Is COL6A3 p.Arg2136Ser (c.6408G>C) pathogenic?

COL6A3 p.Arg2136Ser (c.6408G>C) is classified Uncertain significance in COL6A3 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-04-04). AlphaMissense: ambiguous (0.5037); Very rare (popmax 0.00348%, nfe); Associated with Ullrich congenital muscular dystrophy 1A.

What condition is associated with COL6A3 p.Arg2136Ser (c.6408G>C)?

COL6A3 p.Arg2136Ser (c.6408G>C) is associated with Ullrich congenital muscular dystrophy 1A, Bethlem myopathy 1A (ClinVar).

How common is COL6A3 p.Arg2136Ser (c.6408G>C) in the general population?

COL6A3 p.Arg2136Ser (c.6408G>C) is very rare (popmax 0.00348%, nfe) (gnomAD).

How is Ullrich congenital 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.Arg2136Ser (c.6408G>C)?

AlphaMissense predicts ambiguous (score 0.5037) — an in-silico prediction, not a clinical call.

COL6A3 p.Arg2136Ser

c.6408G>C · rs781675126 · VCV499045

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.5037 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00348%, nfe)

Conditions

Ullrich congenital muscular dystrophy 1A

Computational evidence

Protein change
AlphaMissense	0.5037	ambiguous
REVEL	0.653	pathogenic-leaning
Splicing
SpliceAI	Δ0.24	donor gain · deltas
Pangolin	Δ0.50	loss · gain 0.02 · SpliceAI calls gain · independent
Constraint at this position
Conservation	phyloP 4	GERP 1.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 34 kb · p 0.074 · regional, not allelic
Overall
CADD	32.0	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 0.00348% European (non-Finnish) · 41/1,179,648 alleles

Filtering AF 0.00259% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00233%

Overall 0.00294% 43/1,461,438 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00348%	28,772
Remaining individualsnot grpmax-eligible	0.0032%	31,246

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.Arg2136Ser
Coding: c.6408G>C
MANE Select: NM_004369
dbSNP: rs781675126
Type: single nucleotide variant
Location: chr2:237359035 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 2136: the collagen-like 2 domain; the 'triple-helical region' region; the 'disordered' region

Full COL6A3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Ullrich congenital muscular dystrophy 1A — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Bethlem myopathy 1A

For Ullrich congenital muscular dystrophy (Orphanet):

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

Similar variants

COL6A3 p.Arg2136= Uncertain significance ★ 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-arg2136ser (accessed [today's date]).

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