Is COL6A2 p.Val951Ile (c.2851G>A) pathogenic?

COL6A2 p.Val951Ile (c.2851G>A) is classified Conflicting classifications of pathogenicity in COL6A2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-02). AlphaMissense: likely benign (0.0674); Ultra-rare (popmax 0.0468%, eas); Associated with Bethlem myopathy 1A.

What condition is associated with COL6A2 p.Val951Ile (c.2851G>A)?

COL6A2 p.Val951Ile (c.2851G>A) is associated with Bethlem myopathy 1A (ClinVar).

How common is COL6A2 p.Val951Ile (c.2851G>A) in the general population?

COL6A2 p.Val951Ile (c.2851G>A) is ultra-rare (popmax 0.0468%, eas) (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 COL6A2 p.Val951Ile (c.2851G>A)?

AlphaMissense predicts likely benign (score 0.0674) — an in-silico prediction, not a clinical call.

COL6A2 p.Val951Ile

c.2851G>A · rs111630733 · VCV963540

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0674 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0468%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Bethlem myopathy 1A

Computational evidence

Protein change
AlphaMissense	0.0674	likely benign
REVEL	0.264	benign-leaning
SaProt	LLR -4.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.3, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 16 kb · p 1.4e-07 · regional, not allelic
Overall
CADD	16.66	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 0.0468% East Asian · 21/44,860 alleles

Filtering AF 0.0313% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0263%

Overall 0.00609% 98/1,608,200 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0468%	2,136
South Asian	0.0264%	3,795
African / African-American	0.012%	8,339
Remaining individualsnot grpmax-eligible	0.00641%	15,606
European (non-Finnish)	0.00339%	29,489

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.Val951Ile
Coding: c.2851G>A
MANE Select: NM_001849
dbSNP: rs111630733
Type: single nucleotide variant
Location: chr21:46132343 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.58 · 1 PDB
Residue 951: the vwfa 3 domain; the 'nonhelical region' region

Full COL6A2 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

COL6A2 p.Val951Phe Uncertain significance ★ ⚠ same residue
COL6A2 p.Val951= Likely benign ★ same residue
COL6A2 p.Val951fs Pathogenic ★ 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-val951ile (accessed [today's date]).

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