Is COL6A3 p.Pro2124= (c.6372T>C) pathogenic?

COL6A3 p.Pro2124= (c.6372T>C) is classified Conflicting classifications of pathogenicity in COL6A3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-06-19). Very rare (popmax 0.00246%, nfe); Associated with Bethlem myopathy 1A.

What condition is associated with COL6A3 p.Pro2124= (c.6372T>C)?

COL6A3 p.Pro2124= (c.6372T>C) is associated with Bethlem myopathy 1A (ClinVar).

How common is COL6A3 p.Pro2124= (c.6372T>C) in the general population?

COL6A3 p.Pro2124= (c.6372T>C) is very rare (popmax 0.00246%, 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.Pro2124=

c.6372T>C · rs894679602 · VCV543022

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

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 -9.3	GERP -2.8
Overall
CADD	0.114	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00246% European (non-Finnish) · 29/1,180,000 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.0018% 29/1,614,084 alleles · very rare exomes 27/1,461,842 · genomes 2/152,242 · joint denominator

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.Pro2124=
Coding: c.6372T>C
MANE Select: NM_004369
dbSNP: rs894679602
Type: single nucleotide variant
Location: chr2:237359071 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 2124: the collagen-like 2 domain; the 'triple-helical region' region; the 'disordered' region

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 p.Pro2124Arg Uncertain significance ★ ⚠ same residue
COL6A3 p.Pro2124Ser Uncertain significance ★★ same residue
COL6A3 c.5838+1G>T Pathogenic/Likely pathogenic ★★ same condition
COL6A3 c.6156+1G>A Pathogenic ★★ same condition
COL6A3 c.6157-2A>C Pathogenic ★★ same condition
COL6A3 c.6210+1G>A Pathogenic ★★ same condition
COL6A3 c.6282+1G>A Pathogenic ★★ same condition
COL6A3 c.6309+1G>A 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/col6a3-p-pro2124 (accessed [today's date]).

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