Is COL6A3 p.Pro1630Ser (c.4888C>T) pathogenic?

COL6A3 p.Pro1630Ser (c.4888C>T) is classified Conflicting classifications of pathogenicity in COL6A3 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-06-11). AlphaMissense: likely benign (0.0677); Rare (popmax 0.159%, afr); Associated with Bethlem myopathy 1A.

What condition is associated with COL6A3 p.Pro1630Ser (c.4888C>T)?

COL6A3 p.Pro1630Ser (c.4888C>T) is associated with Bethlem myopathy 1A (ClinVar).

How common is COL6A3 p.Pro1630Ser (c.4888C>T) in the general population?

COL6A3 p.Pro1630Ser (c.4888C>T) is rare (popmax 0.159%, afr) (gnomAD).

How is Bethlem muscular dystrophy inherited?

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

What do computational predictors say about COL6A3 p.Pro1630Ser (c.4888C>T)?

AlphaMissense predicts likely benign (score 0.0677) — an in-silico prediction, not a clinical call.

COL6A3 p.Pro1630Ser

c.4888C>T · rs145560772 · VCV210751

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.0677 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.159%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

Bethlem myopathy 1A

Computational evidence

Protein change
AlphaMissense	0.0677	likely benign
REVEL	0.173	moderately 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 2.1	GERP 1.6, phastCons 0.99
Regional constraint	o/e 1.01	unconstrained · MANE · 6,991 bp · p 0.73 · regional, not allelic
Overall
CADD	17.85	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 0.159% African / African-American · 119/75,038 alleles

Filtering AF 0.135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.127%

Overall 0.0083% 134/1,614,152 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.159%	631
Remaining individualsnot grpmax-eligible	0.0112%	8,930
Admixed American	0.00666%	15,006
European (non-Finnish)	0.000339%	295,001

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.Pro1630Ser
Coding: c.4888C>T
MANE Select: NM_004369
dbSNP: rs145560772
Type: single nucleotide variant
Location: chr2:237368575 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 1630: the 'nonhelical region' region; the 'disordered' region

Full COL6A3 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

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.6309+1G>A Pathogenic ★★ same condition
COL6A3 c.6309+1G>T Pathogenic/Likely pathogenic ★★ same condition
COL6A3 c.6310-2A>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/col6a3-p-pro1630ser (accessed [today's date]).

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