Is COL5A2 p.Pro1266= (c.3798A>G) pathogenic?

COL5A2 p.Pro1266= (c.3798A>G) is classified Likely benign in COL5A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-04). Very rare (popmax 0.00223%, eas); Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is COL5A2 p.Pro1266= (c.3798A>G) in the general population?

COL5A2 p.Pro1266= (c.3798A>G) is very rare (popmax 0.00223%, eas) (gnomAD).

COL5A2 p.Pro1266=

Q: What condition is associated with COL5A2 p.Pro1266= (c.3798A>G)?

COL5A2 p.Pro1266= (c.3798A>G) is associated with familial thoracic aortic aneurysm and aortic dissection, Ehlers-Danlos syndrome, classic type, 1 (ClinVar).

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

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

c.3798A>G · rs1309229319 · VCV2893883

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

familial thoracic aortic aneurysm and aortic dissection

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 -2.2	GERP -5
Overall
CADD	6.558	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,846 alleles

Overall 6.2e-05% 1/1,614,048 alleles · very rare exomes 1/1,461,874 · genomes 0/152,174 · 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: COL5A2
Protein: p.Pro1266=
Coding: c.3798A>G
MANE Select: NM_000393
dbSNP: rs1309229319
Type: single nucleotide variant
Location: chr2:189039399 (GRCh38)
Gene constraint: LOEUF 0.106 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 53.15
Residue 1266: the fibrillar collagen nc1 domain; the 'disordered' region

Full COL5A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Ehlers-Danlos syndrome, classic type, 1

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

COL5A2 p.Pro1266Gln Uncertain significance ★ ⚠ same residue
COL5A2 c.1159-1G>A Likely pathogenic ★★ same condition
COL5A2 c.369+1G>T Likely pathogenic ★★ same condition
COL5A2 p.Gly252Cys Pathogenic/Likely pathogenic ★★ same condition
COL5A2 p.Pro659= Pathogenic ★★ same condition
COL5A2 c.1005+4T>C Uncertain significance ★★ same condition
COL5A2 c.1618-7G>A Uncertain significance ★★ same condition
COL5A2 c.1716+5G>A Uncertain significance ★★ 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/col5a2-p-pro1266 (accessed [today's date]).

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