# NM_000089.4(COL1A2):c.1881T>C (p.Val627=)

https://sugi.bio/variant/col1a2-p-val627

## Summary

**COL1A2 p.Val627= (c.1881T>C)** is classified **Likely benign** in COL1A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-07). Very rare (popmax 0.00521%, amr); Associated with Ehlers-Danlos syndrome, classic type, 1.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 2 linked conditions · very rare (popmax 0.00521%, amr)

## For patients & families {#patients}

This is a change in the COL1A2 gene that is classified as likely 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 | COL1A2 is a diagnostic-grade gene on 6 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 | [COL1A2](https://sugi.bio/atlas/gene/COL1A2/) |
| Protein change (HGVS p.) | p.Val627= |
| Coding change (HGVS c.) | c.1881T>C |
| MANE Select transcript | [NM_000089](https://www.ncbi.nlm.nih.gov/nuccore/NM_000089) |
| Variant type | single nucleotide variant |
| Location | chr7:94417741-94417741 (GRCh38) |
| ClinVar | [VCV4792599](https://www.ncbi.nlm.nih.gov/clinvar/variation/4792599/) |

**All HGVS expressions:** `LRG_2:g.28181T>C`, `LRG_2t1:c.1881T>C`, `NC_000007.13:g.94047053T>C`, `NC_000007.14:g.94417741T>C`, `NG_007405.1:g.28181T>C`, `NM_000089.4:c.1881T>C`

## 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 -7.39, GERP -4.38 — fast-evolving / accelerated position
- CADD: **PHRED 0.28**. 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 (T>A, Δ0.20 acceptor 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 **0.00521%** (amr) · FAF95 0.00138% · FAF99 0.000683% · 3/57,578 in the highest group · 3/1,444,524 alleles overall — very rare (popmax 0.00521%, amr).

*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 **627** 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.Val627= 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-10-07.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-07 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Ehlers-Danlos syndrome, classic type, 1, Osteogenesis imperfecta type I, EHLERS-DANLOS SYNDROME, GRAVIS TYPE, EHLERS-DANLOS SYNDROME, SEVERE CLASSIC TYPE, Ehlers-Danlos syndrome, type 1, Ehlers-Danlos Syndrome, Classic Type, COL5A1-Related, EDS I, OI, TYPE I, OSTEOGENESIS IMPERFECTA TARDA, OSTEOGENESIS IMPERFECTA WITH BLUE SCLERAE.

## Similar variants {#similar}

Related COL1A2 variant pages (same residue, condition, or type): [COL1A2 p.Val627Ala](/variant/col1a2-p-val627ala), [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 4792599). 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.*