Is COL6A3 p.Ala2018Val (c.6053C>T) pathogenic?

COL6A3 p.Ala2018Val (c.6053C>T) is classified Benign/Likely benign in COL6A3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1293); Rare (popmax 0.405%, sas); Associated with Bethlem myopathy 1C.

What condition is associated with COL6A3 p.Ala2018Val (c.6053C>T)?

COL6A3 p.Ala2018Val (c.6053C>T) is associated with Bethlem myopathy 1C, dystonia 27, Bethlem myopathy 1A (ClinVar).

How common is COL6A3 p.Ala2018Val (c.6053C>T) in the general population?

COL6A3 p.Ala2018Val (c.6053C>T) is rare (popmax 0.405%, sas) (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.Ala2018Val (c.6053C>T)?

AlphaMissense predicts likely benign (score 0.1293) — an in-silico prediction, not a clinical call.

COL6A3 p.Ala2018Val

c.6053C>T · rs200239695 · VCV497225

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1293 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.405%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Bethlem myopathy 1C

Computational evidence

Protein change
AlphaMissense	0.1293	likely benign
REVEL	0.213	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.3, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 6,991 bp · p 0.73 · regional, not allelic
Overall
CADD	21.3	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 0.405% South Asian · 369/91,066 alleles

Filtering AF 0.371% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.358%

Overall 0.0325% 525/1,613,486 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.405%	247
Middle Eastern	0.165%	606
Ashkenazi Jewishnot grpmax-eligible	0.125%	800
Remaining individualsnot grpmax-eligible	0.064%	1,562
Admixed American	0.00834%	11,993
European (non-Finnish)	0.005%	19,999
East Asian	0.00446%	22,420
African / African-American	0.00401%	24,933

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.Ala2018Val
Coding: c.6053C>T
MANE Select: NM_004369
dbSNP: rs200239695
Type: single nucleotide variant
Location: chr2:237363263 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 2018: 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 1C — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dystonia 27 Bethlem myopathy 1A Ullrich congenital muscular dystrophy 1C

For Bethlem muscular dystrophy (Orphanet):

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

Similar variants

COL6A3 p.Ala2018Glu Uncertain significance ★★ ⚠ same residue
COL6A3 p.Ala2018= Likely benign ★ same residue
COL6A3 c.3071-2A>G Likely pathogenic ★★ same condition
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

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-ala2018val (accessed [today's date]).

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