Is COL9A2 p.Val441Ala (c.1322T>C) pathogenic?

COL9A2 p.Val441Ala (c.1322T>C) is classified Uncertain significance in COL9A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-09). AlphaMissense: likely benign (0.0716); Very rare (popmax 0.0023%, eas).

How common is COL9A2 p.Val441Ala (c.1322T>C) in the general population?

COL9A2 p.Val441Ala (c.1322T>C) is very rare (popmax 0.0023%, eas) (gnomAD).

What do computational predictors say about COL9A2 p.Val441Ala (c.1322T>C)?

AlphaMissense predicts likely benign (score 0.0716) — an in-silico prediction, not a clinical call.

COL9A2 p.Val441Ala

c.1322T>C · rs1164523172 · VCV2582856

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0716 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0023%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0716	likely benign
REVEL	0.191	benign-leaning
SaProt	LLR -6.09	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 3.1	GERP 0.45, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.018 · regional, not allelic
Overall
CADD	12.7	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 0.0023% East Asian · 1/43,472 alleles

Overall 0.000127% 2/1,578,308 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0023%	43,472
European (non-Finnish)	8.6e-05%	1,162,984

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.Val441Ala
Coding: c.1322T>C
MANE Select: NM_001852
dbSNP: rs1164523172
Type: single nucleotide variant
Location: chr1:40304065 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.99 · 4 PDB
Residue 441: 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 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
COL9A2 c.363+1G>A 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-val441ala (accessed [today's date]).

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