Is COL4A1 p.Pro754= (c.2262C>T) pathogenic?

COL4A1 p.Pro754= (c.2262C>T) is classified Conflicting classifications of pathogenicity in COL4A1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-19). Ultra-rare (popmax 0.0165%, mid); Associated with brain small vessel disease 1 with or without ocular anomalies.

What condition is associated with COL4A1 p.Pro754= (c.2262C>T)?

COL4A1 p.Pro754= (c.2262C>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.Pro754= (c.2262C>T) in the general population?

COL4A1 p.Pro754= (c.2262C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

COL4A1 p.Pro754=

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.2262C>T · rs750538499 · VCV311054

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, 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 -7.4	GERP -3.2
Overall
CADD	0.406	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.00112% 18/1,614,036 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
African / African-American	0.00267%	37,498
East Asian	0.00223%	44,858
Remaining individualsnot grpmax-eligible	0.0016%	62,504
Finnishnot grpmax-eligible	0.00156%	64,000
European (non-Finnish)	0.00102%	98,334

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.Pro754=
Coding: c.2262C>T
MANE Select: NM_001845
dbSNP: rs750538499
Type: single nucleotide variant
Location: chr13:110179353 (GRCh38)
Gene constraint: LOEUF 0.238 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.43 · 4 PDB
Residue 754: 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 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
COL4A1 c.*32G>A Pathogenic/Likely pathogenic ★★ same condition
COL4A1 p.Arg1063Ter 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-pro754 (accessed [today's date]).

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