Is COL4A1 p.Pro605= (c.1815T>C) pathogenic?

COL4A1 p.Pro605= (c.1815T>C) is classified Benign in COL4A1 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). Common (popmax 15.8%, eas) — 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.Pro605= (c.1815T>C)?

COL4A1 p.Pro605= (c.1815T>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.Pro605=

Q: How common is COL4A1 p.Pro605= (c.1815T>C) in the general population?

COL4A1 p.Pro605= (c.1815T>C) is common (popmax 15.8%, eas) — 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.1815T>C · rs61749897 · VCV195950

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Common

common (popmax 15.8%, eas) — 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	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.009	GERP -3.5, phastCons 0.13
Overall
CADD	6.79	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 15.8% East Asian · 7,090/44,868 alleles

Filtering AF 15.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 15.4%

Overall 7.49% 120,800/1,613,636 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	15.8%	6
Admixed American	11.1%	9
Finnishnot grpmax-eligible	8.81%	11
African / African-American	8.77%	11
European (non-Finnish)	7.1%	14
South Asian	6.9%	15
Remaining individualsnot grpmax-eligible	6.75%	15
Amishnot grpmax-eligible	3.95%	25
Middle Eastern	2.31%	43
Ashkenazi Jewishnot grpmax-eligible	1.34%	75

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.Pro605=
Coding: c.1815T>C
MANE Select: NM_001845
dbSNP: rs61749897
Type: single nucleotide variant
Location: chr13:110186467 (GRCh38)
Gene constraint: LOEUF 0.238 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.43 · 4 PDB
Residue 605: a modified residue (3-hydroxyproline); 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.Pro605fs Likely pathogenic ★★ 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
COL4A1 c.*32G>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-pro605 (accessed [today's date]).

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