Is COL4A1 p.Pro445Ser (c.1333C>T) pathogenic?

COL4A1 p.Pro445Ser (c.1333C>T) is classified Uncertain significance in COL4A1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-06-01). AlphaMissense: likely benign (0.0857); Very rare (popmax 0.00133%, afr); Associated with retinal arterial tortuosity.

How common is COL4A1 p.Pro445Ser (c.1333C>T) in the general population?

COL4A1 p.Pro445Ser (c.1333C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about COL4A1 p.Pro445Ser (c.1333C>T)?

AlphaMissense predicts likely benign (score 0.0857) — an in-silico prediction, not a clinical call.

COL4A1 p.Pro445Ser

Q: What condition is associated with COL4A1 p.Pro445Ser (c.1333C>T)?

COL4A1 p.Pro445Ser (c.1333C>T) 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.1333C>T · rs1878826024 · VCV1409803

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0857 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

retinal arterial tortuosity

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.0857	likely benign
REVEL	0.523	indeterminate
SaProt	LLR -10.10	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 9.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 30 kb · p 1.5e-10 · regional, not allelic
Overall
CADD	24.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,008 alleles

Overall 0.000186% 3/1,614,118 alleles · very rare exomes 3/1,461,886 · genomes 0/152,232 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,008
South Asian	0.0011%	91,076
European (non-Finnish)	8.47e-05%	1,180,018

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.Pro445Ser
Coding: c.1333C>T
MANE Select: NM_001845
dbSNP: rs1878826024
Type: single nucleotide variant
Location: chr13:110195071 (GRCh38)

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

For Familial isolated retinal arteriolar tortuosity (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Childhood

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-pro445ser (accessed [today's date]).

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