# NM_001848.3(COL6A1):c.3077C>T (p.Ala1026Val)

https://sugi.bio/variant/col6a1-p-ala1026val

## Summary

**COL6A1 p.Ala1026Val (c.3077C>T)** is classified **Conflicting classifications of pathogenicity** in COL6A1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-12-31). AlphaMissense: likely benign (0.1544); Very rare (popmax 0.00659%, sas); Associated with Bethlem myopathy 1A.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs767414809 · 3 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00659%, sas)

## For patients & families {#patients}

This is a change in the COL6A1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, 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.Ala1026Val |
| Coding change (HGVS c.) | c.3077C>T |
| MANE Select transcript | [NM_001848](https://www.ncbi.nlm.nih.gov/nuccore/NM_001848) |
| dbSNP | [rs767414809](https://www.ncbi.nlm.nih.gov/snp/rs767414809/) |
| Variant type | single nucleotide variant |
| Location | chr21:46004003-46004003 (GRCh38) |
| ClinVar | [VCV1013647](https://www.ncbi.nlm.nih.gov/clinvar/variation/1013647/) |

**All HGVS expressions:** `LRG_475:g.27255C>T`, `NC_000021.8:g.47423917C>T`, `NC_000021.9:g.46004003C>T`, `NG_008674.1:g.27255C>T`, `NM_001848.3:c.3077C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1544)
- REVEL 0.385 (indeterminate)
- SaProt LLR -8.339 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 3.083, GERP 1.56, phastCons 0.997 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.6**. 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.*
- Regional missense constraint: **o/e 0.93** across the covering region of the MANE Select transcript (45,990,418–46,004,010), spanning 13,592 bp. Chi-square p 0.038. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.00659%** (sas) · FAF95 0.00286% · FAF99 0.00195% · 6/91,078 in the highest group · 16/1,612,970 alleles overall — very rare (popmax 0.00659%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00659% | 15,180 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,604 |
| African / African-American | 0.00133% | 74,950 |
| European (non-Finnish) | 0.000678% | 147,501 |

*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 **1026** 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.Ala1026Val 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-12-31.

**Submitter consensus:** conflicting (2 Uncertain significance, 1 Benign).

**Submission history:** 3 submissions (2023–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-12 |
| Revvity Omics, Revvity | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-05-14 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2024-12-31 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Bethlem myopathy 1A, not provided, not specified, none provided, Bethlem Muscular Dystrophy, MYOPATHY, BENIGN CONGENITAL, WITH CONTRACTURES, Bethlem myopathy 1, AllHighlyPenetrant.

## Similar variants {#similar}

Related COL6A1 variant pages (same residue, condition, or type): [COL6A1 p.Ala1026=](/variant/col6a1-p-ala1026), [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), [COL6A1 c.1056+2T>A](/variant/col6a1-c-1056-plus-2t-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 1013647). 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.*