# NM_001844.5(COL2A1):c.163del (p.Cys55fs)

https://sugi.bio/variant/col2a1-p-cys55fs

## Summary

**COL2A1 p.Cys55fs (c.163del)** is classified **Pathogenic** in COL2A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-19). No gnomAD frequency available for this variant.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2540187705 · 1 submitter · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the COL2A1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter.

*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:** [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.Cys55fs |
| Coding change (HGVS c.) | c.163del |
| MANE Select transcript | [NM_001844](https://www.ncbi.nlm.nih.gov/nuccore/NM_001844) |
| dbSNP | [rs2540187705](https://www.ncbi.nlm.nih.gov/snp/rs2540187705/) |
| Variant type | Deletion |
| Location | chr12:48000048-48000048 (GRCh38) |
| ClinVar | [VCV2018053](https://www.ncbi.nlm.nih.gov/clinvar/variation/2018053/) |

**All HGVS expressions:** `NC_000012.11:g.48393831del`, `NC_000012.12:g.48000048del`, `NG_008072.1:g.9455del`, `NM_001844.5:c.163del`, `NM_033150.3:c.86-1617del`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.693, GERP 1.9, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.183, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 2 of 54**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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, 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):

- **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 **55** lies in a β-strand; the vwfc domain.

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.Cys55fs falls in the vwfc domain.


### 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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-07-19.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-07-19 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related COL2A1 variant pages (same residue, condition, or type): [COL2A1 p.Cys55Ser](/variant/col2a1-p-cys55ser), [COL2A1 p.Cys55Tyr](/variant/col2a1-p-cys55tyr), [COL2A1 c.1023+3_1023+6del](/variant/col2a1-c-1023-plus-3-1023-plus-6del), [COL2A1 c.610-17_617del](/variant/col2a1-c-610-minus-17-617del), [COL2A1 c.906_924+9del](/variant/col2a1-c-906-924-plus-9del), [COL2A1 p.1205PGP[2]](/variant/col2a1-p-1205pgp-2), [COL2A1 p.722PGT[1]](/variant/col2a1-p-722pgt-1), [COL2A1 p.Asp1234fs](/variant/col2a1-p-asp1234fs).

### 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 2018053). 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.*