Is COL3A1 p.Pro89= (c.267A>G) pathogenic?

COL3A1 p.Pro89= (c.267A>G) is classified Conflicting classifications of pathogenicity in COL3A1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-08-06). Very rare (popmax 0.000594%, nfe); Associated with Ehlers-Danlos syndrome, vascular type.

What condition is associated with COL3A1 p.Pro89= (c.267A>G)?

COL3A1 p.Pro89= (c.267A>G) is associated with Ehlers-Danlos syndrome, vascular type, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is COL3A1 p.Pro89= (c.267A>G) in the general population?

COL3A1 p.Pro89= (c.267A>G) is very rare (popmax 0.000594%, nfe) (gnomAD).

How is Vascular Ehlers-Danlos syndrome inherited?

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

COL3A1 p.Pro89=

c.267A>G · rs998965783 · VCV896316

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000594%, nfe)

Conditions

Ehlers-Danlos syndrome, vascular type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.7	GERP -3.8
Overall
CADD	4.545	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000594% European (non-Finnish) · 7/1,179,296 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000558% 9/1,612,906 alleles · very rare exomes 9/1,460,832 · genomes 0/152,074 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,221
European (non-Finnish)grpmax	0.000594%	168,471

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: COL3A1
Protein: p.Pro89=
Coding: c.267A>G
MANE Select: NM_000090
dbSNP: rs998965783
Type: single nucleotide variant
Location: chr2:188984947 (GRCh38)
Gene constraint: LOEUF 0.291 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.98 · 11 PDB
Residue 89: the vwfc domain

Full COL3A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Ehlers-Danlos syndrome, vascular type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial thoracic aortic aneurysm and aortic dissection

For Vascular Ehlers-Danlos syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

COL3A1 p.Pro89Arg Uncertain significance ★★ ⚠ same residue
COL3A1 p.Pro89Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
COL3A1 c.1051-1G>C Likely pathogenic ★★ same condition
COL3A1 c.1294-1G>A Pathogenic/Likely pathogenic ★★ same condition
COL3A1 c.1347+1G>A Pathogenic ★★ same condition
COL3A1 c.1348-2A>G Pathogenic/Likely pathogenic ★★ same condition
COL3A1 c.1662+1G>A Pathogenic ★★ same condition
COL3A1 c.1663-1G>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/col3a1-p-pro89 (accessed [today's date]).

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