Is COL2A1 p.Arg533Ter (c.1597C>T) pathogenic?

COL2A1 p.Arg533Ter (c.1597C>T) is classified Pathogenic in COL2A1 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-08-03). Very rare (popmax 6.85e-05%); Associated with connective tissue disorder.

What condition is associated with COL2A1 p.Arg533Ter (c.1597C>T)?

COL2A1 p.Arg533Ter (c.1597C>T) is associated with connective tissue disorder, Stickler syndrome type 1, Stickler syndrome (ClinVar).

How common is COL2A1 p.Arg533Ter (c.1597C>T) in the general population?

COL2A1 p.Arg533Ter (c.1597C>T) is very rare (popmax 6.85e-05%) (gnomAD).

COL2A1 p.Arg533Ter

c.1597C>T · rs1085307608 · VCV426404

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 6.85e-05%)

Conditions

connective tissue disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 25 of 54
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Overall
CADD	46.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.85e-05%

Overall 6.85e-05% 1/1,458,978 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.Arg533Ter
Coding: c.1597C>T
MANE Select: NM_001844
dbSNP: rs1085307608
Type: single nucleotide variant
Location: chr12:47985811 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 533: 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 Stickler syndrome

Similar variants

COL2A1 p.Arg533= Uncertain significance ★ same residue
COL2A1 p.Arg533Gln Uncertain significance ★ ⚠ same residue
COL2A1 c.1221+1G>A Pathogenic ★★ same condition
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.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-arg533ter (accessed [today's date]).

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