Is COL6A2 p.Arg599Ser (c.1797G>C) pathogenic?

COL6A2 p.Arg599Ser (c.1797G>C) is classified Uncertain significance in COL6A2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-07). AlphaMissense: likely pathogenic (0.9772); Very rare (popmax 0.00288%, nfe); Associated with Inborn genetic diseases.

What condition is associated with COL6A2 p.Arg599Ser (c.1797G>C)?

COL6A2 p.Arg599Ser (c.1797G>C) is associated with Inborn genetic diseases, Bethlem myopathy 1A (ClinVar).

How common is COL6A2 p.Arg599Ser (c.1797G>C) in the general population?

COL6A2 p.Arg599Ser (c.1797G>C) is very rare (popmax 0.00288%, nfe) (gnomAD).

What do computational predictors say about COL6A2 p.Arg599Ser (c.1797G>C)?

AlphaMissense predicts likely pathogenic (score 0.9772) — an in-silico prediction, not a clinical call.

COL6A2 p.Arg599Ser

c.1797G>C · rs370858447 · VCV162535

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9772 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00288%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9772	likely pathogenic · top 10% in COL6A2
REVEL	0.715	pathogenic-leaning
SaProt	LLR -8.72	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.53 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.25	GERP -2.5, phastCons 0.92
Regional constraint	o/e 1.16	unconstrained · MANE · 16 kb · p 1.4e-07 · regional, not allelic
Overall
CADD	22.9	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 0.00288% European (non-Finnish) · 34/1,179,406 alleles

Filtering AF 0.00208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00183%

Overall 0.00217% 35/1,611,812 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00288%	34,688
African / African-American	0.00133%	74,918

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.Arg599Ser
Coding: c.1797G>C
MANE Select: NM_001849
dbSNP: rs370858447
Type: single nucleotide variant
Location: chr21:46125292 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.58 · 1 PDB
Residue 599: an α-helix; the 'nonhelical region' 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: Bethlem myopathy 1A

Similar variants

COL6A2 p.Arg599= Likely benign ★ same residue
COL6A2 p.Arg599Gly 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
COL6A2 c.1054-2A>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/col6a2-p-arg599ser (accessed [today's date]).

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