Is COL11A2 p.Arg433Ter (c.1297C>T) pathogenic?

COL11A2 p.Arg433Ter (c.1297C>T) is classified Pathogenic/Likely pathogenic in COL11A2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-10-30). Very rare (popmax 0.0011%, sas); Associated with otospondylomegaepiphyseal dysplasia, autosomal dominant.

What condition is associated with COL11A2 p.Arg433Ter (c.1297C>T)?

COL11A2 p.Arg433Ter (c.1297C>T) is associated with otospondylomegaepiphyseal dysplasia, autosomal dominant, autosomal dominant nonsyndromic hearing loss 13, autosomal recessive nonsyndromic hearing loss 53 (ClinVar).

How common is COL11A2 p.Arg433Ter (c.1297C>T) in the general population?

COL11A2 p.Arg433Ter (c.1297C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

COL11A2 p.Arg433Ter

Q: How is Autosomal recessive otospondylomegaepiphyseal dysplasia inherited?

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

c.1297C>T · rs764045158 · VCV3017031

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

otospondylomegaepiphyseal dysplasia, autosomal dominant

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
NMD	predicted	premature termination codon in exon 12 of 66
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP 0.66, 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

Grpmax group 0.0011% South Asian · 1/91,078 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000274% 4/1,460,384 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0016%	62,676
South Asiangrpmax	0.0011%	91,078
European (non-Finnish)	0.000169%	589,988

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg433Ter
Coding: c.1297C>T
MANE Select: NM_080680
dbSNP: rs764045158
Type: single nucleotide variant
Location: chr6:33180320 (GRCh38)
Gene constraint: LOEUF 0.503 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 50.18
Residue 433: the 'nonhelical region' region; the 'disordered' region; the collagen-like 1 domain

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

Disease context

otospondylomegaepiphyseal dysplasia, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant nonsyndromic hearing loss 13 autosomal recessive nonsyndromic hearing loss 53 fibrochondrogenesis 2 otospondylomegaepiphyseal dysplasia, autosomal recessive

For Autosomal recessive otospondylomegaepiphyseal dysplasia (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Neonatal

Similar variants

COL11A2 p.Arg433Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
COL11A2 p.Arg433Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
COL11A2 c.1819-2A>G Likely pathogenic ★★ same condition
COL11A2 c.3852+1G>T Likely pathogenic ★★ same condition
COL11A2 c.4392+1G>A Pathogenic ★★ same condition
COL11A2 p.Arg1020Ter Pathogenic/Likely pathogenic ★★ same condition
COL11A2 p.Arg1034Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
COL11A2 p.Arg1331Ter 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/col11a2-p-arg433ter (accessed [today's date]).

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