Is COL3A1 p.Pro488Ser (c.1462C>T) pathogenic?

COL3A1 p.Pro488Ser (c.1462C>T) is classified Uncertain significance in COL3A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-30). AlphaMissense: likely benign (0.0705); Very rare (popmax 8.47e-05%, nfe); Associated with Ehlers-Danlos syndrome, vascular type.

What condition is associated with COL3A1 p.Pro488Ser (c.1462C>T)?

COL3A1 p.Pro488Ser (c.1462C>T) is associated with Ehlers-Danlos syndrome, vascular type (ClinVar).

How common is COL3A1 p.Pro488Ser (c.1462C>T) in the general population?

COL3A1 p.Pro488Ser (c.1462C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Vascular Ehlers-Danlos syndrome inherited?

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

What do computational predictors say about COL3A1 p.Pro488Ser (c.1462C>T)?

AlphaMissense predicts likely benign (score 0.0705) — an in-silico prediction, not a clinical call.

COL3A1 p.Pro488Ser

c.1462C>T · rs2153502474 · VCV1686583

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0705 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Ehlers-Danlos syndrome, vascular type

Computational evidence

Protein change
AlphaMissense	0.0705	likely benign
REVEL	0.359	indeterminate
SaProt	LLR -10.67	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.68	unconstrained · MANE · 12 kb · p 4.3e-17 · regional, not allelic
Overall
CADD	23.3	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 8.47e-05% European (non-Finnish) · 1/1,180,006 alleles

Overall 6.2e-05% 1/1,614,102 alleles · very rare exomes 1/1,461,846 · genomes 0/152,256 · 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.Pro488Ser
Coding: c.1462C>T
MANE Select: NM_000090
dbSNP: rs2153502474
Type: single nucleotide variant
Location: chr2:188995052 (GRCh38)
Gene constraint: LOEUF 0.291 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.98 · 11 PDB
Residue 488: a UniProt-annotated variant site (in pmgedsv); the 'disordered' region; the 'triple-helical region' region; a modified residue (4-hydroxyproline)

Full COL3A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

For Vascular Ehlers-Danlos syndrome (Orphanet):

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

Similar variants

COL3A1 p.Pro488= Likely benign ★★ same residue
COL3A1 p.Pro488Leu Uncertain significance ★ ⚠ 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
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-pro488ser (accessed [today's date]).

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