Is COL5A1 p.Pro97Ser (c.289C>T) pathogenic?

COL5A1 p.Pro97Ser (c.289C>T) is classified Uncertain significance in COL5A1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-10). AlphaMissense: likely pathogenic (0.5643); Very rare (popmax 0.0011%, nfe); Associated with Ehlers-Danlos syndrome, classic type, 1.

What condition is associated with COL5A1 p.Pro97Ser (c.289C>T)?

COL5A1 p.Pro97Ser (c.289C>T) is associated with Ehlers-Danlos syndrome, classic type, 1, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is COL5A1 p.Pro97Ser (c.289C>T) in the general population?

COL5A1 p.Pro97Ser (c.289C>T) is very rare (popmax 0.0011%, nfe) (gnomAD).

How is Classical Ehlers-Danlos syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about COL5A1 p.Pro97Ser (c.289C>T)?

AlphaMissense predicts likely pathogenic (score 0.5643) — an in-silico prediction, not a clinical call.

COL5A1 p.Pro97Ser

c.289C>T · rs1189111524 · VCV1496362

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.5643 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Ehlers-Danlos syndrome, classic type, 1

Computational evidence

Protein change
AlphaMissense	0.5643	likely pathogenic
REVEL	0.382	indeterminate
SaProt	LLR -13.21	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 96 kb · p 0.17 · regional, not allelic
Overall
CADD	24.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0011% European (non-Finnish) · 13/1,180,036 alleles

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

Overall 0.000806% 13/1,613,878 alleles · very rare

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.Pro97Ser
Coding: c.289C>T
MANE Select: NM_000093
dbSNP: rs1189111524
Type: single nucleotide variant
Location: chr9:134699920 (GRCh38)
Gene constraint: LOEUF 0.089 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.54 · 1 PDB
Residue 97: the laminin g-like domain

Full COL5A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Ehlers-Danlos syndrome, classic type, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial thoracic aortic aneurysm and aortic dissection

For Classical Ehlers-Danlos syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Worldwide)

Similar variants

COL5A1 p.Pro97= Likely benign ★★ 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
COL5A1 c.2701-25T>G Pathogenic ★★ same condition
COL5A1 c.4338+1G>A Pathogenic/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/col5a1-p-pro97ser (accessed [today's date]).

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