Is COL3A1 p.Pro77Ser (c.229C>T) pathogenic?

COL3A1 p.Pro77Ser (c.229C>T) is classified Uncertain significance in COL3A1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-08-10). AlphaMissense: ambiguous (0.4177); Very rare (popmax 0.000254%, nfe); Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is COL3A1 p.Pro77Ser (c.229C>T) in the general population?

COL3A1 p.Pro77Ser (c.229C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about COL3A1 p.Pro77Ser (c.229C>T)?

AlphaMissense predicts ambiguous (score 0.4177) — an in-silico prediction, not a clinical call.

COL3A1 p.Pro77Ser

Q: What condition is associated with COL3A1 p.Pro77Ser (c.229C>T)?

COL3A1 p.Pro77Ser (c.229C>T) 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.229C>T · rs1688032952 · VCV920607

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4177 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.4177	ambiguous
REVEL	0.544	indeterminate
SaProt	LLR -12.67	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 2, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 12 kb · p 4.3e-17 · regional, not allelic
Overall
CADD	22.6	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

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,416 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,112 alleles · very rare exomes 3/1,461,120 · genomes 0/151,992 · 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.Pro77Ser
Coding: c.229C>T
MANE Select: NM_000090
dbSNP: rs1688032952
Type: single nucleotide variant
Location: chr2:188984909 (GRCh38)
Gene constraint: LOEUF 0.291 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.98 · 11 PDB
Residue 77: the vwfc domain

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.Pro77Arg Uncertain significance ★ ⚠ same residue
COL3A1 p.Pro77Thr Uncertain significance ★ same residue
COL3A1 p.Pro77= Likely benign ★ 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

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-pro77ser (accessed [today's date]).

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