Is COL9A2 p.Pro153Leu (c.458C>T) pathogenic?

COL9A2 p.Pro153Leu (c.458C>T) is classified Conflicting classifications of pathogenicity in COL9A2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-11-19). AlphaMissense: likely benign (0.0672); Rare (popmax 0.103%, afr); Associated with Inborn genetic diseases.

What condition is associated with COL9A2 p.Pro153Leu (c.458C>T)?

COL9A2 p.Pro153Leu (c.458C>T) is associated with Inborn genetic diseases, epiphyseal dysplasia, multiple, 2, Stickler syndrome, type 5 (ClinVar).

How common is COL9A2 p.Pro153Leu (c.458C>T) in the general population?

COL9A2 p.Pro153Leu (c.458C>T) is rare (popmax 0.103%, afr) (gnomAD).

What do computational predictors say about COL9A2 p.Pro153Leu (c.458C>T)?

AlphaMissense predicts likely benign (score 0.0672) — an in-silico prediction, not a clinical call.

COL9A2 p.Pro153Leu

c.458C>T · rs77937237 · VCV547939

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0672 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.103%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0672	likely benign
REVEL	0.383	indeterminate
SaProt	LLR -8.13	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 9.8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.018 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.103% African / African-American · 77/74,996 alleles

Filtering AF 0.0841% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0774%

Overall 0.0062% 100/1,613,964 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.103%	974
Remaining individualsnot grpmax-eligible	0.0208%	4,808
Admixed American	0.005%	20,003
South Asian	0.0011%	91,078
European (non-Finnish)	0.000509%	196,655

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.Pro153Leu
Coding: c.458C>T
MANE Select: NM_001852
dbSNP: rs77937237
Type: single nucleotide variant
Location: chr1:40311675 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.99 · 4 PDB
Residue 153: the 'disordered' region; the 'triple-helical region 4 (col4)' 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: epiphyseal dysplasia, multiple, 2 Stickler syndrome, type 5

Similar variants

COL9A2 p.Pro153Arg Uncertain significance ★★ ⚠ same residue
COL9A2 p.Pro153Ser Uncertain significance ★ ⚠ same residue
COL9A2 c.186+1G>A Pathogenic/Likely pathogenic ★★ same condition
COL9A2 p.Arg136Ter Pathogenic/Likely pathogenic ★★ same condition
COL9A2 c.*67A>G Uncertain significance ★★ same condition
COL9A2 p.Ala118Ser Uncertain significance ★★ ⚠ same condition
COL9A2 p.Ala257Thr Uncertain significance ★★ ⚠ same condition
COL9A2 p.Ala324Val 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-pro153leu (accessed [today's date]).

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