Is COL2A1 p.Pro505Ser (c.1513C>T) pathogenic?

COL2A1 p.Pro505Ser (c.1513C>T) is classified Conflicting classifications of pathogenicity in COL2A1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-11-27). AlphaMissense: likely benign (0.0753); Ultra-rare (popmax 0.0106%, sas); Associated with Stickler syndrome type 1.

What condition is associated with COL2A1 p.Pro505Ser (c.1513C>T)?

COL2A1 p.Pro505Ser (c.1513C>T) is associated with Stickler syndrome type 1, spondyloepiphyseal dysplasia congenita (ClinVar).

How common is COL2A1 p.Pro505Ser (c.1513C>T) in the general population?

COL2A1 p.Pro505Ser (c.1513C>T) is ultra-rare (popmax 0.0106%, sas) (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 COL2A1 p.Pro505Ser (c.1513C>T)?

AlphaMissense predicts likely benign (score 0.0753) — an in-silico prediction, not a clinical call.

COL2A1 p.Pro505Ser

c.1513C>T · rs865903887 · VCV1422585

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0753 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0106%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Stickler syndrome type 1

Computational evidence

Protein change
AlphaMissense	0.0753	likely benign
REVEL	0.772	pathogenic-leaning
SaProt	LLR -9.43	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 21 kb · p 2.4e-45 · regional, not allelic
Overall
CADD	22.6	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 0.0106% South Asian · 9/85,046 alleles

Filtering AF 0.00547% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00409%

Overall 0.000638% 9/1,411,638 alleles · ultra-rare

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.Pro505Ser
Coding: c.1513C>T
MANE Select: NM_001844
dbSNP: rs865903887
Type: single nucleotide variant
Location: chr12:47986350 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 505: the 'disordered' region; the 'triple-helical region' region

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

Disease context

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

Also linked: spondyloepiphyseal dysplasia congenita

For Stickler syndrome (Orphanet):

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

Similar variants

COL2A1 p.Pro505His Uncertain significance ★ ⚠ same residue
COL2A1 p.Pro505= Likely benign ★ 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-pro505ser (accessed [today's date]).

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