Is COL6A3 p.Pro2157= (c.6471G>A) pathogenic?

COL6A3 p.Pro2157= (c.6471G>A) is classified Uncertain significance in COL6A3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-26). Very rare (popmax 0.00223%, eas); Associated with Bethlem myopathy 1A.

What condition is associated with COL6A3 p.Pro2157= (c.6471G>A)?

COL6A3 p.Pro2157= (c.6471G>A) is associated with Bethlem myopathy 1A (ClinVar).

How common is COL6A3 p.Pro2157= (c.6471G>A) in the general population?

COL6A3 p.Pro2157= (c.6471G>A) is very rare (popmax 0.00223%, eas) (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.Pro2157=

c.6471G>A · rs1349524156 · VCV1345361

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Bethlem myopathy 1A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.24	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.65	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 3.2	GERP 1.4, phastCons 1
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,896 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000496% 8/1,613,368 alleles · very rare exomes 7/1,461,224 · genomes 1/152,144 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,896
Admixed American	0.00167%	60,000
Remaining individualsnot grpmax-eligible	0.0016%	62,464
Finnishnot grpmax-eligible	0.00156%	64,008
European (non-Finnish)	0.000339%	294,864

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.Pro2157=
Coding: c.6471G>A
MANE Select: NM_004369
dbSNP: rs1349524156
Type: single nucleotide variant
Location: chr2:237358521 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 2157: 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.Pro2157Leu Uncertain significance ★★ ⚠ same residue
COL6A3 p.Pro2157Thr Uncertain significance ★★ ⚠ same residue
COL6A3 p.Pro2157Ala 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

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-pro2157 (accessed [today's date]).

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