Is COL5A2 p.Ser451Pro (c.1351T>C) pathogenic?

COL5A2 p.Ser451Pro (c.1351T>C) is classified Likely benign in COL5A2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-03). AlphaMissense: likely benign (0.0831); Ultra-rare (popmax 0.0944%, sas); Associated with Ehlers-Danlos syndrome, classic type, 1.

What condition is associated with COL5A2 p.Ser451Pro (c.1351T>C)?

COL5A2 p.Ser451Pro (c.1351T>C) is associated with Ehlers-Danlos syndrome, classic type, 1, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is COL5A2 p.Ser451Pro (c.1351T>C) in the general population?

COL5A2 p.Ser451Pro (c.1351T>C) is ultra-rare (popmax 0.0944%, sas) (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 COL5A2 p.Ser451Pro (c.1351T>C)?

AlphaMissense predicts likely benign (score 0.0831) — an in-silico prediction, not a clinical call.

COL5A2 p.Ser451Pro

c.1351T>C · rs548441536 · VCV519688

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0831 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0944%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Ehlers-Danlos syndrome, classic type, 1

Computational evidence

Protein change
AlphaMissense	0.0831	likely benign
REVEL	0.346	indeterminate
SaProt	LLR -5.37	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.1	GERP 0.048, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 146 kb · p 1.2e-16 · regional, not allelic
Overall
CADD	21.5	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 0.0944% South Asian · 86/91,078 alleles

Filtering AF 0.0782% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0723%

Overall 0.00539% 87/1,614,006 alleles · ultra-rare exomes 85/1,461,788 · genomes 2/152,218 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0944%	1,059
Remaining individualsnot grpmax-eligible	0.0016%	62,510

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: COL5A2
Protein: p.Ser451Pro
Coding: c.1351T>C
MANE Select: NM_000393
dbSNP: rs548441536
Type: single nucleotide variant
Location: chr2:189068065 (GRCh38)
Gene constraint: LOEUF 0.106 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 53.15
Residue 451: the 'disordered' region

Full COL5A2 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

COL5A2 p.Ser451Phe Uncertain significance ★★ ⚠ same residue
COL5A2 c.1159-1G>A Likely pathogenic ★★ same condition
COL5A2 c.369+1G>T Likely pathogenic ★★ same condition
COL5A2 p.Gly252Cys Pathogenic/Likely pathogenic ★★ same condition
COL5A2 p.Pro659= Pathogenic ★★ same condition
COL5A2 c.1005+4T>C Uncertain significance ★★ same condition
COL5A2 c.1618-7G>A Uncertain significance ★★ same condition
COL5A2 c.1716+5G>A 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/col5a2-p-ser451pro (accessed [today's date]).

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