Is COL12A1 p.Arg752= (c.2256A>G) pathogenic?

COL12A1 p.Arg752= (c.2256A>G) is classified Uncertain significance in COL12A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-08). Very rare (popmax 0.000169%, nfe); Associated with Ullrich congenital muscular dystrophy 2.

What condition is associated with COL12A1 p.Arg752= (c.2256A>G)?

COL12A1 p.Arg752= (c.2256A>G) is associated with Ullrich congenital muscular dystrophy 2, Bethlem myopathy 2 (ClinVar).

How common is COL12A1 p.Arg752= (c.2256A>G) in the general population?

COL12A1 p.Arg752= (c.2256A>G) is very rare (popmax 0.000169%, 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.

COL12A1 p.Arg752=

c.2256A>G · rs370677855 · VCV1019504

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

Ullrich congenital muscular dystrophy 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.33	donor gain · deltas
Pangolin	Δ0.27	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.83	GERP 0.86, phastCons 1
Overall
CADD	16.53	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,036 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,024 alleles · very rare exomes 1/1,461,810 · genomes 1/152,214 · 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: COL12A1
Protein: p.Arg752=
Coding: c.2256A>G
MANE Select: NM_004370
dbSNP: rs370677855
Type: single nucleotide variant
Location: chr6:75177844 (GRCh38)
Gene constraint: LOEUF 0.375 · pLI 1.00 (gnomAD)
Residue 752: the fibronectin type-iii 4 domain

Full COL12A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Ullrich congenital muscular dystrophy 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Bethlem myopathy 2

For Ullrich congenital muscular dystrophy (Orphanet):

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

Similar variants

COL12A1 c.4418-1G>A Likely pathogenic ★★ same condition
COL12A1 c.4957+1G>A Likely pathogenic ★★ same condition
COL12A1 c.5230+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL12A1 c.5794+2T>A Pathogenic ★★ same condition
COL12A1 c.7519+1G>A Likely pathogenic ★★ same condition
COL12A1 p.Arg1299Ter Pathogenic/Likely pathogenic ★★ same condition
COL12A1 p.Arg1301Ter Pathogenic/Likely pathogenic ★★ same condition
COL12A1 p.Arg1396Ter 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/col12a1-p-arg752 (accessed [today's date]).

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