Is COL1A2 p.Pro522= (c.1566A>G) pathogenic?

COL1A2 p.Pro522= (c.1566A>G) is classified Conflicting classifications of pathogenicity in COL1A2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-07-09). Ultra-rare (popmax 0.0104%, nfe); Associated with osteogenesis imperfecta type 1.

What condition is associated with COL1A2 p.Pro522= (c.1566A>G)?

COL1A2 p.Pro522= (c.1566A>G) is associated with osteogenesis imperfecta type 1, Ehlers-Danlos syndrome, classic type, 1, Ehlers-Danlos syndrome (ClinVar).

How common is COL1A2 p.Pro522= (c.1566A>G) in the general population?

COL1A2 p.Pro522= (c.1566A>G) is ultra-rare (popmax 0.0104%, nfe) (gnomAD).

COL1A2 p.Pro522=

c.1566A>G · rs749869789 · VCV772932

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0104%, nfe)

Conditions

osteogenesis imperfecta type 1

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 -0.25	GERP -4.4, phastCons 0.003
Overall
CADD	9.268	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0104% European (non-Finnish) · 123/1,180,018 alleles

Filtering AF 0.00892% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00836%

Overall 0.00824% 133/1,614,088 alleles · ultra-rare exomes 125/1,461,858 · genomes 8/152,230 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0104%	9,594
Remaining individualsnot grpmax-eligible	0.0096%	10,415
African / African-American	0.004%	24,981
South Asian	0.0011%	91,086

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: COL1A2
Protein: p.Pro522=
Coding: c.1566A>G
MANE Select: NM_000089
dbSNP: rs749869789
Type: single nucleotide variant
Location: chr7:94413698 (GRCh38)
Gene constraint: LOEUF 0.339 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 55.02 · 5 PDB
Residue 522: the 'disordered' region

Full COL1A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

osteogenesis imperfecta type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

COL1A2 p.Pro522Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
COL1A2 c.1197+5G>A Pathogenic ★★ same condition
COL1A2 c.1404+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL1A2 c.1503+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL1A2 c.1503+1G>C Pathogenic ★★ same condition
COL1A2 c.1557+3A>G Pathogenic ★★ same condition
COL1A2 c.2026-2A>G Pathogenic/Likely pathogenic ★★ same condition
COL1A2 c.2133+6T>A Pathogenic ★★ 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/col1a2-p-pro522 (accessed [today's date]).

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