Is COL5A2 p.Arg128Pro (c.383G>C) pathogenic?

COL5A2 p.Arg128Pro (c.383G>C) is classified Uncertain significance in COL5A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-12). AlphaMissense: likely benign (0.3141); Very rare (popmax 8.48e-05%, nfe); Associated with Ehlers-Danlos syndrome, classic type, 1.

What condition is associated with COL5A2 p.Arg128Pro (c.383G>C)?

COL5A2 p.Arg128Pro (c.383G>C) is associated with Ehlers-Danlos syndrome, classic type, 1 (ClinVar).

How common is COL5A2 p.Arg128Pro (c.383G>C) in the general population?

COL5A2 p.Arg128Pro (c.383G>C) 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 COL5A2 p.Arg128Pro (c.383G>C)?

AlphaMissense predicts likely benign (score 0.3141) — an in-silico prediction, not a clinical call.

COL5A2 p.Arg128Pro

c.383G>C · VCV3670092

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3141 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Ehlers-Danlos syndrome, classic type, 1

Computational evidence

Protein change
AlphaMissense	0.3141	likely benign
REVEL	0.483	indeterminate
SaProt	LLR -4.01	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.4, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 146 kb · p 1.2e-16 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 8.48e-05% European (non-Finnish) · 1/1,179,148 alleles

Overall 6.2e-05% 1/1,612,956 alleles · very rare exomes 1/1,460,706 · genomes 0/152,250 · 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: COL5A2
Protein: p.Arg128Pro
Coding: c.383G>C
MANE Select: NM_000393
Type: single nucleotide variant
Location: chr2:189098746 (GRCh38)
Gene constraint: LOEUF 0.106 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 53.15
Residue 128: 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

For Classical Ehlers-Danlos syndrome (Orphanet):

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

Similar variants

COL5A2 p.Arg128Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
COL5A2 p.Arg128His Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg128pro (accessed [today's date]).

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