Is COL6A2 p.Pro221= (c.663C>T) pathogenic?

COL6A2 p.Pro221= (c.663C>T) is classified Benign in COL6A2 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-03). Common (popmax 12.6%, afr) — too common for a highly-penetrant pathogenic allele; Associated with collagen 6-related myopathy.

What condition is associated with COL6A2 p.Pro221= (c.663C>T)?

COL6A2 p.Pro221= (c.663C>T) is associated with collagen 6-related myopathy, Bethlem myopathy 1A (ClinVar).

COL6A2 p.Pro221=

Q: How common is COL6A2 p.Pro221= (c.663C>T) in the general population?

COL6A2 p.Pro221= (c.663C>T) is common (popmax 12.6%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.663C>T · rs59531343 · VCV93955

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Common

common (popmax 12.6%, afr) — too common for a highly-penetrant pathogenic allele

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 -14	GERP -3.3
Overall
CADD	1.913	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12.6% African / African-American · 9,316/73,656 alleles

Filtering AF 12.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.3%

Overall 8.51% 136,783/1,607,688 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	12.6%	8
Amishnot grpmax-eligible	11.3%	9
East Asian	10.5%	10
Finnishnot grpmax-eligible	9.48%	11
Remaining individualsnot grpmax-eligible	8.55%	12
European (non-Finnish)	8.34%	12
Middle Eastern	8.26%	12
Admixed American	8.12%	12
Ashkenazi Jewishnot grpmax-eligible	7.98%	13
South Asian	6.03%	17

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.Pro221=
Coding: c.663C>T
MANE Select: NM_001849
dbSNP: rs59531343
Type: single nucleotide variant
Location: chr21:46112526 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.58 · 1 PDB
Residue 221: the vwfa 1 domain; the 'nonhelical region' 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.Pro221Leu 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
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-pro221 (accessed [today's date]).

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