Is COL6A2 p.Arg489Trp (c.1465C>T) pathogenic?

COL6A2 p.Arg489Trp (c.1465C>T) is classified Conflicting classifications of pathogenicity in COL6A2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-10-06). AlphaMissense: likely benign (0.1802); Rare (popmax 0.264%, mid); Associated with Inborn genetic diseases.

What condition is associated with COL6A2 p.Arg489Trp (c.1465C>T)?

COL6A2 p.Arg489Trp (c.1465C>T) is associated with Inborn genetic diseases, Ullrich congenital muscular dystrophy 1A, Bethlem myopathy 1A (ClinVar).

How common is COL6A2 p.Arg489Trp (c.1465C>T) in the general population?

COL6A2 p.Arg489Trp (c.1465C>T) is rare (popmax 0.264%, mid) (gnomAD).

What do computational predictors say about COL6A2 p.Arg489Trp (c.1465C>T)?

AlphaMissense predicts likely benign (score 0.1802) — an in-silico prediction, not a clinical call.

COL6A2 p.Arg489Trp

c.1465C>T · rs727502829 · VCV162534

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1802 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.264%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1802	likely benign
REVEL	0.686	pathogenic-leaning
SaProt	LLR -10.78	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP 0.14, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 16 kb · p 1.4e-07 · regional, not allelic
Overall
CADD	28.3	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 0.264% Middle Eastern · 16/6,060 alleles

Filtering AF 0.166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.135%

Overall 0.00316% 51/1,612,818 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.264%	379
African / African-American	0.00533%	18,763
Remaining individualsnot grpmax-eligible	0.0032%	31,244
European (non-Finnish)	0.00229%	43,702
East Asian	0.00223%	44,878
South Asian	0.0011%	91,074

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.Arg489Trp
Coding: c.1465C>T
MANE Select: NM_001849
dbSNP: rs727502829
Type: single nucleotide variant
Location: chr21:46121562 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.58 · 1 PDB
Residue 489: a UniProt-annotated variant site (in); the 'triple-helical region' region; the 'disordered' region

Full COL6A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Ullrich congenital muscular dystrophy 1A Bethlem myopathy 1A collagen 6-related myopathy

Similar variants

COL6A2 p.Arg489Gln Benign/Likely benign ★★ same residue
COL6A2 p.Arg489Gly Uncertain significance ★ ⚠ same residue
COL6A2 p.Arg489Pro Uncertain significance ★ ⚠ 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-arg489trp (accessed [today's date]).

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