Is COL2A1 p.Cys1323Ser (c.3968G>C) pathogenic?

COL2A1 p.Cys1323Ser (c.3968G>C) is classified Pathogenic in COL2A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-06-02). AlphaMissense: likely pathogenic (0.998); Absent from gnomAD v4.1.

How common is COL2A1 p.Cys1323Ser (c.3968G>C) in the general population?

COL2A1 p.Cys1323Ser (c.3968G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about COL2A1 p.Cys1323Ser (c.3968G>C)?

AlphaMissense predicts likely pathogenic (score 0.998) — an in-silico prediction, not a clinical call.

COL2A1 p.Cys1323Ser

c.3968G>C · rs2136508586 · VCV1076958

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.998	likely pathogenic ✓ concordant with ClinVar · top 4% in COL2A1
REVEL	0.952	strongly pathogenic-leaning
SaProt	LLR -13.54	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 2,156 bp · p 0.00057 · 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.Cys1323Ser
Coding: c.3968G>C
MANE Select: NM_001844
dbSNP: rs2136508586
Type: single nucleotide variant
Location: chr12:47974781 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 1323: the fibrillar collagen nc1 domain; a disulfide bond

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

Similar variants

COL2A1 p.Cys1323Ter Pathogenic/Likely pathogenic ★★ same residue
COL2A1 p.Cys1323Trp Pathogenic/Likely pathogenic ★★ same residue
COL2A1 p.Cys1323= Likely benign ★★ same residue
COL2A1 p.Cys1323fs Pathogenic ★ same residue
COL2A1 c.1023+1G>A Pathogenic ★★ same type
COL2A1 c.1024-2A>C Pathogenic ★★ same type
COL2A1 c.1069-2A>G Pathogenic/Likely pathogenic ★★ same type
COL2A1 c.1221+1G>A Pathogenic ★★ same type

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-cys1323ser (accessed [today's date]).

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