# NM_080680.3(COL11A2):c.3020C>T (p.Pro1007Leu)

https://sugi.bio/variant/col11a2-p-pro1007leu

## Summary

**COL11A2 p.Pro1007Leu (c.3020C>T)** is classified **Conflicting classifications of pathogenicity** in COL11A2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-04). AlphaMissense: likely benign (0.1963); Very rare (popmax 0.00237%, nfe); Associated with Inborn genetic diseases.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs771092817 · 4 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00237%, nfe)

## 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 4 submitters, and is linked to Inborn genetic diseases.

*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.Pro1007Leu |
| Coding change (HGVS c.) | c.3020C>T |
| MANE Select transcript | [NM_080680](https://www.ncbi.nlm.nih.gov/nuccore/NM_080680) |
| dbSNP | [rs771092817](https://www.ncbi.nlm.nih.gov/snp/rs771092817/) |
| Variant type | single nucleotide variant |
| Location | chr6:33172072-33172072 (GRCh38) |
| ClinVar | [VCV1687700](https://www.ncbi.nlm.nih.gov/clinvar/variation/1687700/) |

**All HGVS expressions:** `NC_000006.11:g.33139849G>A`, `NC_000006.12:g.33172072G>A`, `NG_011589.1:g.25397C>T`, `NM_080679.3:c.2699C>T`, `NM_080680.3:c.3020C>T`, `NM_080681.3:c.2762C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1963)
- REVEL 0.804 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -8.328 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** REVEL calls this damaging; AlphaMissense and SaProt do not
- SpliceAI predicts **acceptor loss** (Δ 0.23) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 9.956, GERP 1.67, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 31.0**. 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.*
- Regional missense constraint: **o/e 0.81** across the covering region of the MANE Select transcript (33,163,681–33,192,240), spanning 28,559 bp. Chi-square p 3e-20. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.23**, donor loss **0.21**, acceptor gain **0.00**, donor gain **0.04**. Largest is acceptor loss, 31 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.04**.
  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.*
- Pangolin: Δ**0.28** (loss), gain 0.01 / loss 0.28. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00237%** (nfe) · FAF95 0.00164% · FAF99 0.00142% · 28/1,179,938 in the highest group · 36/1,612,634 alleles overall — very rare (popmax 0.00237%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.00636% | 15,728 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,236 |
| European (non-Finnish) (grpmax) | 0.00237% | 42,141 |
| Admixed American | 0.00167% | 59,988 |
| South Asian | 0.0011% | 91,054 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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.Pro1007Leu 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 2025-12-04.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Likely benign).

**Submission history:** 4 submissions (2021–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-11-24 |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-04-05 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-08-22 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases, not provided, COL11A2-related disorder, none provided, COL11A2-related condition, COL11A2-related disorders.

## Similar variants {#similar}

Related COL11A2 variant pages (same residue, condition, or type): [COL11A2 p.Pro1007=](/variant/col11a2-p-pro1007), [COL11A2 p.Pro1007Ser](/variant/col11a2-p-pro1007ser), [COL11A2 p.Ala216Glu](/variant/col11a2-p-ala216glu), [COL11A2 p.Ala66Pro](/variant/col11a2-p-ala66pro), [COL11A2 p.Ala827Gly](/variant/col11a2-p-ala827gly), [COL11A2 p.Arg1596Gln](/variant/col11a2-p-arg1596gln), [COL11A2 p.Arg1667Ser](/variant/col11a2-p-arg1667ser), [COL11A2 p.Arg36Gln](/variant/col11a2-p-arg36gln).

### 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 1687700). 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.*