Is COL2A1 p.Ser1221= (c.3663C>T) pathogenic?

COL2A1 p.Ser1221= (c.3663C>T) is classified Conflicting classifications of pathogenicity in COL2A1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-03). Rare (popmax 0.201%, eas); Associated with type 2 collagenopathy.

What condition is associated with COL2A1 p.Ser1221= (c.3663C>T)?

COL2A1 p.Ser1221= (c.3663C>T) is associated with type 2 collagenopathy, Stickler syndrome type 1 (ClinVar).

How common is COL2A1 p.Ser1221= (c.3663C>T) in the general population?

COL2A1 p.Ser1221= (c.3663C>T) is rare (popmax 0.201%, eas) (gnomAD).

COL2A1 p.Ser1221=

c.3663C>T · rs2276459 · VCV883499

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.201%, eas)

Conditions

type 2 collagenopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP -9.4	GERP -3.5
Overall
CADD	2.501	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.201% East Asian · 90/44,864 alleles

Filtering AF 0.167% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.155%

Overall 0.00654% 105/1,606,620 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.201%	498
African / African-American	0.00267%	37,510
South Asian	0.0022%	45,535
Remaining individualsnot grpmax-eligible	0.0016%	62,460
European (non-Finnish)	0.000847%	117,996

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.Ser1221=
Coding: c.3663C>T
MANE Select: NM_001844
dbSNP: rs2276459
Type: single nucleotide variant
Location: chr12:47975540 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 1221: the 'disordered' region; the 'nonhelical region (c-terminal)' region

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

Disease context

type 2 collagenopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Stickler syndrome type 1

Similar variants

COL2A1 p.Ser1221Cys Uncertain significance ★ ⚠ same residue
COL2A1 p.Ser1221Phe Uncertain significance ★ ⚠ 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-ser1221 (accessed [today's date]).

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