Is COL6A2 p.Arg453= (c.1359C>T) pathogenic?

COL6A2 p.Arg453= (c.1359C>T) is classified Conflicting classifications of pathogenicity in COL6A2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.0245%, amr); Associated with collagen 6-related myopathy.

What condition is associated with COL6A2 p.Arg453= (c.1359C>T)?

COL6A2 p.Arg453= (c.1359C>T) is associated with collagen 6-related myopathy, Bethlem myopathy 1A (ClinVar).

How common is COL6A2 p.Arg453= (c.1359C>T) in the general population?

COL6A2 p.Arg453= (c.1359C>T) is ultra-rare (popmax 0.0245%, amr) (gnomAD).

COL6A2 p.Arg453=

c.1359C>T · rs750842859 · VCV285638

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, amr)

Conditions

collagen 6-related myopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.35	GERP -2.9, phastCons 0.008
Overall
CADD	9.646	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0245% Admixed American · 9/36,776 alleles

Filtering AF 0.0128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00948%

Overall 0.00189% 28/1,478,232 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0245%	4,086
Ashkenazi Jewishnot grpmax-eligible	0.00841%	11,894
Remaining individualsnot grpmax-eligible	0.00707%	14,143
East Asian	0.00508%	19,686
African / African-American	0.00287%	34,834
European (non-Finnish)	0.000806%	124,052

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: COL6A2
Protein: p.Arg453=
Coding: c.1359C>T
MANE Select: NM_001849
dbSNP: rs750842859
Type: single nucleotide variant
Location: chr21:46120541 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.58 · 1 PDB
Residue 453: the 'triple-helical region' region; the 'disordered' region

Full COL6A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: Bethlem myopathy 1A

Similar variants

COL6A2 p.Arg453Cys Uncertain significance ★★ ⚠ same residue
COL6A2 p.Arg453His Conflicting classifications of pathogenicity ★ ⚠ same residue
COL6A2 c.1000-1G>T Pathogenic ★★ same condition
COL6A2 c.1000-2A>C Pathogenic ★★ same condition
COL6A2 c.1053+1G>A Pathogenic ★★ same condition
COL6A2 c.1053+1G>C Pathogenic/Likely pathogenic ★★ same condition
COL6A2 c.1053+2T>C Pathogenic/Likely pathogenic ★★ same condition
COL6A2 c.1054-2A>G Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/col6a2-p-arg453 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown