# NM_001844.5(COL2A1):c.1938T>C (p.Pro646=)

https://sugi.bio/variant/col2a1-p-pro646

## Summary

**COL2A1 p.Pro646= (c.1938T>C)** is classified **Conflicting classifications of pathogenicity** in COL2A1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-06-23). Very rare (popmax 0.00195%, nfe); Associated with Stickler syndrome type 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs368641858 · 3 submitters · 2 linked conditions · very rare (popmax 0.00195%, nfe)

## For patients & families {#patients}

This is a change in the COL2A1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to Stickler syndrome 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, Autosomal recessive |
| Age of onset (of this condition) | Antenatal, Childhood, Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 3 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | COL2A1 is a diagnostic-grade gene on 11 Genomics England panels |

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

- Malar flattening — Very frequent (99-80%)
- Epicanthus — Very frequent (99-80%)
- Microretrognathia — Very frequent (99-80%)
- Hypoplasia of the maxilla — Very frequent (99-80%)
- Long philtrum — Very frequent (99-80%)
- Visual impairment — Very frequent (99-80%)
- Telecanthus — Very frequent (99-80%)
- Cataract — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005018/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COL2A1](https://sugi.bio/atlas/gene/COL2A1/) |
| Protein change (HGVS p.) | p.Pro646= |
| Coding change (HGVS c.) | c.1938T>C |
| MANE Select transcript | [NM_001844](https://www.ncbi.nlm.nih.gov/nuccore/NM_001844) |
| dbSNP | [rs368641858](https://www.ncbi.nlm.nih.gov/snp/rs368641858/) |
| Variant type | single nucleotide variant |
| Location | chr12:47984090-47984090 (GRCh38) |
| ClinVar | [VCV308922](https://www.ncbi.nlm.nih.gov/clinvar/variation/308922/) |

**All HGVS expressions:** `NC_000012.11:g.48377873A>G`, `NC_000012.12:g.47984090A>G`, `NG_008072.1:g.25413T>C`, `NM_001844.5:c.1938T>C`, `NM_033150.3:c.1731T>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 -8.478, GERP -3.5 — fast-evolving / accelerated position
- CADD: **PHRED 0.701**. 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 **0.00195%** (nfe) · FAF95 0.0013% · FAF99 0.00109% · 23/1,179,496 in the highest group · 23/1,612,412 alleles overall — very rare (popmax 0.00195%, 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}

**COL2A1** population constraint: LOEUF 0.183, pLI 1, missense-Z 5.3873; 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):

- **achondrogenesis type II** — Definitive (AD)
- **Kniest dysplasia** — Definitive (AD)
- **Stickler syndrome type 1** — Definitive (AD)
- **dysplasia of the proximal femoral epiphyses** — Definitive (AD)

## Protein context {#protein}

Residue **646** lies in the 'disordered' region; the 'triple-helical region' region.

AlphaFold model confidence (whole protein): pLDDT 53.56, 16% of residues very-high.

**11 experimental structure(s)** (PDB): [1U5M](https://www.rcsb.org/structure/1U5M), [2FSE](https://www.rcsb.org/structure/2FSE), [2SEB](https://www.rcsb.org/structure/2SEB), [5MV4](https://www.rcsb.org/structure/5MV4), [5NIR](https://www.rcsb.org/structure/5NIR), [5OCX](https://www.rcsb.org/structure/5OCX).

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

*Describes the biological roles of COL2A1 (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:** COL2A1's established molecular role includes extracellular matrix structural constituent. p.Pro646= falls in the disordered region.


### Pathways affected {#pathways}

COL2A1 participates in **14 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 |
| [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 |
| [Integrin cell surface interactions](https://reactome.org/content/detail/R-HSA-216083) | electronic |

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

**Molecular function:** extracellular matrix structural constituent, extracellular matrix structural constituent conferring tensile strength, MHC class II protein binding, protein homodimerization activity, proteoglycan binding, platelet-derived growth factor binding.

**Biological process:** skeletal system development, chondrocyte differentiation, visual perception, sensory perception of sound, collagen fibril organization, embryonic skeletal joint morphogenesis.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2023-06-23.

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

**Submission history:** 4 submissions (2018–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-05-27 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-06-23 |

## Associated conditions {#conditions}

[Stickler syndrome type 1](https://sugi.bio/atlas/disease/stickler-syndrome-type-1/), [type 2 collagenopathy](https://sugi.bio/atlas/disease/type-2-collagenopathy/).

**Reported phenotype names (ClinVar):** Stickler syndrome type 1, not provided, Type 2 collagenopathy, not specified, COL2A1-Related Stickler Syndrome, ARTHROOPHTHALMOPATHY, HEREDITARY PROGRESSIVE, STICKLER SYNDROME, MEMBRANOUS VITREOUS TYPE, STICKLER SYNDROME, VITREOUS TYPE 1, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related COL2A1 variant pages (same residue, condition, or type): [COL2A1 c.1222-2A>G](/variant/col2a1-c-1222-minus-2a-g), [COL2A1 c.1365+1G>A](/variant/col2a1-c-1365-plus-1g-a), [COL2A1 c.1420-2A>G](/variant/col2a1-c-1420-minus-2a-g), [COL2A1 c.1527+135G>A](/variant/col2a1-c-1527-plus-135g-a), [COL2A1 c.1581+1G>A](/variant/col2a1-c-1581-plus-1g-a), [COL2A1 c.1833+1G>A](/variant/col2a1-c-1833-plus-1g-a), [COL2A1 c.1887+1G>A](/variant/col2a1-c-1887-plus-1g-a), [COL2A1 c.1888-2A>C](/variant/col2a1-c-1888-minus-2a-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 308922). 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.*