Is COL11A1 p.Pro1499Ser (c.4495C>T) pathogenic?

COL11A1 p.Pro1499Ser (c.4495C>T) is classified Conflicting classifications of pathogenicity in COL11A1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-09-16). AlphaMissense: likely benign (0.153); Rare (popmax 0.174%, eas); Associated with fibrochondrogenesis 1.

What condition is associated with COL11A1 p.Pro1499Ser (c.4495C>T)?

COL11A1 p.Pro1499Ser (c.4495C>T) is associated with fibrochondrogenesis 1, Stickler syndrome type 2 (ClinVar).

How common is COL11A1 p.Pro1499Ser (c.4495C>T) in the general population?

COL11A1 p.Pro1499Ser (c.4495C>T) is rare (popmax 0.174%, eas) (gnomAD).

How is Fibrochondrogenesis inherited?

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

What do computational predictors say about COL11A1 p.Pro1499Ser (c.4495C>T)?

AlphaMissense predicts likely benign (score 0.153) — an in-silico prediction, not a clinical call.

COL11A1 p.Pro1499Ser

c.4495C>T · rs199952288 · VCV291500

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.153 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.174%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

fibrochondrogenesis 1

Computational evidence

Protein change
AlphaMissense	0.153	likely benign
REVEL	0.548	indeterminate
SaProt	LLR -9.76	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 230 kb · p 0.038 · regional, not allelic
Overall
CADD	25.2	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

Grpmax group 0.174% East Asian · 78/44,866 alleles

Filtering AF 0.143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.131%

Overall 0.00508% 82/1,612,614 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.174%	575
Remaining individualsnot grpmax-eligible	0.0048%	20,821
European (non-Finnish)	8.48e-05%	1,178,656

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: COL11A1
Protein: p.Pro1499Ser
Coding: c.4495C>T
MANE Select: NM_001854
dbSNP: rs199952288
Type: single nucleotide variant
Location: chr1:102888889 (GRCh38)
Gene constraint: LOEUF 0.349 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 53.06
Residue 1499: the collagen-like 8 domain; the 'disordered' region; the 'triple-helical region' region

Full COL11A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

fibrochondrogenesis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Stickler syndrome type 2

For Fibrochondrogenesis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Neonatal

Similar variants

COL11A1 c.1245+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL11A1 c.1245+1G>T Pathogenic/Likely pathogenic ★★ same condition
COL11A1 c.2241+5G>T Pathogenic/Likely pathogenic ★★ same condition
COL11A1 c.2808+1G>A Pathogenic ★★ same condition
COL11A1 c.2916+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL11A1 c.3762+2T>C Pathogenic/Likely pathogenic ★★ same condition
COL11A1 c.3816+1G>A Pathogenic ★★ same condition
COL11A1 c.4554+1G>C Pathogenic/Likely 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/col11a1-p-pro1499ser (accessed [today's date]).

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