Is COL6A2 p.Ala558= (c.1674G>A) pathogenic?

COL6A2 p.Ala558= (c.1674G>A) is classified Conflicting classifications of pathogenicity in COL6A2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-11-19). Ultra-rare (popmax 0.0825%, mid); Associated with collagen 6-related myopathy.

What condition is associated with COL6A2 p.Ala558= (c.1674G>A)?

COL6A2 p.Ala558= (c.1674G>A) is associated with collagen 6-related myopathy, Bethlem myopathy 1A (ClinVar).

How common is COL6A2 p.Ala558= (c.1674G>A) in the general population?

COL6A2 p.Ala558= (c.1674G>A) is ultra-rare (popmax 0.0825%, mid) (gnomAD).

COL6A2 p.Ala558=

c.1674G>A · rs144334894 · VCV340368

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0825%, mid)

Conditions

collagen 6-related myopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.82	acceptor gain · deltas
Pangolin	Δ0.22	gain · loss 0.02 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -4.7	GERP -1.8
Overall
CADD	11.84	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0825% Middle Eastern · 5/6,058 alleles

Filtering AF 0.0324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0215%

Overall 0.0224% 361/1,612,912 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0825%	1,212
South Asian	0.0296%	3,374
European (non-Finnish)	0.0247%	4,041
Admixed American	0.0167%	6,001
Remaining individualsnot grpmax-eligible	0.016%	6,249
African / African-American	0.0147%	6,819
Finnishnot grpmax-eligible	0.00635%	15,747
East Asian	0.00446%	22,440

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.Ala558=
Coding: c.1674G>A
MANE Select: NM_001849
dbSNP: rs144334894
Type: single nucleotide variant
Location: chr21:46124653 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.58 · 1 PDB
Residue 558: 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.Ala558Val 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
COL6A2 c.115+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-ala558 (accessed [today's date]).

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