# NM_000089.4(COL1A2):c.2050C>T (p.Pro684Ser)

https://sugi.bio/variant/col1a2-p-pro684ser

## Summary

**COL1A2 p.Pro684Ser (c.2050C>T)** is classified **Uncertain significance** in COL1A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-04). AlphaMissense: likely benign (0.121); Very rare (popmax 0.00134%, afr); Associated with osteogenesis imperfecta type 1.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs747954056 · 2 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00134%, afr)

## For patients & families {#patients}

This is a change in the COL1A2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 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.Pro684Ser |
| Coding change (HGVS c.) | c.2050C>T |
| MANE Select transcript | [NM_000089](https://www.ncbi.nlm.nih.gov/nuccore/NM_000089) |
| dbSNP | [rs747954056](https://www.ncbi.nlm.nih.gov/snp/rs747954056/) |
| Variant type | single nucleotide variant |
| Location | chr7:94419522-94419522 (GRCh38) |
| ClinVar | [VCV1021100](https://www.ncbi.nlm.nih.gov/clinvar/variation/1021100/) |

**All HGVS expressions:** `LRG_2:g.29962C>T`, `LRG_2t1:c.2050C>T`, `NC_000007.13:g.94048834C>T`, `NC_000007.14:g.94419522C>T`, `NG_007405.1:g.29962C>T`, `NM_000089.3:c.2050C>T`, `NM_000089.4:c.2050C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.121)
- REVEL 0.576 (indeterminate)
- SaProt LLR -8.102 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 7.677, GERP 2.04, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.3**. 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 0.71** across the covering region of the MANE Select transcript (94,408,361–94,427,726), spanning 19,365 bp. Chi-square p 2.5e-23. 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 **0.00134%** (afr) · FAF95 0.000183% · FAF99 0.00012% · 1/74,852 in the highest group · 7/1,613,836 alleles overall — very rare (popmax 0.00134%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00134% | 74,852 |
| European (non-Finnish) | 0.000508% | 196,661 |

*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 **684** lies in a UniProt-annotated variant site (in oi2); 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.Pro684Ser 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-04.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-15 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-04 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Osteogenesis imperfecta type I, Ehlers-Danlos syndrome, classic type, 1, Cardiovascular phenotype, OI, TYPE I, OSTEOGENESIS IMPERFECTA TARDA, OSTEOGENESIS IMPERFECTA WITH BLUE SCLERAE, Osteogenesis imperfecta type 1, Classic Non-deforming Osteogenesis Imperfecta with Blue Sclerae, Lobstein's Disease, Lobstein disease.

## Similar variants {#similar}

Related COL1A2 variant pages (same residue, condition, or type): [COL1A2 p.Pro684=](/variant/col1a2-p-pro684), [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.2026-2A>G](/variant/col1a2-c-2026-minus-2a-g), [COL1A2 c.2133+6T>A](/variant/col1a2-c-2133-plus-6t-a), [COL1A2 c.226-2A>G](/variant/col1a2-c-226-minus-2a-g).

### 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 1021100). 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.*