Is COL9A2 p.Pro413Ser (c.1237C>T) pathogenic?

COL9A2 p.Pro413Ser (c.1237C>T) is classified Conflicting classifications of pathogenicity in COL9A2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0764); Rare (popmax 0.225%, eas); Associated with Stickler syndrome, type 5.

What condition is associated with COL9A2 p.Pro413Ser (c.1237C>T)?

COL9A2 p.Pro413Ser (c.1237C>T) is associated with Stickler syndrome, type 5, epiphyseal dysplasia, multiple, 2 (ClinVar).

How common is COL9A2 p.Pro413Ser (c.1237C>T) in the general population?

COL9A2 p.Pro413Ser (c.1237C>T) is rare (popmax 0.225%, eas) (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 COL9A2 p.Pro413Ser (c.1237C>T)?

AlphaMissense predicts likely benign (score 0.0764) — an in-silico prediction, not a clinical call.

COL9A2 p.Pro413Ser

c.1237C>T · rs201985170 · VCV689606

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0764 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.225%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Stickler syndrome, type 5

Computational evidence

Protein change
AlphaMissense	0.0764	likely benign
REVEL	0.307	indeterminate
SaProt	LLR -6.42	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 0.4	GERP -3.1, phastCons 0.01
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.018 · regional, not allelic
Overall
CADD	9.059	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 0.225% East Asian · 99/43,992 alleles

Filtering AF 0.189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.176%

Overall 0.00642% 102/1,588,370 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.225%	444
Remaining individualsnot grpmax-eligible	0.00487%	20,515

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: COL9A2
Protein: p.Pro413Ser
Coding: c.1237C>T
MANE Select: NM_001852
dbSNP: rs201985170
Type: single nucleotide variant
Location: chr1:40304370 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.99 · 4 PDB
Residue 413: the 'disordered' region; a UniProt-annotated variant site (sequence variant); the 'triple-helical region 3 (col3)' region

Full COL9A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Stickler syndrome, type 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: epiphyseal dysplasia, multiple, 2

For Stickler syndrome (Orphanet):

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

Similar variants

COL9A2 c.186+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL9A2 p.Arg136Ter Pathogenic/Likely pathogenic ★★ same condition
COL9A2 c.*67A>G Uncertain significance ★★ same condition
COL9A2 p.Arg136Gln Uncertain significance ★★ ⚠ same condition
COL9A2 p.Arg375Leu Uncertain significance ★★ ⚠ same condition
COL9A2 p.Asp428His Uncertain significance ★★ ⚠ same condition
COL9A2 p.Asp519His Uncertain significance ★★ ⚠ same condition
COL9A2 p.Gly250Ala 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/col9a2-p-pro413ser (accessed [today's date]).

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