# NM_001848.3(COL6A1):c.1839C>T (p.Pro613=)

https://sugi.bio/variant/col6a1-p-pro613

## Summary

**COL6A1 p.Pro613= (c.1839C>T)** is classified **Likely benign** in COL6A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-17). Ultra-rare (popmax 0.0117%, amr); Associated with Bethlem myopathy 1A.

**At a glance:** Likely benign · review: Single submitter · rsID rs753486364 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0117%, amr)

## For patients & families {#patients}

This is a change in the COL6A1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to Bethlem myopathy 1A.

*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) | Childhood, Infancy |
| Prevalence | 1-9 / 1 000 000 (United Kingdom) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | COL6A1 is a diagnostic-grade gene on 10 Genomics England panels |

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

- Muscle weakness — Very frequent (99-80%)
- Flexion contracture — Very frequent (99-80%)
- EMG: myopathic abnormalities — Very frequent (99-80%)
- Muscular dystrophy — Very frequent (99-80%)
- Progressive proximal muscle weakness — Very frequent (99-80%)
- Reduced muscle collagen VI — Very frequent (99-80%)
- Neck muscle weakness — Frequent (79-30%)
- Interphalangeal joint contracture of finger — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0025413/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [COL6A1](https://sugi.bio/atlas/gene/COL6A1/) |
| Protein change (HGVS p.) | p.Pro613= |
| Coding change (HGVS c.) | c.1839C>T |
| MANE Select transcript | [NM_001848](https://www.ncbi.nlm.nih.gov/nuccore/NM_001848) |
| dbSNP | [rs753486364](https://www.ncbi.nlm.nih.gov/snp/rs753486364/) |
| Variant type | single nucleotide variant |
| Location | chr21:46001269-46001269 (GRCh38) |
| ClinVar | [VCV1113757](https://www.ncbi.nlm.nih.gov/clinvar/variation/1113757/) |

**All HGVS expressions:** `LRG_475:g.24521C>T`, `NC_000021.8:g.47421183C>T`, `NC_000021.9:g.46001269C>T`, `NG_008674.1:g.24521C>T`, `NM_001848.3:c.1839C>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 0.756, GERP -2.13, phastCons 0.999 — weakly conserved position
- CADD: **PHRED 12.62**. 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 **0.0117%** (amr) · FAF95 0.00543% · FAF99 0.0038% · 7/60,000 in the highest group · 7/1,609,758 alleles overall — ultra-rare (popmax 0.0117%, amr).

*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}

**COL6A1** population constraint: LOEUF 0.706, pLI 4.5705e-14, missense-Z 0.3978. *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):

- **collagen 6-related myopathy** — Definitive (AD)
- **collagen 6-related myopathy** — Definitive (AR)

## Protein context {#protein}

Residue **613** lies in the 'c-terminal globular domain' region.

AlphaFold model confidence (whole protein): pLDDT 71.28, 30% of residues very-high.

**1 experimental structure(s)** (PDB): [9GTU](https://www.rcsb.org/structure/9GTU).

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

*Describes the biological roles of COL6A1 (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:** COL6A1's established molecular role includes collagen binding. p.Pro613= falls in the c-terminal globular domain region.


### Pathways affected {#pathways}

COL6A1 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 |
| [Collagen degradation](https://reactome.org/content/detail/R-HSA-1442490) | curated |
| [Integrin cell surface interactions](https://reactome.org/content/detail/R-HSA-216083) | curated |
| [NCAM1 interactions](https://reactome.org/content/detail/R-HSA-419037) | curated |
| [Signaling by PDGF](https://reactome.org/content/detail/R-HSA-186797) | curated |
| [ECM proteoglycans](https://reactome.org/content/detail/R-HSA-3000178) | electronic |

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

**Molecular function:** collagen binding, platelet-derived growth factor binding.

**Biological process:** osteoblast differentiation, endodermal cell differentiation.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-10-17.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-10-17 |

## Associated conditions {#conditions}

[Bethlem myopathy 1A](https://sugi.bio/atlas/disease/bethlem-myopathy-1a/).

**Reported phenotype names (ClinVar):** Bethlem myopathy 1A, MYOPATHY, BENIGN CONGENITAL, WITH CONTRACTURES, Bethlem Muscular Dystrophy, Bethlem myopathy 1.

## Similar variants {#similar}

Related COL6A1 variant pages (same residue, condition, or type): [COL6A1 p.Pro613Thr](/variant/col6a1-p-pro613thr), [COL6A1 p.Pro613Ser](/variant/col6a1-p-pro613ser), [COL6A1 c.1002+1G>A](/variant/col6a1-c-1002-plus-1g-a), [COL6A1 c.1003-1G>A](/variant/col6a1-c-1003-minus-1g-a), [COL6A1 c.1003-2A>C](/variant/col6a1-c-1003-minus-2a-c), [COL6A1 c.1003-2A>G](/variant/col6a1-c-1003-minus-2a-g), [COL6A1 c.1056+1G>A](/variant/col6a1-c-1056-plus-1g-a), [COL6A1 c.1056+1G>C](/variant/col6a1-c-1056-plus-1g-c).

### 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 1113757). 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.*