# NM_080680.3(COL11A2):c.3111G>T (p.Pro1037=)

https://sugi.bio/variant/col11a2-p-pro1037

## Summary

**COL11A2 p.Pro1037= (c.3111G>T)** is classified **Benign/Likely benign** in COL11A2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-02-02). Low-frequency (popmax 3.28%, sas); Associated with fibrochondrogenesis 2.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs146093235 · 10 submitters · 3 linked conditions · low-frequency (popmax 3.28%, sas)

## For patients & families {#patients}

This is a change in the COL11A2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 10 submitters, and is linked to fibrochondrogenesis 2.

*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) | Neonatal |
| Diagnostic panels | COL11A2 is a diagnostic-grade gene on 7 Genomics England panels |

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

- Wide anterior fontanel — Very frequent (99-80%)
- Round face — Very frequent (99-80%)
- Short neck — Very frequent (99-80%)
- Proptosis — Very frequent (99-80%)
- Abnormal rib morphology — Very frequent (99-80%)
- Short ribs — Very frequent (99-80%)
- Narrow chest — Very frequent (99-80%)
- Broad ribs — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015815/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.Pro1037= |
| Coding change (HGVS c.) | c.3111G>T |
| MANE Select transcript | [NM_080680](https://www.ncbi.nlm.nih.gov/nuccore/NM_080680) |
| dbSNP | [rs146093235](https://www.ncbi.nlm.nih.gov/snp/rs146093235/) |
| Variant type | single nucleotide variant |
| Location | chr6:33171752-33171752 (GRCh38) |
| ClinVar | [VCV197474](https://www.ncbi.nlm.nih.gov/clinvar/variation/197474/) |

**All HGVS expressions:** `NC_000006.11:g.33139529C>A`, `NC_000006.12:g.33171752C>A`, `NG_011589.1:g.25717G>T`, `NM_080679.3:c.2790G>T`, `NM_080680.3:c.3111G>T`, `NM_080681.3:c.2853G>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 -15, GERP -3.74 — fast-evolving / accelerated position
- CADD: **PHRED 0.123**. 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 **3.28%** (sas) · FAF95 3.18% · FAF99 3.14% · 2,986/91,068 in the highest group · 3,587/1,612,914 alleles overall — low-frequency (popmax 3.28%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 3.28% | 30 |
| Remaining individuals (not grpmax-eligible) | 0.429% | 233 |
| East Asian | 0.227% | 440 |
| Middle Eastern | 0.132% | 758 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.122% | 822 |
| African / African-American | 0.0786% | 1,272 |
| European (non-Finnish) | 0.0105% | 9,516 |
| Admixed American | 0.00666% | 15,006 |

*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 **1037** lies in the 'disordered' region; the 'triple-helical region' region.

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.Pro1037= 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-02.

**Submitter consensus:** conflicting (9 Benign, 2 Likely benign).

**Submission history:** 11 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-03-27 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2015-05-05 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Benign | criteria provided, single submitter | clinical testing | 2021-05-21 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2015-03-16 |
| Genome Diagnostics Laboratory, Amsterdam University Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-02 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Fibrochondrogenesis 2, not specified, Otospondylomegaepiphyseal dysplasia, autosomal recessive, not provided, Connective tissue disorder, Connective tissue disease, AllHighlyPenetrant, none provided, CHONDRODYSTROPHY WITH SENSORINEURAL DEAFNESS, Insley-Astley syndrome.

## Similar variants {#similar}

Related COL11A2 variant pages (same residue, condition, or type): [COL11A2 p.Pro1037Leu](/variant/col11a2-p-pro1037leu), [COL11A2 p.Arg1020Ter](/variant/col11a2-p-arg1020ter), [COL11A2 p.Arg1331Ter](/variant/col11a2-p-arg1331ter), [COL11A2 p.Arg1600Ter](/variant/col11a2-p-arg1600ter), [COL11A2 p.Arg433Ter](/variant/col11a2-p-arg433ter), [COL11A2 p.Arg558Ter](/variant/col11a2-p-arg558ter), [COL11A2 p.Gly1027Glu](/variant/col11a2-p-gly1027glu), [COL11A2 c.2682+5G>A](/variant/col11a2-c-2682-plus-5g-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 197474). 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.*