Is COL6A3 p.Pro2218Leu (c.6653C>T) pathogenic?

COL6A3 p.Pro2218Leu (c.6653C>T) is classified Benign in COL6A3 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-03). AlphaMissense: likely benign (0.07); Common (popmax 17.8%, afr) — too common for a highly-penetrant pathogenic allele; Associated with collagen 6-related myopathy.

What condition is associated with COL6A3 p.Pro2218Leu (c.6653C>T)?

COL6A3 p.Pro2218Leu (c.6653C>T) is associated with collagen 6-related myopathy, Bethlem myopathy 1A (ClinVar).

What do computational predictors say about COL6A3 p.Pro2218Leu (c.6653C>T)?

AlphaMissense predicts likely benign (score 0.07) — an in-silico prediction, not a clinical call.

COL6A3 p.Pro2218Leu

Q: How common is COL6A3 p.Pro2218Leu (c.6653C>T) in the general population?

COL6A3 p.Pro2218Leu (c.6653C>T) is common (popmax 17.8%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.6653C>T · rs36117715 · VCV94967

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.07 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 17.8%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

collagen 6-related myopathy

Computational evidence

Protein change
AlphaMissense	0.07	likely benign
REVEL	0.237	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 0.021	GERP 0.44
Regional constraint	o/e 0.95	unconstrained · MANE · 34 kb · p 0.074 · regional, not allelic
Overall
CADD	12.81	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 17.8% African / African-American · 13,364/74,940 alleles

Filtering AF 17.6% ClinGen BA1/BS1 input FAF95, joint · FAF99 17.5%

Overall 3.83% 61,803/1,613,906 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	17.8%	6
Ashkenazi Jewishnot grpmax-eligible	9.03%	11
Middle Eastern	8.61%	12
Remaining individualsnot grpmax-eligible	4.62%	22
Admixed American	3.38%	30
South Asian	3.37%	30
European (non-Finnish)	3.08%	32
Amishnot grpmax-eligible	1.43%	70
Finnishnot grpmax-eligible	1.07%	94
East Asian	0.37%	270

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.Pro2218Leu
Coding: c.6653C>T
MANE Select: NM_004369
dbSNP: rs36117715
Type: single nucleotide variant
Location: chr2:237353378 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 2218: a UniProt-annotated variant site (in); the collagen-like 3 domain; the 'triple-helical region' region; the 'disordered' region

Full COL6A3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: Bethlem myopathy 1A

Similar variants

COL6A3 p.Pro2218= Conflicting classifications of pathogenicity ★ same residue
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
COL6A3 c.6282+1G>C Pathogenic/Likely pathogenic ★★ same condition
COL6A3 c.6309+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-pro2218leu (accessed [today's date]).

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