Is COL6A3 p.Pro1687Ser (c.5059C>T) pathogenic?

COL6A3 p.Pro1687Ser (c.5059C>T) is classified Benign/Likely benign in COL6A3 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-31). AlphaMissense: likely pathogenic (0.8123); Low-frequency (popmax 2.14%, afr); Associated with Bethlem myopathy 1A.

What condition is associated with COL6A3 p.Pro1687Ser (c.5059C>T)?

COL6A3 p.Pro1687Ser (c.5059C>T) is associated with Bethlem myopathy 1A, Ullrich congenital muscular dystrophy 1A, dystonia 27 (ClinVar).

How common is COL6A3 p.Pro1687Ser (c.5059C>T) in the general population?

COL6A3 p.Pro1687Ser (c.5059C>T) is low-frequency (popmax 2.14%, 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.Pro1687Ser (c.5059C>T)?

AlphaMissense predicts likely pathogenic (score 0.8123) — an in-silico prediction, not a clinical call.

COL6A3 p.Pro1687Ser

c.5059C>T · rs35273032 · VCV94942

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.8123 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.14%, afr)

Conditions

Bethlem myopathy 1A

Computational evidence

Protein change
AlphaMissense	0.8123	likely pathogenic
REVEL	0.58	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 6,991 bp · p 0.73 · regional, not allelic
Overall
CADD	22.8	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 2.14% African / African-American · 1,606/75,014 alleles

Filtering AF 2.05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.02%

Overall 0.128% 2,059/1,614,152 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.14%	47
Ashkenazi Jewishnot grpmax-eligible	0.304%	329
Remaining individualsnot grpmax-eligible	0.202%	496
Admixed American	0.18%	556
Middle Eastern	0.165%	606
South Asian	0.0121%	8,279
European (non-Finnish)	0.00915%	10,926

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.Pro1687Ser
Coding: c.5059C>T
MANE Select: NM_004369
dbSNP: rs35273032
Type: single nucleotide variant
Location: chr2:237367128 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 1687: the vwfa 9 domain; a UniProt-annotated variant site (in); a β-strand; the 'nonhelical region' 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

Also linked: Ullrich congenital muscular dystrophy 1A dystonia 27 collagen 6-related myopathy

For Bethlem muscular dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (United Kingdom)

Similar variants

COL6A3 p.Pro1687= Likely benign ★★ same residue
COL6A3 p.Pro1687His Uncertain significance ★ ⚠ same residue
COL6A3 c.3071-2A>G Likely pathogenic ★★ same condition
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

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-pro1687ser (accessed [today's date]).

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