Is COL6A2 p.Ser960Pro (c.2878T>C) pathogenic?

COL6A2 p.Ser960Pro (c.2878T>C) is classified Uncertain significance in COL6A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-02). AlphaMissense: likely pathogenic (0.8881); Very rare (popmax 8.48e-05%, nfe); Associated with Bethlem myopathy 1A.

What condition is associated with COL6A2 p.Ser960Pro (c.2878T>C)?

COL6A2 p.Ser960Pro (c.2878T>C) is associated with Bethlem myopathy 1A (ClinVar).

How common is COL6A2 p.Ser960Pro (c.2878T>C) in the general population?

COL6A2 p.Ser960Pro (c.2878T>C) is very rare (popmax 8.48e-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 COL6A2 p.Ser960Pro (c.2878T>C)?

AlphaMissense predicts likely pathogenic (score 0.8881) — an in-silico prediction, not a clinical call.

COL6A2 p.Ser960Pro

c.2878T>C · rs2123455695 · VCV1395470

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8881 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Bethlem myopathy 1A

Computational evidence

Protein change
AlphaMissense	0.8881	likely pathogenic
REVEL	0.341	indeterminate
SaProt	LLR -12.81	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -2.6, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 16 kb · p 1.4e-07 · regional, not allelic
Overall
CADD	16.89	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,478 alleles

Overall 6.86e-05% 1/1,456,884 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: COL6A2
Protein: p.Ser960Pro
Coding: c.2878T>C
MANE Select: NM_001849
dbSNP: rs2123455695
Type: single nucleotide variant
Location: chr21:46132370 (GRCh38)
Gene constraint: LOEUF 0.895 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.58 · 1 PDB
Residue 960: the vwfa 3 domain; an α-helix; the 'nonhelical region' region

Full COL6A2 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

COL6A2 p.Ser960Leu Conflicting classifications of pathogenicity ★ same residue
COL6A2 p.Ser960= Likely benign ★ same residue
COL6A2 c.1000-1G>T Pathogenic ★★ same condition
COL6A2 c.1000-2A>C Pathogenic ★★ same condition
COL6A2 c.1053+1G>A Pathogenic ★★ same condition
COL6A2 c.1053+1G>C Pathogenic/Likely pathogenic ★★ same condition
COL6A2 c.1053+2T>C Pathogenic/Likely pathogenic ★★ same condition
COL6A2 c.1054-2A>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/col6a2-p-ser960pro (accessed [today's date]).

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