Is COL5A1 p.Pro463= (c.1389G>A) pathogenic?

COL5A1 p.Pro463= (c.1389G>A) is classified Uncertain significance in COL5A1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-30). Very rare (popmax 0.00223%, eas); Associated with Ehlers-Danlos syndrome, classic type, 1.

What condition is associated with COL5A1 p.Pro463= (c.1389G>A)?

COL5A1 p.Pro463= (c.1389G>A) is associated with Ehlers-Danlos syndrome, classic type, 1, cardiac rhythm disease, Wolff-Parkinson-White syndrome (ClinVar).

How common is COL5A1 p.Pro463= (c.1389G>A) in the general population?

COL5A1 p.Pro463= (c.1389G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

How is Classical Ehlers-Danlos syndrome inherited?

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

COL5A1 p.Pro463=

c.1389G>A · rs1057518771 · VCV373924

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Ehlers-Danlos syndrome, classic type, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.28	donor loss · deltas
Pangolin	Δ0.40	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -8.7	GERP -3
Overall
CADD	11.72	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,902 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000929% 15/1,614,108 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,902
South Asian	0.0022%	45,541
Admixed American	0.00167%	60,018
African / African-American	0.00133%	74,948
European (non-Finnish)	0.000847%	118,003

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.Pro463=
Coding: c.1389G>A
MANE Select: NM_000093
dbSNP: rs1057518771
Type: single nucleotide variant
Location: chr9:134732127 (GRCh38)
Gene constraint: LOEUF 0.089 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.54 · 1 PDB
Residue 463: the 'interrupted collagenous region' region

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: cardiac rhythm disease Wolff-Parkinson-White syndrome 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.Pro463Ala Uncertain significance ★★ ⚠ same residue
COL5A1 p.Pro463Leu Uncertain significance ★★ ⚠ same residue
COL5A1 p.Pro463Ser 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-pro463 (accessed [today's date]).

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