Is COL5A1 p.Pro1104Ser (c.3310C>T) pathogenic?

COL5A1 p.Pro1104Ser (c.3310C>T) is classified Uncertain significance in COL5A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-09). AlphaMissense: likely benign (0.1524); Ultra-rare (popmax 0.018%, mid); Associated with familial thoracic aortic aneurysm and aortic dissection.

How common is COL5A1 p.Pro1104Ser (c.3310C>T) in the general population?

COL5A1 p.Pro1104Ser (c.3310C>T) is ultra-rare (popmax 0.018%, mid) (gnomAD).

What do computational predictors say about COL5A1 p.Pro1104Ser (c.3310C>T)?

AlphaMissense predicts likely benign (score 0.1524) — an in-silico prediction, not a clinical call.

COL5A1 p.Pro1104Ser

Q: What condition is associated with COL5A1 p.Pro1104Ser (c.3310C>T)?

COL5A1 p.Pro1104Ser (c.3310C>T) is associated with familial thoracic aortic aneurysm and aortic dissection, Ehlers-Danlos syndrome, classic type, 1 (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.3310C>T · rs1838292124 · VCV1010310

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1524 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.018%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.1524	likely benign
REVEL	0.83	moderately pathogenic-leaning
SaProt	LLR -9.13	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 85 kb · p 6e-30 · regional, not allelic
Overall
CADD	22.8	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 0.018% Middle Eastern · 1/5,554 alleles

Overall 6.45e-05% 1/1,550,382 alleles · ultra-rare exomes 1/1,398,202 · genomes 0/152,180 · 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: COL5A1
Protein: p.Pro1104Ser
Coding: c.3310C>T
MANE Select: NM_000093
dbSNP: rs1838292124
Type: single nucleotide variant
Location: chr9:134806240 (GRCh38)
Gene constraint: LOEUF 0.089 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.54 · 1 PDB
Residue 1104: the 'disordered' region; the 'triple-helical region' region

Full COL5A1 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, classic type, 1

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

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

COL5A1 p.Pro1104= Likely benign ★ same residue
COL5A1 p.Pro1104Ala Uncertain significance ★ ⚠ same residue
COL5A1 p.Pro1104Arg Uncertain significance ★ ⚠ same residue
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

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-pro1104ser (accessed [today's date]).

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