Is COL5A1 p.Pro488Ser (c.1462C>T) pathogenic?

COL5A1 p.Pro488Ser (c.1462C>T) is classified Uncertain significance in COL5A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-12-12). AlphaMissense: likely benign (0.1104); Very rare (popmax 8.48e-05%, nfe); Associated with Ehlers-Danlos syndrome, classic type.

What condition is associated with COL5A1 p.Pro488Ser (c.1462C>T)?

COL5A1 p.Pro488Ser (c.1462C>T) is associated with Ehlers-Danlos syndrome, classic type (ClinVar).

How common is COL5A1 p.Pro488Ser (c.1462C>T) in the general population?

COL5A1 p.Pro488Ser (c.1462C>T) is very rare (popmax 8.48e-05%, 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.Pro488Ser (c.1462C>T)?

AlphaMissense predicts likely benign (score 0.1104) — an in-silico prediction, not a clinical call.

COL5A1 p.Pro488Ser

c.1462C>T · rs1238395732 · VCV529261

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1104 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Ehlers-Danlos syndrome, classic type

Computational evidence

Protein change
AlphaMissense	0.1104	likely benign
REVEL	0.68	pathogenic-leaning
SaProt	LLR -9.05	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 3.6	GERP -0.92, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 85 kb · p 6e-30 · regional, not allelic
Overall
CADD	22.7	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 8.48e-05% European (non-Finnish) · 1/1,179,664 alleles

Overall 0.000657% 1/152,160 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.Pro488Ser
Coding: c.1462C>T
MANE Select: NM_000093
dbSNP: rs1238395732
Type: single nucleotide variant
Location: chr9:134738776 (GRCh38)
Gene constraint: LOEUF 0.089 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 52.54 · 1 PDB
Residue 488: the 'interrupted collagenous region' region; the 'disordered' region

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

Disease context

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

For Classical Ehlers-Danlos syndrome (Orphanet):

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

Similar variants

COL5A1 p.Pro488= Likely benign ★★ same residue
COL5A1 p.Pro488Arg Uncertain significance ★ ⚠ same residue
COL5A1 c.4338+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL5A1 p.Gln714Ter Pathogenic/Likely pathogenic ★★ same condition
COL5A1 p.Glu1292Lys Pathogenic/Likely pathogenic ★★ same condition
COL5A1 c.492-3C>T Uncertain significance ★★ same condition
COL5A1 p.Cys237Tyr Uncertain significance ★★ ⚠ same condition
COL5A1 p.Lys627Gln Uncertain significance ★★ ⚠ 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-pro488ser (accessed [today's date]).

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