Is COL2A1 p.Pro475Thr (c.1423C>A) pathogenic?

COL2A1 p.Pro475Thr (c.1423C>A) is classified Uncertain significance in COL2A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-01). AlphaMissense: likely benign (0.0562); Very rare (popmax 8.73e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with COL2A1 p.Pro475Thr (c.1423C>A)?

COL2A1 p.Pro475Thr (c.1423C>A) is associated with Inborn genetic diseases (ClinVar).

How common is COL2A1 p.Pro475Thr (c.1423C>A) in the general population?

COL2A1 p.Pro475Thr (c.1423C>A) is very rare (popmax 8.73e-05%, nfe) (gnomAD).

What do computational predictors say about COL2A1 p.Pro475Thr (c.1423C>A)?

AlphaMissense predicts likely benign (score 0.0562) — an in-silico prediction, not a clinical call.

COL2A1 p.Pro475Thr

c.1423C>A · rs757226164 · VCV1981280

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0562 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.73e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0562	likely benign
REVEL	0.563	indeterminate
SaProt	LLR -8.69	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 10	GERP -0.32, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 21 kb · p 2.4e-45 · regional, not allelic
Overall
CADD	24.6	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 8.73e-05% European (non-Finnish) · 1/1,145,960 alleles

Overall 7.14e-05% 1/1,400,506 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.Pro475Thr
Coding: c.1423C>A
MANE Select: NM_001844
dbSNP: rs757226164
Type: single nucleotide variant
Location: chr12:47986440 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 475: the 'disordered' region; the 'triple-helical region' region

Full COL2A1 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

COL2A1 p.Pro475Ser Uncertain significance ★★ ⚠ same residue
COL2A1 p.Cys52Ter Pathogenic/Likely pathogenic ★★ same condition
COL2A1 p.Gln39Ter Pathogenic ★★ same condition
COL2A1 p.Gly546Ser Pathogenic/Likely pathogenic ★★ same condition
COL2A1 p.Gly930Asp Likely pathogenic ★★ same condition
COL2A1 p.Ala1093Val Uncertain significance ★★ ⚠ same condition
COL2A1 p.Ala180Thr Uncertain significance ★★ ⚠ same condition
COL2A1 p.Ala559Ser 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/col2a1-p-pro475thr (accessed [today's date]).

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