Is COL9A2 p.Pro264Leu (c.791C>T) pathogenic?

COL9A2 p.Pro264Leu (c.791C>T) is classified Uncertain significance in COL9A2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-24). AlphaMissense: likely benign (0.0733); Ultra-rare (popmax 0.0187%, sas); Associated with Inborn genetic diseases.

What condition is associated with COL9A2 p.Pro264Leu (c.791C>T)?

COL9A2 p.Pro264Leu (c.791C>T) is associated with Inborn genetic diseases (ClinVar).

How common is COL9A2 p.Pro264Leu (c.791C>T) in the general population?

COL9A2 p.Pro264Leu (c.791C>T) is ultra-rare (popmax 0.0187%, sas) (gnomAD).

What do computational predictors say about COL9A2 p.Pro264Leu (c.791C>T)?

AlphaMissense predicts likely benign (score 0.0733) — an in-silico prediction, not a clinical call.

COL9A2 p.Pro264Leu

c.791C>T · rs534724125 · VCV1507978

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0733 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0733	likely benign
REVEL	0.339	indeterminate
SaProt	LLR -9.31	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 4.6	GERP -1.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.018 · regional, not allelic
Overall
CADD	20.9	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 0.0187% South Asian · 17/91,082 alleles

Filtering AF 0.0118% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00976%

Overall 0.00322% 52/1,614,008 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0187%	5,358
African / African-American	0.00267%	37,510
European (non-Finnish)	0.00263%	38,061
Admixed American	0.00167%	60,026
Remaining individualsnot grpmax-eligible	0.0016%	62,492

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.Pro264Leu
Coding: c.791C>T
MANE Select: NM_001852
dbSNP: rs534724125
Type: single nucleotide variant
Location: chr1:40310112 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.99 · 4 PDB
Residue 264: the 'disordered' region; 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

Similar variants

COL9A2 p.Pro264= Conflicting classifications of pathogenicity ★ 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-pro264leu (accessed [today's date]).

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