Is COL6A2 p.Ala994= (c.2982C>T) pathogenic?

COL6A2 p.Ala994= (c.2982C>T) is classified Likely benign in COL6A2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-09-01). Ultra-rare (popmax 0.0902%, sas); Associated with Bethlem myopathy 1A.

What condition is associated with COL6A2 p.Ala994= (c.2982C>T)?

COL6A2 p.Ala994= (c.2982C>T) is associated with Bethlem myopathy 1A (ClinVar).

How common is COL6A2 p.Ala994= (c.2982C>T) in the general population?

COL6A2 p.Ala994= (c.2982C>T) is ultra-rare (popmax 0.0902%, sas) (gnomAD).

How is Bethlem muscular dystrophy inherited?

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

COL6A2 p.Ala994=

c.2982C>T · rs145460820 · VCV289156

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0902%, sas)

Conditions

Bethlem myopathy 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 -14	GERP -2.9
Overall
CADD	1.314	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0902% South Asian · 82/90,958 alleles

Filtering AF 0.0744% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0686%

Overall 0.0334% 537/1,606,538 alleles · ultra-rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.11%	912
South Asiangrpmax	0.0902%	1,109
Finnishnot grpmax-eligible	0.0437%	2,288
European (non-Finnish)	0.0334%	2,997
Remaining individualsnot grpmax-eligible	0.0289%	3,460
Admixed American	0.0234%	4,278
African / African-American	0.00267%	37,500
East Asian	0.00223%	44,758

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala994=
Coding: c.2982C>T
MANE Select: NM_001849
dbSNP: rs145460820
Type: single nucleotide variant
Location: chr21:46132474 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.58 · 1 PDB
Residue 994: 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.Ala994Thr Benign/Likely benign ★★ 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-ala994 (accessed [today's date]).

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