Is COL2A1 p.Cys64Ter (c.192C>A) pathogenic?

COL2A1 p.Cys64Ter (c.192C>A) is classified Pathogenic in COL2A1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2025-11-14). Absent from gnomAD v4.1; Associated with Stickler syndrome.

What condition is associated with COL2A1 p.Cys64Ter (c.192C>A)?

COL2A1 p.Cys64Ter (c.192C>A) is associated with Stickler syndrome, Stickler syndrome type 1, Stickler syndrome, type I, nonsyndromic ocular (ClinVar).

How common is COL2A1 p.Cys64Ter (c.192C>A) in the general population?

COL2A1 p.Cys64Ter (c.192C>A) is absent from gnomAD v4.1 (gnomAD).

How is Stickler syndrome inherited?

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

COL2A1 p.Cys64Ter

c.192C>A · rs121912897 · VCV17401

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Stickler syndrome

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 2 of 54
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 0.88, phastCons 1
Overall
CADD	37.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: COL2A1
Protein: p.Cys64Ter
Coding: c.192C>A
MANE Select: NM_001844
dbSNP: rs121912897
Type: single nucleotide variant
Location: chr12:48000019 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 64: a β-strand; the vwfc domain

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

Disease context

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

Also linked: Stickler syndrome type 1 Stickler syndrome, type I, nonsyndromic ocular

For Stickler syndrome (Orphanet):

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

Similar variants

COL2A1 p.Cys64Tyr Uncertain significance ★ ⚠ same residue
COL2A1 p.Cys64= Likely benign ★ 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.1420-1G>A Pathogenic ★★ same condition
COL2A1 c.1420-2A>G Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.1527+135G>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-cys64ter (accessed [today's date]).

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