Is COL6A2 p.Arg533= (c.1599C>T) pathogenic?

COL6A2 p.Arg533= (c.1599C>T) is classified Conflicting classifications of pathogenicity in COL6A2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-22). Rare (popmax 0.115%, mid); Associated with Bethlem myopathy 1A.

What condition is associated with COL6A2 p.Arg533= (c.1599C>T)?

COL6A2 p.Arg533= (c.1599C>T) is associated with Bethlem myopathy 1A, collagen 6-related myopathy (ClinVar).

How common is COL6A2 p.Arg533= (c.1599C>T) in the general population?

COL6A2 p.Arg533= (c.1599C>T) is rare (popmax 0.115%, mid) (gnomAD).

How is Bethlem muscular dystrophy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

COL6A2 p.Arg533=

c.1599C>T · rs373635709 · VCV340367

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.115%, mid)

Conditions

Bethlem myopathy 1A

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 -20	GERP -2.7
Overall
CADD	0.094	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.115% Middle Eastern · 7/6,084 alleles

Filtering AF 0.054% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0418%

Overall 0.00577% 93/1,612,616 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.115%	869
Admixed American	0.0633%	1,579
Remaining individualsnot grpmax-eligible	0.00961%	10,411
East Asian	0.00446%	22,424
South Asian	0.00439%	22,771
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
European (non-Finnish)	0.00288%	34,705
African / African-American	0.00134%	74,892

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.Arg533=
Coding: c.1599C>T
MANE Select: NM_001849
dbSNP: rs373635709
Type: single nucleotide variant
Location: chr21:46122522 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.58 · 1 PDB
Residue 533: the 'triple-helical region' region; the 'disordered' region

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

Disease context

Bethlem myopathy 1A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: collagen 6-related myopathy

For Bethlem muscular dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (United Kingdom)

Similar variants

COL6A2 p.Arg533Cys Uncertain significance ★ ⚠ same residue
COL6A2 p.Arg533His 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-arg533 (accessed [today's date]).

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