Is COL6A3 p.Val1985Met (c.5953G>A) pathogenic?

COL6A3 p.Val1985Met (c.5953G>A) is classified Conflicting classifications of pathogenicity in COL6A3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-05-27). AlphaMissense: likely benign (0.2192); Ultra-rare (popmax 0.0117%, amr); Associated with Bethlem myopathy 1A.

What condition is associated with COL6A3 p.Val1985Met (c.5953G>A)?

COL6A3 p.Val1985Met (c.5953G>A) is associated with Bethlem myopathy 1A (ClinVar).

How common is COL6A3 p.Val1985Met (c.5953G>A) in the general population?

COL6A3 p.Val1985Met (c.5953G>A) is ultra-rare (popmax 0.0117%, amr) (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 COL6A3 p.Val1985Met (c.5953G>A)?

AlphaMissense predicts likely benign (score 0.2192) — an in-silico prediction, not a clinical call.

COL6A3 p.Val1985Met

c.5953G>A · rs200478135 · VCV282207

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2192 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Conditions

Bethlem myopathy 1A

Computational evidence

Protein change
AlphaMissense	0.2192	likely benign
REVEL	0.337	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	GERP 1.3, phastCons 0.29
Regional constraint	o/e 1.01	unconstrained · MANE · 6,991 bp · p 0.73 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0117% Admixed American · 7/60,008 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.00167% 27/1,614,038 alleles · ultra-rare exomes 23/1,461,878 · genomes 4/152,160 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,573
European (non-Finnish)	0.00161%	62,108
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Val1985Met
Coding: c.5953G>A
MANE Select: NM_004369
dbSNP: rs200478135
Type: single nucleotide variant
Location: chr2:237363363 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 1985: a UniProt-annotated variant site (in bthlm1c); the vwfa 10 domain; the 'nonhelical region' 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 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
COL6A3 c.6310-2A>G 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-val1985met (accessed [today's date]).

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