# NM_080680.3(COL11A2):c.2682G>A (p.Pro894=)

https://sugi.bio/variant/col11a2-p-pro894

## Summary

**COL11A2 p.Pro894= (c.2682G>A)** is classified **Conflicting classifications of pathogenicity** in COL11A2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-24). Rare (popmax 0.186%, afr); Associated with otospondylomegaepiphyseal dysplasia, autosomal recessive.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs113067047 · 6 submitters · 3 linked conditions · rare (popmax 0.186%, afr)

## For patients & families {#patients}

This is a change in the COL11A2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 6 submitters, and is linked to otospondylomegaepiphyseal dysplasia, autosomal recessive.

*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 recessive |
| Age of onset (of this condition) | Antenatal, Neonatal |
| Diagnostic panels | COL11A2 is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Autosomal recessive otospondylomegaepiphyseal dysplasia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Sensorineural hearing impairment — Very frequent (99-80%)
- Anteverted nares — Very frequent (99-80%)
- Abnormal joint morphology — Very frequent (99-80%)
- Abnormal vertebral morphology — Very frequent (99-80%)
- Disproportionate short stature — Very frequent (99-80%)
- Depressed nasal bridge — Very frequent (99-80%)
- Midface retrusion — Very frequent (99-80%)
- Abnormal pelvis bone morphology — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025881/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COL11A2](https://sugi.bio/atlas/gene/COL11A2/) |
| Protein change (HGVS p.) | p.Pro894= |
| Coding change (HGVS c.) | c.2682G>A |
| MANE Select transcript | [NM_080680](https://www.ncbi.nlm.nih.gov/nuccore/NM_080680) |
| dbSNP | [rs113067047](https://www.ncbi.nlm.nih.gov/snp/rs113067047/) |
| Variant type | single nucleotide variant |
| Location | chr6:33173502-33173502 (GRCh38) |
| ClinVar | [VCV178327](https://www.ncbi.nlm.nih.gov/clinvar/variation/178327/) |

**All HGVS expressions:** `NC_000006.11:g.33141279C>T`, `NC_000006.12:g.33173502C>T`, `NG_011589.1:g.23967G>A`, `NM_080679.3:c.2361G>A`, `NM_080680.3:c.2682G>A`, `NM_080681.3:c.2424G>A`

## 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 -2.147, GERP -3.74 — fast-evolving / accelerated position
- CADD: **PHRED 19.17**. 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 **0.186%** (afr) · FAF95 0.16% · FAF99 0.151% · 137/73,790 in the highest group · 278/1,609,662 alleles overall — rare (popmax 0.186%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.186% | 539 |
| Admixed American | 0.0539% | 1,855 |
| Remaining individuals (not grpmax-eligible) | 0.0256% | 3,902 |
| Middle Eastern | 0.0166% | 6,040 |
| European (non-Finnish) | 0.00729% | 13,712 |
| East Asian | 0.00671% | 14,898 |
| South Asian | 0.0033% | 30,320 |

*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}

**COL11A2** population constraint: LOEUF 0.503, pLI 0.00022512, missense-Z 3.4045. *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):

- **nonsyndromic genetic hearing loss** — Definitive (AD)
- **otospondylomegaepiphyseal dysplasia** — Definitive (AD)
- **otospondylomegaepiphyseal dysplasia** — Definitive (AR)
- **nonsyndromic genetic hearing loss** — Moderate (AR)

## Protein context {#protein}

Residue **894** lies in the 'disordered' region; the 'triple-helical region' region; a UniProt-annotated variant site (in); the collagen-like 5 domain.

AlphaFold model confidence (whole protein): pLDDT 50.18, 13% of residues very-high.

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

*Describes the biological roles of COL11A2 (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:** COL11A2's established molecular role includes extracellular matrix structural constituent conferring tensile strength. p.Pro894= falls in the disordered region.


### Pathways affected {#pathways}

COL11A2 participates in **8 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 |
| [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 |
| [Collagen degradation](https://reactome.org/content/detail/R-HSA-1442490) | electronic |

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

**Molecular function:** extracellular matrix structural constituent conferring tensile strength.

**Biological process:** skeletal system development, sensory perception of sound, collagen fibril organization, cartilage development, roof of mouth development, soft palate development.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-24.

**Submitter consensus:** conflicting (5 Uncertain significance, 3 Likely benign).

**Submission history:** 8 submissions (2016–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-07-21 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-07 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-08-12 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2021-08-31 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-24 |

## Associated conditions {#conditions}

[otospondylomegaepiphyseal dysplasia, autosomal recessive](https://sugi.bio/atlas/disease/otospondylomegaepiphyseal-dysplasia-autosomal-recessive/), [otospondylomegaepiphyseal dysplasia, autosomal dominant](https://sugi.bio/atlas/disease/otospondylomegaepiphyseal-dysplasia-autosomal-dominant/), [fibrochondrogenesis 2](https://sugi.bio/atlas/disease/fibrochondrogenesis-2/).

**Reported phenotype names (ClinVar):** Otospondylomegaepiphyseal dysplasia, autosomal recessive, not specified, Otospondylomegaepiphyseal dysplasia, autosomal dominant, Fibrochondrogenesis 2, not provided, COL11A2-related disorder, COL11A2-related condition, COL11A2-related disorders, AllHighlyPenetrant, Insley-Astley syndrome.

## Similar variants {#similar}

Related COL11A2 variant pages (same residue, condition, or type): [COL11A2 p.Pro894Leu](/variant/col11a2-p-pro894leu), [COL11A2 p.Pro894Arg](/variant/col11a2-p-pro894arg), [COL11A2 c.4392+1G>A](/variant/col11a2-c-4392-plus-1g-a), [COL11A2 p.Arg1020Ter](/variant/col11a2-p-arg1020ter), [COL11A2 p.Arg1331Ter](/variant/col11a2-p-arg1331ter), [COL11A2 p.Arg1379Ter](/variant/col11a2-p-arg1379ter), [COL11A2 p.Arg1600Ter](/variant/col11a2-p-arg1600ter), [COL11A2 p.Arg379Ter](/variant/col11a2-p-arg379ter).

### 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 178327). 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.*