Is COL5A1 p.Pro696= (c.2088C>T) pathogenic?

COL5A1 p.Pro696= (c.2088C>T) is classified Conflicting classifications of pathogenicity in COL5A1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-03). Ultra-rare (popmax 0.0663%, mid); Associated with Ehlers-Danlos syndrome, classic type, 1.

What condition is associated with COL5A1 p.Pro696= (c.2088C>T)?

COL5A1 p.Pro696= (c.2088C>T) is associated with Ehlers-Danlos syndrome, classic type, 1, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is COL5A1 p.Pro696= (c.2088C>T) in the general population?

COL5A1 p.Pro696= (c.2088C>T) is ultra-rare (popmax 0.0663%, mid) (gnomAD).

How is Classical Ehlers-Danlos syndrome inherited?

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

COL5A1 p.Pro696=

c.2088C>T · rs146757272 · VCV264547

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0663%, mid)

Conditions

Ehlers-Danlos syndrome, classic type, 1

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 -13	GERP -2.7
Overall
CADD	0.883	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0663% Middle Eastern · 4/6,034 alleles

Filtering AF 0.0226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00428% 69/1,612,340 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0663%	1,509
African / African-American	0.0213%	4,688
South Asian	0.0165%	6,061
Admixed American	0.0117%	8,555
Remaining individualsnot grpmax-eligible	0.00801%	12,482
European (non-Finnish)	0.00187%	53,584

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: COL5A1
Protein: p.Pro696=
Coding: c.2088C>T
MANE Select: NM_000093
dbSNP: rs146757272
Type: single nucleotide variant
Location: chr9:134765734 (GRCh38)
Gene constraint: LOEUF 0.089 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.54 · 1 PDB
Residue 696: the 'disordered' region; the 'triple-helical region' region; a modified residue (hydroxyproline)

Full COL5A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Ehlers-Danlos syndrome, classic type, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial thoracic aortic aneurysm and aortic dissection

For Classical Ehlers-Danlos syndrome (Orphanet):

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

Similar variants

COL5A1 c.1332+1G>T Pathogenic/Likely pathogenic ★★ same condition
COL5A1 c.1720-11T>A Likely pathogenic ★★ same condition
COL5A1 c.2034+1G>A Pathogenic ★★ same condition
COL5A1 c.2430+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL5A1 c.2430+1G>C Pathogenic ★★ same condition
COL5A1 c.2701-25T>G Pathogenic ★★ same condition
COL5A1 c.4338+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL5A1 c.5067+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/col5a1-p-pro696 (accessed [today's date]).

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