# NM_080680.3(COL11A2):c.3021G>A (p.Pro1007=)

https://sugi.bio/variant/col11a2-p-pro1007

## Summary

**COL11A2 p.Pro1007= (c.3021G>A)** is classified **Likely benign** in COL11A2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-28). Ultra-rare (popmax 0.0417%, amr).

**At a glance:** Likely benign · review: Multiple submitters · rsID rs370652074 · 4 submitters · ultra-rare (popmax 0.0417%, amr)

## For patients & families {#patients}

This is a change in the COL11A2 gene that is classified as likely benign — not considered disease-causing, submitted by 4 submitters.

*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 | [COL11A2](https://sugi.bio/atlas/gene/COL11A2/) |
| Protein change (HGVS p.) | p.Pro1007= |
| Coding change (HGVS c.) | c.3021G>A |
| MANE Select transcript | [NM_080680](https://www.ncbi.nlm.nih.gov/nuccore/NM_080680) |
| dbSNP | [rs370652074](https://www.ncbi.nlm.nih.gov/snp/rs370652074/) |
| Variant type | single nucleotide variant |
| Location | chr6:33172071-33172071 (GRCh38) |
| ClinVar | [VCV1157473](https://www.ncbi.nlm.nih.gov/clinvar/variation/1157473/) |

**All HGVS expressions:** `NC_000006.11:g.33139848C>T`, `NC_000006.12:g.33172071C>T`, `NG_011589.1:g.25398G>A`, `NM_080679.3:c.2700G>A`, `NM_080680.3:c.3021G>A`, `NM_080681.3:c.2763G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.25) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -20, GERP -3.34 — fast-evolving / accelerated position
- CADD: **PHRED 6.6**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.25**, acceptor gain **0.03**, donor gain **0.06**. Largest is donor loss, 5 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.03**, donor gain **0.06**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.0417%** (amr) · FAF95 0.0289% · FAF99 0.0247% · 25/60,016 in the highest group · 97/1,612,862 alleles overall — ultra-rare (popmax 0.0417%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0417% | 2,401 |
| Remaining individuals (not grpmax-eligible) | 0.0064% | 15,625 |
| European (non-Finnish) | 0.00559% | 17,878 |
| African / African-American | 0.00267% | 37,490 |

*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 **1007** 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.Pro1007= 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-28.

**Submitter consensus:** unanimous (4/4 Likely benign).

**Submission history:** 4 submissions (2019–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-10-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-01-28 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-07-22 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-12-14 |

**Reported phenotype names (ClinVar):** not provided, COL11A2-related disorder, not specified, COL11A2-related condition, COL11A2-related disorders, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related COL11A2 variant pages (same residue, condition, or type): [COL11A2 p.Pro1007Leu](/variant/col11a2-p-pro1007leu), [COL11A2 p.Pro1007Ser](/variant/col11a2-p-pro1007ser), [COL11A2 c.1119+1G>A](/variant/col11a2-c-1119-plus-1g-a), [COL11A2 c.1819-2A>G](/variant/col11a2-c-1819-minus-2a-g), [COL11A2 c.3852+1G>T](/variant/col11a2-c-3852-plus-1g-t), [COL11A2 c.4392+1G>A](/variant/col11a2-c-4392-plus-1g-a), [COL11A2 c.607-2A>T](/variant/col11a2-c-607-minus-2a-t), [COL11A2 c.876+1G>A](/variant/col11a2-c-876-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 1157473). 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.*