Is COL6A2 p.Val728= (c.2184G>A) pathogenic?

COL6A2 p.Val728= (c.2184G>A) is classified Benign in COL6A2 (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-02-04). Common (popmax 55.7%, amr) — too common for a highly-penetrant pathogenic allele; Associated with Ullrich congenital muscular dystrophy 1A.

What condition is associated with COL6A2 p.Val728= (c.2184G>A)?

COL6A2 p.Val728= (c.2184G>A) is associated with Ullrich congenital muscular dystrophy 1A, myosclerosis, Bethlem myopathy 1A (ClinVar).

How is Ullrich congenital muscular dystrophy inherited?

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

COL6A2 p.Val728=

Q: How common is COL6A2 p.Val728= (c.2184G>A) in the general population?

COL6A2 p.Val728= (c.2184G>A) is common (popmax 55.7%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2184G>A · rs2839114 · VCV93936

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

gnomAD v4.1

Common

common (popmax 55.7%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

Ullrich congenital muscular dystrophy 1A

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 1.3, phastCons 1
Overall
CADD	9.698	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 55.7% Admixed American · 33,393/60,000 alleles

Filtering AF 55.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 54.9%

Overall 36.6% 589,541/1,612,720 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	55.7%	2
Finnishnot grpmax-eligible	45.7%	2
East Asian	43.2%	2
Amishnot grpmax-eligible	42.4%	2
Ashkenazi Jewishnot grpmax-eligible	37.7%	3
European (non-Finnish)	37%	3
Remaining individualsnot grpmax-eligible	36.2%	3
South Asian	28%	4
Middle Eastern	27.7%	4
African / African-American	13.2%	8

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.Val728=
Coding: c.2184G>A
MANE Select: NM_001849
dbSNP: rs2839114
Type: single nucleotide variant
Location: chr21:46125999 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.58 · 1 PDB
Residue 728: 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

Ullrich congenital muscular dystrophy 1A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: myosclerosis Bethlem myopathy 1A collagen 6-related myopathy

For Ullrich congenital muscular dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (United Kingdom)

Similar variants

COL6A2 p.Val728Met Conflicting classifications of pathogenicity ★ ⚠ 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
COL6A2 c.1054-2A>G Pathogenic/Likely pathogenic ★★ same condition
COL6A2 c.115+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-val728 (accessed [today's date]).

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