Is COL4A2 p.Arg1069Gln (c.3206G>A) pathogenic?

COL4A2 p.Arg1069Gln (c.3206G>A) is classified Uncertain significance in COL4A2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-03). AlphaMissense: likely benign (0.0961); Ultra-rare (popmax 0.0121%, sas); Associated with COL4A2-related disorder.

What condition is associated with COL4A2 p.Arg1069Gln (c.3206G>A)?

COL4A2 p.Arg1069Gln (c.3206G>A) is associated with COL4A2-related disorder, brain small vessel disease 2A, autosomal dominant, hemorrhage, intracerebral, susceptibility to (ClinVar).

How common is COL4A2 p.Arg1069Gln (c.3206G>A) in the general population?

COL4A2 p.Arg1069Gln (c.3206G>A) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about COL4A2 p.Arg1069Gln (c.3206G>A)?

AlphaMissense predicts likely benign (score 0.0961) — an in-silico prediction, not a clinical call.

COL4A2 p.Arg1069Gln

c.3206G>A · rs200275883 · VCV2634514

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0961 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

COL4A2-related disorder

Computational evidence

Protein change
AlphaMissense	0.0961	likely benign
REVEL	0.549	indeterminate
SaProt	LLR -7.37	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP -0.46, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 62 kb · p 6e-16 · regional, not allelic
Overall
CADD	26.1	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 0.0121% South Asian · 11/91,070 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.00558% 90/1,613,208 alleles · ultra-rare exomes 85/1,461,038 · genomes 5/152,170 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,279
European (non-Finnish)	0.00627%	15,943
Remaining individualsnot grpmax-eligible	0.0032%	31,228
African / African-American	0.00267%	37,454
East Asian	0.00223%	44,860

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.Arg1069Gln
Coding: c.3206G>A
MANE Select: NM_001846
dbSNP: rs200275883
Type: single nucleotide variant
Location: chr13:110485835 (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

COL4A2-related disorder

Also linked: brain small vessel disease 2A, autosomal dominant hemorrhage, intracerebral, susceptibility to

Similar variants

COL4A2 p.Arg1069Trp Uncertain significance ★★ ⚠ same residue
COL4A2 p.Arg1069fs Uncertain significance ★ same residue
COL4A2 c.361-1G>A Pathogenic/Likely pathogenic ★★ same condition
COL4A2 p.Gly1389Arg Pathogenic/Likely pathogenic ★★ same condition
COL4A2 p.Gly619Asp Likely pathogenic ★★ same condition
COL4A2 c.2425+3G>A Uncertain significance ★★ same condition
COL4A2 p.Ala370Pro Uncertain significance ★★ ⚠ same condition
COL4A2 p.Ala95Asp 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/col4a2-p-arg1069gln (accessed [today's date]).

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