Is COL3A1 p.Glu658= (c.1974A>G) pathogenic?

COL3A1 p.Glu658= (c.1974A>G) is classified Likely benign in COL3A1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-30). Very rare (popmax 0.0011%, nfe); Associated with Ehlers-Danlos syndrome, vascular type.

What condition is associated with COL3A1 p.Glu658= (c.1974A>G)?

COL3A1 p.Glu658= (c.1974A>G) is associated with Ehlers-Danlos syndrome, vascular type, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is COL3A1 p.Glu658= (c.1974A>G) in the general population?

COL3A1 p.Glu658= (c.1974A>G) is very rare (popmax 0.0011%, 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.Glu658=

c.1974A>G · rs2469141183 · VCV3017608

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, 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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -0.54, phastCons 0.22
Overall
CADD	9.826	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% European (non-Finnish) · 13/1,179,570 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000806% 13/1,613,512 alleles · very rare exomes 13/1,461,174 · genomes 0/152,338 · 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: COL3A1
Protein: p.Glu658=
Coding: c.1974A>G
MANE Select: NM_000090
dbSNP: rs2469141183
Type: single nucleotide variant
Location: chr2:188998316 (GRCh38)
Gene constraint: LOEUF 0.291 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.98 · 11 PDB
Residue 658: a UniProt-annotated variant site (in pmgedsv); the 'disordered' region; the 'triple-helical region' region

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.Glu658Lys Uncertain significance ★★ ⚠ 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
COL3A1 c.1869+1G>C 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-glu658 (accessed [today's date]).

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