Is COL6A2 p.Arg784His (c.2351G>A) pathogenic?

COL6A2 p.Arg784His (c.2351G>A) is classified Benign/Likely benign in COL6A2 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.0837); Rare (popmax 0.711%, nfe); Associated with collagen 6-related myopathy.

What condition is associated with COL6A2 p.Arg784His (c.2351G>A)?

COL6A2 p.Arg784His (c.2351G>A) is associated with collagen 6-related myopathy, Bethlem myopathy 1A (ClinVar).

How common is COL6A2 p.Arg784His (c.2351G>A) in the general population?

COL6A2 p.Arg784His (c.2351G>A) is rare (popmax 0.711%, nfe) (gnomAD).

What do computational predictors say about COL6A2 p.Arg784His (c.2351G>A)?

AlphaMissense predicts likely benign (score 0.0837) — an in-silico prediction, not a clinical call.

COL6A2 p.Arg784His

c.2351G>A · rs75120695 · VCV93938

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.0837 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.711%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

collagen 6-related myopathy

Computational evidence

Protein change
AlphaMissense	0.0837	likely benign
REVEL	0.417	indeterminate
SaProt	LLR -6.64	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.37	donor loss · deltas
Constraint at this position
Conservation	phyloP 8.3	GERP -0.03, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 16 kb · p 1.4e-07 · regional, not allelic
Overall
CADD	23.0	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 0.711% European (non-Finnish) · 8,390/1,179,996 alleles

Filtering AF 0.698% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.693%

Overall 0.581% 9,345/1,608,916 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.711%	141
Admixed American	0.506%	197
Remaining individualsnot grpmax-eligible	0.45%	222
Finnishnot grpmax-eligible	0.229%	436
Ashkenazi Jewishnot grpmax-eligible	0.169%	592
African / African-American	0.112%	893
South Asian	0.104%	959
Middle Eastern	0.0825%	1,212
East Asian	0.00223%	44,870

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: COL6A2
Protein: p.Arg784His
Coding: c.2351G>A
MANE Select: NM_001849
dbSNP: rs75120695
Type: single nucleotide variant
Location: chr21:46126166 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.58 · 1 PDB
Residue 784: the vwfa 2 domain; a UniProt-annotated variant site (in); the 'nonhelical region' region

Full COL6A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: Bethlem myopathy 1A

Similar variants

COL6A2 p.Arg784Cys Uncertain significance ★★ same residue
COL6A2 p.Arg784Pro Uncertain significance ★★ ⚠ same residue
COL6A2 p.Arg784Leu Uncertain significance ★ ⚠ same residue
COL6A2 c.1000-1G>T Pathogenic ★★ same condition
COL6A2 c.1000-2A>C Pathogenic ★★ same condition
COL6A2 c.1053+1G>A Pathogenic ★★ same condition
COL6A2 c.1053+1G>C Pathogenic/Likely pathogenic ★★ same condition
COL6A2 c.1053+2T>C 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/col6a2-p-arg784his (accessed [today's date]).

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