Is COL9A2 p.Leu166Pro (c.497T>C) pathogenic?

COL9A2 p.Leu166Pro (c.497T>C) is classified Uncertain significance in COL9A2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-08). AlphaMissense: likely benign (0.1488); Ultra-rare (popmax 0.0332%, mid); Associated with COL9A2-related disorder.

What condition is associated with COL9A2 p.Leu166Pro (c.497T>C)?

COL9A2 p.Leu166Pro (c.497T>C) is associated with COL9A2-related disorder (ClinVar).

How common is COL9A2 p.Leu166Pro (c.497T>C) in the general population?

COL9A2 p.Leu166Pro (c.497T>C) is ultra-rare (popmax 0.0332%, mid) (gnomAD).

What do computational predictors say about COL9A2 p.Leu166Pro (c.497T>C)?

AlphaMissense predicts likely benign (score 0.1488) — an in-silico prediction, not a clinical call.

COL9A2 p.Leu166Pro

c.497T>C · rs756743515 · VCV1407632

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1488 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0332%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

COL9A2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1488	likely benign
REVEL	0.356	indeterminate
SaProt	LLR -5.69	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 11	GERP 2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.018 · regional, not allelic
Overall
CADD	22.7	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 0.0332% Middle Eastern · 2/6,028 alleles

Filtering AF 0.00585% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00243%

Overall 0.00206% 33/1,601,162 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0332%	3,014
Admixed American	0.00689%	14,511
Remaining individualsnot grpmax-eligible	0.00322%	31,072
European (non-Finnish)	0.00204%	49,043
African / African-American	0.00142%	70,588

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.Leu166Pro
Coding: c.497T>C
MANE Select: NM_001852
dbSNP: rs756743515
Type: single nucleotide variant
Location: chr1:40311522 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.99 · 4 PDB
Residue 166: the 'disordered' region; the 'nonhelical region 4 (nc4)' region

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

Disease context

COL9A2-related disorder

Similar variants

COL9A2 p.Arg546Gly Uncertain significance ★★ ⚠ same condition
COL9A2 c.249+2T>C Likely pathogenic ★ same condition
COL9A2 p.Arg375Ter Likely pathogenic ★ same condition
COL9A2 p.Gln103Ter Likely pathogenic ★ same condition
COL9A2 p.Met1Leu Likely pathogenic ★ same condition
COL9A2 c.303+2T>C Conflicting classifications of pathogenicity ★ same condition
COL9A2 p.Gly612Arg Conflicting classifications of pathogenicity ★ ⚠ same condition
COL9A2 p.Val446Gly 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-leu166pro (accessed [today's date]).

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