Is COL4A1 p.Pro419= (c.1257T>C) pathogenic?

COL4A1 p.Pro419= (c.1257T>C) is classified Benign in COL4A1 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). Common (popmax 33.1%, amr) — too common for a highly-penetrant pathogenic allele; Associated with brain small vessel disease 1 with or without ocular anomalies.

What condition is associated with COL4A1 p.Pro419= (c.1257T>C)?

COL4A1 p.Pro419= (c.1257T>C) is associated with brain small vessel disease 1 with or without ocular anomalies, autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (ClinVar).

COL4A1 p.Pro419=

Q: How common is COL4A1 p.Pro419= (c.1257T>C) in the general population?

COL4A1 p.Pro419= (c.1257T>C) is common (popmax 33.1%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.1257T>C · rs995224 · VCV258246

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Common

common (popmax 33.1%, amr) — too common for a highly-penetrant pathogenic allele

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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -15	GERP -3.2
Overall
CADD	0.015	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 33.1% Admixed American · 19,868/59,990 alleles

Filtering AF 32.7% ClinGen BA1/BS1 input FAF95, joint · FAF99 32.6%

Overall 26.6% 428,877/1,613,652 alleles · common exomes 389,888/1,461,652 · genomes 38,989/152,000 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	33.1%	3
Finnishnot grpmax-eligible	32.8%	3
European (non-Finnish)	27.5%	4
Middle Eastern	25%	4
Remaining individualsnot grpmax-eligible	24.9%	4
Ashkenazi Jewishnot grpmax-eligible	24.2%	4
South Asian	22.9%	4
African / African-American	21.9%	5
Amishnot grpmax-eligible	7.35%	14
East Asian	3.8%	26

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.Pro419=
Coding: c.1257T>C
MANE Select: NM_001845
dbSNP: rs995224
Type: single nucleotide variant
Location: chr13:110198495 (GRCh38)
Gene constraint: LOEUF 0.238 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.43 · 4 PDB
Residue 419: the 'disordered' region; the 'triple-helical region' 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-pro419 (accessed [today's date]).

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