Is COL3A1 p.Pro153Arg (c.458C>G) pathogenic?

COL3A1 p.Pro153Arg (c.458C>G) is classified Uncertain significance in COL3A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-04-27). AlphaMissense: ambiguous (0.3591); Absent from gnomAD v4.1; Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is COL3A1 p.Pro153Arg (c.458C>G) in the general population?

COL3A1 p.Pro153Arg (c.458C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about COL3A1 p.Pro153Arg (c.458C>G)?

AlphaMissense predicts ambiguous (score 0.3591) — an in-silico prediction, not a clinical call.

COL3A1 p.Pro153Arg

Q: What condition is associated with COL3A1 p.Pro153Arg (c.458C>G)?

COL3A1 p.Pro153Arg (c.458C>G) is associated with familial thoracic aortic aneurysm and aortic dissection, Ehlers-Danlos syndrome, vascular type (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.458C>G · rs2469111392 · VCV1741698

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3591 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.3591	ambiguous
REVEL	0.539	indeterminate
SaProt	LLR -7.52	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 12 kb · p 4.3e-17 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: COL3A1
Protein: p.Pro153Arg
Coding: c.458C>G
MANE Select: NM_000090
dbSNP: rs2469111392
Type: single nucleotide variant
Location: chr2:188987069 (GRCh38)
Gene constraint: LOEUF 0.291 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.98 · 11 PDB
Residue 153: the 'disordered' region; the 'nonhelical region (n-terminal)' region

Full COL3A1 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, vascular type

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

COL3A1 p.Pro153Ala 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-pro153arg (accessed [today's date]).

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