Is COL2A1 p.Pro1000= (c.3000G>A) pathogenic?

COL2A1 p.Pro1000= (c.3000G>A) is classified Benign in COL2A1 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-05-09). Common (popmax 7.87%, afr) — too common for a highly-penetrant pathogenic allele; Associated with connective tissue disorder.

What condition is associated with COL2A1 p.Pro1000= (c.3000G>A)?

COL2A1 p.Pro1000= (c.3000G>A) is associated with connective tissue disorder, Stickler syndrome type 1, type 2 collagenopathy (ClinVar).

COL2A1 p.Pro1000=

Q: How common is COL2A1 p.Pro1000= (c.3000G>A) in the general population?

COL2A1 p.Pro1000= (c.3000G>A) is common (popmax 7.87%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.3000G>A · rs1793947 · VCV258232

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Common

common (popmax 7.87%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

connective tissue disorder

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 -2.6	GERP -2.1
Overall
CADD	2.862	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.87% African / African-American · 5,903/75,016 alleles

Filtering AF 7.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.63%

Overall 0.429% 6,917/1,613,818 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.87%	13
Admixed American	0.665%	150
Remaining individualsnot grpmax-eligible	0.547%	183
Middle Eastern	0.413%	242
European (non-Finnish)	0.0191%	5,244
South Asian	0.0176%	5,691
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
East Asian	0.00891%	11,219

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: COL2A1
Protein: p.Pro1000=
Coding: c.3000G>A
MANE Select: NM_001844
dbSNP: rs1793947
Type: single nucleotide variant
Location: chr12:47978294 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 1000: the 'disordered' region; the 'triple-helical region' region

Full COL2A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

connective tissue disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Stickler syndrome type 1 type 2 collagenopathy

Similar variants

COL2A1 p.Pro1000Arg Uncertain significance ★★ ⚠ same residue
COL2A1 p.Pro1000Leu Likely benign ★★ ⚠ same residue
COL2A1 p.Pro1000Thr Uncertain significance ★ ⚠ same residue
COL2A1 c.1222-2A>G Pathogenic ★★ same condition
COL2A1 c.1365+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.1420-2A>G Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.1527+135G>A Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.1581+1G>A Likely 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/col2a1-p-pro1000 (accessed [today's date]).

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