Is COL2A1 p.Cys34Arg (c.100T>C) pathogenic?

COL2A1 p.Cys34Arg (c.100T>C) is classified Pathogenic/Likely pathogenic in COL2A1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-07). AlphaMissense: likely pathogenic (0.9944); Absent from gnomAD v4.1; Associated with Stickler syndrome, type I, nonsyndromic ocular.

What condition is associated with COL2A1 p.Cys34Arg (c.100T>C)?

COL2A1 p.Cys34Arg (c.100T>C) is associated with Stickler syndrome, type I, nonsyndromic ocular (ClinVar).

How common is COL2A1 p.Cys34Arg (c.100T>C) in the general population?

COL2A1 p.Cys34Arg (c.100T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about COL2A1 p.Cys34Arg (c.100T>C)?

AlphaMissense predicts likely pathogenic (score 0.9944) — an in-silico prediction, not a clinical call.

COL2A1 p.Cys34Arg

c.100T>C · rs2540187904 · VCV2428885

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9944 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Stickler syndrome, type I, nonsyndromic ocular

Computational evidence

Protein change
AlphaMissense	0.9944	likely pathogenic ✓ concordant with ClinVar · top 8% in COL2A1
REVEL	0.981	strongly pathogenic-leaning
SaProt	LLR -17.07	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 7,716 bp · p 0.0078 · regional, not allelic
Overall
CADD	26.3	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

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.Cys34Arg
Coding: c.100T>C
MANE Select: NM_001844
dbSNP: rs2540187904
Type: single nucleotide variant
Location: chr12:48000111 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 34: a β-strand; the vwfc domain

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

Disease context

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

Similar variants

COL2A1 p.Cys34Ter Pathogenic ★ same residue
COL2A1 p.Cys34Tyr Likely pathogenic ★ same residue
COL2A1 p.Cys34Trp Uncertain significance ★ ⚠ same residue
COL2A1 c.1420-1G>A Pathogenic ★★ same condition
COL2A1 c.1527+1G>A Likely pathogenic ★★ same condition
COL2A1 p.Ala302Val Pathogenic/Likely pathogenic ★★ ⚠ same condition
COL2A1 p.Arg565Cys Pathogenic/Likely pathogenic ★★ same condition
COL2A1 p.Arg653Ter 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-cys34arg (accessed [today's date]).

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