Is COL2A1 p.Pro673Leu (c.2018C>T) pathogenic?

COL2A1 p.Pro673Leu (c.2018C>T) is classified Uncertain significance in COL2A1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-11). AlphaMissense: likely benign (0.0825); Very rare (popmax 8.47e-05%, nfe); Associated with COL2A1-related disorder.

What condition is associated with COL2A1 p.Pro673Leu (c.2018C>T)?

COL2A1 p.Pro673Leu (c.2018C>T) is associated with COL2A1-related disorder (ClinVar).

How common is COL2A1 p.Pro673Leu (c.2018C>T) in the general population?

COL2A1 p.Pro673Leu (c.2018C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about COL2A1 p.Pro673Leu (c.2018C>T)?

AlphaMissense predicts likely benign (score 0.0825) — an in-silico prediction, not a clinical call.

COL2A1 p.Pro673Leu

c.2018C>T · rs570533789 · VCV1051692

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0825 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

COL2A1-related disorder

Computational evidence

Protein change
AlphaMissense	0.0825	likely benign
REVEL	0.383	indeterminate
SaProt	LLR -8.41	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 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 21 kb · p 2.4e-45 · regional, not allelic
Overall
CADD	26.0	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 8.47e-05% European (non-Finnish) · 1/1,179,992 alleles

Overall 0.000657% 1/152,296 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.Pro673Leu
Coding: c.2018C>T
MANE Select: NM_001844
dbSNP: rs570533789
Type: single nucleotide variant
Location: chr12:47983416 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 673: the 'disordered' region; the 'triple-helical region' region

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

Disease context

COL2A1-related disorder

Similar variants

COL2A1 c.1024-2A>C Pathogenic ★★ same condition
COL2A1 c.1069-2A>G Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.1527+135G>A Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.1681-2A>G Likely pathogenic ★★ same condition
COL2A1 c.1833+1G>A Pathogenic ★★ same condition
COL2A1 c.1995+1G>A Pathogenic ★★ same condition
COL2A1 c.1995+1G>T Pathogenic/Likely pathogenic ★★ same condition
COL2A1 c.2517+1G>A Pathogenic/Likely pathogenic ★★ 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/col2a1-p-pro673leu (accessed [today's date]).

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