Is COL2A1 p.Pro1189His (c.3566C>A) pathogenic?

COL2A1 p.Pro1189His (c.3566C>A) is classified Uncertain significance in COL2A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-25). AlphaMissense: ambiguous (0.4977); Very rare (popmax 0.000678%, nfe).

How common is COL2A1 p.Pro1189His (c.3566C>A) in the general population?

COL2A1 p.Pro1189His (c.3566C>A) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about COL2A1 p.Pro1189His (c.3566C>A)?

AlphaMissense predicts ambiguous (score 0.4977) — an in-silico prediction, not a clinical call.

COL2A1 p.Pro1189His

c.3566C>A · rs755010259 · VCV388165

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4977	ambiguous
REVEL	0.693	pathogenic-leaning
SaProt	LLR -10.78	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP -0.21, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 21 kb · p 2.4e-45 · regional, not allelic
Overall
CADD	24.5	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 0.000678% European (non-Finnish) · 8/1,179,934 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000547% 8/1,461,778 alleles · very 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: COL2A1
Protein: p.Pro1189His
Coding: c.3566C>A
MANE Select: NM_001844
dbSNP: rs755010259
Type: single nucleotide variant
Location: chr12:47975994 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 1189: a UniProt-annotated variant site (in sedc); the 'disordered' region; the 'triple-helical region' region

Full COL2A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

COL2A1 p.Pro1189= Likely benign ★ same residue
COL2A1 c.1023+1G>A Pathogenic ★★ same type
COL2A1 c.1024-2A>C Pathogenic ★★ same type
COL2A1 c.1069-2A>G Pathogenic/Likely pathogenic ★★ same type
COL2A1 c.1221+1G>A Pathogenic ★★ same type
COL2A1 c.1222-2A>G Pathogenic ★★ same type
COL2A1 c.1365+1G>A Pathogenic/Likely pathogenic ★★ same type
COL2A1 c.1420-1G>A Pathogenic ★★ 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/col2a1-p-pro1189his (accessed [today's date]).

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