Is COL2A1 p.Pro970Leu (c.2909C>T) pathogenic?

COL2A1 p.Pro970Leu (c.2909C>T) is classified Conflicting classifications of pathogenicity in COL2A1 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-01-08). AlphaMissense: likely benign (0.0647); Very rare (popmax 0.00229%, nfe); Associated with type 2 collagenopathy.

What condition is associated with COL2A1 p.Pro970Leu (c.2909C>T)?

COL2A1 p.Pro970Leu (c.2909C>T) is associated with type 2 collagenopathy, connective tissue disorder, Stickler syndrome type 1 (ClinVar).

How common is COL2A1 p.Pro970Leu (c.2909C>T) in the general population?

COL2A1 p.Pro970Leu (c.2909C>T) is very rare (popmax 0.00229%, nfe) (gnomAD).

What do computational predictors say about COL2A1 p.Pro970Leu (c.2909C>T)?

AlphaMissense predicts likely benign (score 0.0647) — an in-silico prediction, not a clinical call.

COL2A1 p.Pro970Leu

c.2909C>T · rs371268468 · VCV839628

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0647 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

type 2 collagenopathy

Computational evidence

Protein change
AlphaMissense	0.0647	likely benign
REVEL	0.721	pathogenic-leaning
SaProt	LLR -9.47	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 21 kb · p 2.4e-45 · regional, not allelic
Overall
CADD	24.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00229% European (non-Finnish) · 27/1,179,984 alleles

Filtering AF 0.00157% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00134%

Overall 0.00185% 27/1,461,668 alleles · very rare

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.Pro970Leu
Coding: c.2909C>T
MANE Select: NM_001844
dbSNP: rs371268468
Type: single nucleotide variant
Location: chr12:47978385 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 970: the 'disordered' region; the 'triple-helical region' region

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

Disease context

type 2 collagenopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: connective tissue disorder Stickler syndrome type 1

Similar variants

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
COL2A1 c.1888-2A>C 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-pro970leu (accessed [today's date]).

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