Is COL22A1 p.Arg362Pro (c.1085G>C) pathogenic?

COL22A1 p.Arg362Pro (c.1085G>C) is classified Uncertain significance in COL22A1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely pathogenic (0.7344); Ultra-rare (popmax 0.015%, amr).

How common is COL22A1 p.Arg362Pro (c.1085G>C) in the general population?

COL22A1 p.Arg362Pro (c.1085G>C) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about COL22A1 p.Arg362Pro (c.1085G>C)?

AlphaMissense predicts likely pathogenic (score 0.7344) — an in-silico prediction, not a clinical call.

COL22A1 p.Arg362Pro

c.1085G>C · VCV4005181

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7344 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7344	likely pathogenic
REVEL	0.402	indeterminate
SaProt	LLR -11.09	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.3	GERP 1.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 294 kb · p 0.19 · regional, not allelic
Overall
CADD	28.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.015% Admixed American · 9/60,000 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.000558% 9/1,614,074 alleles · ultra-rare

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: COL22A1
Protein: p.Arg362Pro
Coding: c.1085G>C
MANE Select: NM_152888
Type: single nucleotide variant
Location: chr8:138821296 (GRCh38)
Gene constraint: LOEUF 1.005 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.25
Residue 362: the laminin g-like domain

Full COL22A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COL22A1 p.Arg362Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
COL22A1 p.Arg362Trp Uncertain significance ★ ⚠ same residue
COL22A1 p.Glu736Asp Benign ★★ same type
COL22A1 p.Gly1180= Benign ★★ same type
COL22A1 p.Pro763Leu Benign ★★ same type
COL22A1 p.Ala1005Ser Uncertain significance ★ ⚠ same type
COL22A1 p.Ala103Val Uncertain significance ★ ⚠ same type
COL22A1 p.Ala1077Gly Uncertain significance ★ ⚠ same type

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/col22a1-p-arg362pro (accessed [today's date]).

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