Is COL9A3 p.Pro366Ser (c.1096C>T) pathogenic?

COL9A3 p.Pro366Ser (c.1096C>T) is classified Uncertain significance in COL9A3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-26). AlphaMissense: likely benign (0.2173); Very rare (popmax 0.00401%, afr); Associated with Inborn genetic diseases.

What condition is associated with COL9A3 p.Pro366Ser (c.1096C>T)?

COL9A3 p.Pro366Ser (c.1096C>T) is associated with Inborn genetic diseases (ClinVar).

How common is COL9A3 p.Pro366Ser (c.1096C>T) in the general population?

COL9A3 p.Pro366Ser (c.1096C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about COL9A3 p.Pro366Ser (c.1096C>T)?

AlphaMissense predicts likely benign (score 0.2173) — an in-silico prediction, not a clinical call.

COL9A3 p.Pro366Ser

c.1096C>T · rs1462265085 · VCV1394658

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2173 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2173	likely benign
REVEL	0.626	indeterminate
SaProt	LLR -8.67	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.6, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 24 kb · p 0.0069 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% African / African-American · 3/74,906 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000186% 3/1,609,106 alleles · very rare exomes 1/1,456,932 · genomes 2/152,174 · joint denominator

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: COL9A3
Protein: p.Pro366Ser
Coding: c.1096C>T
MANE Select: NM_001853
dbSNP: rs1462265085
Type: single nucleotide variant
Location: chr20:62829670 (GRCh38)
Gene constraint: LOEUF 1.026 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.83 · 4 PDB
Residue 366: the 'disordered' region; a UniProt-annotated variant site (in stl6); the 'triple-helical region 3 (col3)' region

Full COL9A3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COL9A3 p.Arg471Ter Pathogenic ★★ same condition
COL9A3 p.Ala342Val Uncertain significance ★★ ⚠ same condition
COL9A3 p.Ala542Val Uncertain significance ★★ ⚠ same condition
COL9A3 p.Arg231Trp Uncertain significance ★★ ⚠ same condition
COL9A3 p.Arg234Gly Uncertain significance ★★ ⚠ same condition
COL9A3 p.Arg276Cys Uncertain significance ★★ ⚠ same condition
COL9A3 p.Arg323Cys Uncertain significance ★★ ⚠ same condition
COL9A3 p.Arg351Trp 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/col9a3-p-pro366ser (accessed [today's date]).

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