# NM_001848.3(COL6A1):c.1959C>T (p.Phe653=)

https://sugi.bio/variant/col6a1-p-phe653

## Summary

**COL6A1 p.Phe653= (c.1959C>T)** is classified **Conflicting classifications of pathogenicity** in COL6A1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-02-02). Ultra-rare (popmax 0.0866%, afr); Associated with Bethlem myopathy 1A.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs112104768 · 4 submitters · 1 linked condition · ultra-rare (popmax 0.0866%, afr)

## 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 4 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.Phe653= |
| Coding change (HGVS c.) | c.1959C>T |
| MANE Select transcript | [NM_001848](https://www.ncbi.nlm.nih.gov/nuccore/NM_001848) |
| dbSNP | [rs112104768](https://www.ncbi.nlm.nih.gov/snp/rs112104768/) |
| Variant type | single nucleotide variant |
| Location | chr21:46001963-46001963 (GRCh38) |
| ClinVar | [VCV476423](https://www.ncbi.nlm.nih.gov/clinvar/variation/476423/) |

**All HGVS expressions:** `LRG_475:g.25215C>T`, `LRG_475t1:c.1959C>T`, `NC_000021.8:g.47421877C>T`, `NC_000021.9:g.46001963C>T`, `NG_008674.1:g.25215C>T`, `NM_001848.3:c.1959C>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 -9.532, GERP -2.43 — fast-evolving / accelerated position
- CADD: **PHRED 0.083**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.41 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0866%** (afr) · FAF95 0.0697% · FAF99 0.0636% · 65/75,030 in the highest group · 131/1,612,046 alleles overall — ultra-rare (popmax 0.0866%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0866% | 1,154 |
| Admixed American | 0.015% | 6,664 |
| Remaining individuals (not grpmax-eligible) | 0.0144% | 6,939 |
| South Asian | 0.0044% | 22,721 |
| European (non-Finnish) | 0.00364% | 27,435 |
| Finnish (not grpmax-eligible) | 0.0016% | 62,624 |

*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 **653** lies in the vwfa 2 domain; 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.Phe653= falls in the vwfa 2 domain.


### 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 2026-02-02.

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

**Submission history:** 4 submissions (2017–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2020-01-13 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-05-25 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-02 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2021-09-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Bethlem myopathy 1A, not provided, COL6A1-related disorder, COL6A1-related condition, none provided, Bethlem Muscular Dystrophy, MYOPATHY, BENIGN CONGENITAL, WITH CONTRACTURES, Bethlem myopathy 1.

## Similar variants {#similar}

Related COL6A1 variant pages (same residue, condition, or type): [COL6A1 p.Phe653Leu](/variant/col6a1-p-phe653leu), [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 476423). 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.*