Is COL4A2 p.Arg1069fs (c.3205del) pathogenic?

COL4A2 p.Arg1069fs (c.3205del) is classified Uncertain significance in COL4A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-29). Ultra-rare (popmax 0.0428%, sas); Associated with brain small vessel disease 2A, autosomal dominant.

What condition is associated with COL4A2 p.Arg1069fs (c.3205del)?

COL4A2 p.Arg1069fs (c.3205del) is associated with brain small vessel disease 2A, autosomal dominant (ClinVar).

How common is COL4A2 p.Arg1069fs (c.3205del) in the general population?

COL4A2 p.Arg1069fs (c.3205del) is ultra-rare (popmax 0.0428%, sas) (gnomAD).

COL4A2 p.Arg1069fs

c.3205del · rs746869541 · VCV2441713

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0428%, sas)

Conditions

brain small vessel disease 2A, autosomal dominant

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 34 of 48
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.98	GERP -2.6, phastCons 0.46
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0428% South Asian · 39/91,068 alleles

Filtering AF 0.0322% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0284%

Overall 0.00248% 40/1,613,484 alleles · ultra-rare exomes 39/1,461,148 · genomes 1/152,336 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0428%	2,335
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: COL4A2
Protein: p.Arg1069fs
Coding: c.3205del
MANE Select: NM_001846
dbSNP: rs746869541
Type: Deletion
Location: chr13:110485833 (GRCh38)
Gene constraint: LOEUF 0.618 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 47.97 · 4 PDB
Residue 1069: the 'triple-helical region' region

Full COL4A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

brain small vessel disease 2A, autosomal dominant — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

COL4A2 p.Arg1069Gln Uncertain significance ★★ ⚠ same residue
COL4A2 p.Arg1069Trp Uncertain significance ★★ ⚠ same residue
COL4A2 p.Arg551fs Likely pathogenic ★★ same condition
COL4A2 p.Ala350fs Likely pathogenic ★ same condition
COL4A2 p.Arg1349fs Likely pathogenic ★ same condition
COL4A2 p.Gly1064fs Likely pathogenic ★ same condition
COL4A2 p.Pro496fs Likely pathogenic ★ same condition
COL4A2 p.Thr1384_Gly1389del 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/col4a2-p-arg1069fs (accessed [today's date]).

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