Is COL6A1 p.Arg682Trp (c.2044C>T) pathogenic?

COL6A1 p.Arg682Trp (c.2044C>T) is classified Conflicting classifications of pathogenicity in COL6A1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-05-23). AlphaMissense: likely benign (0.1588); Ultra-rare (popmax 0.0187%, afr); Associated with Bethlem myopathy 1A.

What condition is associated with COL6A1 p.Arg682Trp (c.2044C>T)?

COL6A1 p.Arg682Trp (c.2044C>T) is associated with Bethlem myopathy 1A (ClinVar).

How common is COL6A1 p.Arg682Trp (c.2044C>T) in the general population?

COL6A1 p.Arg682Trp (c.2044C>T) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

How is Bethlem muscular dystrophy inherited?

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

What do computational predictors say about COL6A1 p.Arg682Trp (c.2044C>T)?

AlphaMissense predicts likely benign (score 0.1588) — an in-silico prediction, not a clinical call.

COL6A1 p.Arg682Trp

c.2044C>T · rs777378283 · VCV498325

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1588 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Bethlem myopathy 1A

Computational evidence

Protein change
AlphaMissense	0.1588	likely benign
REVEL	0.378	indeterminate
SaProt	LLR -11.09	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.6	GERP -2.3, phastCons 0.95
Regional constraint	o/e 0.93	unconstrained · MANE · 14 kb · p 0.038 · regional, not allelic
Overall
CADD	18.47	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% African / African-American · 14/74,912 alleles

Filtering AF 0.0112% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00905%

Overall 0.00174% 28/1,611,992 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,351
East Asian	0.00892%	11,213
Admixed American	0.00334%	29,974
South Asian	0.0022%	45,428
European (non-Finnish)	0.000509%	196,624

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: COL6A1
Protein: p.Arg682Trp
Coding: c.2044C>T
MANE Select: NM_001848
dbSNP: rs777378283
Type: single nucleotide variant
Location: chr21:46002048 (GRCh38)
Gene constraint: LOEUF 0.706 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.28 · 1 PDB
Residue 682: the vwfa 2 domain; the 'c-terminal globular domain' region

Full COL6A1 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

COL6A1 p.Arg682Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
COL6A1 c.1002+1G>A Pathogenic ★★ same condition
COL6A1 c.1003-1G>A Pathogenic ★★ same condition
COL6A1 c.1003-2A>C Pathogenic ★★ same condition
COL6A1 c.1003-2A>G Pathogenic ★★ same condition
COL6A1 c.1056+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL6A1 c.1056+1G>C Pathogenic ★★ same condition
COL6A1 c.1056+2T>A 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/col6a1-p-arg682trp (accessed [today's date]).

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