Is COL11A1 p.Pro650Arg (c.1949C>G) pathogenic?

COL11A1 p.Pro650Arg (c.1949C>G) is classified Conflicting classifications of pathogenicity in COL11A1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-28). AlphaMissense: ambiguous (0.3738); Very rare (popmax 0.00475%, nfe); Associated with Stickler syndrome type 2.

What condition is associated with COL11A1 p.Pro650Arg (c.1949C>G)?

COL11A1 p.Pro650Arg (c.1949C>G) is associated with Stickler syndrome type 2, fibrochondrogenesis 1 (ClinVar).

How common is COL11A1 p.Pro650Arg (c.1949C>G) in the general population?

COL11A1 p.Pro650Arg (c.1949C>G) is very rare (popmax 0.00475%, nfe) (gnomAD).

How is Stickler syndrome 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.Pro650Arg (c.1949C>G)?

AlphaMissense predicts ambiguous (score 0.3738) — an in-silico prediction, not a clinical call.

COL11A1 p.Pro650Arg

c.1949C>G · rs199875795 · VCV291527

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3738 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00475%, nfe)

Conditions

Stickler syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.3738	ambiguous
REVEL	0.594	indeterminate
SaProt	LLR -9.62	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 230 kb · p 0.038 · regional, not allelic
Overall
CADD	25.9	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 0.00475% European (non-Finnish) · 56/1,179,620 alleles

Filtering AF 0.00375% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00337%

Overall 0.0036% 58/1,612,488 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00475%	21,065
Remaining individualsnot grpmax-eligible	0.0032%	31,225

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.Pro650Arg
Coding: c.1949C>G
MANE Select: NM_001854
dbSNP: rs199875795
Type: single nucleotide variant
Location: chr1:103003264 (GRCh38)
Gene constraint: LOEUF 0.349 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 53.06
Residue 650: the 'disordered' region; the 'triple-helical region' region; the collagen-like 4 domain; the collagen-like 5 domain

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

Disease context

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

Also linked: fibrochondrogenesis 1

For Stickler syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Antenatal, Childhood, Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

COL11A1 p.Pro650Gln Uncertain significance ★ ⚠ same residue
COL11A1 p.Pro650Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-pro650arg (accessed [today's date]).

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