Is COL5A2 p.Pro437= (c.1311A>G) pathogenic?

COL5A2 p.Pro437= (c.1311A>G) is classified Benign in COL5A2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). Common (popmax 98.3%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with Ehlers-Danlos syndrome, classic type, 2.

What condition is associated with COL5A2 p.Pro437= (c.1311A>G)?

COL5A2 p.Pro437= (c.1311A>G) is associated with Ehlers-Danlos syndrome, classic type, 2, Ehlers-Danlos syndrome, classic type, 1 (ClinVar).

How is Classical Ehlers-Danlos syndrome inherited?

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

COL5A2 p.Pro437=

Q: How common is COL5A2 p.Pro437= (c.1311A>G) in the general population?

COL5A2 p.Pro437= (c.1311A>G) is common (popmax 98.3%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1311A>G · rs2229495 · VCV1164099

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Common

common (popmax 98.3%, nfe) — too common for a highly-penetrant pathogenic allele

Conditions

Ehlers-Danlos syndrome, classic type, 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -20	GERP -5
Overall
CADD	0.153	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 98.3% European (non-Finnish) · 1,159,556/1,179,728 alleles

Filtering AF 98.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 98.1%

Overall 97.4% 1,571,276/1,613,694 alleles · common exomes 1,425,452/1,461,504 · genomes 145,824/152,190 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	100%	1
Finnishnot grpmax-eligible	99.8%	1
European (non-Finnish)grpmax	98.3%	1
South Asian	97.3%	1
Ashkenazi Jewishnot grpmax-eligible	97.2%	1
Remaining individualsnot grpmax-eligible	97.1%	1
Middle Eastern	96.5%	1
East Asian	94.1%	1
African / African-American	91.9%	1
Admixed American	86.4%	1

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro437=
Coding: c.1311A>G
MANE Select: NM_000393
dbSNP: rs2229495
Type: single nucleotide variant
Location: chr2:189068105 (GRCh38)
Gene constraint: LOEUF 0.106 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 53.15
Residue 437: the 'disordered' region

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

Disease context

Ehlers-Danlos syndrome, classic type, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Ehlers-Danlos syndrome, classic type, 1

For Classical Ehlers-Danlos syndrome (Orphanet):

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

Similar variants

COL5A2 p.Pro437Leu 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-pro437 (accessed [today's date]).

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