Is COL2A1 p.Pro1040= (c.3120C>T) pathogenic?

COL2A1 p.Pro1040= (c.3120C>T) is classified Conflicting classifications of pathogenicity in COL2A1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-07-14). Very rare (popmax 0.00534%, afr); Associated with Stickler syndrome type 1.

What condition is associated with COL2A1 p.Pro1040= (c.3120C>T)?

COL2A1 p.Pro1040= (c.3120C>T) is associated with Stickler syndrome type 1, type 2 collagenopathy (ClinVar).

How common is COL2A1 p.Pro1040= (c.3120C>T) in the general population?

COL2A1 p.Pro1040= (c.3120C>T) is very rare (popmax 0.00534%, afr) (gnomAD).

How is Stickler syndrome inherited?

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

COL2A1 p.Pro1040=

c.3120C>T · rs367982631 · VCV511979

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00534%, afr)

Conditions

Stickler syndrome 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 -1.2	GERP -3.8
Overall
CADD	3.816	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00534% African / African-American · 4/74,852 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00267%

Overall 0.00335% 54/1,613,826 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00534%	18,713
European (non-Finnish)	0.0039%	25,651
Remaining individualsnot grpmax-eligible	0.0032%	31,236
East Asian	0.00223%	44,878
South Asian	0.0011%	91,070

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.Pro1040=
Coding: c.3120C>T
MANE Select: NM_001844
dbSNP: rs367982631
Type: single nucleotide variant
Location: chr12:47977645 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 1040: the 'disordered' region; the 'triple-helical region' region

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

Disease context

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

Also linked: type 2 collagenopathy

For Stickler syndrome (Orphanet):

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

Similar variants

COL2A1 p.Pro1040Leu Conflicting classifications of pathogenicity ★ ⚠ 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
COL2A1 c.1833+1G>A Pathogenic ★★ same condition
COL2A1 c.1887+1G>A Pathogenic/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-pro1040 (accessed [today's date]).

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