Is COL2A1 p.Pro1368= (c.4104C>T) pathogenic?

COL2A1 p.Pro1368= (c.4104C>T) is classified Benign/Likely benign in COL2A1 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-05-11). Rare (popmax 0.92%, nfe); Associated with connective tissue disorder.

What condition is associated with COL2A1 p.Pro1368= (c.4104C>T)?

COL2A1 p.Pro1368= (c.4104C>T) is associated with connective tissue disorder, Stickler syndrome type 1, type 2 collagenopathy (ClinVar).

How common is COL2A1 p.Pro1368= (c.4104C>T) in the general population?

COL2A1 p.Pro1368= (c.4104C>T) is rare (popmax 0.92%, nfe) (gnomAD).

COL2A1 p.Pro1368=

c.4104C>T · rs12721379 · VCV197948

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

gnomAD v4.1

Rare

rare (popmax 0.92%, nfe)

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 4	GERP 1.8, phastCons 1
Overall
CADD	9.422	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.92% European (non-Finnish) · 10,862/1,180,038 alleles

Filtering AF 0.906% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.9%

Overall 0.75% 12,098/1,614,108 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.92%	109
Remaining individualsnot grpmax-eligible	0.792%	126
Amishnot grpmax-eligible	0.768%	130
Admixed American	0.55%	182
Finnishnot grpmax-eligible	0.355%	282
Ashkenazi Jewishnot grpmax-eligible	0.203%	493
African / African-American	0.136%	736
Middle Eastern	0.116%	866
South Asian	0.00878%	11,386

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.Pro1368=
Coding: c.4104C>T
MANE Select: NM_001844
dbSNP: rs12721379
Type: single nucleotide variant
Location: chr12:47974302 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 1368: the fibrillar collagen nc1 domain; a disulfide bond

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.Pro1368Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
COL2A1 p.Pro1368Ser 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

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-pro1368 (accessed [today's date]).

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