Is COL6A3 p.Pro2316Ser (c.6946C>T) pathogenic?

COL6A3 p.Pro2316Ser (c.6946C>T) is classified Uncertain significance in COL6A3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-12-06). AlphaMissense: likely benign (0.2194); Very rare (popmax 6.87e-05%); Associated with Bethlem myopathy 1A.

What condition is associated with COL6A3 p.Pro2316Ser (c.6946C>T)?

COL6A3 p.Pro2316Ser (c.6946C>T) is associated with Bethlem myopathy 1A (ClinVar).

How common is COL6A3 p.Pro2316Ser (c.6946C>T) in the general population?

COL6A3 p.Pro2316Ser (c.6946C>T) is very rare (popmax 6.87e-05%) (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.Pro2316Ser (c.6946C>T)?

AlphaMissense predicts likely benign (score 0.2194) — an in-silico prediction, not a clinical call.

COL6A3 p.Pro2316Ser

c.6946C>T · rs1243164167 · VCV1062135

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2194 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.87e-05%)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

Bethlem myopathy 1A

Computational evidence

Protein change
AlphaMissense	0.2194	likely benign
REVEL	0.659	pathogenic-leaning
⇒ REVEL calls this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 34 kb · p 0.074 · regional, not allelic
Overall
CADD	26.1	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 6.87e-05%

Overall 6.87e-05% 1/1,455,692 alleles · very rare

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.Pro2316Ser
Coding: c.6946C>T
MANE Select: NM_004369
dbSNP: rs1243164167
Type: single nucleotide variant
Location: chr2:237348369 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 2316: the collagen-like 5 domain; the 'triple-helical region' region; the 'disordered' region; a modified residue (4-hydroxyproline)

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.Pro2316= 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-pro2316ser (accessed [today's date]).

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