# NM_001849.4(COL6A2):c.1854C>T (p.Phe618=)

https://sugi.bio/variant/col6a2-p-phe618

## Summary

**COL6A2 p.Phe618= (c.1854C>T)** is classified **Likely benign** in COL6A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-03). Very rare (popmax 0.00333%, amr); Associated with Bethlem myopathy 1A.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs770024474 · 2 submitters · 1 linked condition · very rare (popmax 0.00333%, amr)

## For patients & families {#patients}

This is a change in the COL6A2 gene that is classified as likely benign — not considered disease-causing, submitted by 2 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 | COL6A2 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 | [COL6A2](https://sugi.bio/atlas/gene/COL6A2/) |
| Protein change (HGVS p.) | p.Phe618= |
| Coding change (HGVS c.) | c.1854C>T |
| MANE Select transcript | [NM_001849](https://www.ncbi.nlm.nih.gov/nuccore/NM_001849) |
| dbSNP | [rs770024474](https://www.ncbi.nlm.nih.gov/snp/rs770024474/) |
| Variant type | single nucleotide variant |
| Location | chr21:46125502-46125502 (GRCh38) |
| ClinVar | [VCV1137287](https://www.ncbi.nlm.nih.gov/clinvar/variation/1137287/) |

**All HGVS expressions:** `LRG_476:g.32384C>T`, `NC_000021.8:g.47545416C>T`, `NC_000021.9:g.46125502C>T`, `NG_008675.1:g.32384C>T`, `NM_001849.4:c.1854C>T`, `NM_058174.3:c.1854C>T`, `NM_058175.3:c.1854C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor gain** (Δ 0.41) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.363, GERP 0.464, phastCons 0.054 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 19.18**. 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 **0.01**, donor loss **0.00**, acceptor gain **0.41**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.41**, donor gain **0.00**.
- Pangolin: Δ**0.22** (gain), gain 0.22 / loss 0.04. 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 **0.00333%** (amr) · FAF95 0.000615% · FAF99 0.000474% · 2/60,024 in the highest group · 16/1,460,674 alleles overall — very rare (popmax 0.00333%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00333% | 30,012 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,484 |
| European (non-Finnish) | 0.0011% | 90,767 |

*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}

**COL6A2** population constraint: LOEUF 0.895, pLI 5.0534e-23, missense-Z -0.91252. *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 **618** lies in the vwfa 2 domain; the 'nonhelical region' region.

AlphaFold model confidence (whole protein): pLDDT 69.58, 18% 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 COL6A2 (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:** COL6A2's established molecular role includes collagen binding. p.Phe618= falls in the vwfa 2 domain.


### Pathways affected {#pathways}

COL6A2 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, extracellular matrix structural constituent conferring tensile strength.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-03.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-11-03 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Bethlem myopathy 1A, not specified, MYOPATHY, BENIGN CONGENITAL, WITH CONTRACTURES, Bethlem myopathy 1, Bethlem Muscular Dystrophy, AllHighlyPenetrant.

## Similar variants {#similar}

Related COL6A2 variant pages (same residue, condition, or type): [COL6A2 p.Phe618del](/variant/col6a2-p-phe618del), [COL6A2 c.1000-1G>T](/variant/col6a2-c-1000-minus-1g-t), [COL6A2 c.1000-2A>C](/variant/col6a2-c-1000-minus-2a-c), [COL6A2 c.1053+1G>A](/variant/col6a2-c-1053-plus-1g-a), [COL6A2 c.1053+1G>C](/variant/col6a2-c-1053-plus-1g-c), [COL6A2 c.1053+2T>C](/variant/col6a2-c-1053-plus-2t-c), [COL6A2 c.1054-2A>G](/variant/col6a2-c-1054-minus-2a-g), [COL6A2 c.115+2T>C](/variant/col6a2-c-115-plus-2t-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 1137287). 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.*