Is COL6A2 p.Ser488fs (c.1461del) pathogenic?

COL6A2 p.Ser488fs (c.1461del) is classified Pathogenic/Likely pathogenic in COL6A2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-11). Very rare (popmax 0.00133%, afr); Associated with Bethlem myopathy 1B.

What condition is associated with COL6A2 p.Ser488fs (c.1461del)?

COL6A2 p.Ser488fs (c.1461del) is associated with Bethlem myopathy 1B, Ullrich congenital muscular dystrophy 1A, Bethlem myopathy 1A (ClinVar).

How common is COL6A2 p.Ser488fs (c.1461del) in the general population?

COL6A2 p.Ser488fs (c.1461del) is very rare (popmax 0.00133%, afr) (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.Ser488fs

c.1461del · rs398123645 · VCV93907

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

Bethlem myopathy 1B

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 18 of 28
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.3, phastCons 1
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,940 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000682% 11/1,612,730 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,940
European (non-Finnish)	0.000847%	117,997

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.Ser488fs
Coding: c.1461del
MANE Select: NM_001849
dbSNP: rs398123645
Type: Deletion
Location: chr21:46121558 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.58 · 1 PDB
Residue 488: 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 1B — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Ullrich congenital muscular dystrophy 1A Bethlem myopathy 1A

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.Ser488Phe Uncertain significance ★★ same residue
COL6A2 c.1770+1del Pathogenic/Likely pathogenic ★★ same condition
COL6A2 c.1817-3_1817-2del Likely pathogenic ★★ same condition
COL6A2 c.955-2del Pathogenic ★★ same condition
COL6A2 p.Gly277fs Pathogenic ★★ same condition
COL6A2 p.Ile834fs Pathogenic/Likely pathogenic ★★ same condition
COL6A2 p.Pro584fs Pathogenic ★★ same condition
COL6A2 c.1458+3_1458+6del Uncertain significance ★★ 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-ser488fs (accessed [today's date]).

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