Is COL4A1 p.Pro816= (c.2448G>A) pathogenic?

COL4A1 p.Pro816= (c.2448G>A) is classified Benign/Likely benign in COL4A1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-21). Ultra-rare (popmax 0.0836%, amr); Associated with retinal arterial tortuosity.

How common is COL4A1 p.Pro816= (c.2448G>A) in the general population?

COL4A1 p.Pro816= (c.2448G>A) is ultra-rare (popmax 0.0836%, amr) (gnomAD).

COL4A1 p.Pro816=

Q: What condition is associated with COL4A1 p.Pro816= (c.2448G>A)?

COL4A1 p.Pro816= (c.2448G>A) is associated with retinal arterial tortuosity, brain small vessel disease 1 with or without ocular anomalies, autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome (ClinVar).

Q: How is Familial isolated retinal arteriolar tortuosity inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

c.2448G>A · rs144401828 · VCV708895

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0836%, amr)

Conditions

retinal arterial tortuosity

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 -4.6	GERP -3.2
Overall
CADD	1.903	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0836% Admixed American · 50/59,834 alleles

Filtering AF 0.065% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0585%

Overall 0.00416% 67/1,610,862 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0836%	1,197
East Asian	0.00223%	44,844
Remaining individualsnot grpmax-eligible	0.0016%	62,372
African / African-American	0.00133%	75,012
European (non-Finnish)	0.00119%	84,194

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.Pro816=
Coding: c.2448G>A
MANE Select: NM_001845
dbSNP: rs144401828
Type: single nucleotide variant
Location: chr13:110178933 (GRCh38)
Gene constraint: LOEUF 0.238 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 49.43 · 4 PDB
Residue 816: the 'triple-helical region' region; the 'disordered' region

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

Disease context

retinal arterial tortuosity — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: brain small vessel disease 1 with or without ocular anomalies autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome microangiopathy and leukoencephalopathy, pontine, autosomal dominant hemorrhage, intracerebral, susceptibility to COL4A1-related disorder

For Familial isolated retinal arteriolar tortuosity (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Childhood

Similar variants

COL4A1 p.Pro816Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
COL4A1 p.Pro816Ser Uncertain significance ★ ⚠ same residue
COL4A1 p.Pro816Thr Uncertain significance ★ ⚠ same residue
COL4A1 c.1085-2A>G Likely pathogenic ★★ same condition
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

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-pro816 (accessed [today's date]).

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