Is COL9A2 p.Ser363Phe (c.1088C>T) pathogenic?

COL9A2 p.Ser363Phe (c.1088C>T) is classified Uncertain significance in COL9A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-06). AlphaMissense: likely benign (0.1422); Very rare (popmax 0.00144%, nfe).

How common is COL9A2 p.Ser363Phe (c.1088C>T) in the general population?

COL9A2 p.Ser363Phe (c.1088C>T) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about COL9A2 p.Ser363Phe (c.1088C>T)?

AlphaMissense predicts likely benign (score 0.1422) — an in-silico prediction, not a clinical call.

COL9A2 p.Ser363Phe

c.1088C>T · rs767484378 · VCV2004097

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1422 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1422	likely benign
REVEL	0.252	benign-leaning
SaProt	LLR -9.56	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.018 · regional, not allelic
Overall
CADD	22.2	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 0.00144% European (non-Finnish) · 17/1,180,020 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00116% 17/1,461,822 alleles · very 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: COL9A2
Protein: p.Ser363Phe
Coding: c.1088C>T
MANE Select: NM_001852
dbSNP: rs767484378
Type: single nucleotide variant
Location: chr1:40305734 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.99 · 4 PDB
Residue 363: 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

Similar variants

COL9A2 p.Ser363Cys Uncertain significance ★ ⚠ same residue
COL9A2 c.186+1G>A Pathogenic/Likely pathogenic ★★ same type
COL9A2 p.Arg136Ter Pathogenic/Likely pathogenic ★★ same type
COL9A2 p.Arg504Ter Pathogenic/Likely pathogenic ★★ same type
COL9A2 c.1107+4A>G Uncertain significance ★★ same type
COL9A2 c.1792+5G>A Uncertain significance ★★ same type
COL9A2 c.1793-9T>A Uncertain significance ★★ same type
COL9A2 c.1870+5G>C Uncertain significance ★★ same type

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-ser363phe (accessed [today's date]).

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