# NM_001844.5(COL2A1):c.246C>T (p.Phe82=)

https://sugi.bio/variant/col2a1-p-phe82

## Summary

**COL2A1 p.Phe82= (c.246C>T)** is classified **Conflicting classifications of pathogenicity** in COL2A1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-11-03). Rare (popmax 0.18%, sas); Associated with Stickler syndrome type 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs142161948 · 7 submitters · 2 linked conditions · rare (popmax 0.18%, sas)

## 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 7 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.Phe82= |
| Coding change (HGVS c.) | c.246C>T |
| MANE Select transcript | [NM_001844](https://www.ncbi.nlm.nih.gov/nuccore/NM_001844) |
| dbSNP | [rs142161948](https://www.ncbi.nlm.nih.gov/snp/rs142161948/) |
| Variant type | single nucleotide variant |
| Location | chr12:47999965-47999965 (GRCh38) |
| ClinVar | [VCV308936](https://www.ncbi.nlm.nih.gov/clinvar/variation/308936/) |

**All HGVS expressions:** `NC_000012.11:g.48393748G>A`, `NC_000012.12:g.47999965G>A`, `NG_008072.1:g.9538C>T`, `NM_001844.5:c.246C>T`, `NM_033150.3:c.86-1534C>T`

## 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 5.071, GERP 0.877, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 15.28**. 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 (G>T, Δ0.21 donor loss), 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 **0.18%** (sas) · FAF95 0.158% · FAF99 0.149% · 164/91,084 in the highest group · 332/1,614,218 alleles overall — rare (popmax 0.18%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.18% | 555 |
| Middle Eastern | 0.0825% | 1,212 |
| African / African-American | 0.016% | 6,255 |
| Remaining individuals (not grpmax-eligible) | 0.0128% | 7,813 |
| European (non-Finnish) | 0.0119% | 8,429 |
| East Asian | 0.00446% | 22,445 |
| Admixed American | 0.00167% | 60,028 |

*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 **82** lies in 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.Phe82= 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-11-03.

**Submitter consensus:** conflicting (5 Likely benign, 2 Benign, 1 Uncertain significance).

**Submission history:** 8 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2018-05-14 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-07-20 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-10-15 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-06-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-03 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2023-08-01 |

## 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, COL2A1-related disorder, Type 2 collagenopathy, not specified, none provided, COL2A1-Related Stickler Syndrome, ARTHROOPHTHALMOPATHY, HEREDITARY PROGRESSIVE, STICKLER SYNDROME, MEMBRANOUS VITREOUS TYPE, STICKLER SYNDROME, VITREOUS TYPE 1.

## Similar variants {#similar}

Related COL2A1 variant pages (same residue, condition, or type): [COL2A1 p.Phe82Leu](/variant/col2a1-p-phe82leu), [COL2A1 p.Phe82Val](/variant/col2a1-p-phe82val), [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).

### 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 308936). 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.*