Is COL9A2 p.Arg375Pro (c.1124G>C) pathogenic?

COL9A2 p.Arg375Pro (c.1124G>C) is classified Uncertain significance in COL9A2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-17). AlphaMissense: likely benign (0.1052); Very rare (popmax 0.00759%, nfe); Associated with Inborn genetic diseases.

What condition is associated with COL9A2 p.Arg375Pro (c.1124G>C)?

COL9A2 p.Arg375Pro (c.1124G>C) is associated with Inborn genetic diseases (ClinVar).

How common is COL9A2 p.Arg375Pro (c.1124G>C) in the general population?

COL9A2 p.Arg375Pro (c.1124G>C) is very rare (popmax 0.00759%, nfe) (gnomAD).

What do computational predictors say about COL9A2 p.Arg375Pro (c.1124G>C)?

AlphaMissense predicts likely benign (score 0.1052) — an in-silico prediction, not a clinical call.

COL9A2 p.Arg375Pro

c.1124G>C · rs370682522 · VCV1201165

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1052 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00759%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1052	likely benign
REVEL	0.286	benign-leaning
SaProt	LLR -6.42	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 -4.2	GERP -4
Regional constraint	o/e 0.92	unconstrained · MANE · 16 kb · p 0.018 · regional, not allelic
Overall
CADD	8.135	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 0.00759% European (non-Finnish) · 87/1,146,934 alleles

Filtering AF 0.00622% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00581%

Overall 0.00593% 92/1,550,554 alleles · very rare exomes 89/1,398,396 · genomes 3/152,158 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00759%	13,183
East Asian	0.00489%	20,462
Remaining individualsnot grpmax-eligible	0.00333%	30,051
African / African-American	0.00137%	73,030

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.Arg375Pro
Coding: c.1124G>C
MANE Select: NM_001852
dbSNP: rs370682522
Type: single nucleotide variant
Location: chr1:40304831 (GRCh38)
Gene constraint: LOEUF 0.817 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 54.99 · 4 PDB
Residue 375: 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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COL9A2 p.Arg375Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
COL9A2 p.Arg375Gln Uncertain significance ★★ ⚠ same residue
COL9A2 p.Arg375Leu Uncertain significance ★★ ⚠ same residue
COL9A2 p.Arg375Ter Likely pathogenic ★ 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

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-arg375pro (accessed [today's date]).

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