Is COL6A3 p.Ser47Pro (c.139T>C) pathogenic?

COL6A3 p.Ser47Pro (c.139T>C) is classified Uncertain significance in COL6A3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-16). AlphaMissense: likely benign (0.3112); Very rare (popmax 8.47e-05%, nfe); Associated with Bethlem myopathy 1A.

What condition is associated with COL6A3 p.Ser47Pro (c.139T>C)?

COL6A3 p.Ser47Pro (c.139T>C) is associated with Bethlem myopathy 1A (ClinVar).

How common is COL6A3 p.Ser47Pro (c.139T>C) in the general population?

COL6A3 p.Ser47Pro (c.139T>C) is very rare (popmax 8.47e-05%, nfe) (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.Ser47Pro (c.139T>C)?

AlphaMissense predicts likely benign (score 0.3112) — an in-silico prediction, not a clinical call.

COL6A3 p.Ser47Pro

c.139T>C · VCV4704287

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3112 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Bethlem myopathy 1A

Computational evidence

Protein change
AlphaMissense	0.3112	likely benign
REVEL	0.931	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ REVEL calls this damaging; AlphaMissense does not; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 28 kb · p 0.26 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,008 alleles

Overall 6.2e-05% 1/1,613,922 alleles · very rare exomes 1/1,461,560 · genomes 0/152,362 · joint denominator

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.Ser47Pro
Coding: c.139T>C
MANE Select: NM_004369
Type: single nucleotide variant
Location: chr2:237395157 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 47: the vwfa 1 domain; 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

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.Ser47= Likely benign ★ 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.6309+1G>A Pathogenic ★★ same condition
COL6A3 c.6309+1G>T 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-ser47pro (accessed [today's date]).

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