https://www.ncbi.nlm.nih.gov/clinvar/variation/254952/) |

**All HGVS expressions:** `LRG_2:g.23065A>C`, `LRG_2t1:c.1446A>C`, `NC_000007.13:g.94041937A>C`, `NC_000007.14:g.94412625A>C`, `NG_007405.1:g.23065A>C`, `NM_000089.4:c.1446A>C`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 36.3%, nfe) — too common for a highly-penetrant pathogenic allele.

- **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 -2.336, GERP -4.26 — fast-evolving / accelerated position
- CADD: **PHRED 5.392**. 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: **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 **36.3%** (nfe) · FAF95 36.2% · FAF99 36.2% · 428,489/1,179,748 in the highest group · 572,365/1,613,478 alleles overall — common (popmax 36.3%, nfe) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 40.4% | 2 |
| European (non-Finnish) (grpmax) | 36.3% | 3 |
| Ashkenazi Jewish (not grpmax-eligible) | 35.6% | 3 |
| Remaining individuals (not grpmax-eligible) | 35% | 3 |
| African / African-American | 34.8% | 3 |
| East Asian | 33.9% | 3 |
| Middle Eastern | 33.8% | 3 |
| Amish (not grpmax-eligible) | 33.3% | 3 |
| South Asian | 28.7% | 3 |
| Admixed American | 26.5% | 4 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**COL1A2** population constraint: LOEUF 0.339, pLI 1, missense-Z 3.5486; 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):

- **COL1A2-related Ehlers-Danlos syndrome** — Definitive (AD)
- **Ehlers-Danlos syndrome, cardiac valvular type** — Definitive (AR)
- **congenital heart disease** — Disputed (UD)
- **COL1A2-related osteogenesis imperfecta** — Definitive (AD)

## Protein context {#protein}

Residue **482** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 55.02, 16% of residues very-high.

**5 experimental structure(s)** (PDB): [5CTD](https://www.rcsb.org/structure/5CTD), [5CTI](https://www.rcsb.org/structure/5CTI), [5CVA](https://www.rcsb.org/structure/5CVA), [6JEC](https://www.rcsb.org/structure/6JEC), [8YV3](https://www.rcsb.org/structure/8YV3).

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

*Describes the biological roles of COL1A2 (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:** COL1A2's established molecular role includes protease binding. p.Pro482= falls in the disordered region. In Reactome, COL1A2 is annotated in disease pathway(s) including **Defective VWF binding to collagen type I **, **Defective VWF cleavage by ADAMTS13 variant**.

**Disease mechanism (Reactome):** COL1A2 loss or alteration is curated in [Defective VWF binding to collagen type I ](https://reactome.org/content/detail/R-HSA-9845622), [Defective VWF cleavage by ADAMTS13 variant](https://reactome.org/content/detail/R-HSA-9845621), [Defective binding of VWF variant to GPIb:IX:V](https://reactome.org/content/detail/R-HSA-9846298).

