Is COL6A3 p.Arg2136= (c.6408G>A) pathogenic?

COL6A3 p.Arg2136= (c.6408G>A) is classified Uncertain significance in COL6A3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-06). Ultra-rare (popmax 0.033%, mid); Associated with Bethlem myopathy 1A.

What condition is associated with COL6A3 p.Arg2136= (c.6408G>A)?

COL6A3 p.Arg2136= (c.6408G>A) is associated with Bethlem myopathy 1A (ClinVar).

How common is COL6A3 p.Arg2136= (c.6408G>A) in the general population?

COL6A3 p.Arg2136= (c.6408G>A) is ultra-rare (popmax 0.033%, mid) (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.Arg2136=

c.6408G>A · VCV3621692

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

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	all four deltas below 0.2 · C>G here scores Δ0.24 · evaluated, not missing
Pangolin	Δ0.39	loss · gain 0.01 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 4	GERP 1.4, phastCons 1
Overall
CADD	21.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,058 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00031% 5/1,613,728 alleles · ultra-rare exomes 5/1,461,438 · genomes 0/152,290 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,029
South Asian	0.0011%	91,064
European (non-Finnish)	0.00017%	589,824

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.Arg2136=
Coding: c.6408G>A
MANE Select: NM_004369
Type: single nucleotide variant
Location: chr2:237359035 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 2136: 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.Arg2136Ser 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
COL6A3 c.6309+1G>T 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/col6a3-p-arg2136 (accessed [today's date]).

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