Is COL6A2 p.Pro518= (c.1554A>G) pathogenic?

COL6A2 p.Pro518= (c.1554A>G) is classified Likely benign in COL6A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-03). Very rare (popmax 0.00167%, amr); Associated with Bethlem myopathy 1A.

What condition is associated with COL6A2 p.Pro518= (c.1554A>G)?

COL6A2 p.Pro518= (c.1554A>G) is associated with Bethlem myopathy 1A (ClinVar).

How common is COL6A2 p.Pro518= (c.1554A>G) in the general population?

COL6A2 p.Pro518= (c.1554A>G) is very rare (popmax 0.00167%, amr) (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.Pro518=

c.1554A>G · rs779424467 · VCV1145145

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

Bethlem myopathy 1A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -7.5	GERP -2.5
Overall
CADD	2.711	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,972 alleles

Overall 0.000186% 3/1,612,560 alleles · very rare exomes 2/1,460,424 · genomes 1/152,136 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,972
African / African-American	0.00134%	74,892
European (non-Finnish)	8.47e-05%	1,179,981

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.Pro518=
Coding: c.1554A>G
MANE Select: NM_001849
dbSNP: rs779424467
Type: single nucleotide variant
Location: chr21:46122140 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.58 · 1 PDB
Residue 518: a UniProt-annotated variant site (in); 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

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.Pro518Ser Benign/Likely benign ★★ same residue
COL6A2 p.Pro518Arg 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

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-pro518 (accessed [today's date]).

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