Is COL3A1 p.Pro1069Ser (c.3205C>T) pathogenic?

COL3A1 p.Pro1069Ser (c.3205C>T) is classified Uncertain significance in COL3A1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-07-22). AlphaMissense: likely benign (0.0699); Very rare (popmax 0.00136%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with COL3A1 p.Pro1069Ser (c.3205C>T)?

COL3A1 p.Pro1069Ser (c.3205C>T) is associated with Cardiovascular phenotype, Ehlers-Danlos syndrome, vascular type, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is COL3A1 p.Pro1069Ser (c.3205C>T) in the general population?

COL3A1 p.Pro1069Ser (c.3205C>T) is very rare (popmax 0.00136%, nfe) (gnomAD).

What do computational predictors say about COL3A1 p.Pro1069Ser (c.3205C>T)?

AlphaMissense predicts likely benign (score 0.0699) — an in-silico prediction, not a clinical call.

COL3A1 p.Pro1069Ser

c.3205C>T · rs200122671 · VCV263586

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0699 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0699	likely benign
REVEL	0.486	indeterminate
SaProt	LLR -8.73	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 15 kb · p 5.1e-19 · regional, not allelic
Overall
CADD	19.98	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00136% European (non-Finnish) · 16/1,179,638 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.000992% 16/1,613,012 alleles · very rare exomes 16/1,461,228 · genomes 0/151,784 · 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.Pro1069Ser
Coding: c.3205C>T
MANE Select: NM_000090
dbSNP: rs200122671
Type: single nucleotide variant
Location: chr2:189006940 (GRCh38)
Gene constraint: LOEUF 0.291 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.98 · 11 PDB
Residue 1069: 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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Ehlers-Danlos syndrome, vascular type familial thoracic aortic aneurysm and aortic dissection

Similar variants

COL3A1 p.Pro1069= 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.1347+1G>C Pathogenic/Likely 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

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-pro1069ser (accessed [today's date]).

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