Is COL9A2 p.Pro41Leu (c.122C>T) pathogenic?

COL9A2 p.Pro41Leu (c.122C>T) is classified Uncertain significance in COL9A2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-23). AlphaMissense: likely benign (0.1); Ultra-rare (popmax 0.0235%, amr); Associated with Inborn genetic diseases.

What condition is associated with COL9A2 p.Pro41Leu (c.122C>T)?

COL9A2 p.Pro41Leu (c.122C>T) is associated with Inborn genetic diseases (ClinVar).

How common is COL9A2 p.Pro41Leu (c.122C>T) in the general population?

COL9A2 p.Pro41Leu (c.122C>T) is ultra-rare (popmax 0.0235%, amr) (gnomAD).

What do computational predictors say about COL9A2 p.Pro41Leu (c.122C>T)?

AlphaMissense predicts likely benign (score 0.1) — an in-silico prediction, not a clinical call.

COL9A2 p.Pro41Leu

c.122C>T · rs1439694553 · VCV1480073

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0235%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1	likely benign
REVEL	0.733	pathogenic-leaning
SaProt	LLR -9.88	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.018 · regional, not allelic
Overall
CADD	27.0	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 0.0235% Admixed American · 12/51,024 alleles

Filtering AF 0.0135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0105%

Overall 0.000966% 15/1,552,746 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0235%	4,252
Remaining individualsnot grpmax-eligible	0.00166%	60,110
European (non-Finnish)	0.000174%	573,631

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.Pro41Leu
Coding: c.122C>T
MANE Select: NM_001852
dbSNP: rs1439694553
Type: single nucleotide variant
Location: chr1:40315618 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.99 · 4 PDB
Residue 41: 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

Similar variants

COL9A2 p.Pro41Ala 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-pro41leu (accessed [today's date]).

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