Is COL2A1 p.Pro1147Ala (c.3439C>G) pathogenic?

COL2A1 p.Pro1147Ala (c.3439C>G) is classified Conflicting classifications of pathogenicity in COL2A1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-22). AlphaMissense: likely benign (0.0439); Very rare (popmax 0.00891%, eas); Associated with COL2A1-related disorder.

What condition is associated with COL2A1 p.Pro1147Ala (c.3439C>G)?

COL2A1 p.Pro1147Ala (c.3439C>G) is associated with COL2A1-related disorder (ClinVar).

How common is COL2A1 p.Pro1147Ala (c.3439C>G) in the general population?

COL2A1 p.Pro1147Ala (c.3439C>G) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about COL2A1 p.Pro1147Ala (c.3439C>G)?

AlphaMissense predicts likely benign (score 0.0439) — an in-silico prediction, not a clinical call.

COL2A1 p.Pro1147Ala

c.3439C>G · rs139720910 · VCV1023544

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0439 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

COL2A1-related disorder

Computational evidence

Protein change
AlphaMissense	0.0439	likely benign
REVEL	0.306	indeterminate
SaProt	LLR -8.68	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 0.88, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 21 kb · p 2.4e-45 · regional, not allelic
Overall
CADD	22.4	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 0.00891% East Asian · 4/44,888 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000274% 4/1,461,870 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.Pro1147Ala
Coding: c.3439C>G
MANE Select: NM_001844
dbSNP: rs139720910
Type: single nucleotide variant
Location: chr12:47976564 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 1147: an α-helix; 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 p.Pro1147Arg Uncertain significance ★ ⚠ same residue
COL2A1 p.Pro1147Leu Uncertain significance ★ same residue
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

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-pro1147ala (accessed [today's date]).

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