Is COL6A3 p.Ser453fs (c.1357_1364del) pathogenic?

COL6A3 p.Ser453fs (c.13571364del) is classified Pathogenic/Likely pathogenic in COL6A3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-08). Very rare (popmax 8.47e-05%, nfe); Associated with Bethlem myopathy 1A.

What condition is associated with COL6A3 p.Ser453fs (c.1357_1364del)?

COL6A3 p.Ser453fs (c.1357_1364del) is associated with Bethlem myopathy 1A (ClinVar).

How common is COL6A3 p.Ser453fs (c.1357_1364del) in the general population?

COL6A3 p.Ser453fs (c.1357_1364del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Bethlem muscular dystrophy inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

COL6A3 p.Ser453fs

c.1357_1364del · VCV3670676

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

Bethlem myopathy 1A

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 5 of 44
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2.7	GERP -3.7

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,012 alleles

Overall 6.86e-05% 1/1,457,712 alleles · very rare

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: COL6A3
Protein: p.Ser453fs
Coding: c.1357_1364del
MANE Select: NM_004369
Type: Deletion
Location: chr2:237381448 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 453: the 'nonhelical region' region; the vwfa 3 domain

Full COL6A3 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

COL6A3 c.7094del Pathogenic ★★ same condition
COL6A3 p.Ala2978fs Pathogenic ★★ same condition
COL6A3 p.Gln1375fs Pathogenic ★★ same condition
COL6A3 p.Gly1827fs Pathogenic ★★ same condition
COL6A3 p.Gly254fs Pathogenic/Likely pathogenic ★★ same condition
COL6A3 p.Phe2599fs Pathogenic ★★ same condition
COL6A3 p.Val824fs Pathogenic/Likely pathogenic ★★ same condition
COL6A3 c.6211-9del 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/col6a3-p-ser453fs (accessed [today's date]).

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