Is COL4A1 p.Pro669= (c.2007C>T) pathogenic?

COL4A1 p.Pro669= (c.2007C>T) is classified Benign/Likely benign in COL4A1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-21). Ultra-rare (popmax 0.0495%, mid); Associated with brain small vessel disease 1 with or without ocular anomalies.

What condition is associated with COL4A1 p.Pro669= (c.2007C>T)?

COL4A1 p.Pro669= (c.2007C>T) is associated with brain small vessel disease 1 with or without ocular anomalies, autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (ClinVar).

How common is COL4A1 p.Pro669= (c.2007C>T) in the general population?

COL4A1 p.Pro669= (c.2007C>T) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

COL4A1 p.Pro669=

Q: How is COL4A1/2-related familial vascular leukoencephalopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.2007C>T · rs145645897 · VCV311060

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Conditions

brain small vessel disease 1 with or without ocular anomalies

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.59	GERP -3.2
Overall
CADD	12.44	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0495% Middle Eastern · 3/6,056 alleles

Filtering AF 0.0226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0217%

Overall 0.0249% 401/1,612,912 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.189%	528
Middle Easterngrpmax	0.0495%	2,019
Remaining individualsnot grpmax-eligible	0.032%	3,122
European (non-Finnish)	0.025%	3,999
Admixed American	0.02%	4,994
African / African-American	0.012%	8,338
Finnishnot grpmax-eligible	0.00628%	15,914
East Asian	0.00223%	44,852
South Asian	0.0011%	90,780

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: COL4A1
Protein: p.Pro669=
Coding: c.2007C>T
MANE Select: NM_001845
dbSNP: rs145645897
Type: single nucleotide variant
Location: chr13:110183081 (GRCh38)
Gene constraint: LOEUF 0.238 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.43 · 4 PDB
Residue 669: the 'triple-helical region' region; the 'disordered' region

Full COL4A1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

brain small vessel disease 1 with or without ocular anomalies — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome

For COL4A1/2-related familial vascular leukoencephalopathy (Orphanet):

Inheritance: Autosomal dominant

Similar variants

COL4A1 p.Pro669Arg Uncertain significance ★ ⚠ same residue
COL4A1 p.Pro669Leu Uncertain significance ★ ⚠ same residue
COL4A1 c.1991-2A>G Likely pathogenic ★★ same condition
COL4A1 c.2458+1G>A Pathogenic ★★ same condition
COL4A1 c.2458+2T>C Pathogenic/Likely pathogenic ★★ same condition
COL4A1 c.3742+1G>A Pathogenic ★★ same condition
COL4A1 c.388-1G>C Pathogenic/Likely pathogenic ★★ same condition
COL4A1 c.4250-1G>A Pathogenic/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/col4a1-p-pro669 (accessed [today's date]).

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