Is COL2A1 p.Ala1069Asp (c.3206C>A) pathogenic?

COL2A1 p.Ala1069Asp (c.3206C>A) is classified Likely benign in COL2A1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-17). AlphaMissense: ambiguous (0.4106); Ultra-rare (popmax 0.0329%, mid).

How common is COL2A1 p.Ala1069Asp (c.3206C>A) in the general population?

COL2A1 p.Ala1069Asp (c.3206C>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about COL2A1 p.Ala1069Asp (c.3206C>A)?

AlphaMissense predicts ambiguous (score 0.4106) — an in-silico prediction, not a clinical call.

COL2A1 p.Ala1069Asp

c.3206C>A · rs746255869 · VCV2067848

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4106 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Computational evidence

Protein change
AlphaMissense	0.4106	ambiguous
REVEL	0.548	indeterminate
SaProt	LLR -9.98	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 21 kb · p 2.4e-45 · regional, not allelic
Overall
CADD	25.8	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 0.0329% Middle Eastern · 2/6,082 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.000992% 16/1,613,308 alleles · ultra-rare exomes 13/1,461,212 · genomes 3/152,096 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,041
Remaining individualsnot grpmax-eligible	0.0032%	31,230
African / African-American	0.00134%	74,888
European (non-Finnish)	0.000933%	107,238

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.Ala1069Asp
Coding: c.3206C>A
MANE Select: NM_001844
dbSNP: rs746255869
Type: single nucleotide variant
Location: chr12:47977387 (GRCh38)
Gene constraint: LOEUF 0.183 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 53.56 · 11 PDB
Residue 1069: 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.Ala1069Pro Uncertain significance ★ ⚠ same residue
COL2A1 p.Ala1069= Likely benign ★ same residue
COL2A1 p.Ala1069Thr 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

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-ala1069asp (accessed [today's date]).

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