### Pathways affected {#pathways}

COL1A2 participates in **28 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective VWF binding to collagen type I ](https://reactome.org/content/detail/R-HSA-9845622) | curated |
| ⚕ [Defective VWF cleavage by ADAMTS13 variant](https://reactome.org/content/detail/R-HSA-9845621) | curated |
| ⚕ [Defective binding of VWF variant to GPIb:IX:V](https://reactome.org/content/detail/R-HSA-9846298) | curated |
| ⚕ [Enhanced binding of GP1BA variant to VWF multimer:collagen ](https://reactome.org/content/detail/R-HSA-9845620) | curated |
| ⚕ [Enhanced cleavage of VWF variant by ADAMTS13](https://reactome.org/content/detail/R-HSA-9845619) | curated |
| [Anchoring fibril formation](https://reactome.org/content/detail/R-HSA-2214320) | curated |
| [Assembly of collagen fibrils and other multimeric structures](https://reactome.org/content/detail/R-HSA-2022090) | curated |
| [Cell surface interactions at the vascular wall](https://reactome.org/content/detail/R-HSA-202733) | 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 |
| [Crosslinking of collagen fibrils](https://reactome.org/content/detail/R-HSA-2243919) | 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 |
| [GP1b-IX-V activation signalling](https://reactome.org/content/detail/R-HSA-430116) | curated |
| [GPVI-mediated activation cascade](https://reactome.org/content/detail/R-HSA-114604) | curated |
| [Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell](https://reactome.org/content/detail/R-HSA-198933) | curated |
| [Interleukin-4 and Interleukin-13 signaling](https://reactome.org/content/detail/R-HSA-6785807) | curated |
| [MET activates PTK2 signaling](https://reactome.org/content/detail/R-HSA-8874081) | curated |
| [Non-integrin membrane-ECM interactions](https://reactome.org/content/detail/R-HSA-3000171) | curated |
| [Platelet Aggregation (Plug Formation)](https://reactome.org/content/detail/R-HSA-76009) | curated |
| [SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription](https://reactome.org/content/detail/R-HSA-2173796) | curated |
| [Collagen degradation](https://reactome.org/content/detail/R-HSA-1442490) | electronic |
| [ECM proteoglycans](https://reactome.org/content/detail/R-HSA-3000178) | electronic |
| [Integrin cell surface interactions](https://reactome.org/content/detail/R-HSA-216083) | electronic |
| [Platelet Adhesion to exposed collagen](https://reactome.org/content/detail/R-HSA-75892) | 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, extracellular matrix structural constituent conferring tensile strength, protein-macromolecule adaptor activity, identical protein binding, platelet-derived growth factor binding.

**Biological process:** skeletal system development, blood vessel development, transforming growth factor beta receptor signaling pathway, Rho protein signal transduction, regulation of blood pressure, collagen fibril organization.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** unanimous (16/16 Benign).

**Submission history:** 16 submissions (2016–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Athena Diagnostics | Benign | criteria provided, single submitter | clinical testing | 2017-07-26 |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2018-12-04 |
| Genome-Nilou Lab | Benign | criteria provided, single submitter | clinical testing | 2021-07-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2016-03-03 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Genome Diagnostics Laboratory, Amsterdam University Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2019-03-13 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-27 |

## Associated conditions {#conditions}

[osteogenesis imperfecta type 1](https://sugi.bio/atlas/disease/osteogenesis-imperfecta-type-1/), [osteogenesis imperfecta type 2](https://sugi.bio/atlas/disease/osteogenesis-imperfecta-type-2/), [osteogenesis imperfecta type 4](https://sugi.bio/atlas/disease/osteogenesis-imperfecta-type-4/), [osteogenesis imperfecta type 3](https://sugi.bio/atlas/disease/osteogenesis-imperfecta-type-3/), [osteogenesis imperfecta](https://sugi.bio/atlas/disease/osteogenesis-imperfecta/), [Ehlers-Danlos syndrome, classic type, 1](https://sugi.bio/atlas/disease/ehlers-danlos-syndrome-classic-type-1/), [Ehlers-Danlos syndrome, arthrochalasia type, 2](https://sugi.bio/atlas/disease/ehlers-danlos-syndrome-arthrochalasia-type-2/).

**Reported phenotype names (ClinVar):** Osteogenesis imperfecta type I, not specified, Osteogenesis imperfecta, Ehlers-Danlos syndrome, arthrochalasia type, 2, Ehlers-Danlos syndrome, classic type, 1, Osteogenesis imperfecta type III, Osteogenesis imperfecta with normal sclerae, dominant form, Osteogenesis imperfecta, perinatal lethal, Cardiovascular phenotype, not provided.

## Similar variants {#similar}

Related COL1A2 variant pages (same residue, condition, or type): [COL1A2 p.Pro482Ser](/variant/col1a2-p-pro482ser), [COL1A2 p.Pro482Thr](/variant/col1a2-p-pro482thr), [COL1A2 p.Pro482His](/variant/col1a2-p-pro482his), [COL1A2 c.1197+5G>A](/variant/col1a2-c-1197-plus-5g-a), [COL1A2 c.1503+1G>A](/variant/col1a2-c-1503-plus-1g-a), [COL1A2 c.1503+1G>C](/variant/col1a2-c-1503-plus-1g-c), [COL1A2 c.1557+3A>G](/variant/col1a2-c-1557-plus-3a-g), [COL1A2 c.1972-1G>T](/variant/col1a2-c-1972-minus-1g-t).

### 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 254952). 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.*