Is COL6A2 p.Ala189= (c.567C>T) pathogenic?

COL6A2 p.Ala189= (c.567C>T) is classified Conflicting classifications of pathogenicity in COL6A2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-10). Ultra-rare (popmax 0.0406%, sas); Associated with Bethlem myopathy 1A.

What condition is associated with COL6A2 p.Ala189= (c.567C>T)?

COL6A2 p.Ala189= (c.567C>T) is associated with Bethlem myopathy 1A (ClinVar).

How common is COL6A2 p.Ala189= (c.567C>T) in the general population?

COL6A2 p.Ala189= (c.567C>T) is ultra-rare (popmax 0.0406%, sas) (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.Ala189=

c.567C>T · rs563505047 · VCV290115

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0406%, sas)

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 -16	GERP -3.3
Overall
CADD	1.804	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0406% South Asian · 37/91,032 alleles

Filtering AF 0.0303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0267%

Overall 0.00509% 82/1,609,438 alleles · ultra-rare exomes 62/1,457,128 · genomes 20/152,310 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0406%	2,460
African / African-American	0.04%	2,501
Remaining individualsnot grpmax-eligible	0.00801%	12,482
East Asian	0.00446%	22,414
Admixed American	0.00334%	29,975
European (non-Finnish)	0.000509%	196,586

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.Ala189=
Coding: c.567C>T
MANE Select: NM_001849
dbSNP: rs563505047
Type: single nucleotide variant
Location: chr21:46112430 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.58 · 1 PDB
Residue 189: the vwfa 1 domain; the 'nonhelical region' 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

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.Ala189Thr Uncertain significance ★★ ⚠ same residue
COL6A2 p.Ala189Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
COL6A2 p.Ala189Val Uncertain significance ★ ⚠ 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

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-ala189 (accessed [today's date]).

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