Is COL9A2 p.Pro356= (c.1068G>A) pathogenic?

COL9A2 p.Pro356= (c.1068G>A) is classified Conflicting classifications of pathogenicity in COL9A2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-12-28). Ultra-rare (popmax 0.0107%, afr); Associated with Inborn genetic diseases.

What condition is associated with COL9A2 p.Pro356= (c.1068G>A)?

COL9A2 p.Pro356= (c.1068G>A) is associated with Inborn genetic diseases, connective tissue disorder (ClinVar).

How common is COL9A2 p.Pro356= (c.1068G>A) in the general population?

COL9A2 p.Pro356= (c.1068G>A) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

COL9A2 p.Pro356=

c.1068G>A · rs752181922 · VCV1086892

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.38	GERP -3.2, phastCons 0.034
Overall
CADD	5.784	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0107% African / African-American · 8/74,928 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00124% 20/1,613,916 alleles · ultra-rare exomes 16/1,461,754 · genomes 4/152,162 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0107%	9,366
East Asian	0.00446%	22,445
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
South Asian	0.0022%	45,540
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.000508%	196,659

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.Pro356=
Coding: c.1068G>A
MANE Select: NM_001852
dbSNP: rs752181922
Type: single nucleotide variant
Location: chr1:40305754 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.99 · 4 PDB
Residue 356: 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

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

Also linked: connective tissue disorder

Similar variants

COL9A2 p.Pro356Leu Uncertain significance ★ ⚠ same residue
COL9A2 p.Ala118Ser Uncertain significance ★★ ⚠ same condition
COL9A2 p.Ala257Thr Uncertain significance ★★ ⚠ same condition
COL9A2 p.Ala324Val Uncertain significance ★★ ⚠ same condition
COL9A2 p.Ala4Thr Uncertain significance ★★ ⚠ same condition
COL9A2 p.Arg136Gln Uncertain significance ★★ ⚠ same condition
COL9A2 p.Arg198Cys Uncertain significance ★★ ⚠ same condition
COL9A2 p.Arg288Cys 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-pro356 (accessed [today's date]).

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