Is COL11A2 p.Ser1218= (c.3654A>G) pathogenic?

COL11A2 p.Ser1218= (c.3654A>G) is classified Conflicting classifications of pathogenicity in COL11A2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-11-25). Rare (popmax 0.28%, mid); Associated with fibrochondrogenesis 2.

What condition is associated with COL11A2 p.Ser1218= (c.3654A>G)?

COL11A2 p.Ser1218= (c.3654A>G) is associated with fibrochondrogenesis 2, otospondylomegaepiphyseal dysplasia, autosomal recessive (ClinVar).

How common is COL11A2 p.Ser1218= (c.3654A>G) in the general population?

COL11A2 p.Ser1218= (c.3654A>G) is rare (popmax 0.28%, mid) (gnomAD).

How is Fibrochondrogenesis inherited?

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

COL11A2 p.Ser1218=

c.3654A>G · rs146962984 · VCV356390

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.28%, mid)

Conditions

fibrochondrogenesis 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.36	GERP -2.3, phastCons 0.28
Overall
CADD	8.173	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.28% Middle Eastern · 17/6,062 alleles

Filtering AF 0.179% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.147%

Overall 0.0155% 250/1,614,162 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.28%	357
Admixed American	0.055%	1,819
South Asian	0.0461%	2,169
Remaining individualsnot grpmax-eligible	0.0384%	2,604
Ashkenazi Jewishnot grpmax-eligible	0.0304%	3,290
European (non-Finnish)	0.0101%	9,916
African / African-American	0.00666%	15,008
Finnishnot grpmax-eligible	0.00156%	64,036

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: COL11A2
Protein: p.Ser1218=
Coding: c.3654A>G
MANE Select: NM_080680
dbSNP: rs146962984
Type: single nucleotide variant
Location: chr6:33169867 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.18
Residue 1218: the 'disordered' region; the 'triple-helical region' region

Full COL11A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: otospondylomegaepiphyseal dysplasia, autosomal recessive

For Fibrochondrogenesis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Neonatal

Similar variants

COL11A2 p.Ser1218Leu Likely benign ★ same residue
COL11A2 p.Arg1020Ter Pathogenic/Likely pathogenic ★★ same condition
COL11A2 p.Arg1331Ter Pathogenic ★★ same condition
COL11A2 p.Arg1600Ter Pathogenic/Likely pathogenic ★★ same condition
COL11A2 p.Arg433Ter Pathogenic/Likely pathogenic ★★ same condition
COL11A2 p.Arg558Ter Pathogenic ★★ same condition
COL11A2 p.Gly1027Glu Likely pathogenic ★★ same condition
COL11A2 c.2682+5G>A Uncertain significance ★★ 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/col11a2-p-ser1218 (accessed [today's date]).

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