Is COL5A2 p.Arg665= (c.1995A>G) pathogenic?

COL5A2 p.Arg665= (c.1995A>G) is classified Conflicting classifications of pathogenicity in COL5A2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-18). Rare (popmax 0.23%, eas); Associated with Ehlers-Danlos syndrome.

What condition is associated with COL5A2 p.Arg665= (c.1995A>G)?

COL5A2 p.Arg665= (c.1995A>G) is associated with Ehlers-Danlos syndrome, Ehlers-Danlos syndrome, classic type, 1, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is COL5A2 p.Arg665= (c.1995A>G) in the general population?

COL5A2 p.Arg665= (c.1995A>G) is rare (popmax 0.23%, eas) (gnomAD).

COL5A2 p.Arg665=

c.1995A>G · rs140541824 · VCV704416

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.23%, eas)

Conditions

Ehlers-Danlos syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.9	GERP 1.2, phastCons 1
Overall
CADD	13.85	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.23% East Asian · 103/44,776 alleles

Filtering AF 0.194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.181%

Overall 0.00638% 103/1,613,258 alleles · rare exomes 100/1,460,954 · genomes 3/152,304 · 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.Arg665=
Coding: c.1995A>G
MANE Select: NM_000393
dbSNP: rs140541824
Type: single nucleotide variant
Location: chr2:189061598 (GRCh38)
Gene constraint: LOEUF 0.106 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 53.15
Residue 665: the 'disordered' region

Full COL5A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: Ehlers-Danlos syndrome, classic type, 1 familial thoracic aortic aneurysm and aortic dissection

Similar variants

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
COL5A2 c.1717-3C>T 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-arg665 (accessed [today's date]).

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