Is COL6A2 p.Pro288Leu (c.863C>T) pathogenic?

COL6A2 p.Pro288Leu (c.863C>T) is classified Uncertain significance in COL6A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-30). AlphaMissense: ambiguous (0.4141); Ultra-rare (popmax 0.0824%, mid); Associated with Inborn genetic diseases.

What condition is associated with COL6A2 p.Pro288Leu (c.863C>T)?

COL6A2 p.Pro288Leu (c.863C>T) is associated with Inborn genetic diseases, Bethlem myopathy 1A (ClinVar).

How common is COL6A2 p.Pro288Leu (c.863C>T) in the general population?

COL6A2 p.Pro288Leu (c.863C>T) is ultra-rare (popmax 0.0824%, mid) (gnomAD).

What do computational predictors say about COL6A2 p.Pro288Leu (c.863C>T)?

AlphaMissense predicts ambiguous (score 0.4141) — an in-silico prediction, not a clinical call.

COL6A2 p.Pro288Leu

c.863C>T · rs745566911 · VCV476495

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4141 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0824%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4141	ambiguous
REVEL	0.748	pathogenic-leaning
SaProt	LLR -8.84	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 2,603 bp · p 0.0013 · regional, not allelic
Overall
CADD	30.0	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 0.0824% Middle Eastern · 5/6,068 alleles

Filtering AF 0.0324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.021%

Overall 0.00354% 57/1,608,106 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0824%	1,214
African / African-American	0.00535%	18,697
European (non-Finnish)	0.00374%	26,771
Remaining individualsnot grpmax-eligible	0.00322%	31,101
Admixed American	0.00169%	59,174
South Asian	0.00111%	90,426

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.Pro288Leu
Coding: c.863C>T
MANE Select: NM_001849
dbSNP: rs745566911
Type: single nucleotide variant
Location: chr21:46116016 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.58 · 1 PDB
Residue 288: 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: Bethlem myopathy 1A

Similar variants

COL6A2 p.Pro288= 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-pro288leu (accessed [today's date]).

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