Is COL12A1 p.Pro1111= (c.3333T>C) pathogenic?

COL12A1 p.Pro1111= (c.3333T>C) is classified Likely benign in COL12A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-03). Very rare (popmax 0.0011%, sas); Associated with Bethlem myopathy 2.

What condition is associated with COL12A1 p.Pro1111= (c.3333T>C)?

COL12A1 p.Pro1111= (c.3333T>C) is associated with Bethlem myopathy 2, Ullrich congenital muscular dystrophy 2 (ClinVar).

How common is COL12A1 p.Pro1111= (c.3333T>C) in the general population?

COL12A1 p.Pro1111= (c.3333T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Myopathic Ehlers-Danlos syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

COL12A1 p.Pro1111=

c.3333T>C · VCV4791501

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Bethlem myopathy 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.4	GERP -2.9
Overall
CADD	5.183	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,070 alleles

Overall 6.2e-05% 1/1,613,656 alleles · very rare exomes 1/1,461,344 · genomes 0/152,312 · 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.Pro1111=
Coding: c.3333T>C
MANE Select: NM_004370
Type: single nucleotide variant
Location: chr6:75155772 (GRCh38)
Gene constraint: LOEUF 0.375 · pLI 1.00 (gnomAD)
Residue 1111: the fibronectin type-iii 8 domain

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

Disease context

Bethlem myopathy 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Ullrich congenital muscular dystrophy 2

For Myopathic Ehlers-Danlos syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Antenatal, Infancy, Neonatal

Similar variants

COL12A1 p.Pro1111Ala Uncertain significance ★★ same residue
COL12A1 p.Pro1111His Uncertain significance ★ same residue
COL12A1 p.Pro1111Ser Uncertain significance ★ ⚠ same residue
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

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-pro1111 (accessed [today's date]).

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